Boehringer Ingelheim Animal Health USA Inc v Zoetis Services LLC

[2023] FCA 1119

FEDERAL COURT OF AUSTRALIA

Boehringer Ingelheim Animal Health USA Inc v Zoetis Services LLC [2023] FCA 1119   

Appeal from:

Boehringer Ingelheim Animal Health USA Inc. v Zoetis Services LLC [2020] APO 40

File number(s):

VID 632 of 2020

Judgment of:

ROFE J

Date of judgment:

21 September 2023

Catchwords:

 PATENTS – three patent applications on appeal from a decision of a delegate of the Commissioner of Patents ­– patent applications disclose supernatant vaccine for Mycoplasma hyopneumoniae (M. hyo), a disease affecting pigs – applications include a platform, a bivalent and a multivalent vaccine ­– validity

EVIDENCE ­– challenge to independence of expert witness – where expert did not disclose the extent of his prior involvement with the appellant ­– where non-disclosure was not deliberate but nevertheless tainted evidence – where evidence disregarded unless corroborated by other experts

PATENTS – construction of integers of the claims – meaning of the term “comprising” –  whether inclusive or exhaustive definition should be used

PATENTS – common general knowledge – state of knowledge in the field of swine pathogens as at the priority date – vaccines against M. hyo available at the priority date

PATENTS – validity – lack of inventive step – ss 7(2) and (3) of the Patents Act 1990 (Cth) – prior art documents to be considered ­– whether claim 1 in each of the 3 applications is obvious

PATENTS­ – validity – lack of support and lack of disclosure 

PATENTS – validity – best method requirement – whether patentee has satisfied its duty to disclose the best method of performing the invention – duty not satisfied

PATENTS – validity – manner of manufacture – whether certain of claims of the Applications are claims to “mere collocations” of integers rather than a patentable combination  

Legislation:

Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth)

Patents Act 1990 (Cth)

Patents Act1952 (Cth)

Explanatory Memorandum, Intellectual Property Laws Amendment (Raising the Bar) Bill 2011 (Cth)

Cases cited:

Abbott Laboratories v Corbridge Group Pty Ltd (2002) 57 IPR 432

Actavis Pty Ltd v Orion Corporation [2016] FCAFC 121

Aktiebolaget Hässle v Alphapharm Pty Ltd (2002) 212 CLR 411

Apotex Pty Ltd v ICOS Corp (No 3) (2018) 135 IPR 13

Artcraft Urban Group Pty Ltd v Streetworx Pty Ltd (2016) 117 IPR 210

Asahi Kasei Kogyo Kabushiki Kaisha v WR Grace & Co (1991) 22 IPR 491

AstraZeneca AB v Apotex Pty Ltd (2014) 107 IPR 177

AstraZeneca AB v Apotex Pty Ltd; AstraZeneca AB v Watson Pharma Pty Ltd; AstraZeneca AB v Ascent Pharma Pty Ltd (2015) 257 CLR 356

Boehringer Ingelheim Animal Health USA Inc. v Zoetis Services LLC [2020] APO 40

Catnic Components Ltd v Hill & Smith Ltd [1982] RPC 183

CSR BuildingProducts Ltd v United States Gypsum Co [2015] APO 72

Cytec Industries Inc v Nalco Company [2021] FCA 970

DSI Australia (Holdings) Pty Ltd v Garford Pty Ltd (2013) 100 IPR 19

Edison and Swan United Electric Light Company v Holland (1889) 6 RPC 243

Firebelt Pty Ltd v Brambles Australia (2000) 51 IPR 531

Fresenius Medical Care Australia Pty Ltd v Gambro Pty Ltd (2005) 67 IPR 230

Fuel Oils/Exxon (T409/91) [1994] OJ EPO 653

Gambro Pty Ltd v Fresenius Medical Care South East Asia Pty Ltd (2004) 61 IPR 442

General Clutch Corporation vSbriggs Pty Ltd (1997) 38 IPR 359

Generic Health v Bayer Pharma Aktiengesellschaft (2014) 106 IPR 381

Generics (UK) Ltd v H Lundbeck A/S [2009] 2 All ER 955

Gilead Sciences Pty Ltd v Idenix Pharmaceuticals LLC (2016) 117 IPR 252

GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No 2) Ltd v Generic Partners Pty Ltd (2018) 2131 IPR 384

Idenix Pharmaceuticals LLC v Gilead Sciences Pty Ltd (2017) 134 IPR 1

Inhale Therapeutic Systems Inc v Quadrant Healthcare Plc [2002] RPC 21

Jupiters Ltd v Neurizon Pty Ltd (2005) 65 IPR 86

Jusand Nominees Pty Ltd v Rattlejack Innovations Pty Ltd (2022)167 IPR 1

Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1

Kirin-Amgen v Hoechst Marion Roussel (2004) 64 IPR 444

Les Laboratoires Servier v Apotex Pty Ltd (2016) 117 IPR 415

Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2004) 217 CLR 274

Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) (2007) 235 CLR 173

Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) (2020) 155 IPR 1

Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253

Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2

NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1993) 26 IPR 513

Palmer v Dunlop Perdriau Rubber Co Ltd (1937) 59 CLR 30

Pfizer Overseas Pharmaceuticals v Eli Lilly & Co (2005) 68 IPR 1

Pugh v Riley Cycle Co Ltd (1914) 31 RPC 266

Rakman International Pty Ltd v Trafalgar Group Pty Ltd (2022)166 IPR 264

Ranbaxy Laboratories Ltd v AstraZeneca AB (2013) 101 IPR 11

Re Evolva SA (2017) 133 IPR 147

Sandvik Intellectual Property AB v Quarry Mining & Construction Equipment Pty Ltd (2017) 348 ALR 156

Smith & Nephew Pty Ltd vWake Forest University Health Sciences (2002) 82 IPR 467

Streetworx Pty Ltd v Artcraft Urban Group Pty Ltd (2014) 110 IPR 82

Sunbeam Corporation v Morphy Richards (Aust) Pty Limited (1961) 180 CLR 98

TCT Group Pty Ltd v Polaris IP Pty Ltd (2022) 170 IPR 313

Technograph Printed Circuits Litd v Mills & Rockley (Electronics) Ltd [1972] RPC 346

ToolGen Incorporated v Fisher (No 2) [2023] FCA 794

Vidal Dyes Syndicate Ltd v Levinstein Ltd (1912) 29 RPC 245

Warner-Lambert LLC v Generics (UK) Ltd t/a Mylan [2018] UKSC 56

Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588

Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262

WR Grace & Co v Asahi Kasei Kogyo Kabushiki Kaisha (1993) 25 IPR 481

Division:

General Division

Registry:

Victoria

National Practice Area:

Intellectual Property

Sub-area:

Patents and associated Statutes

Number of paragraphs:

770

Date of hearing:

19 October – 3 November 2022

Counsel for the appellant/cross-respondent:

Mr C Dimitriadis SC with Ms C Cunliffe

Solicitor for the appellant/cross-respondent:

Ashurst Australia

Counsel for the respondent/cross-appellant:

Mr P Flynn SC with Mr B Mee

Solicitor for the respondent/cross-appellant:

Spruson & Ferguson Lawyers Pty Ltd

ORDERS

VID 632 of 2020

BETWEEN:

BOEHRINGER INGELHEIM ANIMAL HEALTH USA INC.

Appellant

AND:

ZOETIS SERVICES LLC

Respondent

AND BETWEEN:

ZOETIS SERVICES LLC

Cross-Appellant

AND:

BOEHRINGER INGELHEIM ANIMAL HEALTH USA INC.

Cross-Respondent

ORDER MADE BY:	ROFE J
DATE OF ORDER:	21 SEPTEMBER 2023

THE COURT ORDERS THAT:

1.If the parties agree on the appropriate orders to be made by the Court reflecting these reasons for judgment, the parties file a minute of proposed orders on or before 5 October 2023.

2.If the parties are unable to agree on the orders which should be made, each of the parties file and serve on or before 5 October 2023:

(a)A minute of the orders that the party proposes; and

(b)Any outline of submissions in support of the proposed orders (limited to three pages).

