FEDERAL COURT OF AUSTRALIA

Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) [2020] FCA 1477

ORDERS

THE COURT ORDERS THAT:

1.    The parties provide short minutes of order to chambers as to the appropriate form of orders giving effect to these reasons and costs, with any areas of disagreement marked up, by 4 November 2020.

2.    The interlocutory application filed by the applicants/cross-respondents on 24 July 2020 be dismissed, with no order as to costs.

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

REASONS FOR JUDGMENT

BURLEY J:

1.    INTRODUCTION

1    It is perhaps not inappropriate that, at a time when the world is affected by the COVID-19 pandemic, the present dispute concerns attempts to improve disease immunity. Two pharmaceutical companies are in the race to develop better forms of immunisation against Streptococcus pneumoniae, which is a leading cause of meningitis, pneumonia and severe invasive disease in people, especially infants and young children, throughout the world. These proceedings concern an aspect of that race.

2    Merck Sharp & Dohme Corporation and Merck Sharp & Dohme (Australia) Pty Ltd (collectively, MSD) contend that three patents owned by Wyeth LLC are invalid. Australian Patents No. 2006235013 (013 patent) and No. 2013206844 (844 patent) are entitled “Multivalent pneumococcal polysaccharide-protein conjugate composition” and concern a multivalent immunogenic composition comprising 13 distinct polysaccharide-protein conjugates. The priority date of their claims is 8 April 2005. They are referred to below as the composition patents. The third is Australian Patent No. 2012216628 (container patent) which is entitled “Novel Formulations which Stabilize and Inhibit Precipitation of Immunogenic Compositions”. It concerns a siliconised container means whereby polysaccharide-protein conjugates may be stabilised. The priority date of the claims is 26 April 2006.

3    Wyeth in its Amended Notice of Cross-Claim of 12 November 2019 seeks declaratory, injunctive and other relief against MSD on the basis that MSD will infringe claims 1 – 8, 10 – 13 and 16 – 17 of the 013 patent (asserted 013 patent claims) and claims 1 – 6 and 11 – 14 of the 844 patent (asserted 844 patent claims) (collectively, the asserted composition patent claims) by the launch of a 15-valent vaccine (MSD’s 15-valent vaccine) that it intends to sell in Australia. At the commencement of the trial Wyeth contended that MSD will infringe claims 1 – 8, 16 – 18 and 20 – 23 of the container patent. Somewhat after the trial, Wyeth applied to re-open its case to add an allegation that claim 9 of the container patent will also be infringed. MSD initially opposed that course, but after some considerable delay, following a contested hearing on the subject, MSD changed its position. As a consequence, Wyeth’s case was re-opened and more than a year after the initial hearing had concluded, a further day of hearing concerning allegations of infringement and invalidity of claim 9 was conducted. Accordingly, the container patent claims asserted against MSD are claims 1 – 9, 16 – 18 and 20 – 23 (the asserted container patent claims).

4    In this judgment I first address questions of validity and infringement in relation to the composition patents before turning to the same questions as they arise in relation to the container patent. The law that applies to the 013 and container patents is the form of the Patents Act 1990 (Cth) (or pre-RTB Patents Act) amended by the Patents Amendment (Innovation Patents) Act 2000 (Cth) but prior to the changes implemented by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth) (RTB Act). The post RTB Act version of the Patents Act (post-RTB Patents Act) applies to the 844 patent.

1.1    Issues arising in relation to the composition patents

5    In relation to the question of infringement, there is no dispute as to the make-up of MSD’s 15-valent vaccine. The only issue is whether, as a matter of construction, the claims include that product within their scope. The primary construction issue arises from the use of the term “comprising” in the claims, in circumstances where the claim identifies 13 nominated serotypes, and the alleged infringing product includes those 13 plus two more. If that construction question is resolved adversely to MSD it accepts that its 15-valent vaccine will infringe, but it contends that the asserted composition patent claims are invalid on a number of bases.

6    As to invalidity, MSD first contends that, regardless of the construction adopted, the claims are not novel in the light of the publication authored by C de la Peña et al called “Presente y futuro de la vacunación antineumocócica” published in 2004 by Pediátrika (Volume 24(4)), either read alone or read with the publication authored by S K Obaro et al called “Safety and immunogenicity of a nonavalent pneumococcal vaccine conjugated to CRM197 administered simultaneously but in a separate syringe with diphtheria, tetanus and pertussis vaccines in Gambian infants” published in 2000 by the Pediatric Infectious Disease Journal (Volume 19(5)).

7    MSD next contends that the claims lack an inventive step either in the light of the common general knowledge alone or in the light of a number of other pieces of prior art information falling within s 7(3) of the Patents Act.

8    MSD further contends that the invention claimed in the composition patents is not a manner of manufacture within s 18(1)(a) of the Patents Act, is not useful within s 18(1)(c) and was obtained by a false suggestion or misrepresentation within s 138(3)(e). MSD further contends that the claims lack fair basis (or, in the case of the 844 patent, support) within s 40(3) of the Patents Act, and lack clarity within s 40(2)(b).

1.2    Issues arising in relation to the container patent

9    Wyeth contends that MSD threatens to make its 15-valent vaccine available in a siliconised container means that falls within the scope of the asserted container patent claims. Substantially the same non-infringement argument arises as for the composition patents, although only in respect of claim 18.

10    In its challenge to the validity of the container patent, MSD contends that the asserted claims (with the exception of claim 9) are not fairly based in accordance with s 40(3) of the Patents Act and are not clearly defined within s 40(2)(b). It also contends that all of the asserted container patent claims lack novelty in light of International Patent Application No. PCT/IB02/03495 published as WO 03/009869 on 6 February 2003 and entitled “Vaccines Comprising Aluminium Adjuvants and Histidine” (Chiron patent), and lack an inventive step in the light of the common general knowledge alone or in the light of prior art information within s 7(3) of the Patents Act. MSD also contends that the invention claimed in the container patent is not to a manner of new manufacture within s 18(1) of the Patents Act and is not useful within the requirements of s 18(1)(c).

1.3    Summary of conclusions

11    For the reasons set out in further detail below, I have determined that:

(1)    Wyeth has established that MSD’s 15-valent vaccine will infringe all of the asserted composition patent claims and the asserted container patent claims, subject only to my findings as to validity;

(2)    the novelty, inventive step, manner of manufacture, clarity, fair basis, inutility and false suggestion challenges to the asserted 013 patent claims fail;

(3)    the lack of support challenge to the asserted 844 patent claims succeeds, but that the novelty, inventive step, manner of manufacture, clarity, inutility and false suggestion challenges to that patent fail; and

(4)    the inventive step challenge to the asserted container patent claims succeeds, but the novelty, manner of manufacture, fair basis, clarity and inutility challenges to that patent fail.

12    The result is that Wyeth has established that the asserted 013 patent claims are valid and infringed. MSD has established that the asserted 844 patent claims and the asserted container patent claims are invalid. The only orders that I make are that the parties confer and provide to my chambers proposed short minutes giving effect to these reasons by 4 November 2020, noting any differences in approach in mark up. A case management hearing will be conducted at a convenient date shortly after that.

13    In the reasons that follow, I first consider the composition patents before moving to the container patent.

2.    COMPOSITION PATENTS: THE WITNESSES

14    The composition patents concern multivalent pneumococcal polysaccharide-protein conjugate compositions used for vaccinating an individual to trigger an adaptive immune response. The aim of such a vaccination is to protect the host against the consequences of subsequent exposure to a pneumococcal pathogen bearing one or more antigens contained in the vaccine preparation and/or to provide indirect protection to the community by interrupting transmission of the pathogen. The product claims are for polysaccharide-protein conjugate vaccines, which are to be distinguished from three other forms of vaccines known in April 2005, being whole-cell vaccines, polysaccharide vaccines and protein vaccines. The field of the invention in the composition patents concerns microbiology and immunology. Before addressing the terms of the specification, I first refer to the witnesses relied upon by the parties and then set out parts of a substantial technical primer.

2.1    MSD witnesses

15    James Cleland Paton has since March 2013 been a Professor of Microbiology in the School of Biological Sciences and Director of the Research Centre for Infectious Diseases at the University of Adelaide. Prior to holding this role, from September 2000 he was Professor of Microbiology in the Discipline of Microbiology and Immunology within the School of Molecular and Biomedical Science at the same university. He gained his PhD from the University of Adelaide in 1979 and since then his research has focussed on the study of the molecular basis for bacterial pathogenesis as well as disease prevention and therapeutic strategies for the control of bacterial infectious diseases, including vaccine development. His research has encompassed the pathogenesis of disease caused by Streptococcus pneumoniae, and is aimed at understanding key events in the host-pathogen interaction and identifying and evaluating novel drug targets and vaccine antigens.

16    In the 1980s, Professor Paton’s research focus was on protein antigen vaccines. He began to work on polysaccharide-protein conjugate proteins for Haemophilus influenzae type b (Hib), which was a very common cause of meningitis and other life-threatening diseases. The Hib vaccine was very successful and spurred activity into the development of pneumococcal polysaccharide-protein conjugate vaccines. In 2004 he wrote a review in a book edited by E I Tuomanen entitled The Pneumococcus (ASM Press, Washington D.C.) in which he discussed the developments in pneumococcal vaccines (Paton Review) and where he observed that the development of pneumococcal polysaccharide-protein conjugate vaccines had been “considerably more complex” than was the case with Hib owing to the multiplicity of disease-causing serotypes. In his first affidavit he observes that the development work used established carrier proteins (such as diphtheria toxoid, tetanus toxoid and cross-reacting material 197 (CRM197)), which were favoured by vaccine developers because they were known to be safe in children and had already been approved by regulators, thereby avoiding the need to test the safety of a previously uncharacterised alternative carrier protein.

17    Professor Paton affirmed several affidavits in these proceedings. In his first affidavit he outlines his background and experience relevant to the technology in issue and responds to the following question asked of him (the MSD Problem):

How would you have gone about developing a polysaccharide-protein conjugate pneumococcal vaccine that was an improvement on Prevnar 7 before April 2005?

18    I set out his response in more detail later in these reasons. After providing his answer, Professor Paton then reviewed the composition patents. He was next provided with and reviewed various prior art publications. He gives evidence that he would have expected to find these from a literature search conducted before April 2005.

19    In his second affidavit Professor Paton responds to evidence given on behalf of Wyeth concerning: immune interference and carrier induced epitope suppression (or CIES); which serotypes he would have selected if developing a polysaccharide-protein conjugate pneumococcal vaccine to improve on Prevnar 7 before the priority date; the composition of the skilled team; and example 16 in the composition patents. In his third affidavit he adduces evidence about the 5th International Symposium on Pneumococci and Pneumococcal Disease held in Alice Springs in April 2006.

20    Dennis Lee Kasper has since 1997 been Professor of Medicine and Professor of Microbiology and Immunobiology at Harvard Medical School in Boston in the United States. He completed a degree in Medicine at the University of Illinois in Chicago in 1967 and since 1973 has run his own research laboratory, studying the capsular polysaccharides of several extracellular bacteria, including their interaction with the immune system. A major focus of his work has been the development of human vaccines, including polysaccharide-protein conjugate vaccines. He is the named inventor on dozens of patents and patent applications worldwide. He was elected to the United States National Academy of Medicine in 2001 and was elected a member of the National Academy of Sciences in April 2018. He has consulted for many pharmaceutical and biotechnology companies. Since 1975 his primary interest has been in immunology, immunochemistry and genetics of bacterial polysaccharides and their production, in the context of polysaccharide-containing vaccines.

21    Professor Kasper affirmed two affidavits in these proceedings. In his first, which is the only one of present relevance, he notes that he gave evidence before the United States Patent Trial and Appeal Board in various proceedings between MSD and Wyeth concerning similar patents to the composition patents in suit. Professor Kasper gives evidence in reply to that of Professor Dagan in relation to the subjects of CIES, and the cross-protection between serotypes 6B and 6A, and 19F and 19A.

22    Alison Margaret Jones is a solicitor at Corrs Chambers Westgarth, the solicitors representing MSD. She gives evidence of electronic searches that she conducted in September 2018 using various search terms.

2.2    Wyeth Witnesses

23    Richard Anthony Strugnell has since 2001 been a Professor of Microbiology at the University of Melbourne. He obtained a PhD from Monash University in 1985 and his postdoctoral research first focussed on Treponema pallidum and the pathogenesis of syphilis, and then later on a recombinant Salmonella vaccine. Since 1995 he has conducted research into the underlying immunopathogenesis of Salmonella infections. His research work was re-focussed in 2005, when he was involved in research to develop recombinant Salmonella vaccines expressing pneumococcal proteins. He has also initiated studies into the nosocomial pathogen Klebsiella pneumoniae, which is a major cause of morbidity in the world as it has become very drug resistant. That work involved testing to see whether Klebsiella pneumoniae could usefully be a target of a conjugate vaccine.

24    From 1998 until about 2011 Professor Strugnell held the position of Regional Editor of Vaccine, a peer reviewed medical journal targeted towards medical professionals who are interested in vaccines. He is the named inventor on three patents and two patent applications. Since 1992 Professor Strugnell has regularly lectured undergraduate students at the University of Melbourne in the areas of microbiology and immunology. His more recent undergraduate teaching responsibilities have been in the areas of bacterial pathogenesis, host/pathogen relationships, vaccine development and medical bacteriology.

25    In his first affidavit Professor Strugnell responds to the question of how he would go about solving the problem of developing an improved pneumococcal vaccine on the basis of what was known to him and what he understands to have been well-known to others working in the field of immunology and microbiology, including as it relates to vaccine development and particularly pneumococcal vaccines, as at April 2005 (the Wyeth Problem). He was asked to describe the steps that he would have taken, as a matter of routine, at April 2005, to address the Wyeth Problem with a reasonable expectation of success. I address his answer in more detail later in these reasons. Professor Strugnell then addresses the content of the composition patents, the Peña and Obaro publications and the other prior art documents relied upon by MSD in support of its obviousness case. He then responds to the evidence of Professor Paton.

26    In his second affidavit Professor Strugnell responds to the second affidavit of Professor Paton and the first affidavit of Professor Kasper.

27    Ron Dagan has since 1992 been a Professor of Pediatrics and Infectious Diseases at the Ben-Gurion University of the Negev in Israel, and has since 2015 held the position of Distinguished Professor at the University. He is also an Emeritus Director of the Pediatric Infectious Disease Unit of the Soroka University Medical Centre in Israel. He obtained a medical degree from the Hebrew University in Jerusalem in 1974 and from 1987 until 2014 he was the Director of the Pediatric Infectious Disease Unit at the Soroka University Medical Centre. His research has focussed on pneumococcal vaccines, the epidemiology and introduction of hepatitis A vaccines, the epidemiology of vaccine-preventable diseases, the pathology of otitis media and prediction of its bacteriological and clinical response to various antibiotics, and the epidemiology and prevention of enteric and invasive infections in young children.

28    Professor Dagan gives evidence that he has been a leader in clinical development of many pneumococcal conjugate vaccine candidates and was one of the first to describe the importance of carriage in indirect protection (or herd immunity) and the potential for serotype replacement as a result of pneumococcal vaccination.

29    Professor Dagan has in the past been engaged by Wyeth to give evidence in the European Patent Office and the Intellectual Property Tribunal in the Republic of Korea in relation to patents related to the composition patents. He has been and remains a consultant, adviser and researcher for numerous pharmaceutical companies.

30    Professor Dagan was asked by Allens, the solicitors for Wyeth, to describe the field of pneumococcal vaccines, including what he and others in the field considered as at April 2005 to be future options for pneumococcal vaccinations. He gives evidence that pneumococcal polysaccharide vaccines have been used widely since the late 1970s, and that as at April 2005, a 23-valent pneumococcal polysaccharide vaccine was in use throughout much of the world. However, these were considered to be poorly immunogenic in infants and young children. As at April 2005 the only commercially available pneumococcal conjugate vaccine was Prevnar 7. Professor Dagan identifies other known pneumococcal conjugate vaccines that were also being tested in clinical trials.

31    Professor Dagan addresses an article that he and others wrote in 2004 entitled “Reduction of Antibody Response to an 11-Valent Pneumococcal Vaccine Coadministered with a Vaccine Containing Acellular Pertussis Components” (Dagan 2004). He explains that his view in 2004 was that existing adjuvants and carrier protein technologies were not the solution to providing improved pneumococcal vaccines, and that he thought that novel approaches would be needed.

32    Professor Dagan gives evidence about the difficulties that he expects would have been encountered if he had been asked to increase the coverage of pneumococcal conjugate vaccines by adding more serotypes to existing formulations in April 2005, and he also addresses the Wyeth Problem. I address his evidence in relation to this in more detail later in these reasons.

33    Professor Dagan then reviewed the compositions patents, the prior art information relied upon by MSD in its novelty and obviousness cases, and responded to parts of the evidence given by Professor Paton.

34    Thomas Kis-Major is a professional translator. He reviewed the English translation of Peña provided by MSD and criticised its accuracy. He was not cross-examined.

2.3    The composition patents joint expert report and concurrent evidence

35    Professors Paton, Kasper, Dagan and Strugnell joined in the preparation of a joint expert report (composition JER) in which they confronted their many differences of opinion. For the most part they adhered to their differences. They gave concurrent evidence during which they were cross-examined.

36    As a general matter, I have found that the experts gave evidence to the best of their ability in an attempt to assist the Court. Each is distinguished in his field. I consider in section 7.4 below their respective experience and qualifications in the context of their ability to assist the Court in assessing whether or not the composition patents claim an invention which involves an inventive step. Except where otherwise noted, I reject the assertions made by each side that the opposing witnesses were not prepared or able to give objective or credible evidence.

3.    COMPOSITION PATENTS: BACKGROUND PRIMER

37    The parties cooperated to produce a detailed primer of background information relevant to the composition patents. They accept that the material in it forms part of the common general knowledge before 8 April 2005. What follows in this section has been extracted from the primer.

