Merck Sharp & Dohme Corporation v Wyeth LLC (No 3)
[2020] FCA 1477
•14 October 2020
FEDERAL COURT OF AUSTRALIA
Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) [2020] FCA 1477
File number: NSD 1381 of 2017 Judge: BURLEY J Date of judgment: 14 October 2020 Catchwords: PATENTS – two standard patents relating to a 13-valent pneumococcal conjugate vaccine (composition patents) – one standard patent relating to a container means for stabilising an immunogenic composition (container patent) – infringement – validity
PATENTS – infringement – construction of product claims – whether “comprising” inclusive or exhaustive – infringement found
PATENTS – validity – novelty – implied disclosure – whether person skilled in the art can supply integers by assumption or from common general knowledge – no anticipation of claims
PATENTS – validity – lack of inventive step – s 7(2) of the Patents Act 1990 (Cth) – findings of common general knowledge – availability of prior art information under s 7(3) of the Patents Act – invention in composition patents not shown to lack an inventive step – invention in container patent found to lack an inventive step in light of the common general knowledge alone and in light of prior art information within s 7(3) of the Patents Act
PATENTS – validity – lack of support – legal test – United Kingdom and European Law – technical contribution to the art – lack of support established for one composition patent
PATENTS – validity – lack of fair basis – legal test – claims fairly based
PATENTS – validity – lack of utility – promise of the invention – whether promises met – ground not established
PATENTS – validity – manner of manufacture – threshold test – face of the specification – ground not established
PATENTS – validity – lack of clarity – ground not established
Legislation: Acts Interpretation Act1901 (Cth) s 15AB
Federal Court of Australia Act 1976 (Cth) s 37M
Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth)
Intellectual Property Laws Amendment (Raising the Bar) Bill 2011 [2012] (Cth) Explanatory Memorandum
Patents Act 1990 (Cth) ss 7(1), 7(2), 7(3), 7A, 18, 40(2)(b), 40(3), 138(3)(e)
Patents Amendment (Innovation Patents) Act 2000 (Cth)
Convention on the Grant of European Patents, opened for signature 5 October 1973, 1065 UNTS 199 (entered into force 7 October 1977) art 83, 84
Patents Act 1977 (UK) ss 5(2)(a), 14(3), 14(5)(c), 72(1)(c)
Statute of Monopolies (21 Jac, c 3) s 6
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Actavis Pty Ltd v Orion Corporation [2016] FCAFC 121
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Bitech Engineering v Garth Living Pty Ltd [2010] FCAFC 75; 86 IPR 468
Bristol-Meyers Squibb Company v F H Faulding & Co Limited [2000] FCA 316; 97 FCR 524
Commissioner of Patents v Microcell Ltd [1959] HCA 71; 102 CLR 232
CSR Building Products Ltd v United States Gypsum Company [2015] APO 72
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Décor Corp Pty Ltd v Dart Industries Inc [1988] FCA 682; 13 IPR 385
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F.Y.D Investments Pty Ltd v Promptair Pty Ltd [2017] FCA 1097
Flexible Steel Lacing Co v Beltreco Ltd [2000] FCA 890; 49 IPR 331
Fresenius Medical Care Australia Pty Limited v Gambro Pty Limited [2005] FCAFC 220; 224 ALR 168
Garford Pty Ltd v DYWIDAG Systems International Pty Ltd [2015] FCAFC 6; 110 IPR 30
Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73; 222 FCR 336
GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No 2) Limited v Generic Partners Pty Limited [2018] FCAFC 71; 264 FCR 474
Grant v Commissioner of Patents [2006] FCAFC 120; 154 FCR 62
H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70; 177 FCR 151
ICI Chemicals & Polymers Ltd v The Lubrizol Corporation Inc [2000] FCA 1349; 106 FCR 214
Idenix Pharmaceuticals LLC v Gilead Sciences Pty Ltd [2017] FCAFC 196; 134 IPR 1
Insta Image Pty Ltd v KD Kanopy Australasia Pty Ltd [2008] FCAFC 139; 239 FCR 117
Jupiters Ltd v Neurizon Pty Ltd [2005] FCAFC 90; 65 IPR 86
Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; 207 CLR 1
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; 235 CLR 173
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; 217 CLR 274
Merck & Co Inc v Arrow Pharmaceuticals Limited [2006] FCAFC 91; 154 FCR 31
Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; 137 CLR 228
Minnesota Mining and Manufacturing Company v Beiersdorf (Australia) Limted [1980] HCA 9; 144 CLR 253
Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd [2020] FCAFC 116; 380 ALR 582
N V Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15; 183 CLR 655
National Research Development Corporation v Commissioner of Patents [1959] HCA 67; 102 CLR 252
Nichia Corporation v Arrow Electronics Australia Pty Ltd (No 4) [2017] FCA 864
Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2
NSI Dental Pty Ltd v University of Melbourne [2006] FCA 1216; 69 IPR 542
Olin Corporation v Super Cartridge Co Pty Ltd [1977] HCA 23; 180 CLR 236
Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd (No 4) [2015] FCA 634; 113 IPR 191