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

REASONS FOR JUDGMENT

ROFE J:

INTRODUCTION	[1]
GLOSSARY/BACKGROUND	[10]
Immune Response	[11]
THE PATENT APPLICATIONS	[28]
Summary of the disclosure	[81]
STATUTORY PROVISIONS	[85]
OVERVIEW OF EVIDENCE	[88]
Dr Nordgren	[90]
Professor Chase	[95]
Professor McVey	[99]
Professor Browning	[103]
Mr Eichmeyer	[110]
Zoetis’ challenge to Dr Nordgren	[112]
Ongoing consulting role with Boehringer	[118]
Regard to confidential information not part of common general knowledge	[130]
Not representative of non-inventive person skilled in the art	[147]
Conclusion on Dr Nordgren	[154]
PERSON SKILLED IN THE ART	[158]
CONSTRUCTION	[175]
“Substantially free”	[184]
Antigen issue – “comprising”	[189]
Merck and the meaning of “comprising”	[211]
Further authorities on the meaning of “comprising”	[224]
Consideration	[235]
OVERVIEW OF VALIDITY CHALLENGES	[259]
COMMON GENERAL KNOWLEDGE	[261]
Animal vaccination	[263]
Types of commercially available vaccines	[267]
Swine pathogens	[277]
Culturing M. hyo	[284]
Maternal antibodies	[292]
Vaccines available for M. hyo	[294]
Commercially available vaccines for swine pathogens	[306]
Immunological and assay interference	[320]
Protein A/G affinity chromatography	[345]
Pierce Biotechnology catalogue	[360]
LACK OF INVENTIVE STEP	[370]
Principles	[372]
Section 7(3)	[378]
The Okada papers	[384]
Okada 1999	[389]
Okada 2000a	[393]
Okada 2000b	[409]
Statistical issues with Okada papers	[417]
Expert comments on Okada papers	[421]
The parties’ submissions	[425]
Boehringer’s submissions	[425]
Zoetis’ submissions	[437]
Confidential research work	[447]
Zoetis’ actual work	[455]
Boehringer’s actual work	[472]
Zoetis’ commercial success	[476]
Hindsight and Boehringer’s inventive step case	[477]
Dr Nordgren’s work on an M. hyo/PCV-2 combination vaccine	[489]
Consideration	[494]
The 535 Application	[496]
The 537 Application	[519]
The 540 Application	[525]
LACK OF SUPPORT	[532]
The facts	[556]
Consideration	[584]
LACK OF DISCLOSURE	[599]
Scope of the invention as claimed	[610]
Conclusions on disclosure	[612]
BEST METHOD	[618]
Principles	[618]
Boehringer’s pleaded best method case	[636]
Boehringer’s submissions	[647]
Zoetis’ submissions	[650]
The evidence	[656]
Dr Nordgren’s evidence as to the examples in the Applications	[656]
Tendered documents	[684]
Boehringer’s detailed submissions	[697]
Nature of the invention in each Application	[716]
Consideration	[725]
MANNER OF MANUFACTURE	[744]
CONCLUSION	[769]

INTRODUCTION

1. These proceedings are an appeal pursuant to s 60(4) of the Patents Act 1990 (Cth) (the Patents Act or Act) from a decision of a delegate of the Commissioner of Patents by the opponent, Boehringer Ingelheim Animal Health USA Inc, and a cross-appeal by the patent applicant, Zoetis Services LLC, to the grant of three related patent applications: Boehringer Ingelheim Animal Health USA Inc. v Zoetis Services LLC [2020] APO 40 (Delegate’s decision).  

2. The three patent applications were each filed on 3 April 2013, and their claim of a priority date of 4 April 2012 was not challenged. The three Australian Patent applications are the:

   (a)535 Application, entitled “Mycoplasma hyopneumoniae vaccine”;

   (b)537 Application, entitled “PCV/Mycoplasma hyopneumoniae combination vaccine”; and

   (c)540 Application entitled “PCV/Mycoplasma hyopneumoniae/PRRS combination vaccine”.  

3. The delegate found claims 1–2, 4–6, 9–10 and 12–18 of the 535 Application did not involve an inventive step. The oppositions to the 537 and 540 Applications were unsuccessful.

4. Boehringer filed a notice of appeal and notice of contention. Zoetis filed a notice of cross-appeal and a notice of contention.

5. Ultimately on appeal, the following grounds of opposition were pressed for each Application:

   (1)That the invention claimed is not supported by the matter disclosed in the specification within s 40(3) of the Act;

   (2)That the complete specification does not disclose the invention in a manner which is clear enough and complete enough for it to be performed by a person skilled in the relevant art within s 40(2)(a) of the Act;

   (3)That the complete specification does not disclose the best method known to Zoetis within the requirements of s 40(2)(aa) of the Act;

   (4)That the invention claimed does not involve an inventive step because it was obvious in light of the common general knowledge considered together with information in any one or more of the Okada papers (defined later); and

   (5)That the invention claimed in certain “kit” claims is not for a “manner of manufacture” within s 18(1)(a) of the Act.

6. Although styled as an appeal, the present proceeding is in the original jurisdiction of this Court and involves a hearing de novo on the grounds and evidence before the Court. As the opponent to the grant of a patent on each of the Applications, Boehringer bears the onus in relation to each ground of opposition raised.

7. Section 60(3A) of the Act, which was introduced with the passage of the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth) (RTB Act), provides that the Commissioner may refuse an application if satisfied, on the balance of probabilities, that a ground of opposition exists. That is the standard by which the present proceeding is to be judged.

8. The Patents Act that applies to the present dispute is in the form as amended by the introduction of the RTB Act.

9. For the reasons that follow, I have concluded that the opposition to the grant succeeds in respect of the following claims:

   (a)535 Application:

   (i)Claims 1, 3, 7–8, 11–12, 16–17  

   (b)537 Application: 

   (i)Claims 1 to 24

   (c)540 Application:  

   (i)Claims 1 to 25

   GLOSSARY/BACKGROUND

10. Before going further, I will set out a brief background to vaccines, taken principally from uncontroversial parts of the first affidavits of Professor Chase and Dr Nordgren and supplemented with extracts from Professor Browning’s affidavit.

    Immune Response

11. A pathogen is an organism that can infect and cause disease to a host such as a pig or a human. There are four main types of pathogens:

    (a)bacteria;

    (b)viruses;

    (c)fungi; and

    (d)parasites, such as protozoa and helminths (eg nematodes or roundworms).

12. The immune system protects its host from infection by pathogens. The immune system is a complex system comprised of different types of cells, tissues and chemotypic messengers, each of which have specific roles, and which work together to protect and heal the host from damage caused by foreign invading pathogens.

13. There are three main types of immunity:

    (a)innate immunity (also known as the “innate immune system”, “innate immune response”, or “primary immune response”);

    (b)adaptive immunity (also known as the “adaptive immune system”, “adaptive immune response”, or “secondary immune response”); and

    (c)passive immunity (also known as the “passive immune system” or “passive immune response”).

14. Each pathogen has unique lifecycles and components, typically proteins or carbohydrates, which stimulate the immune response of a host. The components of pathogens which are capable of being recognised by the immune system and generating a response are known as “antigens”.

15. The innate immune response is the first line of defence against infection. Most components of innate immunity are present before the onset of infection and consist of a set of disease-resistant mechanisms that are not specific to a particular pathogen. These include physical barriers such as skin and the mucosal membranes, as well as phagocytic cells such as macrophages. The innate system is able to recognise a given class of molecules but does not change its response based on its previous exposure to the same pathogen.

16. Macrophages can engulf, or “phagocytize”, invading pathogens and foreign particles and expose them to other intracellular compounds involved in the innate immune response, such as lysozymes (enzymes which can cleave bacterial cell wall membranes). Macrophages, and other components of the innate immune response such as dendritic cells, also stimulate the adaptive immune response, by displaying antigens on their cell surface.

17. The adaptive immune response is typically triggered when there is a recognised antigenic challenge to a host organism. Adaptive immunity provides a second, specific and comprehensive line of defence that eliminates pathogens that evade the innate responses or persist in spite of them. An important consequence of adaptive immune response is memory. If the same pathogen infects the body a second time, memory cells provide the means for the adaptive immune system to make a rapid and often highly effective attack on the invading pathogen.

18. Two characteristics of the adaptive immune system that are crucial to a successful immune response are its antigenic specificity and its diversity. The antigenic specificity of the adaptive immune response enables it to recognise subtle differences among antigens, such as a difference of one amino acid in two otherwise identical proteins. The diversity of the adaptive immune response allows it to recognise billions of unique structures on foreign antigens.

19. The major agents of adaptive immunity are lymphocytes and the antibodies that they produce. Lymphocytes are a class of white blood cells that are produced in the bone marrow, and that produce and display antibodies. The two major types of lymphocytes are B lymphocytes (or B cells) and T lymphocytes (or T cells).