3.1    General background

The immune system

38    The immune system protects the body against infections that might be caused by exposure to pathogens. There are two major interconnected immune responses in humans – the innate immune response and the adaptive immune response. The innate and adaptive immune responses do not operate in isolation. The adaptive immune response is dependent on, and enhanced by, elements of the innate immune response.

The innate immune response

39    The innate immune response is the first line of defence against pathogens. In many cases, an infection is completely controlled by innate immune mechanisms before adaptive immunity is triggered. The most virulent pathogens, however, usually have ways to overcome the innate defences. The innate system is not augmented by previous exposure to the same pathogen. Should the same pathogen infect on a subsequent occasion, the innate immune system will respond in the same way as during the first encounter.

40    The cells of the innate immune system include a diverse range of leukocytes, also known as white blood cells. These cells can, individually or in combination, identify and eliminate pathogens.

41    Some white blood cells are capable of killing pathogens by engulfing them, a process called phagocytosis. Others express a set of receptors which recognise and bind to molecular patterns on pathogens. This binding activates the release of signalling proteins, defensins and other anti-bacterial peptides, and degradative enzymes.

42    Inflammation is an important feature of the innate immune response to a bacterial infection, such as an infection by pneumococcus. An infection-driven inflammatory response is characterized by redness, heat and swelling at the site of the infection. Cytokines mediate the inflammatory response, increasing the permeability of blood vessels to fluid and proteins. This leads to local swelling and an accumulation of proteins that assist in eliminating pathogens. Cytokines may also stimulate other cells in order to attract, and facilitate the movement of, leukocytes to the site of the infection.

43    The innate immune system includes the complement system, which consists of over 20 interacting proteins. These complement proteins enhance other parts of the immune system. The complement proteins are activated in a cascade, where the activation of one protein leads to the activation of the next. The individual proteins are given designations C1 to C9, and the sub-fragments of these proteins are given designations such as C3a, C3b and C5a. The complement system can be activated directly, by a pathogen, or indirectly, by pathogen-bound antibodies produced during an adaptive immune response. The complement system assists the immune system in various ways: by attachment of C3b to the surface of pathogens, to mark them and make them susceptible to phagocytosis; by promoting an inflammatory response (through C3a and C5a) and thereby bringing more phagocytes and lymphocytes to the site of infection; and by direct killing of some types of bacteria by rupturing the bacterial membrane (through a complex comprising C5b, C6, C7, C8 and C9).

The adaptive immune response

44    Many pathogens have developed features that enable them to evade the innate immune response. Some bacteria (including pneumococci) have evolved a polysaccharide coating, or “capsule”, which is not recognised as a pathogen by the body’s receptors and which may inhibit the deposition of the complement protein fragment, C3b. Pathogens that are able to evade the innate immune response can multiply rapidly and cause disease or death.

45    Adaptive immunity is typically triggered when an infection eludes the innate defence mechanisms and reaches a threshold level. The adaptive immune response involves recognition and actions that are specific to features of the pathogen. Adaptive immunity takes days to weeks to become fully established; much longer than the innate immune response. However, the adaptive immune response can learn from previous encounters with specific pathogens and then destroy them more quickly and effectively if they are encountered again, through a process called immunological memory (a phenomenon which is the target of most vaccines).

46    There are two broad classes of adaptive immune responses – humoral immune responses and cell-mediated immune responses. As humoral immunity is particularly important in the defence against infection caused by bacteria such as the pneumococcus, it merits some further explanation.

47    There are two main types of lymphocytes: B-cells and T-cells. These make and secrete antibodies, also known as immunoglobulins, which mediate the humoral immune response. The five major types of antibodies are IgM, IgD, IgG, IgA and IgE. Antibodies are proteins that bind specifically to a particular antigen. An antigen is a molecule that is capable of being recognised by the immune system. B-cells and T-cells carry receptors of only one specificity; that is, they only carry receptors for one antigen. B-cells and T-cells that have not interacted with their specific antigen are known as naïve B-cells or T-cells. Antigen recognition by mature B-cells involves the binding of a B-cell receptor to a binding site – or epitope – on an antigen. Antigens can have multiple epitopes, each recognised by a different receptor on a different B-cell. Some antigens, including polysaccharides, can have the same epitope repeated multiple times.

48    While B-cell receptors can recognise and bind to virtually any structure, the receptors on conventional T-cells recognise only antigenic peptides that are bound to major histocompatibility (MHC) molecules that are displayed on the surfaces of antigen-presenting cells.

49    The humoral immune response is initiated when naïve B-cells bind to their specific epitope on an antigen and become activated. The activation of a naïve B-cell may depend on various factors, including:

(1)    the strength of the association, or affinity, of the B-cell receptor for a particular epitope on an antigen;

(2)    competition with other B-cells or antibody for binding with the epitope on an antigen;

(3)    the abundance of the antigen and the epitope on that antigen;

(4)    the duration over which the antigen is present;

(5)    how and where the epitope on an antigen is encountered by the B-cell;

(6)    the magnitude, duration and frequency of B-cell receptor signalling; and

(7)    a range of regulatory factors influenced by matters such as the presence or absence of cytokines, including those produced by the innate immune response and by regulatory T-cells.

50    Humoral immune responses can be either T-cell-dependent (TD response) or T-cell-independent (TI response). In a TD response, a T-cell-dependent antigen (TD antigen) binds to the antigen receptor on the B-cell. The B-cell internalises and processes the bound antigen, which causes it to present certain peptides and MHC molecules on its surface. It is typically trapped in the lymph node and then migrates to the zone in the lymph node where it can interact with activated helper T-cells which bind to that particular peptide-MHC complex (as noted above, T-cells recognise peptides bound to MHC molecules). The T-cells may directly bind to the B-cell and may secrete cytokines. The combination of these factors can stimulate activation and proliferation of the B-cells. Some of the proliferating B-cells immediately secrete antibodies that provide some measure of short-term protection to the host. Other proliferating B-cells migrate to a different part of the lymph node and form a germinal centre where they can rapidly proliferate.

51    The B-cells produced undergo differentiation into either plasma cells or memory B-cells. Most become plasma B-cells, which are the main antibody-secreting cells. Some of these plasma B-cells migrate to the bone marrow, where they can live for months or years and continue to secrete antibodies. This provides for the longevity of vaccine responses. The memory B-cells do not secrete antibodies. They are long-lived and can continue to live for the lifetime of the host. The role of memory B-cells is to be activated by a later encounter with the same antigen in what is known as a secondary immune response. The secondary immune response is more rapid, stronger and of higher affinity than the primary immune response. A secondary immune response is characterised in its first few days by the production of large amounts of certain immunoglobins: IgG antibody, with some IgA and IgE. In the absence of a memory response, repeated exposure to an antigen does not provide a secondary immune response and instead simply replicates, at best, the primary immune response.

52    Some antigens, particularly polysaccharides, are generally not capable of inducing a TD response because they are not processed and presented to T-cells as a peptide-MHC complex. However, some of these antigens can still produce an adaptive immune response because they have repeated epitopes which bind to multiple B-cell receptors on the same B-cell, bypassing the need for the helper T-cells. This is a TI response, generated by T-cell-independent antigens (TI antigens).

53    Capsular polysaccharides, like those which encapsulate pneumococcus bacteria, have long repeating structures with many copies of the same epitope. They belong to the TI-2 group of antigens. These repetitive antigens are capable of delivering prolonged and repetitive signaling to a specific B-cell by simultaneously binding and cross-linking a critical minimum number of B-cell receptors which can induce a TI (specifically, TI-2) response.

54    Compared with TD responses, TI responses are relatively rapid and elicit the transient production of antibodies of low affinity, usually without substantial affinity maturation and usually without inducing immunological memory. Although there is no binding between B-cells and helper T-cells in response to a TI antigen, if TD antigens are also present, nearby T-cells may still release cytokines in response to the TD antigens, which increase the magnitude of the response. Additionally, these T-cells may induce some degree of isotype switching (particularly from IgM to IgG), some low-level affinity maturation and some low-level memory B-cell generation.

55    Importantly, the human response to TI-2 antigens usually develops only after the age of 2 years. Children do not generally make fully effective immune responses against some polysaccharide antigens until about 5 years of age. However, antibody responses to pneumococcal polysaccharides can vary depending on the age of the person to whom it is administered and the pneumococcal serogroup. The typically poor response in infants and young children to polysaccharide antigens renders them particularly susceptible to infections with encapsulated bacteria, where the body relies on a TI response.

Antibodies

56    Antibodies are of great importance to the adaptive immune system.

57    The three main functions of antibodies are: neutralisation of pathogens by binding to them; opsonisation of pathogens (binding them so that they can be engulfed by phagocytes); and activating the complement system to destroy pathogens.

58    An antibody can theoretically bind to any epitope for which it has affinity and with which it comes into contact. Different molecules closely related in shape or chemical sequence may all bind to a given antibody with varying degrees of strength. This means that an antibody can bind to epitopes which are similar but not identical to the epitope which originally induced its production. This can lead to cross-protection from antibodies that have specificity for different antigens which bear sufficiently similar epitopes.

3.2    The pneumococcus

59    The pneumococcus is an infectious bacterium. Pneumococcal infections are a major cause of morbidity and mortality in humans of all ages but particularly in the very young, the very old and individuals with specific immunodeficiencies. Under certain conditions, the pneumococcus can generate a protective polysaccharide covering or capsule that provides protection against phagocytosis.

60    The pneumococcal cell wall is a complex structure. Relevantly, it contains a variety of surface proteins, including pneumococcal surface protein A (PspA) and pneumococcal surface adhesin A (PsaA), which are associated with virulence. These proteins are involved in direct interactions with host cells or in concealing the bacterial surface from the host defence mechanisms. The pneumococcus also expresses non-surface proteins, such as pneumolysin, which is a pore-forming toxin.

61    The polysaccharide capsule of pneumococci is variable. In clinical practice, polysaccharide variants – called serotypes – are identified by their reactions with type-specific antisera.

62    About 90 different capsular polysaccharide serotypes had been described as at April 2005. Further serotypes continue to be found. The “Danish system” is the most widely used system for classifying pneumococcal serotypes. This system allocates new serotypes with a sequential number. Serotypes which are cross-reactive with known serotypes (that is, the antigen of that serotype can combine with the antibody for a closely related antigen of another serotype) are not given a new number but are allocated a letter. For example, when a new serotype which was cross-reactive with serotype 7 was found, serotype 7 was renamed 7F (F for 'first') and the related serotype was named 7A.

63    Factors relating to the polysaccharide capsule that are likely to influence the virulence of different serotypes include:

(a)    the molecular mass, charge and hydrophobicity of the capsular polysaccharide;

(b)    the number, shape and form of specific epitopes within the polysaccharide;

(c)    their accessibility; and

(d)    the length of the polysaccharide chains.

64    The polysaccharide capsule is one important virulence factor for pneumococci, but there are other very important factors which vary between different clones of any one serotype, including: their ability to adhere to, and penetrate, mucosal and other membranes; their ability to express enzymes capable of degrading complement proteins; and their ability to resist killing after phagocytosis. Expression of these factors is variable and depends upon intrinsic bacterial genetic factors, as well as the environmental conditions to which the bacterium is exposed.

65    The distribution of serotypes common in carriage and disease varies over time and by geographical region, and by age within geographical regions.

66    The pneumococcus has not traditionally been a bacterium associated with high levels of clinical antibiotic resistance compared with other pathogens, but clinical resistance is nevertheless a relevant issue. As at April 2005, antibiotic-resistant pneumococci had been found throughout the world.

Pneumococcal disease

67    Colonisation of the nasopharynx by the pneumococcus in humans is common and most humans are colonised at least once early in life. This is not usually symptomatic, although it can be associated with low-level inflammation. However, the movement of pneumococci from the nasopharynx into other sites in the body can cause serious, and potentially life-threatening, disease. The detailed mechanisms that allow transition from carriage to onset of disease were not fully understood as at April 2005, nor are they fully understood today. At a general level, however, the development of pneumococcal disease results from disturbance of the balance between host and pathogen. This can occur, for example, through concurrent viral infection, malnutrition, exposure to cold, immune deficiency, or the arrival of a new, more pathogenic, clone or serotype.

68    The pneumococcus can cause pneumonia (infection of the lung), as well as invasive diseases such as meningitis (infection of the tissue covering the brain and spinal cord), which can cause death or permanent disability, and sepsis (bacteria growing in the blood) and bacteremia (bacteria in the blood), which are also potentially fatal.

69    The pneumococcus is also a major cause of otitis media (middle ear infection) and sinusitis. Otitis media is one of the most common causes of visits to doctors by infants and children. Otitis media therefore places a high economic burden on health care systems. Although otitis media is usually not life-threatening, untreated infections may cause damage to the structures of the middle ear that can result in permanent hearing loss.

70    The pneumococcus is one of the most important bacterial pathogens that affects humans. As at April 2005, global pneumococcal infections were estimated to cause around one to two million childhood deaths per year, and a similar number of adult deaths.

Host defence against the pneumococcus

71    Colonising pneumococci can be removed from the nasopharynx by innate immune mechanisms. However, if the innate immune system is avoided or overwhelmed, the adaptive immune system becomes of critical importance. In the context of pneumococcal infections, adaptive immunity is largely mediated by antibodies. These antibodies can be directed to the capsular polysaccharide or to other components of the bacterium.

72    Capsular pneumococcal polysaccharides are TI-2 antigens. As discussed above, TI-2 antigens can stimulate antibody responses in adults without T-cell help. As the TI-2 response is generally poor in young children and infants, they are particularly susceptible to pneumococcal infections (although in the first few months of life they may be protected by maternal antibodies).

73    As noted above, antibodies are crucial to the adaptive immune response to pneumococcal infections. Antibodies can bind to the polysaccharide capsule around the pneumococcus, allowing for phagocytosis. For some types of antibodies, binding to the surface of the pneumococcus can also lead to the activation of the complement system. Antibodies can also neutralise pneumococci by blocking attachment to host surfaces. Some antibodies are less effective at opsonisation and therefore do not make the pneumococci susceptible to phagocytosis. An antibody that binds to the pneumococcus but does not promote effective clearance of it is called a non-functional antibody.

3.3    Pneumococcal vaccines

74    A vaccine is a preparation containing one or more antigens which is intended to trigger an adaptive immune response in the host to whom the vaccine is administered. The intention of vaccination is to protect the host against the consequences of subsequent exposure to a pathogen bearing that antigen, or to provide indirect protection to the community by interrupting transmission of a pathogen, or both.

75    As at April 2005, the following types of pneumococcal vaccines had been or were being developed, and had been tested in either or both of animals and humans:

(1)    whole-cell vaccines;

(2)    polysaccharide vaccines;

(3)    polysaccharide-protein conjugate vaccines; and

(4)    protein vaccines.

76    Only polysaccharide and polysaccharide-protein conjugate pneumococcal vaccines were approved and in commercial use at April 2005. This is still the case today.

77    The claims of the composition patents are directed to polysaccharide-protein conjugate vaccines where 13 serotypes are capsular polysaccharide antigens each conjugated separately to the carrier protein CRM197.

78    A whole-cell vaccine is an inactivated vaccine which contains whole pathogens that have been killed or inactivated by irradiation or chemical treatment, so that they can no longer cause disease. Whole-cell vaccines have been highly effective and are used to protect against important pathogens (e.g. influenza and polio). Whole-cell pneumococcal vaccines were the first type of pneumococcal vaccines, and were marketed in the United States from around 1900. The first large-scale clinical trial of any pneumococcal vaccine was a trial of a crude whole-cell vaccine conducted in South Africa in 1911. These early vaccines were developed without regard to serotype.

79    By the 1940s, an increased understanding of serotype specificity led to whole-cell pneumococcal vaccine development giving way to the development of polysaccharide vaccines (and later conjugate vaccines). By April 2005, some researchers were also working on whole-cell vaccines in animal models. Whole-cell vaccines are among the simplest and cheapest vaccines to produce and because whole-cell killed pneumococci contain many non-capsular antigens that are common to all strains and serotypes of pneumococci, they have the potential to provide a level of serotype-independent immunity. Since April 2005, the development of a whole-cell pneumococcal vaccine has continued.

80    Polysaccharide vaccines contain purified capsular polysaccharides as antigens. Polysaccharide vaccines are relatively simple, stable and cheap to produce. They are intended to provide protection against the specific serotypes included in the vaccine.

81    A 14-valent polysaccharide vaccine was marketed by Merck in the US from 1977. It contained capsular polysaccharides from serotypes 1, 2, 3, 4, 5, 6A, 7F, 8, 9N, 12F, 18C, 19F, 23F and 25F. From 1983, the 14-valent polysaccharide vaccine was replaced by two 23-valent polysaccharide vaccines, one marketed by Merck under the brand name “Pneumovax 23”, and the other marketed by Lederle Laboratories.

82    As capsular polysaccharides are TI-2 antigens, antibody responses to pneumococcal polysaccharide vaccines are usually characterised by a failure to induce significant and sustained amounts of antibodies in children under 2 years of age. Antibody responses to pneumococcal polysaccharides vary depending on the age of the person to whom they are administered and the serogroups of the polysaccharide.

83    In adults, antibody levels decrease rapidly in a few months after vaccination with a polysaccharide vaccine and a repeated vaccination does not typically result in a secondary immune response. Further polysaccharide vaccines do not reduce nasopharyngeal carriage of vaccine serotypes by children or by adults, and so their use does not confer indirect protection (“herd protection”) on the population.

84    Protein vaccines are composed of purified or recombinant protein antigens from a pathogen. Protein vaccines are typically used for pathogens which have exposed external proteins, as the protein antigen(s) selected must be readily accessible to antibody in order to provide effective protection against subsequent exposure to the pathogen.

85    For many years before April 2005, some researchers had been working on a vaccine approach based on immunity against non-capsular antigens common to all pneumococcal serotypes to avoid the issues of serotype specificity and limits to the number of serotypes that could be covered with polysaccharide vaccines or pneumococcal conjugate vaccines, on the one hand, and lack of efficacy in children, in particular, with polysaccharide vaccines, on the other.