Palmer v Dunlop Perdriau Rubber Company Limited [1937] 43; 59 CLR 30
R D Werner & Co Inc v Bailey Aluminium Products Pty Ltd [1989] FCA 57; 25 FCR 565
Ranbaxy Australia Pty Ltd (ACN 110 781 826) v Warner-Lambert Company LLC [2008] FCAFC 82; 77 IPR 449
Rehm Pty Limited v Websters Security Systems (International) Pty Limited [1988] FCA 232; 81 ALR 79
Sandvik Intellectual Property AB v Quarry Mining & Construction Equipment Pty Ltd [2017] FCAFC 138; 348 ALR 156
Sequenom, Inc. v Ariosa Diagnostics, Inc. [2019] FCA 1011; 143 IPR 24
Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2011] FCAFC 132; 119 IPR 194
SNF (Australia) Pty Limited v BASF Australia Ltd [2019] FCA 425; 140 IPR 276
Stefanovski v Digital Central Australia (Assets) Pty Ltd [2018] FCAFC 31; 368 ALR 607
Welch Perrin & Co Pty Ltd v Worrel [1961] HCA 91; 106 CLR 588
Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; 148 CLR 262
WM Wrigley Jr Co v Cadbury Schweppes Pty Ltd [2005] FCA 1035; 66 IPR 298
Asahi Kasei Kogyo KK’s Application [1991] 5 WLUK 114; RPC 485
Biogen Inc v Medeva Plc [1996] 10 WLUK 486; [1997] RPC 1
Brugger v Medic-Aid Ltd [1996] WLUK 122; RPC 635
C. Van der Lely N.V. v Bamfords Ltd [1963] RPC 61
Eli Lily v Human Genome Sciences [2008] 7 WLUK 978; RPC 29
Exxon/Fuel Oils (T 409/91) [1993] 3 WLUK 282; [1994] EPOR 149
General Tire & Rubber Co Ltd v Firestone Tyre & Rubber Co Ltd [1971] 7 WLUK 130; [1972] RPC 457
Generics (UK) Ltd v H Lundbeck A/S [2008] EWCA Civ 311; RPC 19
Generics (UK) Ltd v H Lundbeck A/S [2009] UKHL 12; RPC 13
Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2004] UKHL 46; [2005] 1 All E.R. 667
Lane Fox v Kensington and Knightsbridge Electric Lighting Co [1892] 3 Ch. 424
Mentor Corp v Hollister Inc (No 2) [1992] 7 WLUK 465; [1993] RPC 7
Mentor Corp v Hollister Inc [1991] 3 WLUK 167; FSR 557
Novartis AG v Johns & Johnson Medical Ltd [2010] EWCA Civ 1039; [2011] E.C.C. 10
Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157
Regeneron Pharmaceuticals Inc (Respondent) v Kymab Ltd (Applicant) [2020] UKSC 27; Bus LR 1394
Regeneron Pharmaceuticals, Inc v Kymab Ltd [2018] EWCA Civ 671; RPC 14
Schering Biotech Corp’s Application [1993] RPC 249
Zipher Ltd v Markem Systems Ltd [2009] EWHC 1379; FSR 1
Sir Colin Birss et al, Terrell on the Law of Patents (19th ed, Sweet & Maxwell, London, 2020)
Date of hearing: 3 – 7, 10 – 14 December 2018, 6 – 8 February 2019, 16 March 2020 Date of last submissions: 14 August 2020 Registry: New South Wales Division: General Division National Practice Area: Intellectual Property Sub-area: Patents and Associated Statutes Category: Catchwords Number of paragraphs: 959 Counsel for the Applicants/Cross-Respondents: Ms K J Howard SC with Mr D B Larish Solicitor for the Applicants/Cross-Respondents: Corrs Chambers Westgarth Counsel for the Respondent/Cross-Claimant: Mr A J L Bannon SC with Ms C L Cochrane and Mr R W Clark Solicitor for the Respondent/Cross-Claimant: Allens
Table of Corrections 1 June 2021 In paragraph 439, the phrase “[check]” has been removed from the final sentence 1 June 2021 In paragraphs 527, 531 and 532 “Hoffman LJ” has been changed to “Lord Hoffmann” 1 June 2021 In paragraphs 168 and 537-540 “Lord Hoffman” has been changed to “Lord Hoffmann” ORDERS
NSD 1381 of 2017 BETWEEN: MERCK SHARP & DOHME CORPORATION
First Applicant
MERCK SHARP & DOHME (AUSTRALIA) PTY LTD
Second Applicant
AND: WYETH LLC
Respondent
AND BETWEEN: WYETH LLC
Cross-Claimant
AND: MERCK SHARP & DOHME CORPORATION
First Cross-Respondent
MERCK SHARP & DOHME (AUSTRALIA) PTY LTD
Second Cross-Respondent
JUDGE:
BURLEY J
DATE OF ORDER:
14 October 2020
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
1 INTRODUCTION
[1]
1.1 Issues arising in relation to the composition patents
[5]
1.2 Issues arising in relation to the container patent
[9]
1.3 Summary of conclusions
[11]
2 COMPOSITION PATENTS: THE WITNESSES
[14]
2.1 MSD witnesses
[15]
2.2 Wyeth Witnesses
[23]
2.3 The composition patents joint expert report and concurrent evidence
[35]
3 COMPOSITION PATENTS: BACKGROUND PRIMER
[37]
3.1 General background
[38]
3.2 The pneumococcus
[59]
3.3 Pneumococcal vaccines
[74]
3.4 Polysaccharide-protein conjugate vaccines
[87]
3.5 Vaccine formulation and development
[97]
4 COMPOSITION PATENTS – SPECIFICATION AND CLAIMS
[112]
4.1 The specification of the 013 patent
[112]
4.2 The claims of the 013 patent
[155]
4.3 The specification and claims of the 844 patent
[156]
4.4 Summary of the disclosure
[158]
4.5 The person skilled in the art
[160]
5 COMPOSITION PATENTS: CONSTRUCTION ISSUES
[164]
5.1 The principles of patent construction
[165]
5.2 The comprising issue
[169]
5.2.1 The arguments
[169]
5.2.2 Consideration
[175]
5.2.3 Infringement of the asserted composition patent claims
[204]
5.3 The meaning of “immunogenic”
[205]
6 COMPOSITION PATENTS: LACK OF NOVELTY
[211]
6.1 Introduction
[211]
6.2 The disclosure of Peña
[214]
6.3 The submissions
[221]
6.4 The law of novelty
[223]
6.5 Consideration
[230]
6.6 The disclosure of Peña when read with Obaro