20. Antibodies, also known as immunoglobulins (or Ig), are proteins that mediate the humoral immune response by recognising and binding to antigens.

21. Antibodies bind to specific portions of an antigen. Each antibody-binding site of an antigen is called an “epitope”. The combined strength of the interactions between a single antigen-binding site on an antibody and a single epitope is referred to as the affinity of the antibody for that epitope.

22. There are five major antibody classes, or immunoglobulins: IgG, IgM, IgD, IgA and IgE, each of which plays a specific role in the immune response of a host.

23. Antibodies consist of “heavy” polypeptide chains and “light” polypeptide chains. Each chain comprises a “constant” region and a “variable” region. The constant region is common across all antibodies of a class, while the variable region of each antibody is specific to the antigen against which it was generated.  

24. The most abundant immunoglobulin is immunoglobulin G (IgG), which is released by Plasma B cells. There are several sub-classes of IgG. IgG consists of two “heavy” polypeptide chains and two “light” polypeptide chains in a “Y” shape:

25. A vaccine is a preparation containing one or more antigens which is intended to trigger an adaptive immune response, but not cause disease, or at least not cause severe symptoms of disease, associated with that pathogen. The vaccine is intended to generate memory cells against a pathogen. This protects the host against the consequences of subsequent exposure to a pathogen bearing that antigen.

26. Vaccines involve presenting a killed or weakened version of a pathogen (or an antigen or antigens, or specific parts of an antigen or antigens of a pathogen) to the immune system, in a form suitable for the immune system to recognise the antigen or antigens and stimulate the body to produce antigen-specific antibodies and related memory cells in response. If the vaccinated individual is exposed to the pathogen again after vaccination, the immune system will be primed and able to rapidly produce antigen-specific antibodies in order to neutralize and prevent the pathogen from reproducing and the disease from developing. 

27. Pathogens often have more than one antigen against which hosts will generate antibodies and memory cells that are capable of providing adaptive immunity. This means that, for a given pathogen, a number of different antigenic compositions may be able to confer acceptable levels of immunity.

    THE PATENT APPLICATIONS

1. There are three patent applications in issue.

2. The Applications have substantially the same specification, save for different introductory statements as to the field of the invention and consistory statements, and different examples being included in the 537 and 540 Applications.

3. The 535 Application is entitled “Mycoplasma hyopneumoniae vaccine” and the invention is said to relate to Mycoplasma hyopneumoniae (M. hyo). More particularly, the invention relates to the soluble portion of an M. hyo whole cell preparation and its use in a vaccine for protecting pigs against enzootic pneumonia.

4. The 537 Application is entitled “PCV/Mycoplasma hyopneumoniae combination vaccine”, and the invention is said to relate to porcine circovirus and M. hyo. More particularly, the invention relates to a multivalent immunogenic composition including a soluble portion of an M. hyo whole cell preparation and a PCV-2 antigen and its use in a vaccine for protecting pigs against enzootic pneumonia and Post-weaning Multisystemic Wasting Syndrome (PMWS).

5. The 540 Application is entitled “PCV/Mycoplasma hyopneumoniae/PRRS combination vaccine” and the invention is said to relate to porcine circovirus, M. hyo and porcine reproductive and respiratory syndrome (PRRS) virus. More particularly, the invention relates to a trivalent immunogenic composition including a soluble portion of an M. hyo whole cell preparation, a PCV-2 antigen and a PRRS virus antigen and its use in a vaccine for protecting pigs against enzootic pneumonia and PMWS.

6. Relevant parts of the specification (of all three Applications), referred to throughout these reasons for judgment, include the following.

7. The background of the invention notes enzootic pneumonia in swine, also called mycoplasmal pneumonia, is caused by M. hyo. Whilst infected pigs show only mild cough and fever symptoms, the disease has significant economic impact due to reduced feed efficiency and reduced weight gain. The primary M. hyo infection may be followed by secondary infection by other mycoplasma species as well as other bacterial pathogens.

8. The specification describes M. hyo as a small, prokaryotic microbe capable of a free living existence, although it is often found in association with eukaryotic cells because it has absolute requirements for exogenous sterols and fatty acids. These requirements generally necessitate growth in serum-containing media. M. hyo is bounded by a cell membrane, but not a cell wall.

9. After describing in more detail the mechanism and effect of an M. hyo infection in a pig, and the characteristic lung lesions found in infected pigs, the specification observes (at page 1a, line 3) that there is a great need for effective preventative and treatment measures.

10. The specification continues (at page 2, lines 5–11):

    Vaccines containing preparations of mycoplasmal organisms grown in serum-containing medium have been marketed, but raise concerns regarding adverse reactions induced by serum components (such as immunocomplexes or non-immunogenic specific proteins) present in the immunizing material. Other attempts to provide M. hyo vaccines have been successful, but the disease remains widespread.

11. The specification then explains that M. hyo and porcine circovirus type 2 (PCV-2) are the two most prevalent pathogens that are encountered in the pig industry. Swine infected with PCV-2 exhibit a syndrome commonly referred to as Post-weaning Multisystemic Wasting Syndrome (defined above as PMWS). In addition to PMWS, PCV-2 has been associated with several other infections, one of which is PRRS.

12. At page 2a, lines 1–2, the specification states that it is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. An example given is an improved vaccine against mycoplasma infection in swine.

13. The specification continues (at page 3, lines 1–4):

    M. hyo vaccine will be compatible with other porcine antigens, such as PCV2 and PRRS virus, whether they are given concurrently as separate single vaccines or combined in a ready-to-use vaccine. It would be highly desirable to provide a ready-to-use, single-dose M. hyo/PCV2 combination vaccine. 

14. Under the heading “summary of the invention”, the specification describes four aspects of the invention, the first aspect being (page 3, lines 7–11):

    According to a first aspect, the present invention relates to an immunogenic composition comprising the supernatant of a Mycoplasma hyopneumoniae (M.hyo) culture, wherein the supernatant of the M.hyo culture has been separated from insoluble cellular material by centrifugation, filtration, or precipitation and is substantially free of both (i) IgG and (ii) immunocomplexes comprised of antigen bound to immunoglobulin.

15. The second aspect of the invention relates to a kit for use in carrying out the invention, the third aspect, a method for preparing an immunogenic composition, and the fourth, a method for immunising a pig against M. hyo.

16. At page 3a, lines 10–12, the specification states that in one aspect, the soluble portion of the M. hyo whole cell preparation has been treated with Protein A or Protein G prior to being added to the immunogenic composition.

17. The specification then describes some embodiments of the invention (at page 3a, line 14–page 5, line 13):

    In one embodiment, the soluble portion of the M. hyo preparation includes at least one M. hyo protein antigen. In another embodiment, the soluble portion of the M. hyo preparation includes two or more M. hyo protein antigens.

    In some embodiments, the immunogenic composition of the present invention further includes at least one additional antigen. In one embodiment, the at least one additional antigen is protective against a microorganism that can cause disease in pigs.

    In one embodiment, the microorganism includes bacteria, viruses, or protozoans. In another embodiment, the microorganism is selected from, but is not limited to, the following: porcine circovirus type 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSV), porcine parvovirus (PPV), Haemophilus parasuis, Pasteurella multocida, Streptococcum [sic] suis, Staphylococcus hyicus, Actinobacilllus [sic] pleuropneumoniae, Bordetella bronchiseptica, Salmonella choleraesuis, Salmonella enteritidis, Erysipelothrix rhusiopathiae, Mycoplama [sic] hyorhinis, Mycoplasma hyosynoviae, leptospira bacteria, Lawsonia intracellularis, swine influenza virus (SIV), Escherichia coli antigen, Brachyspira hyodysenteriae, porcine respiratory coronavirus, Porcine Epidemic Diarrhea (PED) virus, rotavirus, Torque teno virus (TTV), Porcine Cytomegalovirus, Porcine enteroviruses, Encephalomyocarditis virus, a pathogen causative of Aujesky's [sic] Disease, Classical Swine fever (CSF) and a pathogen causative of Swine Transmissable [sic] Gastroenteritis, or combinations thereof.

    In certain embodiments, the at least one additional antigen is a porcine circovirus type 2 (PCV2) antigen, a PRRS virus antigen or a combination thereof. In one embodiment, the composition elicits a protective immune response in a pig against both M. hyo and PCV2. In another embodiment, the composition elicits a protective immune response in a pig against M. hyo, PCV2 and PRRS virus.