86    Pneumococcal proteins that had been considered or trialed as potential vaccine candidates at April 2005 included pneumolysoid (genetically modified pneumolysin), PspA and PsaA. As at April 2005, it was proposed that pneumococcal proteins could potentially be used as stand-alone vaccines, or in combination with pneumococcal conjugate vaccines, or as carrier proteins for polysaccharide antigens in pneumococcal conjugate vaccines.

3.4    Polysaccharide-protein conjugate vaccines

87    A polysaccharide-protein conjugate vaccine contains purified capsular polysaccharides as antigens, each of which are covalently bonded (conjugated) to a carrier protein. By conjugating a capsular polysaccharide to a carrier protein, a stronger antibody response to the polysaccharide is obtained.

88    The coupling of a capsular polysaccharide to a protein carrier is intended to improve the immunogenicity of the vaccine by inducing a TD response, rather than a TI response, to the polysaccharide antigens in the conjugates.

89    The conjugation process involves a chemical reaction between the carrier protein and the polysaccharide antigen. The efficiency of this reaction may vary, depending upon: the polysaccharide antigen, in particular its constituent sugars; the carrier protein, in particular its amino acid content; and the conjugation chemistry that is used.

90    The first commercially available conjugate vaccine – a Hib conjugate vaccine – was marketed in the US from 1987. Formulations of Hib conjugate vaccines which had been licensed before April 2005 used different carrier proteins, known generally to be safe for human use, including the following:

(a)    Tetanus toxoid.

(b)    Diphtheria toxoid.

(c)    CRM197 – which is a non-toxic form of diphtheria toxin that contains a single amino acid substitution. This single amino acid substitution removes its enzymatic activity, making CRM197 non-toxic without the further chemical modification required for diphtheria toxin and tetanus toxin.

(d)    Outer membrane protein complex of Neisseria meningitidis serogroup B (OMPC).

91    A simplified representation of the immune response to polysaccharide vaccines and polysaccharide-protein conjugate vaccines described above is shown below:

Figure 4. The immune response to (a) polysaccharide vaccines (TI-2 response) and (b) conjugate vaccines (TD response)

92    As explained above, the failure to generate memory cells from a polysaccharide vaccine means that a secondary immune response cannot usually be elicited by immunisation with a further dose of the polysaccharide vaccine. The generation of memory B-cells from a conjugate vaccine allows a secondary immune response to be elicited upon immunisation with a booster dose.

93    The first commercial conjugate vaccine, directed against Hib, involved only conjugates of a single serotype. The development of pneumococcal conjugate vaccines was more complex than in the case of Hib because of the need to provide protection against multiple serotypes.

94    As at April 2005, the following pneumococcal conjugate vaccines had been developed, or had been or were being tested in clinical trials:

(1)    A 7-valent vaccine, developed by Wyeth, containing polysaccharides of serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, each conjugated to CRM197. This vaccine, marketed as ‘Prevnar’ (or ‘Prevenar’ in some countries, including Australia, and later called ‘Prevnar 7’), was the only pneumococcal conjugate vaccine licensed anywhere in the world at April 2005.

(2)    A 7-valent vaccine, developed by MSD, containing polysaccharides from the same serotypes as Prevnar 7, each conjugated to OMPC.

(3)    A 9-valent vaccine, developed by Wyeth, containing polysaccharides of serotypes 1 and 5 in addition to the seven serotypes included in the Wyeth 7-valent vaccines, each conjugated to CRM197 (Prevnar 9).

(4)    An 11-valent vaccine, developed by Aventis-Pasteur (the predecessor of Sanofi), containing polysaccharides of serotypes 3 and 7F in addition to the nine serotypes included in the Wyeth 9-valent vaccine, with the polysaccharides from serotypes 3, 6B, 14 and 18C conjugated to diphtheria toxoid and the polysaccharides from serotypes 1, 4, 5, 7F, 9V, 19F and 23F conjugated to tetanus toxoid.

(5)    An 11-valent vaccine, developed by GlaxoSmithKline (GSK), containing polysaccharides of serotypes 3 and 7F in addition to the nine serotypes included in the Wyeth 9-valent vaccine, each conjugated to Haemophilus influenzae protein D.

95    The introduction of routine use of Prevnar 7 in the United States, in about 2000, resulted in a significant decline in the rates of invasive pneumococcal disease, not only among vaccinated individuals but also among the population more generally, and especially in the elderly, indicating a substantial indirect protection effect.

96    There was evidence before April 2005 that pneumococcal conjugate vaccines were having the effect of reducing nasopharyngeal carriage of pneumococci of the same serotype as those included in the pneumococcal conjugate vaccines (i.e., vaccine serotypes). The mechanisms by which pneumococcal conjugate vaccines could interrupt nasopharyngeal carriage were not completely understood as at April 2005. The interruption of carriage of vaccine serotypes had the potential to leave a niche for carriage of, and infection by, non-vaccine serotypes, a phenomenon known as serotype replacement. These new serotypes might have been as virulent, or more virulent, or less virulent, than the vaccine serotypes.

3.5    Vaccine formulation and development

97    An adjuvant is a substance that, when mixed with an antigen, increases its ability to provoke an adaptive immune response.

98    Adjuvants typically serve at least two functions. First, they may provide the signals discussed above that induce low-level local inflammation, drawing immune system cells to the site of injection. This enhances and accelerates the adaptive immune response to the vaccine antigens. Secondly, by adsorbing or trapping the vaccine antigen, adjuvants may provide a depot at the site of injection, which releases vaccine antigen more slowly after administration. The sustained release of vaccine antigen assists in maintaining vaccine antigen presence during the development of an adaptive immune response and, as a result, helps to promote B-cell activation.

99    One class of adjuvants is aluminium adjuvants. Aluminium-containing adjuvants include aluminium salts, most commonly aluminium hydroxide and aluminium phosphate.

100    Some vaccines are presented in a freeze-dried (lyophilised) form, which must be reconstituted with a liquid (diluent) before administration. There is a preference for vaccines to be presented in a liquid ready-to-use form, if a stable and effective liquid formulation can be made, optimally pre-loaded into single use syringes.

101    Vaccines may contain additional components, or excipients. An excipient is a substance other than the active substance, included for various purposes such as improving stability of the active ingredients, appearance of the vaccine, and patient tolerability.

102    Vaccines are administered in the expectation that they will be effective in protecting at least some people to whom they are administered or, depending on the vaccine, the community as a whole, from disease. Vaccines do not prevent disease in 100% of vaccinated individuals in diverse populations such as human populations, given the variability between individuals of the immune responses generated.

103    Vaccines undergo pre-clinical testing in animals to demonstrate that they are suitable for testing in humans. Several animal species have been used in pre-clinical trials including mice, rats, rabbits, chinchillas and monkeys. These trials are designed to detect evidence of local or systemic toxicity that might indicate a potential safety issue in humans. They also assess immunogenicity and experimental efficacy in animal models (including challenge studies) and the effects of administering multiple doses. In challenge studies using animal models, vaccinated and unvaccinated animals are compared after direct challenge (infection) with the target pathogen under controlled experimental conditions.

104    Animal models are typically used to assess: vaccine safety and toxicity; vaccine dose and formulation; the nature, magnitude and duration of the immune response; protection against challenge infection and cross-protection from the pathogen of interest; and the potential for preventing disease transmission within a specific population.

105    The predictive value of animal models for immunogenicity and vaccine efficacy in humans depends on the pathogen, the robustness of the animal model, and the correlates of protection.

106    Ordinarily, to evaluate the immunogenicity of a vaccine, animals are injected with the candidate vaccine. The animals are bled before and after vaccination to obtain sera for in vitro analysis. In the context of pneumococcal vaccines, assays which are commonly used in these analyses include those which detect and quantify the level of antibody (e.g. enzyme-linked immunosorbent assay (ELISA)) and which measure the opsonophagocytic activity of antibody (e.g. opsonophagocytic assay (OPA)).

107    The ELISA is the most common method used to detect the presence of specific antibodies in serum. An ELISA uses enzyme to cause a colour change to indicate that the relevant antibody has been detected. The amount of antibody in serum (expressed in terms of titre) may be quantified in an ELISA. Titres are typically measured on a logarithmic scale. A higher titre means there is a greater concentration of antibodies in serum.

108    An ELISA can identify the presence and quantity of antibodies in a sample but cannot determine whether the antibodies are functional (i.e. whether they effectively opsonise or neutralise the pathogen). The OPA is used to test the opsonophagocytic activity of vaccine-induced antibodies in vitro. The classic OPA determines the titres of sera that, when incubated with the bacteria of interest, reduce the number of live bacteria (or colony-forming units) by more than half.

109    ELISAs and OPAs can both be performed using sera from various test animals or humans.

110    The next stage in vaccine development is to carry out clinical trials in humans. These are classified into four phases: Phase I through to IV. In Phase I, small numbers of human volunteers are given the vaccine to assess the safety of the vaccine preparation. In Phases II and III, the vaccine is tested on larger groups of volunteers in order to confirm the proposed dose, assess immunogenicity and collect additional safety data.

111    Following regulatory approval of a vaccine, Phase IV studies are used to monitor effectiveness of the vaccine in the general population and to collect information about any low frequency adverse effects associated with widespread use of the vaccine in larger cohorts, over longer periods of time.

4.    COMPOSITION PATENTS – SPECIFICATION AND CLAIMS

4.1    The specification of the 013 patent

112    The 013 patent is entitled “Multivalent pneumococcal polysaccharide-protein conjugate composition”. The Field of the Invention is said to relate generally to medicine and specifically to microbiology, immunology, vaccines and the prevention of infection by bacterial pathogen by immunisation. The patent often refers to “Prevnar”, which I refer to in this judgment as Prevnar 7.

113    The “Background of the Invention” commences by noting that Streptococcus pneumoniae is a leading cause of meningitis, pneumonia and severe invasive disease in infants and young children throughout the world. It says that multivalent pneumococcal polysaccharide vaccines have been licensed for many years and have proved valuable in preventing pneumococcal disease in elderly adults and high-risk patients, but not infants and young children. It says:

The 7-valent pneumococcal conjugate vaccine (7vPnC, Prevnar) was the first of its kind demonstrated to be highly immunogenic and effective against invasive disease and otitis media in infants and young children. This vaccine is now approved in many countries around the world. Prevnar contains the capsular polysaccharides from serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, each conjugated to a carrier protein designated CRM197. Prevnar covers approximately 80-90%, 60-80% and 40-80% of invasive pneumococcal disease (IPD) in the US, Europe and other regions around the world respectively [1,2]. Surveillance data gathered in the years following Prevnar’s introduction has clearly demonstrated a reduction of invasive pneumococcal disease in US infants as expected (FIG. 1) [3,4].

(parenthetical references “[ ]” are to cited publications)

114    I refer below to the capsular polysaccharides from serotypes 4, 6B, 9V, 14, 18C, 19F and 23F each conjugated to carrier protein CRM197 as the Prevnar 7 serotypes. The Background continues by referring to the effect of particular additional serotypes on the prevalence of invasive pneumococcal disease (page 1 line 25 – page 2 line 5):

Surveillance of IPD conducted in US infants prior to the introduction of Prevnar demonstrated that a significant portion of disease due to serogroups 6 and 19 was due to the 6A (approximately one-third) and 19A (approximately one-fourth) serotypes [5,6]. Pneumococcal invasive disease surveillance conducted in the US after licensure of Prevnar suggests that a large burden of disease is still attributable to serotypes 6A and 19A (FIG 1) [3]. Moreover, these two serotypes account for more cases of invasive disease than serotypes 1, 3, 5 and 7F combined (8.2 vs 3.3 cases/100,000 children 2 years and under). In addition, serotypes 6A and 19A are associated with high rates of antibiotic resistance (FIG 2) [7,8,9]. While it is possible that serogroup cross-protection will result in a decline of serotype 6A and 19A disease as more children are immunized, there is evidence to suggest that there will be a limit to the decline, and a significant burden of disease due to these serotypes will remain (see below).

115    The Background concludes (page 2 lines 7 – 12):

Given the relative burden and importance of invasive pneumococcal disease due to serotypes 1, 3, 5, 6A, 7F, and 19A, adding these serotypes to the Prevnar formulation would increase coverage for invasive disease to >90% in the US and Europe, and as high as 70%-80% in Asia and Latin America. This vaccine would significantly expand coverage beyond that of Prevnar, and provide coverage for 6A and 19A that is not dependent on the limitations of serogroup cross-protection.

116    It is apparent that a problem to which the specification is directed is that of increasing coverage of the existing Prevnar 7 vaccine by the addition of further nominated serotypes.

117    The “Summary of the Invention” then provides a series of statements as to what is said to be the invention, the first of which is (page 2 lines 15 – 20):

Accordingly, the present invention provides generally a multivalent immunogenic composition comprising 13 distinct polysaccharide-protein conjugates, wherein each of the conjugates contains a capsular polysaccharide from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, together with a physiologically acceptable vehicle. Optionally, an adjuvant, such as an aluminium-based adjuvant, is included in the formulation.

118    Where this paragraph refers to a generally multivalent immunogenic composition, it is apparent that the multivalent composition of the patent is specific, insofar as it concerns the choice of serotypes included. As Professor Paton says, and the specification confirms, it is not possible to extrapolate the data in the 013 patent to other serotypes beyond the 13 claimed.

119    The next statement identifies the 13-valent conjugate, entitled 13vPnC, by reference to the seven serotypes from Prevnar 7 with the addition of six further serotypes, being 1, 3, 5, 6A, 7F, and 19A (I refer to these as the 13 chosen serotypes):

More specifically, the present invention provides a 13-valent pneumococcal conjugate (13vPnC) composition comprising the seven serotypes in the 7vPnC vaccine (4, 6B, 9V, 14, 18C, 19F and 23F) plus six additional serotypes (1, 3, 5, 6A, 7F and 19A).

120    The Summary of the Invention next identifies that the carrier protein may be CRM197 (page 2 lines 30 – 33):

The present invention also provides a multivalent immunogenic composition, wherein the capsular polysaccharides are from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F of Streptococcus pneumonia, the carrier protein is CRM197…

121    The specification then states that an aluminium-based adjuvant may be added to this combination, before including the following, which appears to be a statement of a broad invention involving two or more serotypes, one of which must be serotype 3 (page 3 lines 4 – 9):

The present invention also provides a multivalent immunogenic composition, comprising polysaccharide-protein conjugates together with a physiologically acceptable vehicle, wherein each of the conjugates comprises a capsular polysaccharide from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, and the capsular polysaccharides are prepared from serotype 3 and at least one additional serotype.

122    The next paragraph describes one embodiment of the composition wherein an additional serotype is selected from the remaining 12 chosen serotypes. Another embodiment involves this composition with an aluminium-based adjuvant. The Summary of the Invention next states that the invention provides a multivalent immunogenic composition comprising polysaccharide-protein conjugates together with a physiologically acceptable vehicle (page 3 lines 21 – 24):

...wherein each of the conjugates comprises a capsular polysaccharide from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, and the capsular polysaccharides are prepared from serotypes 4, 6B, 9V, 14, 18C, 19F, 23F and at least one additional serotype.

123    The next embodiment provides that the additional serotype is selected from the group consisting of serotypes 1, 3, 5, 6A, 7F and 19A, while the next two embodiments add CRM197 as the protein carrier and an aluminium-based adjuvant respectively.

124    The “Detailed Description of the Invention” then proceeds from page 4 until page 10 to explain, by reference to published data, how the 13 chosen serotypes came to be selected.

125    It begins by stating that data from invasive pneumococcal disease surveillance between 1995 and 1998 indicated the success of Prevnar 7, such that there could be no justification for the removal of any of the Prevnar 7 serotypes from the next generation of pneumococcal conjugate vaccines. Thereafter, the specification reviews published and unpublished literature for the balance of the six additional serotypes making up the 13 chosen serotypes, concluding in respect of each that coverage against invasive pneumococcal disease will increase if it is included in a conjugate vaccine.

126    For example, in respect of serotypes 1 and 5, the specification states at page 5 lines 2 – 8:

In the US, the rate of IPD caused by serotype 1 in children under the age of 5 is <2%, about the same as for each of types 3 and 7F [1,6]. Serotypes 1 and 5 account for higher rates of IPD in US populations at high risk for invasive pneumococcal disease. Specifically, serotype 1 causes 3.5% of IPD in Alaskan native children <2 years of age, and 18% in children 2-4 years of age [11]. Both serotype 1 and serotype 5 significantly cause disease in other parts of the world and in indigenous populations in developed countries [12,13,14].

127    Parenthetical reference [1] refers to an article authored by W P Hausdorff et al entitled “Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I” published in 2000 by the Clinical Infectious Diseases Journal (Volume 30) (Hausdorff 2000). It and the other 33 cited articles are incorporated into the specification by reference. MSD relies on some of these in its validity challenges.

128    The following passage appears in relation to serotype 3. The final sentence in particular is relied upon by MSD in its inutility challenge to the 013 patent (page 6 lines 5 – 22) (emphasis added):

However, attempts to produce a multivalent pneumococcal conjugate vaccine that exhibits significant immunogenicity with respect to serotype 3 polysaccharides have been unsuccessful. For example, in a study of the immunogenicity and safety of an 11-valent pneumococcal protein D conjugate vaccine (11-Pn-PD), no priming effect was observed for serotype 3 in infants who had received three doses of the vaccine followed by a booster dose of either the same vaccine or a pneumococcal polysaccharide vaccine (Nurka et al. (2004) Ped. Inf. Dis. J., 23:1008-1014...[further studies are then identified]...Accordingly, a pneumococcal conjugate vaccine comprising capsular polysaccharide from serotype 3 and capable of eliciting an immunogenic response to serotype 3 polysaccharides provides a significant improvement of the existing state of the art.