[238]
7 COMPOSITION PATENTS: LACK OF INVENTIVE STEP – INTRODUCTION
[242]
7.1 Overview
[242]
7.2 The relevant law
[246]
7.3 The arguments
[261]
7.4 The approach taken to inventive step by the experts
[265]
7.4.1 Professor Paton
[265]
7.4.2 Professor Strugnell
[272]
7.4.3 Professor Dagan
[278]
7.4.4 Professor Kasper
[282]
7.5 The relative expertise of the experts
[284]
8 COMPOSITION PATENTS: ASPECTS OF THE COMMON GENERAL KNOWLEDGE
[291]
8.1 Known pneumococcal conjugate vaccines
[294]
8.1.1 Prevnar 7
[296]
8.1.2 Merck’s 7-valent vaccine
[299]
8.1.3 Wyeth’s 9-valent pneumococcal conjugate vaccine
[300]
8.1.4 GSK’s 11-valent vaccine
[303]
8.1.5 Aventis’s 11-valent vaccine
[306]
8.1.6 Wyeth’s 11-valent vaccine
[312]
8.1.6.1 MSD’s application to re-open of 24 July 2020
[320]
8.1.7 Plotkin
[326]
9 COMPOSITION PATENTS: ANALYSIS OF INVENTIVE STEP IN LIGHT OF COMMON GENERAL KNOWLEDGE ALONE
[328]
9.1 Introduction
[328]
9.2 Moving to a 13-valent pneumococcal conjugate vaccine
[334]
9.3 Technical challenges
[345]
9.4 Choice of additional serotypes
[363]
9.5 Choice of carrier protein
[375]
9.6 Immune interference
[378]
9.6.1 Introduction
[378]
9.6.2 The expert evidence concerning immune interference
[380]
9.6.3 Findings in relation to immune interference
[399]
9.7 Primary conclusions in relation to lack of inventive step in the light of the common general knowledge
[401]
9.8 Secondary indicia of inventiveness
[403]
10 COMPOSITION PATENTS: ANALYSIS OF INVENTIVE STEP IN LIGHT OF THE PRIOR ART INFORMATION WITHIN S 7(3)
[410]
10.1 Introduction
[410]
10.2 Peña and Obaro
[413]
10.3 Hausdorff 2000 and Hausdorff 2002
[419]
10.4 Yu
[428]
11 COMPOSITION PATENTS: AN EVIDENTIARY RULING
[432]
12 COMPOSITION PATENTS: INUTILITY
[432]
12.1 The relevant law
[432]
12.2 MSD’s inutility case
[442]
12.3 Were the asserted promises made?
[445]
12.4 Consideration of whether modified promise 2 is met – serotype 14
[456]
12.5 Consideration of whether modified promise 3 is met – inutility consequence of the resolution of the comprising issue
[467]
13 COMPOSITION PATENTS: FALSE SUGGESTION
[471]
13.1 Introduction
[471]
13.2 The relevant law
[476]
13.3 The asserted serotype 3 representation
[477]
13.4 The asserted 13-valent representation
[486]
14 COMPOSITION PATENTS: LACK OF CLARITY
[491]
15 013 PATENT: LACK OF FAIR BASIS
[493]
16 844 PATENT: LACK OF SUPPORT
[502]
16.1 Introduction
[502]
16.2 Secondary materials
[511]
16.3 The law in Europe and the United Kingdom
[515]
16.3.1 The disclosure obligation: “classical insufficiency”
[523]
16.3.2 The claim support obligation: “Biogen insufficiency”
[530]
16.4 The law of support in Australia
[544]
16.5 Analysis on the facts
[548]
17 COMPOSITION PATENTS: MANNER OF MANUFACTURE
[558]
17.1 Introduction
[558]
17.2 The face of the specification argument
[560]
17.3 The more than 13 serotypes argument and the generally inconvenient argument
[575]
18 CONTAINER PATENT: INTRODUCTION
[584]
19 CONTAINER PATENT: THE WITNESSES
[587]
19.1 MSD’s witnesses
[587]
19.2 Wyeth’s witnesses
[595]
19.3 The container patent joint expert report and concurrent evidence
[600]
20 CONTAINER PATENT: BACKGROUND COMMON GENERAL KNOWLEDGE
[601]
21 CONTAINER PATENT: THE SPECIFICATION AND CLAIMS
[628]
21.1 The specification
[628]
21.2 The claims
[659]
21.3 The field of the invention, the person skilled in the art and the experts
[660]
22 CONTAINER PATENT: INFRINGEMENT
[667]
22.1 Container patent construction dispute
[667]
22.2 The siliconised container dispute
[673]
23 CONTAINER PATENT: LACK OF NOVELTY
[683]
23.1 Introduction
[683]
23.2 The disclosure of the Chiron patent
[684]
23.3 The relevant law
[702]
23.4 Consideration
[703]
24 CONTAINER PATENT: LACK OF INVENTIVE STEP
[711]
24.1 Introduction
[711]
24.2 The submissions
[712]
24.3 The expert evidence
[717]
24.4 Findings of common general knowledge and other relevant matters
[723]
24.4.1 The formulator’s approach to reformulation
[724]
24.4.2 Containers and silicone
[734]
24.4.3 Vaccines
[741]
24.4.4 Prevnar 7
[744]
24.4.5 Stability testing
[746]
24.4.6 The problem of aggregation generally for polysaccharide conjugate vaccines and protein vaccines
[750]
24.4.7 Silicone oil induced aggregation
[763]
24.4.8 Buffers
[772]
24.4.9 Adjuvants
[784]
24.4.10 Surfactants
[794]
25 CONTAINER PATENT: ANALYSIS OF LACK OF INVENTIVE STEP IN THE LIGHT OF THE COMMON GENERAL KNOWLEDGE ALONE
[805]
25.1 The approach
[805]
25.2 Consideration
[809]
26 CONTAINER PATENT: LACK OF INVENTIVE STEP IN LIGHT OF THE S 7(3) PRIOR ART INFORMATION
[838]
26.1 Chiron patent
[840]
26.2 Kanra
[853]
26.3 Katkocin
[864]
26.4 Hausdorff 2000 and Hausdorff 2002
[869]
26.5 ISPPD abstracts
[870]
27 CONTAINER PATENT: MANNER OF MANUFACTURE
[872]
27.1 Introduction
[872]
27.2 Consideration
[876]
28 CONTAINER PATENT: LACK OF FAIR BASIS AND LACK OF CLARITY
[905]
28.1 Absence of surfactant
[907]
28.2 Disclosure of serotypes in addition to the 13 chosen serotypes
[911]
28.3 Histidine buffer at pH 5.8
[914]
28.4 Lack of clarity
[917]
29 CONTAINER PATENT: INUTILITY
[921]
29.1 Introduction
[921]