    In one embodiment, the PCV2 antigen is in the form of a chimeric type-1-type 2 [sic] circovirus, the chimeric virus including an inactivated recombinant porcine circovirus type 1 expressing the porcine circovirus type 2 ORF2 protein. In another embodiment, the PCV2 antigen is in the form of a recombinant ORF2 protein. In still another embodiment, the recombinant ORF2 protein is expressed from a baculovirus vector.

    In some embodiments, the composition of the present invention further includes an adjuvant. In one embodiment, the adjuvant is selected from, but is not limited to, the following: an oil-in-water adjuvant, a polymer and water adjuvant, a water-in-oil adjuvant, an aluminum hydroxide adjuvant, a vitamin E adjuvant and combinations thereof. In another embodiment, the composition of the present invention further includes a pharmaceutically acceptable carrier.

    In certain embodiments, the composition of the present invention elicits a protective immune response against M. hyo when administered as a single dose administration. In further embodiments, the composition elicits a protective immune response against M. hyo and at least one additional microorganism that can cause disease in pigs when administered as a single dose administration. In still further embodiments, a composition of the present invention elicits a protective response against both M. hyo and at least one additional microorganism that causes disease in pigs when administered as a two dose administration.

    The present invention also provides a method of immunizing a pig against M. hyo. This method includes administering to the pig an immunogenic composition including a soluble portion of an M. hyo whole cell preparation, wherein the soluble portion of the M. hyo preparation is substantially free of both (i) IgG and (ii) immunocomplexes comprised of antigen bound to immunoglobulin. In one embodiment, the soluble portion of the M. hyo preparation of the administered composition includes at least one M. hyo protein antigen.

    In one embodiment of the method of the present invention, the composition is administered intramuscularly, intradermally, transdermally, or subcutaneously. In another embodiment of the method of this invention, the composition is administered in a single dose. In yet another embodiment of the method of this invention, the composition is administered as two doses.

    In a further embodiment of the method of the present invention, the composition is administered in conjunction with at least one additional antigen that is protective against a microorganism that can cause disease in pigs, such as one or more of the microorganisms described above. Such other antigens can be given concurrently with the M. hyo composition (i.e., as separate single vaccines) or combined in a ready-to-use vaccine.

18. There follows a brief description of the drawings and the sequences.

19. At page 8, lines 15–24, there is the following detailed description of the invention:

    The present invention provides an immunogenic composition including a soluble portion of an M. hyo whole cell preparation, wherein the soluble portion of the M. hyo preparation is substantially free of both (i) IgG and (ii) antigen-bound immunocomplexes. Applicants have surprisingly discovered that the insoluble fraction of the M. hyo whole cell preparation is non-immunogenic. In contrast, the IgG-free M. hyo soluble preparation is immunogenic and can be effectively combined with antigens from other pathogens, such as PCV2, without analytical or immunological interference between the antigens. This makes the M. hyo soluble preparation of this invention an effective platform for multivalent vaccines, including one-bottle, ready-to-use formulations. Applicants have also surprisingly discovered that removing the immunoglobulin and the insoluble cell debris enhances the safety of the immunogenic composition.

20. The specification then includes (at page 8, line 26–page 13, line 4) a number of definitions of terms used in the specification, including “comprising” at page 8, lines 30–2:

    As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.

21. At page 9, lines 1–9, the specification states that, as defined, a soluble portion of an M. hyo whole cell preparation refers to a soluble liquid fraction of an M. hyo whole cell preparation after separation of the insoluble material and substantial removal of IgG and antigen-bound immunocomplexes. The specification continues:

    The M. hyo soluble portion may alternatively be referred to as the supernatant fraction, culture supernatant and the like. It includes M. hyo expressed soluble proteins (M. hyo protein antigens) that have been separated or isolated from insoluble proteins, whole bacteria, and other insoluble M. hyo cellular material by conventional means, such as centrifugation, filtration, or precipitation. In addition to including M. hyo-specific soluble proteins, the soluble portion of the M. hyo whole cell preparation also includes heterologous proteins, such as those contained in the culture medium used for M. hyo fermentation.

    The term “antigen” as used in the specification refers to a compound, composition, or immunogenic substance that can stimulate the production of antibodies or a T-cell response, or both, in an animal, including compositions that are injected or absorbed into an animal. The immune response may be generated to the whole molecule, or to a portion of the molecule (e.g., an epitope or hapten).

22. The term an “immunogenic or immunological composition”, as used in the specification, refers to a composition of matter that comprises at least one antigen which elicits an immunological response in the host of a cellular and or antibody-mediated immune response to the composition or vaccine of interest.

23. At page 9, lines 20–30 the specification continues:

    The term "immune response" as used in the specification refers to a response elicited in an animal. An immune response may refer to cellular immunity (CMI); humoral immunity or may involve both. The present invention also contemplates a response limited to a part of the immune system. Usually, an “immunological response” includes, but is not limited to, one or more of the following effects: the production or activation of antibodies, B cells, helper T cells, suppressor T cells, and/or cytotoxic T cells and/or yd T cells, directed specifically to an antigen or antigens included in the composition or vaccine of interest. Preferably, the host will display either a therapeutic or protective immunological response such that resistance to new infection will be enhanced and/or the clinical severity of the disease reduced. Such protection will be demonstrated by either a reduction or lack of symptoms normally displayed by an infected host, a quicker recovery time and/or a lowered viral titer in the infected host.

24. The term “adjuvant”, as used in the specification (at page 10, line 5), means:

    [A] composition comprised of one or more substances that enhances the immune response to an antigen(s). The mechanism of how an adjuvant operates is not entirely known. Some adjuvants are believed to enhance the immune response by slowly releasing the antigen, while other adjuvants are strongly immunogenic in their own right and are believed to function synergistically.

25. The term “multivalent”, as used in the specification, means a vaccine containing more than one antigen whether from the same species (ie different isolates of Mycoplasma hyopneumoniae), from a different species (ie isolates from both Pasteurella hemolytica and Pasteurella multocida), or a vaccine containing a combination of antigens from different genera (eg a vaccine comprising antigens from Pasteurella multocida, Salmonella, Escherichia coli, Haemophilus somnus and Clostridium).

26. The term “vaccine composition”, as used in the specification, includes at least one antigen or immunogen in a pharmaceutically acceptable vehicle useful for inducing an immune response in a host.

27. At page 13, lines 5–9, the specification states:

    All currently available M. hyo vaccines are made from killed whole cell mycoplasma preparations (bacterins). In contrast, the present invention employs a soluble portion of a Mycoplasma hyopneumoniae (M. hyo) whole cell preparation, wherein the soluble portion of the M. hyo preparation is substantially free of both (i) IgG and (ii) immunocomplexes comprised of antigen bound to immunoglobulin.

28. The specification then discusses the growth media requirements specific to M. hyo at page 13, lines 11–23:

    M. hyo has absolute requirements for exogenous sterols and fatty acids. These requirements generally necessitate growth of M. hyo in serum-containing media, such as porcine serum. Separation of the insoluble material from the soluble portion of the M. hyo whole cell preparation (e.g., by centrifugation, filtration, or precipitation) does not remove the porcine IgG or immune complexes. In one embodiment of the present invention, the M. hyo soluble portion is treated with protein-A or protein-G in order to substantially remove the IgG and immune complexes contained in the culture supernatant. In this embodiment, it is understood that protein A treatment occurs post- M. hyo fermentation. This is alternatively referred to herein as downstream protein A treatment. In another embodiment, upstream protein A treatment of the growth media (i.e., before M. hyo fermentation) can be employed. Protein A binds to the Fc portion of IgG. Protein G binds preferentially to the Fc portion of IgG, but can also bind to the Fab region. Methods for purifying/removing total IgG from crude protein mixtures, such as tissue culture supernatant, serum and ascites fluid are known in the art.

29. At page 13, lines 25–27, the specification notes that in some embodiments, the soluble portion of the M. hyo preparation includes at least one M. hyo protein antigen. In other embodiments, the soluble portion of the M. hyo preparation includes two or more M. hyo protein antigens.

30. The specification discusses (at page 13, line 29–page 14, line 25) at least one M. hyo antigen included in the M. hyo soluble portion. In one embodiment, the M. hyo supernatant fraction is said to include one or more of the following M. hyo protein specific antigens: M. hyo proteins of approximately 46kD (p46), 64kD (p64) and 97kD (p97); kD being molecular weight expressed in kilo Daltons. In another embodiment, the M. hyo culture supernatant may include further M. hyo specific antigens such as, but not limited to, proteins of approximately 41 kD (p41), 42kD (p42), 89kD (p89), and 65kD (p65). The specification cites Okada et al, “Protective effect of Vaccination with Culture Supernate of M. hyopneumoniae against Experimental Infection in Pigs” (2000) Journal of Veterinary Medicine, Series B 47(7) 527–533 (Okada 2000a) following the list of specific protein antigens.