129    The inclusion of serotypes 6A and 19A is the subject of particular attention in submissions in relation to the lack of inventive step challenge. The specification at pages 6 – 10 refers to the reasons for including these serotypes, based primarily on published literature, which is cited, and also internal data generated by the patentee. This part of the specification commences by stating that surveillance data in the literature suggests that serotypes 6A and 19A account for more invasive pneumococcal disease in US children less than 2 years of age than serotypes 1, 3, 5 and 7F combined, and that 6A and 19A are commonly associated with antibiotic resistance and play an important role in otitis media. It says that “[t]he ability of the current Prevnar vaccine to protect against disease due to 6A and 19A is not clear” (emphasis added).

130    The specification first discusses the immune responses to serotypes 6A and 19A that have been induced by the inclusion of the 6B and 19F polysaccharides in Prevnar 7. This is a reference to cross-protection induced by 6B and 19F. The specification states that the data from several trials suggest that IgG (that is, a particular type of antibody) responses to 6A are induced by 6B antigens, but that they are generally lower, and that the OPA activity with 6A organisms is different than with 6B organisms. The specification also refers to low levels of cross-reactive IgG and OPA responses to serotype 19A after immunisation with 19F polysaccharide. Internal Wyeth data concerning OPA responses are reported in the specification to be consistent with the published findings of others, and demonstrate “induction of cross-reactive functional antibody to 6A polysaccharide after immunization with 6B polysaccharide, although at a lower level, and very little functional antibody to 19A after immunization with 19F”. The specification then looks at the impact of serotypes 6B and 19F on 6A and 19A immunisation in animal models and efficacy/effectiveness trials on humans. It concludes (page 10 lines 17 – 24):

The post-marketing surveillance data and the case-control study results noted in FIG. 1 and Table 2 with the 7vPnC vaccine suggest that, consistent with the other information on immune responses and performance in the animals models described above, there may be some cross-protection against 6A disease, but to a lesser extent than 6B disease. Furthermore, it appears the protection against 19A is limited. Therefore, a 13vPnC vaccine containing serotypes 6A and 19A provides coverage that is not dependent on the limitations of serogroup cross-protection by serotypes 6B and 19F.

131    After providing a justification for the inclusion of each of the chosen 13 serotypes, the specification then repeats at page 11 lines 1 – 9 the statement of one embodiment of the invention, being a multivalent immunogenic composition comprising the 13 chosen serotypes, together with a physiologically acceptable vehicle, wherein each of the conjugates contains a different capsular polysaccharide conjugated to a carrier protein, one such carrier protein being CRM197, and optionally having an adjuvant.

132    The specification then describes how to make the 13-valent vaccine. It says (page 11 line 11 – page 12 line 2):

Capsular polysaccharides are prepared by standard techniques known to those skilled in the art. In the present invention, capsular polysaccharide are prepared from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F of Streptococcus pneumoniae. These pneumococcal conjugates are prepared by separate processes and formulated into a single dosage formulation. For example, in one embodiment, each pneumococcal polysaccharide serotype is grown in a soy-based medium. The individual polysaccharides are then purified through centrifugation, precipitation, ultra-filtration, and column chromatography. The purified polysaccharides are chemically activated to make the saccharides capable of reacting with the carrier protein.

Once activated, each capsular polysaccharide is separately conjugated to a carrier protein to form a glycoconjugate. In one embodiment, each capsular polysaccharide is conjugated to the same carrier protein. In this embodiment the conjugation is effected by reductive amination.

The chemical activation of the polysaccharides and subsequent conjugation to the carrier protein are achieved by conventional means. See, for example, [US patents are identified].

Carrier proteins are preferably proteins that are non-toxic and non-reactogenic and obtainable in sufficient amount and purity. Carrier proteins should be amenable to standard conjugation procedures. In a particular embodiment of the present invention, CRM197 is used as the carrier protein.

133    Other carrier proteins that the specification says can be used are then identified, including OMPC. The specification says that after the individual glycoconjugates are purified, they are compounded to formulate the immunogenic composition of the invention using “art-recognised methods”. It then describes the use of adjuvants. An “adjuvant” is defined as “a substance that serves to enhance the immunogenicity of an immunogenic composition of this invention” (page 13 line 5).

134    The specification then identifies in general terms dosing levels for the serotypes to be used in a vaccine. At page 16 reference is made to the use of additional antigens against otitis media caused by infection from other (non-Streptococcus pneumoniae) bacteria:

The compositions of this invention may further include one or more additional antigens for use against otitis media caused by infection with other bacteria. Such bacteria include nontypable Haemophilus influenza, Moraxella catarrhalis...and Alloiococcus otitidis.

...

The compositions of this invention may also include one or more proteins from Streptococcus pneumoniae.

135    The specification then notes that the disclosure given so far “generally describes the present invention” (page 17 line 1). A more complete understanding is said to be able to be obtained by reference to the examples which follow.

136    Examples 1, 3, 5, 7, 9, and 11 respectively refer to the preparation of serotypes 1, 3, 5, 6A, 7F and 19A, while examples 2, 4, 6, 8, 10 and 12 refer respectively to the preparation of the same serotypes but conjugated to CRM197. Example 13 refers to the preparation of each of serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (that is, the Prevnar 7 serotypes) and example 14 refers to the preparation of CRM197 conjugates for each of those serotypes.

137    Detail is given in example 1 of the preparation of the master and working cell banks for serotype 1, the fermentation and harvesting required, the purification of the pneumococcal polysaccharide and then the characterisation of the serotype.

138    An issue arises in the context of the inventive step challenge concerning the method used in the specification to effect the conjugation of the 13 purified polysaccharides individually to CRM197. In this regard, notwithstanding the observations made in the introduction to the examples that the polysaccharides are prepared by “standard techniques” and that chemical activation and subsequent conjugation to the carrier protein are achieved by “conventional means”, particular ingredients, steps and ratios of polysaccharide to CRM197 are identified and explained in the specification. They are different for each serotype. I describe some of the differences below.

139    Example 2 addresses the preparation of the activation and conjugation of the purified polysaccharide for serotype 1. It provides that pH 9.0 was added for partial deacetylation for 3 hours at 50 degrees to a vessel containing the polysaccharide. The reaction was cooled to 20 degrees and neutralized. Oxidation in the presence of sodium periodate was performed by incubation at 2 – 8 degrees, and the mixture stirred for 15 – 21 hours.

140    The mixture was concentrated and diafiltered and the activated saccharide was filled into 100 mL glass lyophilisation bottles and “shell-frozen” at -75 degrees and lyophilized. The process of shell-freezing is described.

141    Bottles of lyophilized material were then brought to room temperature and resuspended in CRM197 solution at a saccharide/protein ratio of 2:1. 1M buffer was added at a nominated ionic strength and pH, and sodium cyanoborohydride was added. The reaction was incubated at 23 degrees for 18 hours, followed by a second incubation at 37 degrees for 72 hours. The mixture was diluted with cold saline followed by the addition of 1M of sodium carbonate to adjust the pH level. Unreacted aldehydes were quenched by addition of sodium borohydride at a specified temperature for 3 – 6 hours. The reaction mixture was then diluted with saline, diafiltered with phosphate buffer and saline and filtered again. It was diluted to a target of 0.5mg/mL in 0.9% saline and then filtered into final bulk concentrate and stored. It was then characterised.

142    In example 4, the preparation of the activation and conjugation of serotype 3 is described. The details of the process described are somewhat different compared with serotype 1. Containers of purified serotype were thawed and WFI and 2M of acetic acid added to a final concentration of 0.2M and 2mg/mL of saccharide. The temperature was raised to 85 degrees for one hour to hydrolyze the polysaccharide. The reaction was cooled to less than or equal to 25 degrees and 1M of magnesium chloride added to a final concentration of 0.1M. Oxidation in the presence of sodium periodate was performed for 16 – 24 hours at 23 degrees. The activation reaction mixture was concentrated and diafiltered with WFI and further filtered. For compounding, 0.2M of sodium phosphate, pH 7.0, was added to the activated saccharide into a final concentration of 10mM and a pH of 6.0 – 6.5. CRM197 was mixed with it to a ratio of 2g of saccharide per 1g CRM197. The combined solution was shell-frozen, then brought to room temperature and resuspended in 0.1M of sodium phosphate buffer of pH 7.0 to a final saccharide concentration of 20mg/mL. A molar equivalent of sodium cyanoborohydride was added. The reaction was incubated at 37 degrees for 48 hours. The reaction mixture was diluted, quenched, and then incubated at 23 degrees for 3 – 6 hours. It was then diafiltered and further filtered and then characterised.

143    In example 6 the preparation of the activation and conjugation serotype 5 is explained. The ration of activated serotype to CRM197 is 0.8:1. The concentrations, pH levels and steps are different to those described for serotypes 1 and 3.

144    In example 8 the preparation of the activation and conjugation of serotype 6A is described. It commences by noting that the serotype 6A polysaccharide is a high molecular weight polymer that had to be reduced in size prior to oxidation, a step not taken in the earlier examples. The steps and concentrations used are also different. The saccharide/protein ratio is also different, being 1:1.

145    Similar differences in the method of activation and conjugation may be perceived from the other examples.

146    Example 15 is entitled “Formulation of a multivalent Pneumococcal Conjugate Vaccine” and describes the formulation of the final vaccine. The final bulk concentrates of the 13 chosen serotypes are prepared in a manner set out in some detail.

147    Example 16 provides results of experiments concerning the immunogenicity of the 13-valent conjugate vaccine. It states that to date, the preclinical studies performed on the 13vPnC vaccine have been in rabbits. The results were characterised by antigen-specific ELISA for serum IgG concentrations and for antibody function by OPA. Study #HT01-0021 examines the ability of the 13vPnC vaccine with AIPO4 adjuvant to elicit vaccine serotype-specific immune responses.

148    In relation to study #HT01-0021, the results for functional responses were assessed in rabbits following immunisation with two 13vPnC formulations, one with AIPO4 adjuvant and the other without the adjuvant, but both with the 13 chosen serotypes. Secondary objectives included an evaluation of the kinetics and duration of the antibody response. When comparing vaccine formulations, the one with the adjuvant had higher OPA geometric mean titers (GMT). For the majority of the serotypes, OPA titers measured at week 4 were at least four times higher than those at the baseline week zero. The kinetic responses were also evaluated for each of the serotypes from serum pools of both treatment groups. The specification reports that with the exception of serotype 1, antibody responses were superior for rabbits receiving the vaccine with adjuvant added. It says (page 44 lines 4 – 9):

Overall, the data indicate that the 13vPnC vaccine formulated with aluminium phosphate is immunogenic in rabbits, eliciting substantial antibody responses to the pneumococcal capsular polysaccharide contained in the vaccine and these responses are associated with functional activity. The responses observed to the seven core serotypes following immunization with 13vPnC + AIPO4 are consistent with historical responses of rabbits to the heptavalent formulation.

149    In this passage the seven “core” serotypes are the Prevnar 7 serotypes which make up the heptavalent formulation mentioned in the final line of the passage.

150    Table 4 then sets out the results of 13vPnC with and without AIPO4 as an adjuvant.

151    Study #HT01-0036 is described as comparing rabbit immune responses to the polysaccharides contained in the vaccine after immunisation with the 13vPnC vaccine, and with or without conjugation to the CRM197 protein. Immune responses were evaluated using an IgG ELISA and complement-mediated OPA measuring functional antibody. The data is reported to indicate that the conjugate vaccine elicited higher serum IgG titers than free polysaccharide or free polysaccharide mixed with unconjugated CRM197 vaccine. The specification states (page 46 line 21 – page 47 line 2):

With the exception of S. pneumoniae type 14, the 13vPnC vaccine was able to induce functional antibodies to the representative strains of S. pneumoniae in an OPA (Table 6).

152    MSD relies on this statement, and the results reported in Table 6, in its inutility challenge.

153    The specification then makes four general statements to which the parties refer in their submissions. The first is to the effect that the foregoing discussion and examples are merely present to provide a detailed description of certain embodiments. The second is that all journal articles, other references, patents and patent applications that are identified in the 013 patent are incorporated by reference in their entirety. In this regard, the specification lists 35 references, some of which are identified by number in passages quoted above. The third general statement may be regarded as a boilerplate reference, but is nevertheless important in the context of the construction arguments. I refer to it below as the comprising passage. It is as follows:

Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

154    Finally, the specification states that the reference in the specification to any prior publication or information derived from a publication, or to any matter which is known, is not and should not be taken as an acknowledgement or admission that such publication or information forms part of the common general knowledge in the field.

4.2    The claims of the 013 patent

155    The asserted claims are as follows:

1.    A multivalent immunogenic composition, comprising: 13 distinct polysaccharide-protein conjugates, together with a physiologically acceptable vehicle, wherein each of the conjugates comprises a capsular polysaccharide from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, and the capsular polysaccharides are prepared from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F and wherein said carrier protein is CRM197.

2.    The immunogenic composition of claim 1, further comprising an adjuvant.

3.    The immunogenic composition claim 2, wherein the adjuvant is an aluminum-based adjuvant.

4.    The immunogenic composition of claim 3, wherein the adjuvant is selected from the group consisting of aluminum phosphate, aluminum sulfate and aluminum hydroxide.

5.    The immunogenic composition of claim 4, wherein the adjuvant is aluminum phosphate.

6.    The immunogenic composition of any one of claims 1 to 5 comprising 1 to 5 μg of each polysaccharide.

7.    The immunogenic composition of any one of claims 1 to 5 comprising 2 μg of each polysaccharide, except for 6B at 4 μg.

8.    The immunogenic composition of claim 6 or 7 comprising 0.125 mg of elemental aluminum (0.5 mg aluminum phosphate) adjuvant.

9.    The immunogenic composition of any one of claims 1 to 5 wherein each 0.5 mL dose is formulated to contain: 2 μg of each polysaccharide, except for 6B at 4 μg; approximately 29 μg CRM197 carrier protein; 0.125 mg of elemental aluminum (0.5 mg aluminum phosphate) adjuvant; and sodium chloride and sodium succinate buffer as excipients.

10.    A method of inducing an immune response to a Streptococcus pneumoniae capsular polysaccharide conjugate, comprising administering to a human an immunologically effective amount of the immunogenic composition of any one of claims 1 to 9.

11.    A sterile liquid formulation comprising pneumococcal capsular polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F individually conjugated to CRM197.

12.    The sterile liquid formulation of claim 11 comprising 1 to 5 μg of each polysaccharide.

13.    The sterile liquid formulation of claim 11 comprising 2 μg of each polysaccharide, except for 6B at 4 μg.

14.    A sterile liquid formulation of pneumococcal capsular polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F individually conjugated to CRM197 wherein each 0.5 mL dose is formulated to contain: 2 μg of each polysaccharide, except for 6B at 4 μg; approximately 29 μg CRM197 carrier protein; 0.125 mg of elemental aluminum (0.5 mg aluminum phosphate) adjuvant; and sodium chloride and sodium succinate buffer as excipients.

15.    A sterile liquid formulation of pneumococcal capsular polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F individually conjugated to CRM197 wherein each 0.5 mL dose is formulated to contain: 2.2 μg of each polysaccharide, except for 6B at 4.4 μg; approximately 29 μg CRM197 carrier protein; 0.125 mg of elemental aluminum (0.5 mg aluminum phosphate) adjuvant; and sodium chloride and sodium succinate buffer as excipients.

16.    A method of protecting a human susceptible to pneumococcal infection, by means of administering the composition of anyone of claims 1 to 9 or 11 to 15 via a systemic route.

17.    The method of claim 16 wherein said administration is via the intramuscular, route.

18.    The immunogenic composition of claim l and the sterile liquid formulation of any one of claims 11, 14 and 15, substantially as hereinbefore described and with reference to any of the Examples and/or figures.

4.3    The specification and claims of the 844 patent

156    The specification of the 844 patent is substantially the same as that of the 013 patent. No party relies on any difference in the text of the 844 patent for the purpose of considering its disclosure.

157    The 844 claims are as follows:

1.    A multivalent immunogenic composition, comprising polysaccharide-protein conjugates together with a physiologically acceptable vehicle, wherein each of the conjugates comprises a capsular polysaccharide from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, and the capsular polysaccharides are prepared from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, wherein the carrier protein is CRM197 for use as a vaccine to protect or treat a human susceptible to pneumococcal infection.

2.    The immunogenic composition of claims 1, wherein conjugation is effected by reductive amination.

3.    The immunogenic composition of claim 1 or claim 2, further comprising an adjuvant.

4.    The immunogenic composition of claim 3, wherein the adjuvant is an aluminum-based adjuvant.

5.    The immunogenic composition of claim 5, wherein the adjuvant is selected from the group consisting of aluminium phosphate, aluminium sulfate and aluminium hydroxide.

6.    The immunogenic composition of claim 4, wherein the adjuvant is aluminium phosphate.

7.    The immunogenic composition according to any one of claims 1 to 6 which further comprises one or more antigens for use against otitis media caused by infection with other bacteria.

8.    The immunogenic composition of claim 7 wherein said other bacteria is selected from the group consisting of nontypable Haemophilus influenza, Moraxella catarrhalis and Alloiococcus otitidis.

9.    The immunogenic composition of any one of claims 1 to 8 which further comprises one or more proteins from Streptococcus pneumoniae.

10.    The immunogenic composition of any one of claims 1 to 9 which further comprises one or more proteins from Neisseria meningitidis type B.

11.    The immunogenic composition of any one of claims 1 to 10 for use in vaccination wherein following an initial vaccination, subjects receive one or several booster immunizations adequately spaced.

12.    The immunogenic composition of any one of claims 1 to 10 for use in the vaccination of infants or toddlers, wherein the vaccination schedule is 2, 4, 6 and 12-15 months of age.