29.2 Were the asserted promises made?
[925]
29.3 Consideration of whether the promise is met
[929]
30 CONCLUSION
[958]
BURLEY J:
1. INTRODUCTION
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.
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.
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).
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
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.
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)).
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.
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
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.
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
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.
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.
In the reasons that follow, I first consider the composition patents before moving to the container patent.
2. COMPOSITION PATENTS: THE WITNESSES
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
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.
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.
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?
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.
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.
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.
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.
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
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.
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.
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.
In his second affidavit Professor Strugnell responds to the second affidavit of Professor Paton and the first affidavit of Professor Kasper.
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.
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.
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.
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.
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.
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.
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.
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
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.
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
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
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
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.
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.
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.
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.
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
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.
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).
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.
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.
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.
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.
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.
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.
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).
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.
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.
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
Antibodies are of great importance to the adaptive immune system.
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.
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
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.
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.
The polysaccharide capsule of pneumococci is variable. In clinical practice, polysaccharide variants – called serotypes – are identified by their reactions with type-specific antisera.
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.
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.
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.
The distribution of serotypes common in carriage and disease varies over time and by geographical region, and by age within geographical regions.
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
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.
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.
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.
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
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.
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).
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
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.
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.
Only polysaccharide and polysaccharide-protein conjugate pneumococcal vaccines were approved and in commercial use at April 2005. This is still the case today.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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).
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)
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.
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.
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.
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.
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
An adjuvant is a substance that, when mixed with an antigen, increases its ability to provoke an adaptive immune response.
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.
One class of adjuvants is aluminium adjuvants. Aluminium-containing adjuvants include aluminium salts, most commonly aluminium hydroxide and aluminium phosphate.
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.
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.
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.
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.
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.
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.
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)).
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.
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.
ELISAs and OPAs can both be performed using sera from various test animals or humans.
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.
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
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.
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)
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).
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.
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.
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.
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.
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).
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…
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.
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.
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.
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.
In the Results and Discussion section the article states (emphasis added):
The solution parameters for the aggregation study were selected to permit detection of protein aggregates due to the presence of silicone oil over a relatively short time...Although we have attributed the increases in turbidity to protein aggregation, it is possible that the observed increases are caused, at least in part, by the effect of the protein on the silicone oil dispersion itself. Unfortunately, there is no obvious experimental method to easily distinguish between this and turbidity increases due to protein aggregation. Our assumption that protein association is responsible for turbidity is based on the fact that aggregated protein can be separated by centrifugation from the protein/silicone oil emulsions and directly identified in the pelleted material.
Professor Petrovsky accepted the emphasised passage as indicating that the authors demonstrated aggregation in the manner described. Professor Dalby was more sceptical, and considered that because the methodology was not set out, he could not be comfortable that protein aggregation was the cause of detected turbidity. He considered that the cause could be protein, both protein and silicone oil, or just silicone oil. However, the statement of fact in the emphasised passage – which I understand to mean that aggregated protein was separated by centrifugation – indicates that this is the finding of the authors. Whilst there is no report showing the data from the centrifugation, I share the view expressed by Professor Petrovsky that in a peer reviewed article the clear statement that the authors had centrifuged the products should be accepted. As Dr Jones explained, if he were the editor of the journal, he would want peripheral material, such as data not key to the main argument, excluded.
The authors then go on to characterise the aggregation from the centrifugation in Figure 1.
The results of the study are discussed at page 922 (emphasis added):
The results of this silicone oil-induced aggregation study of several proteins reveal only limited information regarding general trends. The most obvious one is that the more hydrophobic proteins, BSA (classified as hydrophobic based on the well known presence of its apolar binding sites) and ConA, have a greater tendency to aggregate than the relatively more hydrophilic ones (lysozyme and Rnase A). This result was not unexpected and suggests that the interactions are at least in part apolar in nature. All proteins exhibited a pH-dependence in their tendency to aggregate in the presence of the oil. There was, however, no clear trend...to this dependence....
Professor Petrovsky and Dr Jones considered that the emphasised statement was supported by Figure 1, which shows that there is a pH-dependent effect on the aggregation. Professor Dalby accepted that the authors saw a difference in aggregation that was pH-dependent.
The Conclusions state that in general, methods that are commonly used to monitor changes in protein structure do not provide consistent evidence that silicone oil induces major structural changes that might be responsible for inducing aggregation. Aggregation is most commonly thought to arise from molten globule like states of proteins. Such states are usually detected by structure alterations, but that was not the case here. It is possible that more subtle structural changes may be involved in the aggregation processes. It says:
Most importantly, a direct effect of the oil on the interactions that mediate protein/protein interactions responsible for aggregation seems likely. Whatever the molecular basis for the observed aggregation behaviour, however, it can clearly be minimized by reducing the content of silicone oil in protein pharmaceutical formulations.