31. At page 15, lines 18–22, the specification details another embodiment:

    In one embodiment, M. hyo soluble p46 antigen is included in the compositions of the invention at a final concentration of about 1.5 µg/ml to about 10 µg/ml, preferably at about 2 µg/ml to about 6 µg/ml. It is noted that p46 is the protein used for the M. hyo potency test (see example section below). In another embodiment, the M. hyo antigen can be included in the compositions at a final amount of about 5.5% to about 35% of the M. hyo whole culture protein A-treated supernatant.

32. At page 15, lines 24–30, the specification states that the M. hyo soluble preparation of the present invention is both safe and efficacious against M. hyo and is suitable for single dose administration. In addition, it is said that it has been surprisingly discovered that the M. hyo soluble preparation can be effectively combined with antigens from other pathogens without immunological interference between the antigens. That is said to make the M. hyo soluble preparation of the invention an effective platform for multivalent vaccines. The additional antigens may be given concurrently with the M. hyo composition (ie as separate single vaccines) or combined in a ready-to-use vaccine.

33. At page 16, the specification provides details of other embodiments, including where:

    (a)The immunogenic composition includes at least one M. hyo soluble antigen and at least one additional antigen; or

    (b)The immunogenic composition includes the combination of at least one M. hyo soluble antigen (eg two or more) and a PCV-2 antigen.

34. See also page 19, lines 23–26, which describes further embodiments, including a combination of at least one M. hyo soluble antigen (eg two or more), a porcine circovirus type 2 (PCV-2) antigen and a PRRS virus antigen.

1. Page 19, lines 9–21, includes the following examples of absolute concentration:

   In one embodiment, a chimeric PCV1-2 virus is included in the compositions of the invention at a level of at least 1.0 < RP< 5.0, wherein RP is the Relative Potency unit determined by ELISA antigen quantification (in vitro potency test) compared to a reference vaccine. In another embodiment, a chimeric PCV1-2 virus is included in the composition of the invention at a final concentration of about 0.5% to about 5% of 20-times (20X) concentrated bulk PCV1-2 antigen.

   In another embodiment, the PCV2 ORF2 recombinant protein is included in the compositions of the invention at a level of at least 0.2 µg antigen/ml of the final immunogenic composition (µg/ml). In a further embodiment, the PCV2 ORF2 recombinant protein inclusion level is from about 0.2 to about 400 µg/ml. In yet another embodiment, the PCV2 ORF2 recombinant protein inclusion level is from about 0.3 to about 200 µg/ml. In a still further embodiment, the PCV2 ORF2 recombinant protein inclusion level is from about 0.35 to about 100 µg/ml. In still another embodiment, the PCV2 ORF2 recombinant protein inclusion level is from about 0.4 to about 50 µg/ml.

2. Examples of suitable adjuvants for use in the compositions of the invention are listed at page 24.

3. The specification notes at page 26, lines 24–27 the methods used to separate the M. hyo whole cell preparation from the insoluble cellular material. These conventional methods include filtration, centrifugation and precipitation across various embodiments.

4. The 535 Application has 13 examples. Example 1 provides a high level description of a method by which an M. hyo cell culture is fermented and inactivated for the purposes of producing a PCV-2 combinable M. hyo antigen. Example 2 provides a description of methods by which chimeric porcine circovirus (cPCV)1-2 can be produced. Examples 1 and 2 are replicated in the 537 and 540 Applications.

5. Example 3 (in each of the Applications) is entitled “Down Stream Processing of M. hyo antigens and Analytical Testing of these Processed Antigens”. This example describes how a number of M. hyo preparations prepared as described in example 1 were treated and then analysed for M. hyo specific p46 antigen. The processed M. hyo antigens were then employed in example 4 (in each of the Applications) to prepare M. hyo vaccine formulations. Formulations relevant to BI’s validity case, which are discussed later, include:

   ·T03: (10X UF (ultra filtration) concentrated) Concentrated by tangential flow filtration via a 100KDa molecular weight cut-off membrane (hollow fibre). Final volume reduction was equal to 10X.

   ·T04 and T05: (10X UF concentrated and centrifuged) Concentrated mycoplasma cells (from T03) were collected and washed one time with PBS via centrifugation at ~20,000xg (Sorvall model RCB).

   ·T06 and T07: (10X centrifuged) Inactivated fermentation fluid was centrifuged at ~20,000xg (Sorvall RC5B) and washed one time by resuspending the cells in PBS followed by additional centrifugation. Final volume reduction was equal to 10X.

   ·T08: (10X centrifuged and heated) Mycoplasma cells were concentrated and washed per T06 and heated to 65°C for 10 minutes.

   ·T09: (cell-free supernatant) Supernatant collected from the first centrifugation as described for T06 was filter sterilized through a 0.2 micron filter (Nalgene).

   ·T10: (cell-free-supernatant-Protein-A treated) Sterile supernatant (prepared per T09) was mixed with Protein A resin (Protein A Sepharose, Pharmacia Inc) at a 10:1 volume ratio for 4 hours. Resin was removed and sterile filtration and filtered fluid was stored at 2-8˚C. This process uses post-fermentation “downstream” Protein A treatment to remove antibodies and immunocomplexes.

6. The specification notes (at page 32) that, although the present invention does not preclude upstream Protein A treatment, the present inventors have found that, in the case of M. hyo, upstream processing of the growth media led to P46 results which were lower and inconsistent as compared to untreated media.

7. The specification continues at page 33, line 13:

   Since it is known in the art that Protein A binds IgG, it is understood by those of ordinary skill in the art that not only PCV2 antibody, but other swine antibodies, including PRRS antibody, HPS antibody, and SIV antibody will be effectively removed by the Protein-A treatment. This makes the Cell-free Protein-A treated M.  hyo supernatant of this invention compatible not only with PCV2 antigen, but also with other porcine antigens due to the lack of immunological interference between the antigens. Additionally, the removal of the non-protective cell debris and removal of the immunoglobulin and antigen/immunoglobulin complexes is reasonably expected to make a safer vaccine.

8. The differences between the three specifications as far as the examples are concerned can be summarised as follows:

   (a)Examples 12 and 13 of the 537 Application are not present in the 535 or 540 Applications. These examples describe two studies, the first designed to evaluate the efficacy of the PCV1-2 chimera, killed virus fraction of an experimental 1-bottle PCV-2/M. hyo combination vaccine, administered once to piglets, and the second to evaluate the efficacy of the M. hyo fraction of an experimental PCV1-2 chimera.  

   (b)Examples 14 and 15 of the 537 Application are labelled example 12 and 13, respectively, in the 535 and 540 Applications.

   (c)The 540 Application contains three additional examples not present in the 535 or 537: examples 14 to 16. Examples 14 to 16 describe various further studies designed to evaluate the efficacy of the M. hyo, PCV-2 and PRRS components respectively of a trivalent vaccine of the invention.

9. The 535 Application’s specification ends with 18 claims. Claim 1 of the 535 Application claims:

   An immunogenic composition comprising the supernatant of a Mycoplasma hyopneumoniae (M. hyo) culture, wherein the supernatant of the M. hyo culture has been separated from insoluble cellular material by centrifugation, filtration, or precipitation and is substantially free of both (i) IgG and (ii) immunocomplexes comprised of antigen bound to immunoglobulin.

10. Claim 2 of the 535 Application is dependent upon claim 1, and adds “wherein the soluble portion has been treated with Protein A or Protein G prior to being added to the immunogenic composition”.

11. Claim 3 of the 535 Application is dependent upon claims 1 or 2, and claims:

    The composition of claim 1 or claim 2, wherein the composition further comprises at least one additional antigen which is protective against a microorganism selected from the group consisting of porcine reproductive and respiratory syndrome virus (PRRSV), porcine parvovirus (PPV), Haemophilus parasuis, Pasteurella multocida, Streptococcum [sic] suis, Staphylococcus hyicus, Actinobacilllus [sic] pleuropneumoniae, Bordetella bronchiseptica, Salmonella choleraesuis, Salmonella enteritidis, Erysipelothrix rhusiopathiae, Mycoplama [sic] hyorhinis, Mycoplasma hyosynoviae, leptospira bacteria, Lawsonia intracellularis, swine influenza vims (SIV), Escherichia coli antigen, Brachyspira hyodysenteriae, porcine respiratory coronaviruses, Porcine Epidemic Diarrhea (PED) vims, rotavims, Torque teno virus (TTV), Porcine Cytomegalovirus, Porcine enterovimses, Encephalomyocarditis virus, a pathogen causative of Aujesky’s [sic] Disease, Classical Swine fever (CSF) and a pathogen causative of Swine Transmissable [sic] Gastroenteritis, or combinations thereof.