13.    The immunogenic composition of any one of claims 1 to 10 for use in the vaccination of adolescents or adults.

14.    The immunogenic composition of any one of claims 1 to 10 for intramuscular administration.

4.4    Summary of the disclosure

158    The invention described and claimed in the specification may be broadly summarised as the idea to add serotypes 1, 3, 5, 6A, 7F and 19A to the Prevnar 7 serotypes and to conjugate each to CRM197 to yield an immunogenic composition, coupled with the disclosure of the practical means by which this is achieved.

159    The specification and claims are directed to pharmaceuticals products for the purpose of achieving vaccines.

4.5    The person skilled in the art

160    As I have noted, the composition patents are entitled “Multivalent pneumococcal polysaccharide-protein conjugate composition”. The invention is described to relate generally to the field of medicine, and in particular to microbiology, immunology, vaccines and the prevention of infection by a bacterial pathogen by immunisation. However, the particular focus of the invention described in the specification is the development and use of multivalent pneumococcal polysaccharide conjugate vaccines. The person skilled in the art is likely to have a practical interest in this subject matter and this is the field of the invention.

161    Persons with a practical interest in the subject matter of the invention will include microbiologists and immunologists. There is no real dispute that all of the expert witnesses called in the present have such an interest. The parties agree that for the purposes of considering the question of inventive step within s 7(2) the hypothetical person skilled in the art will be a team. They agree that the team will include persons skilled in the disciplines of microbiology and immunology. MSD contends that such persons will preferably have experience working with pneumococcal vaccines. Wyeth contends that such persons will have experience in particular with encapsulated bacteria. The divide reflects the differing levels of experience between Professors Kasper and Paton on the one hand, whose experience before the priority date was substantially in working with pneumococcal vaccines, and the experience of Professor Strugnell, whose experience was in encapsulated bacteria more generally, but mostly not in pneumococcal vaccines. In my view all of these experts are qualified to assist the Court in ascertaining the approach of the hypothetical skilled team. I refer below, where necessary, to the effect of the relatively lesser experience of Professor Strugnell in the central aspects of the subject matter of the inventive step enquiry, and make allowance for it.

162    There was some debate as to whether an epidemiologist would also participate in the team and whether a person in that discipline would be a clinician. Having regard to the disclosure of the specification, in my view there is little doubt that a person skilled in reviewing data about demographics and populations at risk would provide the scientific members of the team with what is expected from the improved vaccine. This was the view of Professors Kasper, Strugnell and Dagan, with whom I agree. In my view all of the experts were sufficiently experienced and qualified to opine on this subject. Professor Dagan, as a clinician whose experience is primarily in relation to clinical matters, is in a lesser position to give authoritative evidence about other aspects of vaccine development.

163    Where I refer below to the skilled team I refer to persons with the particular characteristics in the two above paragraphs.

5.    COMPOSITION PATENTS: CONSTRUCTION ISSUES

164    The following issues arise between the parties in relation to the construction of terms in the composition patents:

(1)    Whether the asserted composition patent claims include within their scope one or more Streptococcus pneumoniae serotypes in addition to the 13 serotypes. This focusses attention on the meaning of the words “comprises” and “comprising” where they appear in the asserted claims (the comprising issue).

(2)    What is the proper construction of “immunogenic” as it appears in claim 1 of the 013 patent?

5.1    The principles of patent construction

165    The principles of construction are not in dispute. It is for the Court to determine and characterise the invention having regard to the principles of construction that are now well settled. Many are summarised in Jupiters Ltd v Neurizon Pty Ltd [2005] FCAFC 90; 65 IPR 86 (Hill, Finn and Gyles JJ) at [67]:

There is no real dispute between the parties as to the principles of construction to be applied in this matter although there is some difference in emphasis. It suffices for present purposes to refer to the following:

(i)     the proper construction of a specification is a matter of law: Décor Corp Pty Ltd v Dart Industries Inc (1988) 13 IPR 385 at 400;

(ii)     a patent specification should be given a purposive, not a purely literal, construction: Flexible Steel Lacing Company v Beltreco Ltd (2000) 49 IPR 331 at [81]; and it is not to be read in the abstract but is to be construed in the light of the common general knowledge and the art before the priority date: Kimberley-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1 at [24];

(iii)     the words used in a specification are to be given the meaning which the normal person skilled in the art would attach to them, having regard to his or her own general knowledge and to what is disclosed in the body of the specification: Décor Corp Pty Ltd at 391;

(iv)     while the claims are to be construed in the context of the specification as a whole, it is not legitimate to narrow or expand the boundaries of monopoly as fixed by the words of a claim by adding to those words glosses drawn from other parts of the specification, although terms in the claim which are unclear may be defined by reference to the body of the specification: Kimberley-Clark v Arico at [15]; Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 at 610; Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461 at 478; the body of a specification cannot be used to change a clear claim for one subject matter into a claim for another and different subject matter: Electric & Musical Industries Ltd v Lissen Ltd [1938] 56 RPC 23 at 39;

(v)     experts can give evidence on the meaning which those skilled in the art would give to technical or scientific terms and phrases and on unusual or special meanings to be given by skilled addressees to words which might otherwise bear their ordinary meaning: Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd (1994) 30 IPR 479 at 485-486; the Court is to place itself in the position of some person acquainted with the surrounding circumstances as to the state of the art and manufacture at the time (Kimberley-Clark v Arico at [24]); and

(vi)     it is for the Court, not for any witness however expert, to construe the specification; Sartas No 1 Pty Ltd, at 485–486.

166    It is important to emphasise the need to read a patent specification as a whole and in the light of the common general knowledge and to give it a practical and common sense construction that is “purposive”. Such an approach requires the Court to read the specification through the eyes of the skilled addressee, with practical knowledge and experience in the field of work in which the invention was intended to be used, and a proper understanding of the purpose of the invention: GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No 2) Limited v Generic Partners Pty Limited [2018] FCAFC 71; 264 FCR 474 at [106] (Middleton, Nicholas and Burley JJ).

167    As Lord Hoffmann explained in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2004] UKHL 46; [2005] 1 All E.R. 667 at [34]:

“Purposive construction” does not mean that one is extending or going beyond the definition of the technical matter for which the patentee seeks protection in the claims. The question is always what the person skilled in the art would have understood the patentee to be using the language of the claim to mean. And for this purpose, the language he has chosen is usually of critical importance. The conventions of word meaning and syntax enable us to express our meanings with great accuracy and subtlety and the skilled man will ordinarily assume that the patentee has chosen his language accordingly. As a number of judges have pointed out, the specification is a unilateral document in words of the patentee’s own choosing. Furthermore, the words will usually have been chosen upon skilled advice. The specification is not a document inter rusticos for which broad allowances must be made. On the other hand, it must be recognised that the patentee is trying to describe something which, at any rate in his opinion, is new; which has not existed before and of which there may be no generally accepted definition. There will be occasions upon which it will be obvious to the skilled man that the patentee must in some respect have departed from conventional use of language or included in his description of the invention some element which he did not mean to be essential. But one would not expect that to happen very often.

168    Lord Hoffmann was referring here to the meaning conveyed to the skilled addressee by the language used and was not directing himself to a situation in which the skilled addressee deduced that the language of the claim, although conveying to him or her a particular meaning, could never have been intended to mean what it conveyed.

5.2    The comprising issue

5.2.1    The arguments

169    Wyeth submits that the position is straightforward. It contends that “comprising” in the claims, read in the context of the specification, is used in an inclusive sense (“including”), as opposed to an exhaustive sense (“consisting of”). This is said to accord with the comprising passage set out at [153]. It submits that MSD has not established otherwise, and therefore it has not rebutted that express presumption. Due to this inclusive construction, each of the asserted composition patent claims includes within its scope any immunogenic composition which has the integers of the claim, including polysaccharide-protein conjugate that includes each of the chosen 13 serotypes, notwithstanding such an immunogenic composition may also contain other integers, such as polysaccharide-protein conjugates of one or more Streptococcus pneumoniae serotypes in addition to the 13 chosen serotypes.

170    The primary construction advanced by MSD is that the claimed compositions are only to polysaccharide-protein conjugates of each of the chosen 13 serotypes and do not encompass immunogenic compositions which also have conjugates from any other Streptococcus pneumoniae serotypes.

171    MSD submits that the language used in the claim mandates the conclusion that the asserted claims are limited to a composition with polysaccharide-protein conjugates from the chosen 13 serotypes. MSD submits that its construction is the only one that is consistent with the description in the specification of the “invention”. It submits that the language of each of the independent claims makes clear that they are limited to the 13 serotypes specified and that where, as here, one or more things in a class are expressly mentioned, other serotypes are excluded.

172    Furthermore, MSD submits that the use of the words “comprising” and its accompanying definition in the specification do not assist Wyeth. MSD submits that the comprising passage requires the word “comprises” in the third line of claim 1 to be understood in an exhaustive sense, unlike its counterpart “comprising”, because of various contextual matters, an understanding of the disclosure of the specification as a whole, the language of the consistory clause for claim 1 and the language of the dependent claims.

173    MSD additionally submits that the construction that it proposes yields a common sense and practical result. By the priority date of April 2005 around 90 different serotypes had been described and since then that number has risen to 98. MSD submits that if Wyeth’s construction is accepted then the claims will necessarily extend to an immunogenic composition of 90 or more serotypes and could cover millions of different combinations. Such a construction would be untenable and the Court would not interpret a claim in that way: Abbott Laboratories v Corbridge Group Pty Ltd [2002] FCAFC 314; 57 IPR 432 at [30] – [35] (Lee, Emmett and Hely JJ). Furthermore, such an invention may not work, because MSD submits it was common general knowledge as at April 2005 that such a large increase in the number of serotypes would require a greater amount of carrier protein to be included in the vaccine. As the amount increases, there is a risk that this will impede the operation of the vaccine by causing aggregation and/or leading to adverse reactions. It may also lead to immune interference, if, contrary to MSD’s contention, that was a realistic concern to the person skilled in the art.

174    Finally, MSD submits that the position taken by Wyeth in advancing its present construction argument is contrary to that which it adopted in correspondence with the Commissioner of Patents, where in a letter dated 20 April 2016 its patent attorneys stated that the claimed composition “is 13-valent” without any suggestion that the claimed invention covers a valency of 13 or more.

5.2.2    Consideration

175    I first address claim 1 of the 013 patent, upon which the parties focussed in the course of argument. It is repeated below, with integer numbers added for convenience:

(1)    A multivalent immunogenic composition, comprising:

(2)    13 distinct polysaccharide-protein conjugates,

(3)    together with a physiologically acceptable vehicle,

(4)    wherein each of the conjugates comprises a capsular polysaccharide from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, and the capsular polysaccharides are prepared from [the chosen 13 serotypes] and

(5)    wherein said carrier protein is CRM197.

176    It may be seen that claim 1 is for a multivalent immunogenic composition (integer (1)) with three constituents. The first is 13 distinct polysaccharides (integer (2)), each of which comprises a capsular polysaccharide from a different serotype conjugated to a carrier protein (integer 4). The second is a physiologically acceptable vehicle (integer (3)). The third is the carrier protein CRM197 (integer (5)).

177    MSD contends that claim 1 is limited to a multivalent immunogenic composition with polysaccharide-protein conjugates from the 13 chosen serotypes in it. Put another way, it submits that any combination that includes more than the nominated 13 serotypes cannot infringe. Wyeth submits that any multivalent immunogenic composition that has integers (2) – (5) within it will infringe, even if additional components are included.

178    The question is to be resolved by consideration first of the language used in the claim. In this regard there is no ambiguity. The words “comprising” and “comprises” are clearly defined in the specification in an inclusive sense, or in other words, “including” and “includes”. The only exception is whether the context requires otherwise.

179    There can be no doubt that where in integer (1) the claim refers to “[a] multivalent immunogenic composition comprising...” the word “comprising” means “including”. If the definition of the term “comprising” in the body of the specification is not sufficient to establish this point, as much is confirmed as a matter of context, when one considers the claims dependent upon claim 1. For instance, in accordance with orthodox claim drafting, claim 9, which narrows the scope of claim 1, identifies amongst other things additional excipients to be included in the form of the excipients sodium chloride and sodium succinate buffer. If “comprising” was not inclusive, then claim 9 would make little sense.

180    Accordingly, the scope of claim 1 is apparently defined by reference to what the multivalent immunogenic composition under consideration for the purposes of infringement includes, not by reference to what it consists of. If it includes all of the elements of integers (2) – (5), then it is likely to infringe, even if it also contains things additional to the elements so identified (I say “likely” because that is subject to exceptions not presently relevant, such as whether or not the allegedly infringing composition is properly characterised as a different combination of elements: see Fresenius Medical Care Australia Pty Limited v Gambro Pty Limited [2005] FCAFC 220; 224 ALR 168 at [70] and [92] (Wilcox, Branson and Bennett JJ), an approach that MSD eschews (transcript 1193)).

181    The question then posed by MSD’s submissions, is whether any aspect of the language of the claim supports a construction that the composition is limited to containing the 13 polysaccharide-protein conjugates nominated in integer (4).

182    MSD does not provide a satisfactory answer to this question.

183    First, it submits that a proper understanding of the “invention” as described in the specification compels this conclusion. I shall return to this argument, but it does not grapple with the question of construction of the words used in the claim. It is trite to observe that the monopoly is set out by the patentee in words of its own choosing. It is those words that must first be construed. Contrary to the suggestion made by MSD, I do not understand Welch Perrin & Co Pty Ltd v Worrel [1961] HCA 91; 106 CLR 588 at 609 – 617 (Dixon CJ, Kitto and Windeyer JJ) to suggest otherwise.

184    Secondly, MSD submits claim 1 is expressly limited to the 13 chosen serotypes by the inclusion in integer (4) of the words “... are prepared from [the chosen 13 serotypes]”, which must be understood to mean that the polysaccharide-protein conjugates must be prepared from those 13 serotypes, and no others. However, while there is no doubt that to be within the scope of the claim the 13 chosen serotypes must be present, the question is whether any language precludes the inclusion of further serotypes, having regard to the conceded meaning of the word “comprising” in the first line of claim 1. The words singled out in MSD’s submission do not advance the debate. Nor do I consider that reliance on the maxim expressio unius exclusio alterius (“the express inclusion of one thing is the exclusion of another”) assists, for much the same reason.

185    Thirdly, MSD relies on various aspects of the claim set, when read as a whole, to influence the construction of claim 1. None of these matters address the real issue of the language used in the claim itself. In one such argument MSD contends that because all of the independent claims identify a specific number of polysaccharide-protein conjugates to be included, it would be “absurd” for the claim to be construed as applicable to a variable number of serotypes, extending potentially to 90 or more serotypes. However, the question at this point is what the claim under consideration means. If it is ambiguous, a construction that is not absurd might be chosen, but the first question is to identify ambiguity. This argument does not do so.

186    In another contention MSD observes that there is no dependent claim that expressly allows for any further serotypes, such that it may be assumed that the inclusive meaning of the word “comprising” does not apply to additional serotypes. However, this point does not address the breadth of the meaning of “comprising” having regard to the definition in the specification.

187    In another argument, MSD states that if Wyeth had wanted to claim immunogenic compositions with more than the 13 chosen serotypes, it could have done so by using the words “at least” before listing the serotypes”, but it did not. In this regard the claims must be understood on the basis of the proposition that what is not claimed is disclaimed (citing Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2 at [48] – [49] (Jagot J, with whom Besanko and Nicholas JJ agreed)). However, one is here fixed with the task of construing the particular claim before the Court – it is of no particular assistance to cast about wistfully for other words that were not chosen.

188    Perhaps MSD’s most persuasive argument is that whereas the word “comprising” in the first line of claim 1 should be construed as meaning “including”, the word ”comprises” in the third line of claim 1 should be understood to mean “consists of” and accordingly be exhaustive of the serotypes included. In this regard, MSD emphasises that the body of the specification is directed towards an invention that specifically identifies and nominates the 13 chosen serotypes. By identifying in integer (4) that each of the conjugates comprises a particular capsular polysaccharide, the patentee is making express that the composition must only include those 13 polysaccharide-protein conjugates.

189    However, the difficulty with this argument is that the context does not “require” such a construction. Indeed the comprising passage makes plain that there is a bias towards reading the word as meaning “includes”. In my view the words emphasised above do not do so. Furthermore, it is unlikely that the same root word used twice in the same claim would be construed to have different meanings.

190    In this regard MSD places reliance on the decision of the Full Court in Actavis Pty Ltd v Orion Corporation [2016] FCAFC 121 (Allsop CJ, Nicholas and Yates JJ), where the Full Court overturned the decision at first instance insofar as it construed the word “comprise” and its variants to contort the claimed process into one different to that described in the specification (at [176] – [181]). However, I do not consider that the present position is relevantly similar to that which was considered by the Full Court in Actavis, which concerned the construction of a method claim in quite different circumstances. The position is perhaps more analogous to that which was considered by the Full Court in Bitech Engineering v Garth Living Pty Ltd [2010] FCAFC 75; 86 IPR 468 (Sundberg, Bennett and Yates JJ) where an apparatus claim also included the word “comprising” (at [6]). There, the Court found that the primary judge fell into error by failing to conclude that because the impugned device contained all of the integers of the claim, the device infringed the claim (at [26]). The Court found that the claims in that case did not expressly or impliedly exclude the presence of features additional to those identified in the claim, and so long as an apparatus possessed the features of the claim, it would infringe the patent: see [27] – [29] and [32].

191    Accordingly, in my view the language of claim 1 is to be understood to have the meaning contended for by Wyeth. I do not consider that this language is ambiguous having regard to the definition in the specification.

192    However, a patent specification should be given a purposive, not a purely literal, construction: Flexible Steel Lacing Co v Beltreco Ltd [2000] FCA 890; 49 IPR 331 at [81] (Hely J); and it is not to be read in the abstract but is to be construed in the light of the common general knowledge and the art before the priority date: Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; 207 CLR 1 at [24] (Gleeson CJ, McHugh, Gummow, Hayne and Callinan JJ); Neurizon at [67]. Accordingly, I now turn to the specification to ascertain whether it mandates a different outcome.