Certainly it is the case that Jones 2005 teaches not only the fact of protein aggregation, but also that altering the pH by using a buffer can affect the degree of protein aggregation. However, this does not materially alter the calculus in relation to the manner of manufacture ground. The particular combination of claim 1 – the broadest claim – shows that the invention is a combination of a pneumococcal polysaccharide-protein conjugate where the composition is not only buffered, but also contains an aluminium salt adjuvant. The disclosure of Jones 2005 does teach that using a buffer is likely to have an effect on aggregation. But the specification, on its face, does not disclose the combination including an adjuvant (claim 1). Nor does it disclose the effects or use of a surfactant (claim 9).
The admissions on the face of the specification are insufficient to yield the conclusion that the claims are in truth nothing more than for the use of a known article for the purpose for which its known properties make that material useful, within Microcell. Nor, having regard to the disclosure of the identified passages, and to the statement on page 42 of the specification, is the Philips ground established.
28. CONTAINER PATENT: LACK OF FAIR BASIS AND LACK OF CLARITY
MSD pleads that the asserted container patent claims are not fairly based on the matter described in the specification within s 40(3) of the Patents Act on the three bases set out below:
(1)the asserted claims, other than claim 9, travel beyond the matter described in the specification in that they do not include a surfactant;
(2)the asserted claims travel beyond the matter described in the specification in that there is no real and reasonably clear disclosure in the specification of a formulation which has polysaccharide-protein conjugates of Streptococcus pneumoniae serotypes in addition to the 13 chosen serotypes; and
(3)claims 8 and 17 travel beyond the matter described in the specification in that there is no real or reasonably clear disclosure in the specification of histidine at pH 5.8 as a buffer.
I address each of the bases separately below.
28.1 Absence of surfactant
MSD correctly submits that, with the exception of claim 9, the asserted container patent claims do not require a surfactant. The consequence, it submits, is that the claims are not fairly based because there is no real and reasonably clear disclosure of an invention without a surfactant. In particular, MSD submits that a critical passage in the specification is page 13 lines 32 – 25, which states:
…the present invention relates to the unexpected and surprising results that formulating an immunogenic composition with a surfactant such as Tween 80 significantly enhances the stability and inhibits precipitation of an immunogenic composition.
It submits that this passage demonstrates that the asserted invention is the use of the surfactant, and any combination that does not require the inclusion of a surfactant is not fairly based.
I do not consider that this ground is made out.
Neither the Patents Act nor the statement of principle in Lockwood No 1 at [69] imposes an obligation upon the patentee to disclose or identify an asserted inventive step in the specification. In any event, the specification makes a number of statements as to what the patentee considers to be the invention. In the Summary of the Invention is a consistory clause that matches the broadest claim, being claim 1. No surfactant is included. Furthermore, on page 13 lines 5 – 9, prior to the passage emphasised by MSD is the statement (emphasis added):
The present invention addresses an ongoing need in the art to improve the stability of immunogenic compositions such as polysaccharide-protein conjugates and protein immunogens. Thus, the present invention broadly relates to novel surfactant formulations and/or novel aluminium salt formulations which stabilize and inhibit precipitation of immunogenic compositions.
The second sentence quoted makes plain that the patent asserts as the invention, not only a novel surfactant formulation, but also other novel aluminium salt formulations. In this regard the position in Sigma at [242] is not analogous. In that case, there was a clear statement of the impossibility to achieve the invention with technology that fell within the claims.
28.2 Disclosure of serotypes in addition to the 13 chosen serotypes
MSD submits that the specification uses the 13 chosen serotypes in the examples to demonstrate a group of antigens that can be used in the claimed formulation, but does not disclose any formulation with conjugates of any additional serotypes to the 13 chosen serotypes. Due to the “one or more” phrasing used in claim 1 (and dependent claims), it has no upper limit, and accordingly encompasses formulations which have more than 13 serotypes. On this basis, it submits that all claims except for claim 18 include formulations in addition to the 13 chosen serotypes and so are not fairly based.
For similar reasons to those set out in the previous section, this fair basis challenge fails. The consistory clause for claim 1 (page 3 lines 18 – 22) makes clear that the patentee considers that an aspect of the invention is any formulation comprising the integers of a siliconised container, a pH buffered solution with a pKa of about 3.5 to about 7.5, an aluminium salt together and any number of polysaccharide-protein conjugates of one or more pneumococcal polysaccharides.
In relation to claim 18, MSD submits that it must be read as limited to the 13 chosen serotypes, such that MSD’s 15-valent vaccine cannot infringe. I have rejected that argument. The fall back argument advanced by MSD is that if the claim is not so limited, the claim must lack fair basis, for substantially the same reasons as set in section 15. For substantially the same reasons as set out in that section, this argument must also be rejected.
28.3 Histidine buffer at pH 5.8
MSD submits that the specification contains no real and reasonably clear disclosure of the integer contained in claims 8 and 17 that “the buffer is histidine at pH 5.8”. In particular, it argues that while the specification discloses in several places that histidine may be used as the buffer, there is no disclosure of its use at pH 5.8.
The specification includes several passages where the use of a histidine buffer is described. An example of such a disclosure is at page 3 lines 32 – 34:
In certain embodiments, the pH buffered saline solution of the formulations has a pH of 5.5 to 7.5. In other embodiments, the buffer is phosphate, succinate, histidine or citrate. In certain embodiments, the buffer is succinate at a final concentration of 1mM to 10mM and pH 5.8 to 6.0.
In a number of other places in the specification, the patentee provides first a pH range for the buffer of 5.5 to 7.5 and for a range for a succinate buffer of between pH 5.8 to 6.0. Accordingly, the disclosure of the specification is that the histidine buffer may be within the range of 5.5 to 7.5. The selection of a pH from that range for the purposes of claims 8 and 17 is not explained anywhere in the specification. It might be considered it represents a narrow point within the available range that the patentee has chosen for the purpose of the claim. I was directed to no expert evidence on the subject in closing submissions to suggest that this selection was not available within the range that the skilled formulator might chose. I am conscious that in considering lack of fair basis, the Court should not make a meticulous verbal analysis. The question is whether the invention as claimed is disclosed in a “general sense”: Lockwood No 1 at [69]. I am not satisfied that MSD has established that it is not disclosed in the requisite sense. This challenge fails.