    (Emphasis added.)

12. The bolded references above are to the “5 Pathogens” which were the subject of discussion by the experts and which are relevant to Boehringer’s validity case. Four of the 5 Pathogens are viruses, and one, Brachyspira hyodysenteriae, is a bacteria.

13. Claim 16 of the 535 Application is a “kit” claim, which claims:

    A kit for use in carrying out the method of claim 9 comprising:

    a bottle comprising an immunogenic composition including the supernatant of a Mycoplasma hyopneumoniae (M. hyo) culture, wherein the supernatant of the M. hyo culture has been separated from insoluble cellular material by centrifugation, filtration, or precipitation and is substantially free of both (i) IgG and (ii) antigen/immunoglobulin immunocomplexes.

14. The 537 Application contains 24 claims, the broadest of which is claim 1, which claims:

    A multivalent immunogenic composition comprising the supernatant of a Mycoplasma hyopneumoniae (M. hyo) culture; and a porcine circovirus type 2 (PCV2) antigen, wherein the supernatant of the M. hyo culture has been separated from insoluble cellular material by centrifugation, filtration, or precipitation and is substantially free of both (i) IgG and (ii) immunocomplexes comprised of antigen bound to immunoglobulin.

    (Emphasis added.)

15. Claim 2 of the 537 Application is dependent on claim 1 and claims where the soluble portion of the M. hyo preparation has been treated with Protein A or Protein G prior to being added to the immunogenic composition.

16. Claim 3 claims the composition of claim 1 or 2 wherein the composition is in the form of a ready-to-use liquid composition.

17. Dependent claim 8 of the 537 Application claims the composition of any one of claims 1 to 7, further comprising at least one additional antigen which is protective against a microorganism selected from the same group listed in claim 3 of the 535 Application with the exception of PRRSV which is in the list of antigens in claim 3 of the 535 Application but is not found in the list in claim 8 of the 537 Application.

18. The 540 Application contains 25 claims. Claim 1 of the 540 Application claims:

    A trivalent immunogenic composition comprising the supernatant of a Mycoplasma hyopneumoniae (M. hyo) culture; a porcine circovirus type 2 (PCV2) antigen; and a porcine reproductive and respiratory syndrome (PRRS) virus antigen, wherein the supernatant of the M. hyo culture has been separated from insoluble cellular material by centrifugation, filtration, or precipitation and is substantially free of both (i) IgG and (ii) immunocomplexes comprised of antigen bound to immunoglobulin.

    (Emphasis added.)

19. Claims 2 to 13 of the 540 Application are dependent claims that also define trivalent immunogenic compositions, adding various characteristics to claim 1. In particular, claim 3 defines a “ready-to-use” composition containing the M. hyo and PCV-2 antigens but not the PRRS virus antigen. Claims 24 and 25 are claims to methods of preparing an immunogenic composition comprising the M. hyo supernatant, and PCV-2 and PRRS antigens.

    Summary of the disclosure

20. The invention described and claimed in the specification of each Application may be broadly summarised as the provision of an immunogenic composition being an M. hyo supernatant platform which may itself be used as a vaccine, or which can be combined with other vaccines to form a preferably single dose ready-to-use vaccine. Relevant to each application, the nature of the M. hyo supernatant platform is such that immunogenic interference when combined with other antigens is absent due to the removal of IgG and immunocomplexes comprised of antigen bound to immunoglobulin (immunocomplexes) in the production of the M. hyo supernatant.

21. The 535 Application claims an immunogenic composition being an M. hyo supernatant platform, which may itself be used as a vaccine, or which can be combined with other vaccines to form a preferably single dose ready-to-use vaccine.

22. The invention as claimed in the 537 Application is a multivalent immunogenic composition being an M. hyo supernatant platform combined with a PCV-2 antigen, which may be combined with other vaccines to form a preferably single dose ready-to-use vaccine.

23. The invention as claimed in the 540 Application is a trivalent immunogenic composition being an M. hyo supernatant platform combined with a PCV-2 antigen and a PRRS antigen.

    STATUTORY PROVISIONS

24. The statutory provisions of particular relevance to this matter are as follows.

25. Section 7 of the Act states:

    7 Novelty, inventive step and innovative step

    Novelty

    (1)  For the purposes of this Act, an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the following kinds of information, each of which must be considered separately:

    (a)  prior art information (other than that mentioned in paragraph (c)) made publicly available in a single document or through doing a single act;

    (b)  prior art information (other than that mentioned in paragraph (c)) made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art would treat them as a single source of that information;

    (c)  prior art information contained in a single specification of the kind mentioned in subparagraph (b)(ii) of the definition of prior art base in Schedule 1.

    Inventive step

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

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

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

    (b) a combination of any 2 or more pieces of prior art information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have combined.

26. Section 40, which deals with sufficiency, support and best method, states:

    40 Specifications

    …

    Requirements relating to complete specifications

    (2)       A complete specification must:

    (a)  disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art; and

    (aa)  disclose the best method known to the applicant of performing the invention; and

    (b)  where it relates to an application for a standard patent—end with a claim or claims defining the invention; and

    (c)  where it relates to an application for an innovation patent—end with at least one and no more than 5 claims defining the invention.

    (3)  The claim or claims must be clear and succinct and supported by matter disclosed in the specification.

    (3A)  The claim or claims must not rely on references to descriptions, drawings, graphics or photographs unless absolutely necessary to define the invention.

    (4)  The claim or claims must relate to one invention only.

    OVERVIEW OF EVIDENCE

27. Four expert witnesses gave evidence at trial. Boehringer engaged Dr Nordgren and Professor Chase, and Zoetis engaged Professor McVey and Professor Browning.

28. Prior to the trial, the experts prepared a Joint Expert Report (JER). They were each cross-examined in the course of a joint session over 3 days. Dr Nordgren was also cross-examined in a separate session which followed the completion of the joint session.

    Dr Nordgren

29. Dr Nordgren has more than 35 years of experience in vaccine development and formulation for animals and has been involved in the registration of over 80 animal health products. He has a Bachelor of Science, a Master of Science (Veterinary Parasitology) and a Doctorate of Philosophy in Veterinary Immunology.

30. Dr Nordgren has worked for leading animal healthcare companies, including Solvay Animal Health, Boehringer Ingelheim Vetmedica and Merial Ltd. Dr Nordgren has managed global teams which have been responsible for over 80 unique animal products, including vaccines. A significant number of the vaccines for which he was responsible were developed before 2012.

31. While working at BIV in approximately 1998, Dr Nordgren was involved in a vaccine development project which created a one-dose inactivated whole cell bacterin vaccine for M. hyo in pigs. During the joint expert session Dr Nordgren agreed with senior counsel for Zoetis, Mr Flynn, that bacterins were a state of the art product and the best available option by 1998.

32. While working at Merial from 1999, Dr Nordgren was responsible for reviewing patents, and on occasion gave evidence in patent proceedings for Merial. His role at Merial also required the surveillance of products entering the market and acquisition of innovative competitor products.

33. Zoetis strongly challenged Dr Nordgren’s independence and ability to give impartial and relevant expert evidence on four grounds which I consider at the end of the evidence section.

    Professor Chase

34. Professor Chase has over 30 years of experience in veterinary immunology, including experience developing and researching vaccines for the treatment of diseases in swine. He is currently a Professor in the Department of Veterinary and Biomedical Science at South Dakota University. He holds a professional doctorate degree in Veterinary Medicine and a Master of Science and PhD.

35. During the period before the priority date, Professor Chase was involved in swine and ruminant disease diagnostics while teaching virology and immunology and undertaking research in infectious disease and immunology. Since 1 June 1998, Professor Chase has also held the position of President at his contract research company that undertakes, amongst other research, swine vaccine studies.

36. No challenge was made to Professor Chase’s independence. Professor Chase answered questions directly and engaged with the views expressed by his colleagues on technical matters. I consider that Professor Chase was a helpful witness who did his best to assist the Court throughout his evidence.