193    I have in section 4.1 referred to the disclosure of the specification in the 013 patent. In the Background of the Invention the patentee refers to Prevnar 7, and to surveillance reported in various publications of the effects on invasive pneumococcal disease before and after the introduction of Prevnar 7, to demonstrate that adding serotypes 1, 3, 5, 6A, 7F and 19A to the Prevnar 7 serotypes “would increase coverage for invasive disease” in the US, Europe, Asia and Latin America, significantly expand coverage beyond that of Prevnar 7, and provide coverage for serotypes 6A and 19A that is not dependent on the limitations of cross-protection.

194    The Summary of the Invention states that the invention provides generally a multivalent composition comprising 13 serotypes, each conjugated to a carrier protein, with a physiologically acceptable vehicle and optionally with an adjuvant (page 2 lines 20 – 23):

More specifically, the invention provides a 13-valent pneumococcal conjugate (13vPnC) composition comprising the seven serotypes in the 7vPnC vaccine...plus six additional serotypes...

195    The Summary of the Invention also refers to the invention providing a multivalent composition comprising polysaccharide-protein conjugates, together with a physiologically acceptable vehicle, with each conjugate comprising a capsular polysaccharide from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, and the capsular polysaccharides being “prepared from serotype 3 and at least one additional serotype”. No maximum number of potential serotypes is given. Another embodiment identifies that the additional serotype is selected from one of the 13 chosen serotypes (other than serotype 3).

196    The Summary of the Invention refers to another embodiment, being a multivalent composition comprising polysaccharide-protein conjugates, together with a physiologically acceptable vehicle, with each conjugate comprising a capsular polysaccharide from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, and the capsular polysaccharides are prepared from the Prevnar 7 serotypes and at least one additional serotype. Another embodiment identifies that the additional serotype is selected from the group consisting of 1, 3, 5, 6A, 7F and 19A.

197    The Detailed Description of the Invention identifies the benefits, apparently based on cited articles cited in the specification, of inclusion of each of the chosen serotypes conjugated to a carrier protein. On page 11 at lines 1 – 6 the specification reinforces the focus on the inclusion of the chosen 13 serotypes by stating:

Accordingly, the present invention provides a multivalent immunogenic composition comprising 13 distinct polysaccharide-protein conjugates, wherein each of the conjugates contains a different capsular polysaccharide conjugated to a carrier protein [prepared from the chosen 13 serotypes] together with a physiologically acceptable vehicle...

198    The examples address various matters including the preparation of the chosen 13 serotypes and CRM197. The experiments address their efficacy in certain environments.

199    There can be little doubt that the invention disclosed and described in the specification is for a combination that involves a multivalent immunogenic composition of the 13 chosen serotypes conjugated to CRM197 in combination with a physiologically acceptable vehicle and optionally an adjuvant. The invention as disclosed is the careful nomination of six serotypes in addition to the Prevnar 7 serotypes that have been used in a multivalent immunogenic composition as claimed. That is the focus of the passages in the Summary of the Invention and also the Detailed Description and the examples. However, in my view nothing within the body of the specification indicates that a composition that includes those serotypes and also other matters, including further serotypes conjugated to CRM197, could not fall within the scope of the invention described.

200    Accordingly, the view that I have taken as to the construction of the claims, having regard to the inclusive meaning of “comprises”, is not in discord with the disclosure of the specification as a whole.

201    At this point I note that the language of the second independent claim, claim 11 of the 013 patent, is less favourable to MSD. It is (emphasis added):

A sterile liquid formulation comprising pneumococcal capsular polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F individually conjugated to CRM197.

202    In submissions MSD emphasises that the formulation is of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F individually conjugated to CRM197 and submits that as a matter of construction the formulation must be only of those serotypes. However, having regard to the construction to be given to “comprising” with respect to claim 1, I cannot see how the context could be understood as requiring that comprising be given an exhaustive meaning in this claim.

203    Finally, MSD submits that Wyeth adopted a different position as to the construction of the claims in its correspondence with the Commissioner of Patents to that which it now asserts. It submits that Wyeth’s willingness to alter its position on the construction of the composition patents, as suits its need, does not reflect well on Wyeth and the cogency of the construction in these proceedings. I return to this subject in the context of allegations of false suggestion, in section 13.4 below. It suffices to say for present purposes that, as the authorities note, the question of construction is a matter of law which is for the Court to determine. The submissions made by the patent attorneys representing Wyeth in the course of prosecution do not preclude the Court from arriving at the correct construction.

5.2.3    Infringement of the asserted composition patent claims

204    I have resolved the comprising issue in favour of Wyeth. The parties agree that the consequence of this is that MSD’s 15-valent vaccine that it proposes to launch will infringe the asserted composition patent claims.

5.3    The meaning of “immunogenic”

205    The term “immunogenic” appears in claim 1 of the each of the composition patents. MSD contends that it means that the composition elicits an immune response, but at no particular level. Wyeth contends that the term appears in both claims as part of a composite expression “A multivalent immunogenic composition...” It contends the phrase means that the composition must be capable of being administered with the intention that it will elicit an adaptive immune response that is effective against disease or carriage of each of the 13 chosen serotypes (that is, a protective response), drawing on the meaning of the word “multivalent”.

206    I prefer the construction offered by MSD.

207    The word “immunogenic” is the adjective of that noun “immunity” and is defined to mean “causing immunity”: Macquarie Dictionary (Rev. 3rd ed, 2001, Sydney). “Immune” is defined in the Macquarie Dictionary to mean “protected from a disease or the like, as by inoculation”. However, it is apparent from the expert evidence that those in the art understand that there may be levels of immunity that fall short of protective immunity. In the light of the expert evidence, immunogenic is used in the composition patents as a relative term. In his oral evidence Professor Dagan said that he did not understand claim 1 to require a particular level of immunogenicity. In his affidavit evidence he gives evidence that an “immunogenic” composition according to claim 1 may not result in protective immunity in the recipient. Protective immunity is the ability of the immune system to protect the host against future infections by the same pathogen. As Professor Paton explains, it results from the body’s learned response to pathogens through acquired memory of specific antigens, resulting in adaptive immunity. He understands that there may be a level of immunity that falls short of adaptive immunity, and that claim 1 refers to a composition that produces an immune response, which may be short of an adaptive immune response.

208    In my view the construction propounded by MSD is also supported by the language in the specification, which discusses relative levels of immunity. In the Background of the Invention, Prevnar 7 is referred to as the first pneumococcal conjugate vaccine of its kind to be “highly immunogenic and effective against invasive disease and otitis media...” (page 1 line 15 – 17), implying that a lower level of immunogenicity may be ineffective against disease. In the Summary of the Invention a method is identified for inducing an “immune response”, comprising administering to a human “an immunologically effective amount of any of the immunogenic compositions just described”, which includes the composition of claim 1 (page 4 lines 1 – 4). Such language distinguishes an immunologically effective composition from a merely immunogenic composition. Later, in the Detailed Description of the Invention, a pneumococcal conjugate vaccine comprising capsular polysaccharides from serotype 3 is said to be “capable of eliciting an immunogenic response to serotype 3 polysaccharides” (page 6 line 19 – 23). The efficacy of the immunogenic response is left open; it may or may not be protective.

209    Finally, it may be noted that claim 10 in the 013 patent refers directly to a method of inducing an immune response by administering an “immunologically effective amount of the immunogenic composition” of any of claims 1 – 9, thereby distinguishing between simply immunogenic on the one hand and immunologically effective on the other. As I have noted, that distinction is also made in the body of the specification at page 4 lines 1 – 4.

210    Contrary to the submission advanced by Wyeth, I am not persuaded that the definition of “multivalent” operates to require that the immunogenic composition elicit an adaptive immune response that is effective against disease or the carriage of disease of each of the named serotypes. In the context of the phrase “[a] multivalent immunogenic composition”, the word “multivalent” refers to the fact that more than one serotype is in the composition.

6.    COMPOSITION PATENTS: LACK OF NOVELTY

6.1    Introduction

211    Under each of the pre-RTB and post-RTB versions of the Patents Act, an invention is taken to be novel when compared to the prior art base unless it is not novel in light of, amongst other things, prior art information made publicly available in a single document pursuant to s 7(1)(a), or prior art information made publicly available in two or more related documents, if the relationship between the documents is such that a person skilled in the art would treat them as a single source of that information pursuant to s 7(1)(b).

212    MSD pleads that the invention claimed in the composition patents was not novel as at the priority date of 8 April 2005 when compared with the prior art base which, for the purpose of s 18(1)(b)(i) of the Patents Act, was:

(1)    Peña; and

(2)    Peña considered together with Obaro.

213    There is no dispute that Peña is prior art information made publicly available in a single document within s 7(1)(a) of the Patents Act. Nor is there any dispute that Peña and Obara together constitute prior art information made publicly available in two or more related documents such that a person skilled in the relevant art would treat them as a single source of that information within s 7(1)(b) of the Patents Act.

6.2    The disclosure of Peña

214    There was a controversy at trial about the translation of Peña from Spanish to English, which was resolved by the provision of a substitute translation, to which reference is made below. In English, the title to Peña is “Present and future of the anti-pneumococcal vaccination”. Beneath the title, the authors are identified in conjunction with the words “Commercial Department of Wyeth Farma, S.A. Madrid (Spain)”.

215    The Summary in the article provides:

Pneumococcal infections are a significant cause of morbidity, hospitalization and mortality worldwide; are one of the ten main causes of mortality; and represent 40% of pneumonia deaths in subjects less than five years of age. Universal vaccination would have a significant impact on the community. Currently, there are two available vaccines to prevent invasive pneumococcal illness in Spain: 23-valent polysaccharides (VNP-23V) and 7-valent conjugated (VNC-7V).

There are other conjugated vaccines for 9, 11 and 13 serotypes, although they have not yet been marketed and are in a very advanced study phase.

216    Under the heading “Vaccination”, the article identifies details of the 23-valent pneumococcal capsular polysaccharide vaccine and then says:

The 7-valent pneumococcal conjugate vaccine contains the purified saccharides of the capsular antigens of seven serotypes of Streptococcus pneumoniae (4, 6B, 9V, 14, 18C, 19F and 23F) conjugated individually with a protein, a nontoxic mutant of the diphtheria toxin, CRM197, and forming [sic: forms] glycoconjugates.

217    There is no doubt that the 7-valent vaccine so identified is Prevnar 7.

218    After addressing matters concerning the 23-valent polysaccharide vaccine and Prevnar 7, the following passage appears:

Other pneumococcal vaccines

As we know, there are currently two vaccines available for the prevention of invasive pneumococcal disease: the 23-valent polysaccharide (VNP-23V) and the 7-valent conjugate vaccine (VNC-7V).

There are other pneumococcal conjugate vaccines that have not yet been marketed and that are in advanced phases of study:

-    The vaccine of 9- serotypes (adds 1 and 5), which increases the coverage up to 87% in children less than two years of age and in children between two and five years of age.

-    Of 11- serotypes (adds 3 and 7F). Serotype 3 is the most likely to cause invasive disease in adults in Spain; therefore, the use of these vaccines could have a favorable impact on the incidence of the infection by this serotype.

-    Of 13- serotypes (adds 6A and 19A).

219    Immediately following is a commentary on the 9-valent vaccine which refers to several studies conducted with that vaccine that assessed its safety and immunogenicity. Reference is made to the 9-valent vaccine being administered simultaneously with a DTP vaccine, but in separate syringes, to Gambian children. A footnote then refers the reader to Obaro. There is no dispute that a skilled worker in the field would have concluded that the 9-valent vaccine referred to is the vaccine referred to in Obaro, which is the 9-valent Wyeth composition.

220    On the same page, a little after the heading “The future of pneumococcal vaccination”, the following paragraphs appear (emphasis added):

The geographic variability of pneumococcal serotypes represents a problem when developing a vaccine with worldwide coverage. We would almost have to design a specific vaccine for each geographic area, conducting a prior epidemiological study of the most common serotypes, which would only be possible in developed countries.

Furthermore, we know that the spectrum of serotypes widens with advancing age, which complicates the acquisition of vaccines for age groups other than children, although children are the group at greatest risk and for whom the current vaccine is most effective. In this respect, work is being conducted to incorporate new serotypes to the 7-valent conjugate vaccine, with the 9-valent (which incorporates the serotypes 1 and 5), 11-valent (adding 3 and 7F) and 13-valent (6A and 19a) vaccines in various stages of research. This could broaden the spectrum of ages and countries, although we will continue to have much diversity in coverage. In addition, attempts are being made to incorporate the pneumococci that show the greatest resistance to antibiotics.

6.3    The submissions

221    MSD submits that the disclosure of Peña anticipates a number of claims of both the 013 patent and the 844 patent. It submits that the only integer of claims 1 and 11 of the 013 patent and claim 1 of the 844 patent that is not expressly referred to is that each serotype of the 13-valent vaccine is conjugated to CRM197. It submits that the person skilled in the art would perceive that Peña implicitly discloses that the carrier protein for the 13-valent vaccine is CRM197. That is because first, Peña states that the additional serotypes were “incorporated” into the 7-valent conjugate vaccine, Prevnar 7, which (as Professors Paton and Kasper understood) implies that the 13-valent vaccine would also use CRM197 as the carrier protein. Secondly, the person skilled in the art would assume that the 13-valent vaccine was being developed by Wyeth because Peña “is a Wyeth publication and its authors worked for Wyeth in Spain”, and because Peña does not refer to any non-Wyeth vaccines. Accordingly, the person skilled in the art would assume that the 13-valent vaccine had the same carrier protein as used by Wyeth in previous vaccines, which was disclosed as CRM197.

222    Wyeth submits that to anticipate the patentee’s claim, the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented, citing AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99; 226 FCR 324 (AstraZeneca (FC)) at [293] (Besanko, Foster, Nicholas and Yates JJ, with whom Jessup J agreed). Further, the disclosure must be enabling in that it must allow the skilled reader to create what is disclosed using only the disclosure, common general knowledge and routine trial and experimentation, citing Olin Corporation v Super Cartridge Co Pty Ltd [1977] HCA 23; 180 CLR 236 at 260 – 261 (per Stephen and Mason JJ). It submits that at most Peña discloses that a pneumococcal conjugate vaccine with 13 serotypes was under development. No other information about the composition of the 13-valent vaccine is disclosed. It does not disclose the carrier protein or proteins to which the serotypes were conjugated. Even if the use of CRM197 was disclosed, no directions are stated to make the claimed product or perform any method in respect of that product, and as such any disclosure was not enabling.

6.4    The law of novelty

223    To say that a claim of a patent is not novel in the light of prior art information is to say that it adds nothing new to that with which it is compared. In the case of a paper anticipation, it assumes that the product described is made, or the process outlined is followed. Each integer of the claimed invention must be disclosed in the prior publication. The reverse infringement test is a practical way of detecting whether that is so in most cases: Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; 137 CLR 228 at 235 (Aickin J).

224    That is not to say that the person skilled in the art cannot exercise some degree of skill and experience in considering a prior disclosure. In C. Van der Lely N.V. v Bamfords Ltd [1963] RPC 61 Lord Reid considered whether a skilled reader would infer from photographs of a machine in magazine articles that the rake wheels of the alleged anticipating machine were ground driven rather than gear driven. He said at 72 (emphasis added):

The appellants’ first argument is that it is not enough that the photograph should disclose a probability that the wheels were ground driven. There cannot be anticipation, they say, unless this is shown clearly and unmistakably. I cannot accept that argument. I would agree that the anticipating material must be as good for practical purposes as the material in the appellants' specification. But I can see no practical difference between a definite statement of fact and material from which the skilled man would clearly infer its existence.

So the question is whether the typical skilled man would infer ground drive from the photograph. It would not be enough that a quick-witted man would guess that. But in this case I think that it is proved that the ordinary skilled man would have had good grounds for reaching the conclusion that these wheels were ground driven. He could not have been certain, but practical men act on something less than absolute certainty.

225    The Full Court in AstraZeneca (FC) at [293] noted that the touchstone for determining whether a prior publication anticipates a claimed invention is stated in General Tire & Rubber Co Ltd v Firestone Tyre & Rubber Co Ltd [1971] 7 WLUK 130; [1972] RPC 457 at 485 – 486 (Sachs, Buckley and Orr LJJ) as follows:

When the prior inventor’s publication and the patentee’s claim have respectively been construed by the court in the light of all properly admissible evidence…the question whether the patentee’s claim is new…falls to be decided as a question of fact. If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor’s publication will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.

If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee’s claim the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented…A signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentees.

226    In AstraZeneca (FC) the Full Court makes plain that the limited role that common general knowledge may play in the context of novelty:

[352] Although the common general knowledge can be used in a limited way to construe a prior art document, s 7(1) does not permit the common general knowledge to be used as a resource that can be deployed complementarily to arrive at a disclosure which the document alone, properly construed, does not make. If it were otherwise, the separate requirement of an inventive step to support a patentable invention (see s 18(1)(b)(ii) of the Act) would be otiose. The test of novelty would encompass the test for inventive step, without the need to satisfy the threshold requirements of s 7(3) (as it then stood) that the information in the document be information that the person skilled in the art could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area. All that would be required is that the information in the prior art document be publicly available.

227    The question of lack of novelty was recently revisited by an expanded Full Court in Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd [2020] FCAFC 116; 380 ALR 582 (Middleton, Jagot, Yates, Beach and Moshinsky JJ). After considering relevant authorities, the Full Court re-emphasised the longstanding test in simple terms at [104]:

We do not accept that a documentary disclosure containing an hypothesis cannot be an anticipatory disclosure that deprives an invention of novelty. In such a case the question, simply put, remains: what does the prior document disclose? The occasion on which, or the context in which, a particular documentary disclosure is made may well inform the interpretation of the document’s content. But if, as a matter of interpretation, the document nonetheless discloses that which is later claimed as an invention, that disclosure will anticipate the invention and deprive it of novelty.