28.4 Lack of clarity
MSD relies on the same three bases discussed above in support of a submission that the claims do not sufficiently or clearly define the alleged invention within s 40(2)(a) of the Patents Act.
MSD directed none of its closing submissions towards explaining why it relies upon the first and third bases with respect to the lack of definition ground. For similar reasoning as above, these challenges fail.
In relation to the second basis, MSD submits that a patent claim must define the monopoly in a way that is not reasonably capable of being misunderstood, citing Welch Perrin at 610. It submits that the claims lack clarity because it is unclear whether the proper construction of the claims is that put forward by MSD, Wyeth or otherwise.
Whilst not clearly identified, this argument can only apply to claim 18 as there is no relevant construction dispute arising from the other asserted container patent claims. However, the argument cannot succeed. The invention as defined by claim 18 is for the composition there defined, including the 13 serotypes identified.
29. CONTAINER PATENT: INUTILITY
29.1 Introduction
MSD contends that the invention claimed in any of the asserted container patent claims is not useful within s 18(1)(c) of the Patents Act in that the claims include siliconised containers filled with vaccine formulations that do not achieve the promises of the specification. MSD contends that there are two relevant promises, namely that the formulation of the claims:
(a)will be stable; and
(b)will inhibit silicone oil induced aggregation sufficiently to result in a stable vaccine.
MSD next contends that neither of the asserted promises is met by formulations within the asserted container patent claims. It couches its arguments by reference to four points, which I describe in more detail below as: the pH range argument; the protein concentration argument; the surfactant argument; and the absence of surfactant argument.
Wyeth disputes that the stability promise is made in the specification and contends that the only promised result made in respect of silicone oil induced aggregation is for a formulation that stabilises the immunogen to an acceptable level against silicone oil induced aggregation, being a level where it no longer presents a problem in the form of visible precipitation, and ensuring that silicone oil induced aggregation does not increase above that level over the stated shelf life of the vaccine. Wyeth characterises the absence of surfactant argument as the primary ground upon which MSD relies, and contends that it has not been pleaded. Wyeth disputes that there has been any failure to meet the only promise made, which it contends is the asserted silicone oil induced aggregation promise, as qualified by it above.
The relevant law relating to this ground is summarised in section 12.1 above.
29.2 Were the asserted promises made?
Although framed by MSD as involving two separate promises, in my view the single promise of the invention is that the formulations described and claimed will provide a stable formulation. The promise includes that, to the extent necessary, the stable formulations described and claimed will also inhibit precipitation of immunogenic compositions. That is the natural meaning to be attributed to the words first appearing in the Summary of the Invention (page 3 lines 12 – 13):
The present invention broadly relates to novel formulations which stabilize and inhibit precipitation of immunogenic compositions.
The context provided by the Background of the Invention serves to confirm that this is correct, given that attention is paid not only to the background art and knowledge in relation to silicone oil induced aggregation, but also the challenges arising in relation to the stability of an immunogenic composition generally.
The point is reinforced in other passages, such as in the Detailed Description of the Invention where the patentee states (page 13 lines 5 – 9) (emphasis added):
The present invention addresses an ongoing need in the art to improve the stability of immunogenic compositions such as polysaccharide-protein conjugates and protein immunogens. Thus, the present invention broadly relates to novel surfactant formulations and/or novel aluminium salt formulations which stabilize and inhibit precipitation of immunogenic compositions.
Having regard to the whole of the disclosure of the specification, aspects of which I have addressed in more detail in section 21.1 above, I consider that the promise made is that the formulation described and claimed will be stable and includes that in achieving stability, precipitation and aggregation will be inhibited, including silicone oil induced aggregation.
29.3 Consideration of whether the promise is met
MSD first advances the pH range argument, which applies to all of the asserted container patent claims. Claim 1 includes a pH buffered saline solution within a pKa range of about 3.5 to about 7.5. Claim 2 includes a pH from 5.5 to 7.5. MSD’s argument runs as follows.
Professor Dalby gives evidence that as a general rule of thumb, a buffer is effective within one pH unit of its pKa value. He says that “accordingly” for the pKa range of 3.5 to 7.5, he would expect solutions “with pH of around 4 to 8 to be covered” (this appears to involve a typographical error). Professor Petrovsky agrees with the rule of thumb, but says that in relation to claim 1, the pH range would therefore extend from 2.5 to 8.5. Professor Petrovsky gives evidence that he “would not expect” a conjugate at pH 2.5 to be stable. He also gives evidence that formulations that have a pH of around 4 to 5, or a pH of around 7 to 7.5, “may hydrolyse the polysaccharide”. No evidence in the way of experimentation or otherwise supports this assertion. Conversely, no evidence contradicts either proposition, and Professor Petrovsky was not taken to either in cross-examination.
Although there is no requirement to prove inutility by experiment (Idenix at [257]), it is nevertheless necessary for MSD to establish to the requisite standard that the claimed combination is not useful as a stable formulation.
The statement to the effect that formulations within the range claimed in claim 2 “may hydrolyse” in my view is not sufficient to warrant a conclusion that a formulation within the claim would not work. Put another way, the strength of this evidence is not sufficient to yield the conclusion that, on the balance of probabilities, the claimed formulation is not stable.
In relation to claim 1, Professor Petrovsky’s statement that he would not expect a conjugate of pH 2.5 to be stable is somewhat stronger. However, without further development by explanation, that evidence amounts to a theoretical statement of expectation that may or may not prove to be correct. It is an hypothesis yet to be tested, and accordingly is unlike the position accepted in Alphapharm at [470], where Lindgren J was able to conclude, on the basis of the unequivocal evidence of Professor Montgomery, that the dosage range claimed included quantities well below the useful minimum and well above the useful maximum.