37. Zoetis made a hindsight challenge in relation to some of Professor Chase’s evidence. This challenge was based on the manner in which Professor Chase was briefed with the prior art and the questions put to him in the preparation of his evidence for the opposition proceeding. I deal with this challenge later where it is relevant to the issue of inventive step.

    Professor McVey

38. Professor McVey has around 40 years’ experience in animal health and veterinary microbiology. He has worked with both academic institutions and pharmaceutical and animal health companies in the field of vaccine formulation and development. Professor McVey holds a Doctor of Veterinary Medicine degree and a PhD in Veterinary Microbiology. He also has experience in the field working as a veterinarian, including treating endemic diseases of commercial farm animals, and has been employed by Merial from 1995–1998, and Pfizer Animal Health from 1998–2006.

39. Professor McVey is currently a Professor and Director of the School and Veterinary Medicine and Biomedical Sciences at the University of Nebraska-Lincoln and the Associate Dean of the Nebraska/Iowa Program for Veterinary Medicine. 

40. Professor McVey has particular expertise in the immunology of infectious diseases of livestock, including diseases associated with M. hyo, PCV-2 and PRRS, and associated control measures including vaccine development.

41. No challenge was made to Professor McVey’s independence as an expert witness and he gave helpful affidavit and oral evidence.

    Professor Browning

42. Professor Browning is a Professor of Veterinary Microbiology in the Faculty of Veterinary and Agricultural Sciences at the University of Melbourne and has been since 2003. He has more than 35 years’ experience in veterinary microbiology, including the pathogenesis and epidemiology of infectious diseases and related animal vaccines.

43. Professor Browning’s research focuses on vaccines to control bacterial and viral respiratory diseases in swine and other livestock. He has particular expertise in relation to mycoplasmas including M. hyo.

1. Professor Browning has some industry experience, having collaborated on research projects on vaccine development and diagnostics with a range of industry partners including Pfizer, Bioproperties Pty Ltd, Grange Laboratories and BioBest Laboratories.

2. From 1998 to 2017, Professor Browning advised the Australian Pesticides and Veterinary Medicines Authority on the safety, efficacy, chemistry and manufacture of veterinary vaccines.

3. During oral evidence, Professor Browning described himself as “a bit pedantic”. This characteristic made him consider carefully all propositions put to him, or comments made by the other experts before accepting or rejecting them. Professor Browning was not afraid to depart from the comments of the other three expert witnesses where he felt it appropriate.

4. Boehringer pursued a line of questioning during the joint expert session which called Professor Browning’s independence into question. Professor Browning has worked on a number of projects that had received industry funding, including from Pfizer Animal Health (now Zoetis). As a result of these research projects, he is a named inventor on a number of patents co-owned by Zoetis and the University of Melbourne. The other named inventors on at least one of those patents are Zoetis employees. Professor Browning confirmed that he is entitled to a share of the royalties from this patent.

5. All of the research projects funded by Zoetis were declared in Professor Browning’s extensive CV, along with any patents on which he is a named inventor. I consider that Professor Browning was an independent, careful expert who gave considered and useful evidence.

   Mr Eichmeyer

6. Mr Eichmeyer is Boehringer’s Director of International Project Management – Vaccines. He has been employed by Boehringer, and its predecessors, since 2001, and is responsible for leading teams involved in vaccine registration across the world. Mr Eichmeyer was the head of a research project undertaken by Boehringer to develop a ready-to-use bivalent M. hyo/PCV-2 vaccine combination product. This project did not lead to the development of a bivalent, ready-to-use vaccine that was superior to Boehringer’s monovalent offerings.

7. Mr Eichmeyer swore one affidavit in the proceeding but was not called by either party. Zoetis tendered part of his affidavit

   Zoetis’ challenge to Dr Nordgren

8. Zoetis challenged Dr Nordgren’s independence and ability to give impartial and relevant expert evidence on four grounds.

9. First, as a result of his lengthy and ongoing consulting arrangements with Boehringer and its predecessors, Zoetis contends that Dr Nordgren cannot be considered to be an independent witness.

10. Second, Zoetis submits that Dr Nordgren took into account significant non-common general knowledge in forming his opinions. Dr Nordgren failed to disclose his involvement in highly relevant confidential in-house M. hyo research work during his time at Merial. This, combined with a failure in his evidence to differentiate his use of the knowledge derived from his involvement with in-house research work from information generally known to all in the field in the formation of his opinions, means that the Court cannot disentangle the confidential in-house information and the common general knowledge used to form the basis of his opinions.

11. Third, Zoetis submits that Dr Nordgren is not representative of the hypothetical non-inventive person skilled in the art. Zoetis contends that Dr Nordgren’s inventorship on relevant patents and patent applications, and his participation in inventive research work relevant to the subject matter of the Applications, before the priority date, means that he is particularly ill-equipped to opine on the knowledge or approach of an uninventive person of ordinary skill in the field of swine vaccine development.

12. Fourth, Zoetis submits that Dr Nordgren’s role at Merial and Boehringer was not limited to undertaking research and experiments in the development of animal vaccine products. His ongoing consultancy role at Boehringer and its predecessors required him to review, and be involved in (including by providing expert witness testimony), challenges to competitors’ patents and patent applications relating to vaccine products. Zoetis submits that, in giving evidence in this proceeding, Dr Nordgren was acting under an obligation to act in the best interests of Boehringer and was not acting as an independent expert.

13. Accordingly, Zoetis submits that the Court should be reluctant to rely on Dr Nordgren’s evidence other than where it has been corroborated by the other experts.

    Ongoing consulting role with Boehringer

14. Zoetis submits that Dr Nordgren’s relationship with Boehringer, its predecessor companies, and related entities is unique by reason of its longevity and, in particular, having regard to the fact that the services provided by Dr Nordgren relate not only to technical matters, but also to patent reviews, strategy and providing expert evidence.

15. Over a 20-year period from 1996 to 2016, Dr Nordgren held senior positions in Boehringer’s predecessor companies, including Vice President, Global Biologics Research & Development at Boehringer Ingelheim Vetmedica (1996-1999), Executive Director, Global Biologics Research & Development at Merial Ltd (1999-2001), Head of Research & Technology Acquisition at Merial Ltd (2001-2006), Vice President & Global Head of Biologics Research & Development at Merial Ltd (2006-2013) and Vice President & Global Head of External Innovation at Merial Ltd (2013-2016).

16. In his first affidavit, Dr Nordgren stated in paragraph 3 that “[a]part from my role as an expert witness, I have no direct relationship with either the Boehringer Ingelheim or Zoetis groups of companies”.

17. Dr Nordgren’s third affidavit was filed the day before the trial commenced. In his third affidavit, Dr Nordgren was asked to “describe in greater detail any work that I undertake for the Boehringer Ingelheim group of companies, referred to in paragraph 3 of my First Affidavit”.  Dr Nordgren clarified that his reference in his first affidavit to his role as an expert witness was intended to encompass his role as an expert witness in this proceeding and other cases, and stated:

    I undertake consulting work for the Boehringer Ingelheim group of companies on matters including contract disputes and patent litigation. This work includes acting as an independent expert witness for the Boehringer Ingelheim group of companies. However, the work is broader than being an expert witness. This is because, from time to time, I review and provide comments to the Boehringer Ingelheim group of companies on patents and patent applications in matters where I am not also asked to act as an expert witness. I wish to correct paragraph 3 of my First Affidavit to the extent it suggested that I am always formally engaged by the Boehringer Ingelheim group of companies as an expert witness in matters where I provide consulting services.

    (Emphasis added.)

18. As revealed in his third affidavit, after ceasing his employment with Merial in 2016, Dr Nordgren was engaged by Merial as a consultant pursuant to a confidential agreement. Sometime later, Dr Nordgren entered into a “very similar” agreement pursuant to which he provides consulting services for the Boehringer Ingelheim group of companies (which includes Boehringer). The consultancy services provided by Dr Nordgren under the terms of that agreement do not relate to vaccine development, but rather to “contract disputes and patent litigation”.

19. Dr Nordgren agreed that part of his Boehringer consultancy role required him to review, and be involved in (including by providing expert witness testimony) challenges to competitors’ patents and patent applications relating to vaccine products. Since November 2015, Dr Nordgren has been called by Merial and Boehringer as an expert witness in eight domestic animal vaccine related patent proceedings, including in the European Patent Office, the US Patent Office, this Court and the Australian Patent Office. Dr Nordgren did not recall being aware of, or exposed to, the Applications prior to being asked about them in the course of preparing his evidence in this proceeding.