228    In that case, the argument on appeal was whether a document anticipated the claims because it advanced no more than a reasoned hypothesis for treatment, not a method of treatment as such ([66]). The primary judge found that it did so anticipate because he found that the document clearly disclosed a method within the claims. The Full Court upheld that conclusion, noting at [82]:

The combined passages from Hill v Evans speak of the need for a prior documentary disclosure to provide information that is equal to the invention that is claimed, if the prior documentary disclosure is to be anticipatory and thereby deprive the invention of novelty. As Hill v Evans makes clear, equality in this context refers to both the specificity of the information and its completeness. Unless these twin qualities are present, the prior disclosure will not be sufficient to deprive the invention of novelty.

229    Having said this, I do not accept Wyeth’s submission that in respect of a product claim, the prior disclosure must do more than describe the product the subject of the claim.

6.5    Consideration

230    Nevertheless, I consider that the approach taken by MSD to the construction of Peña is in error. It exceeds the permissible use of the common general knowledge, which is to be used to understand the disclosure of the prior art document, not to supplement it with matters not disclosed but instead drawn from the common general knowledge. Instead, it relies on inference and assumption, not upon disclosure, as the means by which it arrives at a novelty defeating disclosure. The crucial passage in the article upon which MSD relies, “[i]n this respect, work is being conducted to incorporate new serotypes to the 7-valent conjugate vaccine, with the 9-valent (which incorporates the serotypes 1 and 5), 11-valent (adding 3 and 6F) and 13-valent (6A and 19a) vaccines in various stages of research”, makes no reference to the company that is said to be developing the vaccines. Nor does the article as a whole. MSD relies on an inference that all of these products are being developed by Wyeth. The article does disclose that the 7-valent conjugate vaccine is Prevnar 7 (a Wyeth product). But it does not identify to what carrier protein or proteins the 9-, 11- or 13-valent vaccines under development are conjugated, or who is developing them.

231    Professor Paton gives evidence that he would have assumed that the 13-valent vaccine referred to was being developed by Wyeth. That inference is based on the fact that no other reference is made to any other company or publication in relation to the vaccines under development. Considering the statement in the Summary that the other vaccines “have not yet been marketed and are in a very advanced study phase”, he would have assumed that only a company developing a vaccine would have detailed information about that vaccine. He would also have assumed that the 9- and 11-valent vaccines to which the article refers were those under development by Wyeth. He was aware of the 9-valent pneumococcal conjugate vaccine under development by Wyeth and knew that it used CRM197 as the protein carrier. Based on these several assumptions, Professor Paton considers that although Peña does not explicitly say that each serotype of the 13-valent vaccine under development was conjugated to CRM197, it implied that this was the case. In that sense, he draws attention to the language Peña uses that the additional serotypes were being “incorporated” into the pre-existing vaccines. Furthermore, the only carrier protein mentioned in Peña is CRM197. These matters implied to him that the 13-valent vaccine would also use CRM197.

232    Professor Strugnell notes that Peña does not state to which carrier protein the polysaccharides from each serotype included in the 9-, 11- and 13-valent vaccines are conjugated. Had he read Peña at April 2005, he would have assumed that the 9-valent vaccine is a reference to the Wyeth 9-valent CRM197 conjugate vaccine which is referred to in Obaro, and that the 11-valent vaccine is a reference to either the Aventis 11-valent bi-carrier vaccine or the GSK 11-valent vaccine, or both. He was not aware of any 13-valent pneumococcal conjugate vaccine at the time and would not have known what carrier protein or proteins would be used. Furthermore, he notes that Peña does not disclose a pneumococcal conjugate vaccine that includes polysaccharide-protein conjugates prepared using polysaccharides from each of the 13 serotypes in claim 1, where these are all individually conjugated to CRM197.

233    Professor Dagan takes the same approach as Professor Strugnell.

234    Having regard to the assistance provided by these witnesses, it is for the Court to construe the prior art document. The relevant language is in ordinary English.

235    I consider that the assumptions made by Professor Paton demonstrate that he goes beyond the disclosure of the document in arriving at the conclusion that it teaches a composition in accordance with claim 1 of the composition patents. Whilst it is plain enough to the skilled reader from the text of the article that the 7-valent pneumococcal conjugate vaccine referred to is that developed by Wyeth, and accordingly is conjugated to CRM197, I do not think that it is legitimate to assume that the 9-, 11- and 13- valent vaccines are also conjugated CRM197. There is simply no disclosure of the carrier protein used. In my view it reads too much into the words “work is being conducted to incorporate new serotypes to the 7-valent conjugate vaccine”, to find that this is a disclosure that the serotypes are necessarily being conjugated to CRM197. To reach that conclusion, it would be necessary to assume that because the Prevnar 7 serotypes are being incorporated, so too is the carrier protein. Furthermore, nowhere does Peña state that it refers exclusively to compositions under development by Wyeth. Professor Paton assumes this as a fact. His assumption is in the nature of the quick-witted guess of the type that Lord Reid identified in Van der Lely. The same may be said of a similar conclusion reached by Professor Kasper.

236    Furthermore, if one were to stray from the disclosure of the article, and draw on the common general knowledge to supplement it (which is impermissible: AstraZeneca (FC) at [352]), then the person skilled in the art would have knowledge that a 9-valent pneumococcal conjugate vaccine was under development by Wyeth conjugated to CRM197, that 11-valent pneumococcal conjugate vaccines were under development by Aventis and GSK using different protein carriers, and that a Wyeth 11-valent pneumococcal conjugate vaccine was under development, but with an unidentified protein carrier (see section 8.1). Accordingly, one would remain uncertain as to what carrier protein was used in the 13-valent vaccine mentioned in Peña. That uncertainty cannot be remedied by inference or intelligent guesswork.

237    Accordingly, I find that the disclosure of Peña is not sufficient to defeat the novelty of the claims of the composition patents. Given my findings with respect to the CRM197 integer, it unnecessary to address the rest of MSD’s s 7(1)(a) challenges to the balance of the asserted composition patent claims.

6.6    The disclosure of Peña when read with Obaro

238    There is no dispute that by reason of the cross-reference in the footnote to Peña, Obaro is a document within s 7(1)(b) that a person skilled in the art would treat as a single source of information with Peña.

239    Obaro states its objective is to evaluate the safety and immunogenicity of a nonavalent pneumococcal conjugate vaccine and the antigenic interaction when administered simultaneously with diphtheria, tetanus and pertussis vaccines. It does so by reference to results of a study on Gambian infants. Under the heading “Vaccines” the article says:

The nonavalent pneumococcal conjugate vaccine (PnCV) used in the study was manufactured by Wyeth-Lederle Vaccines and Pediatrics, Rochester NY...It is prepared in a lyohpilized form and contains 2 μg of types 1, 4, 5, 9V, 14, 19F and 23F pneumococcal polysaccharides, 2 μg of type 18C oligosaccharide and 4 μg of type 6B polysaccharide. Each polysaccharide or oligosaccharide is coupled independently to CRM197, a nontoxic mutant of diphtheria toxoid, to give a total of ~20 μg of CRM197 per dose. The vaccine was prepared in single dose vials, reconstituted before injection with 0.75 ml of a saline diluent containing aluminium phosphate. Each 0.5-ml dose contained 0.5 mg of aluminium phosphate.

240    MSD does not rely on Obaro to supplement the disclosure of Peña by reference to the use of a 13-valent vaccine; only a nonavalent vaccine is disclosed. Whilst the serotypes in the 9-valent vaccine are conjugated to CRM197, the deficiencies that I have addressed in terms of the 13-valent vaccines are not resolved. Obaro is relied upon to provide a disclosure of the inclusion and quantity of an aluminium adjuvant, the physiologically acceptable vehicle, and other aspects of the dependent claims.

241    Having regard to my findings in relation to the disclosure of Peña, Obaro does not assist MSD further in relation to its lack of novelty allegations, which must accordingly be rejected.

7.    COMPOSITION PATENTS: LACK OF INVENTIVE STEP – INTRODUCTION

7.1    Overview

242     MSD pleads that the invention claimed in the asserted 013 patent claims was obvious and did not involve an inventive step for the purposes of s 18(1)(b)(ii) and s 7(2) of the Patents Act as at the priority date. It relies for this purpose on the common general knowledge before 8 April 2005. Having regard to the form of the Patents Act that applies to the 013 patent, being the pre-RTB Patents Act, the common general knowledge is to be considered as it existed in the “patent area”, defined in Schedule 1 to mean Australia, as at the priority date: s 7(2). MSD also relies in its closing submissions on the single pieces of prior art information listed below, which it contends the skilled person in the art could reasonably be expected to have ascertained, understood and regarded as relevant within s 7(3)(a) of the Patents Act, and in the case of two or more publications itemised together below multiple pieces of prior art information which the skilled person could before 8 April 2005 be reasonably expected to have combined within s 7(3)(b):

(a)    Peña alone or with Obaro;

(b)    Hausdorff 2000 alone or with another article by Hausdorff et al entitled “Multinational study of pneumococcal serotypes causing acute otitis media in children” published in 2002 by the Pediatric Infectious Disease Journal (Volume 21(11)) (Hausdorff 2002);

(c)    an article by X Yu et al entitled “Immunity to Cross-Reactive Serotypes Induced by Pneumococcal Conjugate Vaccines in Infants” published in 1999 by the Journal of Infectious Diseases (Volume 180);

(d)    chapter 23 of the fourth edition of a book edited by S A Plotkin and W A Orenstein entitled Vaccines published in 2004 by Elsevier Inc.;

(e)    an article by C G Whitney et al entitled “Decline in Invasive Pneumococcal Disease after the Introduction of Protein-Polysaccharide Conjugate Vaccine” published in 2003 by the New England Journal of Medicine (Volume 348(18)) (Whitney 2003); and

(f)    an article by J Eskola et al entitled “Efficacy of a Pneumococcal Conjugate Vaccine Against Acute Otitis Media” published in 2001 by the New England Journal of Medicine (Volume 344(6)).

243    Other publications identified in the particulars to MSD’s lack of inventive step case were not advanced in closing submissions.

244    MSD also contends that the invention claimed in the asserted 844 patent claims was obvious and did not involve an inventive step for the purposes of s 18(1)(b)(ii) and s 7(2) and (3) of the post-RTB Patents Act. It relies on the same pieces of prior art information and the same combinations of prior art information as those identified in relation to the 013 patent.

245    As it turns out, one aspect of the distinction between the pre- and post-RTB forms of s 7(2) and 7(3) is not material to the present case. Whilst the pre-RTB form of s 7(2) confines the common general knowledge to that information as it existed at the priority date within the patent area and the post-RTB form does not, I have no difficulty in finding that the field of the art is an international one, where the common general knowledge in Australia (the patent area) is the same as that outside the patent area.

7.2    The relevant law

246    Section 18(1)(b)(ii) of the pre-RTB Patents Act provide that an invention is a patentable invention for the purposes of a standard patent if the invention, so far as claimed in any claim, involves an inventive step when compared with the prior art base as it existed before the priority date of that claim.

247    Sub-sections 7(2) and (3) provide:

(2)    For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with the information mentioned in subsection (3).

(3)    The information for the purposes of subsection (2) is:

(a)    any single piece of prior art information; or

(b)    a combination of any 2 or more pieces of prior art information;

being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded as relevant and, in the case of information mentioned in paragraph (b), combined as mentioned in that paragraph.

248    By s 7(2) an hypothetical person skilled in the art, notionally possessed with the common general knowledge as it existed before the priority date, must find the invention to be obvious, whether or not the common general knowledge is supplemented by prior art information within s 7(3): AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30; 257 CLR 356 (AstraZeneca (HC)) at [18] (per French CJ).

249    The law concerning the requirement for an inventive step reflects a balance of policy considerations in patent law of encouraging and rewarding inventors without impeding advances and improvements by skilled, non-inventive persons: Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; 235 CLR 173 (Lockwood No 2) at [48] (Gummow, Hayne, Callinan, Heydon and Crennan JJ). The cases over the years have made a number of statements as to what is required to answer the “jury question” of whether or not an invention is obvious. It is a question of fact. The question is not what is obvious to a court, but depends on analysis of the invention as claimed having regard to the state of the common general knowledge, any information relied upon for the purpose of s 7(3), and the approach taken to it by the person skilled in the art: Lockwood No 2 at [51].

250    As a basic premise, the question is always “is the step taken over the prior art an ‘obvious step’ or an ‘inventive step’”? This is often an issue borne out by the evidence of the experts: Lockwood No 2 [52]. Whilst the question remains one for the courts to determine, the courts do so by reference to the available evidence, including that of persons who might be representative of the skilled person in the art: AstraZeneca (HC) at [70] (Kiefel J, as her Honour then was). Various formulations of the question have been set out in the cases. In R D Werner & Co Inc v Bailey Aluminium Products Pty Ltd [1989] FCA 57; 25 FCR 565 at 574 Lockhart J said that there must be “some difficulty overcome, some barrier crossed”. A “scintilla of invention” is sufficient to support the validity of a patent: Aktiebolaget Hässle v Alphapharm Pty Limited [2002] HCA 59; 212 CLR 411 at [48] (per Gleeson CJ, Gaudron, Gummow and Hayne JJ). In Allsop Inc v Bintang Ltd [1989] FCA 428; 15 IPR 686 at 701 the Full Court (Bowen CJ, Beaumont and Burchett JJ) noted that for the invention to be inventive, it must be “beyond the skill of the calling”.

251    Although identified as a single person, it is established that the person skilled in the art may be a composite or team of persons: General Tire at 485. The hypothetical construct represented by that notional team is intended as an aid to the Court in addressing the “hypothetical question of whether a person, with the same knowledge in the field and aware of the problem to which the patent was directed, would be led directly to the claimed invention”: AstraZeneca (HC) at [70].

252    In AstraZeneca (HC) French CJ noted at [15] that relevant content was given to the word “obvious” by Aickin J in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; 148 CLR 262 at 286, where Aickin J posed the test:

whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.

253    At [15] French CJ (with whom Gageler and Keane JJ and Nettle J agreed) (citations omitted and square brackets in the original) explained:

The idea of steps taken "as a matter of routine" did not, as was pointed out in AB Hässle, include "a course of action which was complex and detailed, as well as laborious, with a good deal of trial and error, with dead ends and the retracing of steps". The question posed in AB Hässle was whether, in relation to a particular patent, putative experiments, leading from the relevant prior art base to the invention as claimed, are part of the inventive step claimed or are "of a routine character" to be tried "as a matter of course". That way of approaching the matter was said to have an affinity with the question posed by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd. The question, stripped of references specific to the case before Graham J, can be framed as follows:

"Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art and of the facts of the nature and success of [the existing compound], directly be led as a matter of course to try [the claimed inventive step] in the expectation that it might well produce a useful alternative to or better drug than [the existing compound]?"

That question does not import, as a criterion of obviousness, that the inventive step claimed would be perceived by the hypothetical addressee as "worth a try" or "obvious to try". As was said in AB Hässle, the adoption of a criterion of validity expressed in those terms begs the question presented by the statute.

254    The approach proposed by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 to which French CJ refers is often referred to as the “modified Cripps question”. The application of the modified Cripps question has been the subject of recent consideration. In Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73; 222 FCR 336, the Full Court said at [71] (Besanko, Middleton and Nicholas JJ) (emphasis added):

We do not think that the plurality in Alphapharm were saying that the reformulated Cripps question was the test to be applied in every case. Rather, it is a formulation of the test which will be of assistance in cases, particularly those of a similar nature to Alphapharm. The plurality did not reject as an alternative expression of the test the question whether experiments were of a routine character to be tried as a matter of course (The Wellcome Foundation Limited v VR Laboratories (Aust) Proprietary Limited (1981) 148 CLR 262, at 280-281, 286, per Aickin J). We do not think there is a divide here in terms of whether an expectation of success is relevant between a test which refers to routine steps to be tried as a matter of course and the reformulated Cripps question. It is difficult to think of a case where an expectation that an experiment might well succeed is not implicit in the characterisation of steps as routine and to be tried as a matter of course. On the other hand, we think a test formulated in terms of worthwhile to try was firmly rejected by the High Court in Alphapharm (see also Pfizer, at 476, [287], per French and Lindgren JJ [Pfizer Overseas Pharmaceuticals v Eli Lilly and Co (2005) 225 ALR 416]). The fact (if it be the fact) that the position in the United States may have shifted does not affect the binding nature of what the plurality said in Alphapharm.

255    In Nichia the Full Court picked up on the emphasised passage in concluding that, in finding that there were “a number of unknowns” and that the patentee “did not know” that a combination would produce a satisfactory result within the claim, the primary judge strayed from “the test of steps taken in an expectation that they might well produce the invention or a useful result towards a test of an expectation of knowing that steps will produce a useful result based on predictive capacity” (emphasis added) (at [88] – [89]). The relevant test is expecting that the steps may well work, rather than knowing that steps will or would or even may well work (at [99]).

256    In relation to having multiple avenues to try, in Nichia the Full Court adopted as orthodox the statement of Laddie J in Brugger v Medic-Aid Ltd [1996] WLUK 122; RPC 635 at 661:

…if a particular route is an obvious one to take or try, it is not rendered any less obvious from a technical point of view merely because there are a number, and perhaps a large number, of other obvious routes as well. If a number of obvious routes exist it is more or less inevitable that a skilled worker will try some before others. The order in which he chooses to try them may depend on factors such as the ease and speed with which they can be tried, the availability of testing equipment, the costs involved and the commercial interests of his employer. There is no rule of law or logic which says that only the option which is likely to be tried first or second is to be treated as obvious for the purpose of patent legislation.