Accordingly, the pH range argument does not succeed.
MSD secondly advances what it calls the protein concentration argument. It notes that claim 1 does not limit the protein concentration in the formulation of claim 1. The argument runs as follows.
Professor Dalby gives evidence that as a rule of thumb, problems may arise with protein aggregation in solution where there is a protein concentration above 1000 μg/ml. Example 3 of the container patent concerns a formulation within the scope of the asserted container patent claims, namely, a 13-valent polysaccharide-protein conjugate with a buffer, salt and adjuvant. An experiment was conducted whereby serotypes 4 and 6B were formulated with protein concentrations ranging from 25 μg/ml to 200 μg/ml in the absence and presence of AIPO4 (aluminium adjuvant) in containers using siliconised stoppers. Where the concentration of serotypes 4B and 6B was 100 μg/ml and 200 μg/ml respectively, fibre-like particulates were observed for both the adjuvanted and the unadjuvanted formulations. These results are displayed in table 5 of the container patent.
MSD submits that, by applying the rule of thumb that the experts adopt of 1000 μg/ml, the person skilled in the art may have been led, in the absence of a limitation of the protein concentration to be used in claim 1, to adopt a protein concentration that produced visible precipitate. In short, the results in example 3 demonstrate that visible precipitation may be caused by the use of 100 μg/ml or 200 μg/ml. This shows that the person skilled in the art could have used what he or she considered to be a normal amount of protein concentration for different serotypes in a formulation within the claims which would not have achieved the promise of the invention.
The decision of the Full Court in Sandvik demonstrates that where a claim is broad in compass, it is not to be applied in such a way that it is to be made unworkable. In that case, claims 1 to 3 did not lack utility, even though they included within their scope the breadth of claim 4, because the skilled addressee would understand that a drill rod with a round end cannot be driven by a drive chuck or an adaptor and would therefore not use a rod with a round end (at [201]). Accordingly, it was only claim 4, which upon its proper construction required the rod profile to be round, that was rendered inutile (at [202]).
The present case is somewhat different. MSD submits here that by applying a sensible construction to claim 1, the person skilled in the art could select a protein concentration of up to 1000 μg/ml and not expect protein aggregation. Yet at much lower concentrations, specifically at 100 or 200 μg/mL, visible aggregation was not only encountered, but was not resolved by the use of the formulation claimed in claim 1. Put another way, by adopting an entirely orthodox approach to formulating a polysaccharide-protein conjugate within a formulation, within the range of protein concentration usual in the art, the person skilled in the art would have found that the formulation of claim 1 did not avoid visible precipitation.
It may be thought that this leads to the conclusion that claim 1 accordingly lacks utility, but two points stand in the way of that conclusion. First, claim 1 is silent as to protein concentration. Nothing compels a conclusion that any particular protein concentration must be selected. It is well within the skills of the person skilled in the art to determine the appropriate protein concentration to avoid visible precipitation, using the techniques and applying the principles to which I have referred in my consideration of the common general knowledge in section 25.2.
Secondly, example 3, including table 5, provides a clear disclosure that fibre-like white particulates were visible when concentrations of 100 μg/mL and 200 μg/mL were used for serotypes 4 and 6B respectively. The argument advanced by MSD skilfully seeks to avoid the difficulty that a person would not construe a claim in a way that is not sensible. However, it does not overcome the fact that the person skilled in the art also has the benefit of the disclosure of the specification when applying the invention. The utility of the alleged invention depends on whether by following the directions in the complete specification, the effects which the patentee proposed to produced could be produced: Lane Fox at 431. It appears to me that a skilled reader would understand from example 3 that, whatever the rule of thumb may be, low concentrations of protein may be necessary, at least for serotypes 4 and 6B, to avoid visible precipitation.
In a final thread to this argument, MSD contends that claim 1 contains no limitation on the protein concentration in the formulation. There is no limit to the number of conjugates that may be included. As a result, protein amounts that do not work will fall within the claims. However, I am satisfied that a person skilled in the art would understand to limit the amount of protein in a formulation to a workable level.
Accordingly, the protein concentration argument does not establish that the claims lack utility.
The third argument advanced by MSD is called the surfactant argument and concerns all of the asserted container patent claims, because MSD submits each claim may include a surfactant. MSD notes that none of claims 1 – 8 require the presence of a surfactant. Claim 9 then adds an integer specific to surfactants. Claim 11 then identifies that the final concentration of the polysorbate 80 surfactant in the formulation is at least 0.01% to 10% polysorbate 80 weight/volume of the formulation. This, MSD submits, is a range of polysorbate of 1000 fold. Claim 18 is dependent on claim 11. As MSD puts it, claims 1 – 9 necessarily include within their scope claim 11, with the consequence that the broad range of 0.01% to 10% weight/volume of polysorbate 80 to the formulation is included within their scope. This, it submits, is an unworkable range, on the basis of the evidence of the experts. Professor Dalby’s opinion is that surfactants in high concentrations can reduce the stability of proteins by disrupting bonds within the protein. Professor Petrovsky agrees, and says that he would have selected a surfactant such as Tween 80 and used it at a concentration, as a general rule of thumb, of between 0.02% and 1%. He gives evidence that if one uses a surfactant at a concentration of 10%, it would denature the protein, which, as the primer notes, is a known form of physical degradation of a saccharide-protein conjugate.
However, it seems to me that this argument fails for the same reason that the argument in respect of claims 1 – 3 failed in Sandvik. Claim 11 is not one of the asserted container patent claims and its validity is not challenged. If it were, and the evidence remained unchanged, it may well be that the broad range presents a difficulty. However, it is not. It is apparent that the skilled formulator who approaches the construction of the asserted container patent claims would not select Tween 80 at the ends of the spectrum that were unworkable. To the contrary, as I have found, the normal skills in the art would be applied to select a workable amount of Tween 80.
The fourth point MSD refers to as the absence of surfactant argument, which in oral submissions MSD re-labelled as concerning the presence of adjuvants rather than the absence of surfactants. The challenge does not concern claim 9, or claims dependent on claim 9. The argument is as follows.
Example 4 in the container patent includes an experiment using a siliconised, commercially available container (BD Hypak syringes capped with West 4432 ready to use plungers) containing polysaccharide-protein conjugates of the 13 chosen serotypes together with salt (sodium chloride) and succinate buffer at a pH of 5.8. A similar experiment was tested with and without an adjuvant. The reported results of the formulation with the adjuvant (relevant to all claims except claim 9), using that commercially available container with a high level of silicone, agitated in controlled conditions, are that:
(a)there is a significant loss of antigenicity; and
(b)that loss is reported in figure 2 to be above 30% for 3 serotypes.
The evidence of the experts is that antigenicity can be a measure of stability. Professor Petrovsky gives evidence that the figure 2 formulation is an example of a failed vaccine. Professor Dalby accepts that the formulation did not completely stabilise the vaccine. Accordingly, MSD submits that claim 1, and the claims dependent on it that do not involve the use of a surfactant, are invalid for want of utility.
Wyeth first submits that example 4 does not establish that the claimed combination without a surfactant fails to reduce the silicone oil induced aggregation to an acceptable level, being one where it no longer presents a problem in the form of visible precipitation. However, this submission depends on acceptance of Wyeth’s interpretation of the promise of the invention, which I have rejected. It next submits that figure 2 of the specification does not provide an appropriate comparison, because it was the positive control, and the specification also includes a negative control, demonstrating that the patentee is attempting to determine the nature of the problem. It submits that without the buffer and adjuvant, the loss of antigen would be worse and, having regard to the teaching of example 4, the skilled reader would know to avoid containers with a high silicone content.
Wyeth further contends that this argument is not available to MSD, because it was not sufficiently pleaded. However, having regard to the content of the Third Further Amended Consolidated Statement of Claim at [12(c)(xi)], the opening submissions advanced by MSD, and the evidence adduced, in my view the argument is adequately pleaded and notified to Wyeth, and I propose to address it.
I have described the disclosure of the specification in section 21.1 above. The examples are presented for illustrative purposes (page 25 line 31). Example 4 is entitled “Aluminium adjuvants inhibit the formation of 13vPnC particulates in the presence of siliconized container means”. It involves the use of liquid formulations of the 13 chosen serotypes in a buffer of pH 5.8, with and without aluminium adjuvant. A number of different containers are used. One, identified as the “positive control” is a “BD Hypak syringe” and is said in the specification to be available from a catalogue, and purchased by the patentee. Another, identified as a “negative control” is an unsiliconised syringe.
The containers were subject to controlled agitation conditions, and the total antigenicity of each serotype was measured. The experts agree that antigenicity tests are a form of stability testing.
The positive control was reported in figure 2 of the specification to have antigenicity losses of over 30% for three serotypes after agitation of 8 and 24 hours. Professor Petrovsky gave evidence that in his view this is “a perfect example of a failed vaccine” that was “highly unstable”. Professor Dalby agrees that in this container the formulation failed to stabilise the vaccine.
However, in his oral evidence, Professor Dalby contended that the conditions applied by the patentee to the samples were not representative of appropriate stability testing. He says, referring to page 38 of the specification, that the agitation conditions were optimised based on antigenicity loss for the two controls, and that the agitation in the system of 500 rpm was not of the type used in a long-term stability test.
Professor Dalby’s evidence does not withstand scrutiny. The whole of the passage on pages 38 – 39 of the specification is as follows:
Prior to the study, the agitation conditions were optimized based on the antigenicity loss of the two controls: (1) the worst-case control (positive control, high silicone; FIG 2) and (2) the best-case control (negative control, no silicone; FIG 3). The conditions were then optimized such that the antigenicity loss was low in positive control, yet detectable in the negative control. This was to ensure that the agitation was neither too weak to produce precipitation in the syringes; nor too strong, such that the precipitation might be caused by factors other than the silicone interaction (e.g., by shear forces). Thus, agitation at 500 rpm (pause mode) for twenty-four hours was chosen as the most suitable agitation condition, while a temperature of 2-8 degrees°C and a horizontal position were used to simulate the conditions in real time product shipping and handling.
The final sentence makes plain that the experiment was designed as an accelerated stability study. That is what Professor Petrovsky understood the patentee to intend. In my view that is plainly the preferable construction of the specification. I reject Professor Dalby’s contrary view.
The consequence is that example 4 provides a clear teaching that the positive control produces an unstable formulation. However, that does not yield the result that the ground of inutility succeeds. The specification teaches in no uncertain terms that the positive control failed because of the high amount of silicone used. Containers with lesser amounts significantly reduced the antigenicity losses to minor amounts. The experiment showed something of the parameters of the invention. The skilled reader is able to understand and interpret the results, and then apply them to produce something within the claims. Put another way, by following the directions in the complete specification, the effects which the patentee professed to produce could be produced. Accordingly, this final ground of inutility must also fail.
30. CONCLUSION
For the reasons set out perhaps far too fully above, I have found that the asserted 013 patent claims are valid and will be infringed by MSD’s 15-valent vaccine. I have found that the asserted 844 patent claims would have been infringed, but are invalid because they lack support within s 40(3) of the post-RTB Patents Act. I have also found that the asserted container patent claims would have been infringed, but that they are invalid for want of inventive step.
I will direct that the parties confer and propose short minutes of order giving effect to this judgment.
I certify that the preceding nine hundred and fifty-nine (959) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Burley.
Associate:
Dated: 14 October 2020
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