257    In AstraZeneca (FC) Jessup J considered the approach to be taken by a primary judge in characterising an invention. Jessup J recorded that in that case the primary judge reviewed the specification and found that it made plain that the inventors had come up with the administration of a particular dose or dosage range of rosuvastatin but not rosuvastatin itself, which had previously been invented (at [462]). One of the relevant claims was for a method of treating a patient with a particular dose range of rosuvastatin (at [463]). The primary judge approached the question of inventive step by characterising the inventive concept as lying in the dosage range alone. The primary judge found that knowledge of rosuvastatin was not part of the common general knowledge at the priority date. However, having regard to the disclosure of the specification, the specification itself made the existence of rosuvastatin “a given”, and located the inventive concept in the discovery of a dosage range (at [468]). Accordingly the primary judge considered that the relevant problem was the dosage range of rosuvastatin to achieve the objective of lowering cholesterol without significant side effects. It was not, as the patentee, submitted, finding dosages of alternative statins of rosuvastatin in general (on the basis that rosuvastatin could not be considered to form part of the relevant knowledge).

258    The primary judge then proceeded to consider inventive step on the basis that rosuvastatin was known to the notional skilled team. That approach met with the problem that rosuvastatin, as noted above, was not found to be part of the common general knowledge as at the priority date. The primary judge answered that by finding that the skilled addressee must be imputed with a knowledge of rosuvastatin and of its membership of the known class of statins useful for a known purpose, being the treatment of hypercholesterolemia (at [471]).

259    That approach was rejected by Jessup J and by the balance of the Full Court. The latter definitively concluded that the Patents Act does not expressly or impliedly contemplate that the body of knowledge and information against which the question of inventive step is to be determined may be enlarged by reference to the content of the specification including, in particular, any problem that the invention is explicitly or implicitly directed at solving (at [202]). The High Court did not criticise this reasoning in dismissing the appeal.

260    In Insta Image Pty Ltd v KD Kanopy Australasia Pty Ltd [2008] FCAFC 139; 239 FCR 117 at [80] (Lindgren, Bennett and Logan JJ) the Full Court considered lack of inventive step in the context of the Patents Act. It held at [80] that, in determining the issue of obviousness it was necessary:

(1)        to identify the invention “so far as claimed in any claim”;

(2)        to identify the “person skilled in the relevant art”;

(3)        to identify the common general knowledge as it existed in Australia before the priority date;

(4)        to inquire under s 7(2) whether the invention referred to in (1) above would have been obvious to the person referred to in (2) above in light of the knowledge referred to in (3) above; and

(5)        to inquire whether that invention would have been obvious to that person in the light of that knowledge when that knowledge is considered together with either kinds of information mentioned in s 7(3) (additional prior art information).

7.3    The arguments

261    MSD contends that an affirmative answer should be given to the question:

At April 2005, would the person skilled in the art be directly led as a matter of course to try the claimed invention in the expectation that it might well produce a useful alternative to or better vaccine than existing pneumococcal vaccines, particularly Prevnar 7?

262    MSD submits that all of the 13 chosen serotypes in the composition patents were “a given”. Other vaccines had already included 11 of these, and serotypes 6A and 19A would have been included based on publicly available epidemiological data – as Wyeth itself did and as explained in the composition patents. MSD submits that the common general knowledge included knowledge of Prevnar 7 and also of vaccines under development as at April 2005, being the Wyeth 9-valent vaccine, and also two 11-valent vaccines, one being developed by GSK and the other by Aventis. MSD submits that an effective vaccine is one which can elicit an antibody response that protects the recipient from disease caused by each serotype in it and that the ELISA and OPA tests were conventionally used to determine the presence and quantity of antibodies in a sample. The OPA test was preferred because it determined whether antibodies are functional. Insofar as the claims include adjuvants, it submits that the adjuvant in Prevnar 7 was aluminium phosphate, and that it would be the natural choice to enhance immunogenicity. MSD submits that there was a clear advantage in using a single carrier for making conjugates and that the obvious choice was to use CRM197, which was used in Prevnar 7. It submits that the approach of Wyeth to contending that CIES/immune interference would have deterred the skilled team from using CRM197 is a false issue.

263    Wyeth submits that: the number of serotypes, and the particular choice of the 13 chosen serotypes, was not a given; immune interference was a concern with the addition of serotypes; serotype 3 had problems; serotypes and 19A and 6A were unnecessary and undesirable; and CRM197 was one option which others had eschewed in favour of other carriers even though it had been freely available since the 1970s. Further, it submits that making such a conjugate would have been technically difficult to achieve.

264    Wyeth submits that MSD must establish that the skilled team would have been directly led as a matter of course to try the composition with a reasonable expectation of success. In this regard, it relies on its construction of “immunogenic” to mean that the composition will elicit an adaptive immune response that is effective against disease or carriage of each of the 13 chosen serotypes. I have addressed and rejected Wyeth’s submission on the construction of this term in section 5.4 above.

7.4    The approach taken to inventive step by the experts

7.4.1    Professor Paton

265    Professor Paton’s evidence relevant to the question of inventive step began with a summary of his involvement and recollection of matters concerning immunisation against pneumococcal disease in the 1990s through to the priority date. Set out below is a summary of his evidence in chief.

266    In the 1990s Professor Paton’s research involved the study of pneumococcal pathogenesis in order to identify the disease-causing components of Streptococcus pneumoniae and the identification of vaccine antigens that provide non-serotype dependent protection against pneumococcus. His focus was on creating a universal vaccine that was capable of covering all serotypes, such that the vaccine would provide non-serotype dependent protection. He says in the Paton Review that in the mid to late 1990s there was an increased prevalence in vaccinated populations of non-vaccine serotypes, which had the potential to result in increased spread of disease caused by those serotypes. He also notes that there were limits to cross-protection between serotypes and that an assumption of cross-protection may be incorrect, referring to studies where there was weaker than expected cross-protection.

267    In 2000, Wyeth released Prevnar 7. Professor Paton read an article about it shortly after its publication. It was based on serotypes which were prevalent in developed countries, where there had been active surveillance of serotypes. He knew that it was typically administered as a course of three injections at two, four and six months of age, followed by a booster at 12 – 15 months. He knew that Prevnar 7 was very successful in inducing an immune response in children under five and also resulted in a significant decrease in infection among the elderly. In the Paton Review, he says that:

Conjugate vaccines developed to date by various manufacturers are either 7-, 9- or 11- valent, using different cross-linking chemistries, and employ a range of protein carriers such as tetanus or diphtheria toxoids, the diphtheria toxin derivative CRM197, or outer membrane proteins from Neisseria meningitidis group B or non typeable H. influenzae. The 7-valent formulation includes types 4, 6B, 9V, 14, 18C, 19F and 23F...The 9-valent formulation includes these same types with the addition of types 1 and 5, which although uncommon in Europe and North America are important causes of invasive pediatric disease in other geographic regions...Types 3 and 7F were also included in the 11-valent formulation.

268    In his affidavit, Professor Paton says that the reference in this article to 9- and 11-valent vaccines was to experimental vaccines of those valencies that Professor Paton understood were being developed by Wyeth and an 11-valent vaccine being developed by GSK. Professor Paton’s reference to an 11-valent Wyeth vaccine provoked some controversy at trial. It became apparent in cross-examination that the other 11-valent vaccine to which he refers in the Paton Review was that of Aventis, which used the bi-carrier approach, and which was discontinued in 2002, rather than that of Wyeth. I refer to this further below.

269    Professor Paton identifies that before April 2005 he was aware that there were two main types of conjugation chemistries: reductive amination and carbodiimide chemistry. He had experience using the latter in his own laboratory and was aware that Prevnar 7 used the former when he wrote his Review Article.

270    In his first affidavit he outlines his background and experience relevant to the technology in issue and responds to the MSD Problem, set out again below:

How would you have gone about developing a polysaccharide-protein conjugate pneumococcal vaccine that was an improvement on Prevnar 7 before April 2005?

271    MSD advances its case on lack of inventive step from Professor Paton’s answer to this question, which I set out below:

85. The starting point when developing a new conjugate vaccine is the existing conjugate vaccine because, as I explained above, a new vaccine must not be inferior compared with the existing vaccine.

86. As I have discussed above, the aim of developing an improved polysaccharide-protein conjugate vaccine was (and still is) to increase coverage against additional prevalent serotypes.

87. As I have discussed above, it was well known which serotypes were prevalent and issues with cross-protection were also well known.

88. I would have searched the literature for studies and recommendations on serotypes to include in a vaccine and I would have adopted the same strategy for searching that I had already been using, as I have described above. However, given that the specific task related to a polysaccharide-protein conjugate pneumococcal vaccine, I would have added the search term "conjugate". I would have considered the most recent publications first. Later publications may well have included summaries or references to earlier work of relevance.

89. Having identified the additional serotypes to include in the conjugate vaccine, I would have obtained purified polysaccharides from the additional serotypes using standard extraction and purification techniques (e.g., those used by previous manufacturers of polysaccharide vaccines). I would have conjugated those purified polysaccharides to the same carrier protein, in the same way as Prevnar 7. I then would have performed the stock standard experimental assays to test the immunogenicity of the new vaccine components (individually and then in combination with each other and with the serotypes of the original 7 valent vaccine). This would involve immunisation of laboratory animals with the new formulation followed by standard serological analysis (i.e., an ELISA) of blood serum collected after the course of immunisation. This would have given me an indication of whether the new vaccine components elicited an immune response.

7.4.2    Professor Strugnell

272    Professor Strugnell was asked to address the Wyeth Problem by Allens, set out again below:

…how I would go about solving the problem of developing an improved pneumococcal vaccine…on the basis of what was known to me and what I understand to have been well-known to others working in the field of immunology and microbiology, including as it relates to vaccine development and particularly pneumococcal vaccines, as at April 2005.

273    Professor Strugnell says that in developing any new pneumococcal vaccine he would consider its purposes. Having done so, one strategy that was consistent with his work before the priority date was to develop a recombinant Salmonella vaccine expressing pneumococcal proteins. He notes that he commenced work of this type in 2005, but that although protein vaccine trials are still being conducted today, no pneumococcal protein vaccine has yet been marketed.

274    Another option would have been to add one of the protein vaccine candidates to an existing pneumococcal conjugate vaccine, such as Prevnar 7, which would have the benefit of conferring serotype specific protection. Professor Strugnell says that as at April 2005 and today, it was not possible to predict whether such a combination would work.

275    A third option would have been to try to expand the serotype coverage of a pneumococcal conjugate vaccine by adding further serotypes in order to expand the protection afforded by the existing formulations. He notes that he would only have regarded such a vaccine as acceptable if the protection afforded was not diminished by reason of the inclusion of additional serotypes. One approach in this regard could have included researching combinations of serotypes specific to particular geographic regions or countries, enabling a smaller number of serotypes to be chosen. Another approach would have been researching and adding important serotypes that are prevalent globally.

276    Professor Strugnell gives evidence that in order to pursue the third option, he would have confirmed the status of pneumococcal conjugate vaccines on the market and in development as at April 2005 and, if necessary, conducted specific searches to obtain this information. He would also have obtained the product information for Prevnar 7. He then gives evidence concerning the pneumococcal conjugate vaccines that he knew were in development before April 2005. He says that it was his understanding as at April 2005 that the number of serotypes that could be included in a conjugate vaccine was limited, citing Plotkin and another article in support, and states that there was no expectation that a pneumococcal conjugate vaccine with more than 10 serotypes could be successfully achieved, but that it would be a major research project to attempt to do so. Moreover, he expresses the view that there would be a number of further questions to ask, including:

(a)    Which serotypes to include? This he considers is a question for clinicians and epidemiologists in the team, and would involve balancing a number of considerations, which he addresses in detail.

(b)    Whether to use short lengths of saccharide (oligosaccharides) or longer lengths (polysaccharides)?

(c)    Which protein or proteins to use as carriers? He would have expected to use multiple carrier proteins rather than a single one for all serotypes to develop a high valency pneumococcal conjugate vaccine, because of the teaching of Plotkin.

(d)    Whether immune interference issues would impair the value of adding further serotypes and require the use of different/multiple carrier proteins or a different conjugation method.

277    Professor Strugnell expresses the view that these issues would lead him away from trying to add further serotypes to the Prevnar 7 pneumococcal conjugate vaccine, and instead to try one of the other options.

7.4.3    Professor Dagan

278    Professor Dagan gives evidence that had he been asked to increase the coverage of pneumococcal conjugate vaccines by adding more serotypes to existing formulations, he would have expected a number of difficulties.

279    One is immune interference, a term that he uses to describe all types of interference phenomena which may occur in the immune system. One concern with respect to immune interference is that pre-existing immunity to a carrier protein may suppress the immune response to a polysaccharide linked to the same carrier protein, thus jeopardising the polysaccharide immune responses. He calls this form of carrier-mediated interference “carrier-induced epitope suppression” or CIES. He considered that CRM197 was no different to any other carrier protein in its likelihood of being affected by immune interference generally or CIES. Professor Dagan identifies a number of other difficulties with pneumococcal conjugate vaccines that he says as at April 2005 were well-known, being that there were drawbacks with the complexity of the manufacturing process for pneumococcal conjugate vaccines which increased their cost, the limited number of capsular polysaccharides that was considered could be included in them, and the potential for replacement disease as a result of serotype replacement, because not all serotypes were covered. These concerns, he considers, were driving research efforts before April 2005 to develop a “universal” pneumococcal vaccine based on immunity against non-capsular antigens common to all serotypes. He also refers to other potential approaches that were being explored at the time.

280    Professor Dagan considers that in April 2005 there were various options for research and investigation in relation to pneumococcal conjugate vaccines, including:

(a)    researching into protein vaccines, either as stand-alone vaccines or as components to be added to pneumococcal conjugate vaccines – he considered this the area of greatest interest;

(b)    increasing the coverage of pneumococcal conjugate vaccines by adding more serotypes to existing ones, using more and different carrier proteins, or using pneumococcal proteins as carrier proteins; and

(c)    developing country-specific pneumococcal conjugate vaccines containing the most prevalent serotypes for particular countries.

281    Professor Dagan was also asked to comment specifically on how he would go about solving the Wyeth Problem if he were directed to try to develop a new pneumococcal conjugate vaccine based on Prevnar 7. He gives evidence that he would have expected that the polysaccharides from the nine serotypes in the Wyeth 9-valent pneumococcal conjugate vaccine could be conjugated to CRM197 to produce a vaccine that could protect recipients against disease caused by those nine serotypes, but he would not have known whether more serotypes could be added. He says that if they were all conjugated to CRM197, he would have expected it to interfere with the antibody responses to one or more of the serotypes in the vaccine, compromising the protection afforded. To try to avoid the risk of CIES he would instead have considered conjugating some of the serotypes to one carrier protein and others to a different carrier protein. This, he says, was the approach adopted by Aventis for its 11-valent pneumococcal conjugate vaccine and he would have considered protein D (the carrier protein used in the GSK 11-valent pneumococcal conjugate vaccine) an attractive option because it was not present in any co-administered vaccines. He would not have known without experimentation whether any expanded pneumococcal conjugate vaccine would solve the Wyeth Problem.

7.4.4    Professor Kasper

282    Professor Kasper gives evidence, in response to the evidence given by Professor Dagan, about his knowledge of immune interference and CIES before April 2005, the state of knowledge as to cross-protection between serotypes 6B and 6A, and 19F and 19A, and whether he would have included serotypes 6A and 19A in a new multivalent immunogenic pneumococcal conjugate vaccine before April 2005. He gives evidence that he would not have been deterred from pursuing a 13-valent pneumococcal conjugate vaccine with CRM197 as a single carrier protein because of immune interference or CIES. He says that CRM197 was first developed in the 1970s and has been used as a carrier protein since the 1980s. Before April 2005 it had been shown to be a good carrier protein in a number of approved conjugate vaccines, including in Prevnar 7 and against meningococcus. Prevnar 7 is itself an expanded form of earlier lower-valency compositions using CRM197 as the only carrier protein. He considers that there was typically a preference for particular carrier proteins for which there was prior successful experience and know-how within the vaccine development industry, and clear advantages to using a single carrier protein in a multivalent conjugate vaccine in terms of efficiency, costs, simplicity and minimisation of the risk of adverse reactions. He considers that a multi-carrier composition is inherently inefficient and expensive. Given what he considers to be the strong immunogenicity reported for all nine pneumococcal serotypes of the Wyeth 9-valent CRM197 conjugate vaccine, he would have a reasonable expectation that a 13-valent CRM197 vaccine would be immunogenic as well. Expanding from 9-valent composition to a 13-valent composition does not require adding large amounts of carrier protein, and he would expect it to work.

283    In relation to serotype selection, Professor Kasper was asked to comment on the state of knowledge as to cross-protection between serotypes 6B and 6A, and 19F and 19A. He considers that the literature, before the introduction of Prevnar 7, identified serotypes 6A and 19A as clinically relevant serotypes for which there was no conjugate vaccine. He cites a number of documents relied upon by MSD in support of its case under s 7(3) of the Patents Act. He gives the opinion that based on the literature, he would not have assumed that serotypes 6B and 19F of Prevnar 7 would provide sufficient cross-protection to serotypes 6A and 19A respectively.

7.5    The relative expertise of the experts

284    The parties made various submissions going to the expertise and relevance of the experts. In my view Professor Paton had relevant experience in the field before the priority date. He wrote articles relevant to that area and was involved in research and development work that qualified him as a person to speak about the subject matter. I consider that his expertise is squarely within the field of the composition patents and that before the priority date he was working in that field. His work encompassed the pathogenesis of disease caused by Streptococcus pneumoniae, aiming to understand key events in the host-pathogen interaction and to identify and evaluate novel drug targets and vaccine antigens that provide non-serotype dependent protection against pneumococcus.

285    Professor Strugnell is an expert in microbiology and immunology, including encapsulated bacteria, who has worked as part of several groups that developed vaccines against several pathogens, and who has familiarised himself with the literature in the field of pneumococcal vaccines as at April 2005. He had not before the priority date worked on multivalent pneumococcal polysaccharide conjugate vaccines or formulated any vaccines for use in humans and had no experience in making glycoconjugates. His evidence in answer to that of Professor Paton was based on many publications that he read after April 2005 for the purposes of preparing his affidavit evidence. Nevertheless, his evidence as to the approach that he would have taken before April 2005 was informed by his prior training and experience.