20. The existence of Dr Nordgren’s consulting agreements with Merial and Boehringer was disclosed for the first time in his third affidavit. In cross-examination, Dr Nordgren confirmed that his work for the Boehringer group of companies and their predecessors under those agreements is “wider than acting as an independent expert witness”.

21. The first approach to Dr Nordgren to act as an expert in this proceeding was made by Boehringer, rather than Boehringer’s instructing solicitors in this proceeding.

22. In the course of cross-examination, the following exchange took place between Zoetis’ senior counsel and Dr Nordgren:

    [Counsel]: And under that contract [i.e., the Boehringer Consultancy Agreement], although we don’t have it, you tell us in paragraph 5 [of your third affidavit], that under that contract, you undertake consulting work from BI group of companies on matters including contract dispute and patent litigation; correct?

    DR NORDGREN: That’s correct.

    [Counsel]: And under that contract, you’re required to act in the best interests of BI; correct?

    DR NORDGREN: On those cases that I’m working on; yes.

    [Counsel]: And there’s no requirement in that contract that you act independently of BI if you’re acting as an expert witness; do you agree?

    DR NORDGREN: I would agree.

    [Counsel]: And in these proceedings, you are engaged, pursuant to that contract with BI, aren’t you?

    DR NORDGREN: Yes, sir. 

23. Zoetis submits that Dr Nordgren’s answers in the exchange set out above make clear that, in giving evidence in this proceeding, Dr Nordgren understood himself, first, to be under an obligation to act in the best interests of Boehringer and, secondly, to be under no obligation to act independently, an approach which is inconsistent with the Court’s Expert Evidence Practice Note and the Harmonised Expert Witness Code of Conduct.

24. Boehringer sought to explain the reason for Dr Nordgren’s third affidavit as being to clarify that Dr Nordgren’s reference to his “role as an expert witness” was intended to encompass his role as an expert witness in other proceedings in addition to the present. Boehringer says that it became apparent at a hearing before the Registrar that Zoetis had interpreted the words as only referring to this proceeding. However, the third affidavit goes beyond clarifying Dr Nordgren’s role as an expert witness.

25. Dr Nordgren’s third affidavit makes plain that his role with Boehringer is broader than his being engaged as an expert witness. His statement in his first affidavit: “Aside from my role as an expert witness, I have no direct relationship with either Boehringer Ingelheim or Zoetis groups of companies” (emphasis added), was not correct when the first affidavit was made. If Dr Nordgren’s third affidavit had not been filed on the eve of the trial, the Court would not have been informed of Dr Nordgren’s ongoing consulting role with Boehringer.

    Regard to confidential information not part of common general knowledge

26. In his first affidavit Dr Nordgren mentioned two instances of experience with M. hyo: he oversaw or supervised the development of “an industry-first, one-dose inactivated whole cell vaccine, also known as a bacterin for M. hyo in pigs”, and whilst at Merial, his involvement in “the development of a significant number of vaccine products, including for the following diseases of swine: (a) M. hyo; (b) PRRS; and (c) Porcine circovirus 2 (PCV-2), including the first PCV-2 vaccine, which was released first in Europe and subsequently in other countries”. No further details of his prior experience with M. hyo were provided.

27. It emerged in the course of the concurrent evidence session that, before the priority date, in approximately 2008 or 2009, Dr Nordgren had led a team of researchers at Merial engaged in experimental work aimed at combining a PCV-2 vaccine with, amongst others, an M. hyo vaccine.

28. Dr Nordgren’s experimental M. hyo and PCV-2 work included efforts aimed at addressing impediments the M. hyo formulation may present to combining it with a PCV-2 antigen. Strategies investigated by Dr Nordgren and his colleagues at Merial included attempting to source serum with a reduced likelihood of containing anti-PCV-2 antibodies, as well as attempting to clarify serum of anti-PCV-2 antibodies. The research work was done in an effort to develop a process that would eliminate to a substantial degree the antibodies from the serum to enable Merial to formulate a vaccine (the in-house Merial M. hyo research work). 

29. According to Dr Nordgren, the M. hyo experimental work was regarded by Merial as being highly confidential and a trade secret that Merial was concerned to ensure that its competitors did not find out. The confidential information obtained by Dr Nordgren as a result of the Merial M. hyo experimental work was not publicly disclosed. The confidential in-house knowledge gained by Dr Nordgren in the course of the Merial M. hyo experimental work did not form part of the common general knowledge of the person skilled in the art.

30. Boehringer submitted that it was “unsurprising” that Dr Nordgren did not expressly mention his prior work at Merial on combination vaccines, even after reviewing the Applications. According to Boehringer, the Applications concern the use of an M. hyo supernatant, whereas Dr Nordgren’s work at Merial involved its existing bacterin product and seeing if they could be improved with a goal to potentially combining them with PVC-2.

31. Boehringer also submitted that Dr Nordgren’s first affidavit “does impliedly” refer to his in-house M. hyo/PCV-2 research work. Boehringer explained that part of that work involved looking for PCV-2 antibody free serum, and that Dr Nordgren discussed his experience in trying to source PCV-2 antibody free serum in his affidavit, but was not taken to that in cross-examination.

32. However, in Dr Nordgren’s first affidavit, he stated that in April 2012 there was a need for bivalent M. hyo/PCV-2 and trivalent M. hyo/PCV-2/PRRS combination vaccines. There was no requirement or limitation that the M. hyo be in the form of a supernatant.

33. Dr Nordgren conceded that he did not refer to the in-house Merial M. hyo research work in any of his affidavits filed in the proceeding, including his third affidavit filed on the eve of the trial.

34. Dr Nordgren agreed that it would have been “highly relevant” and “important” to disclose this work to the Court. In particular, Dr Nordgren agreed that the fact he had engaged in the in-house Merial M. hyo research work was material to assessing the difference between his own knowledge and the knowledge of others in the field.

35. Dr Nordgren agreed in cross-examination that he took information from the confidential in-house Merial M. hyo research work into account in reaching the views he expressed in his affidavits in these proceedings.

    [Counsel]: And to the extent that you had held any view as at April 2012 about the potential preparations based on the supernatant of M. hyo vaccines, that view was based on matters including your particular knowledge regarding experimental vaccines. Correct?

    DR NORDGREN: That’s correct.

36. Zoetis submits that Dr Nordgren’s failure to disclose his involvement in the in-house Merial M. hyo research work, or the fact that he took this work into account when preparing his affidavits, presents insurmountable difficulties for the evaluation of Dr Nordgren’s evidence. According to Zoetis, it is impossible to determine which of the opinions expressed by Dr Nordgren in his affidavits and the joint expert session are based upon material which formed part of the common general knowledge of those skilled in the art, and those which are infected with the confidential in-house Merial information.

37. Zoetis contends that the effect of Dr Nordgren’s failure to disclose his involvement in the in-house Merial M. hyo research work is compounded by the absence of any instruction to Dr Nordgren in the course of preparing his affidavits to differentiate between his own particular knowledge (such as that obtained from confidential in-house research projects) and matters he considered to be generally well known and accepted by those skilled in the area.

38. Dr Nordgren was aware in April 2012 of studies demonstrating that specific enrichments of different culture fractions can improve the effectiveness of a vaccine response. He provided no details of the studies but observed that the exact compositions of commercially available M. hyo vaccines were most often kept confidential, as a trade secret.

39. Before the priority date, Dr Nordgren had collaborated with Professor Ross (the author of the Ross 1984 paper referred to in the Okada papers discussed below in the inventive step section) to research an experimental subunit vaccine against M. hyo using the 97kD antigen. The 97kD antigen research program was not pursued further as the 97kD antigen on its own did not produce sufficient protection. The collaborative work with Professor Ross was not published. Dr Nordgren agreed that he knew from the Ross paper and his teams’ own experiments that the combination of different antigens in supernatant based M. hyo vaccines were immunogenic and provided an adaptive immune response.

40. In addition, Dr Nordgren was involved, before the priority date, in the development of a first-in-class one-dose inactivated whole-cell (bacterin) vaccine against M. hyo that was commercially released around 1998, the first commercially available vaccine against PRRS virus, and the first PCV-2 vaccine to be released.

41. Before the priority date, Dr Nordgren worked with and tested experimental M. hyo vaccine preparations made from M. hyo cell culture supernatant fractions in the course of his work at Solvay and in the course of supervising the work of his team at Boehringer. In both cases, the project did not result in the launch of a commercial product and the information concerning those M. hyo supernatant was never made public.

42. I consider that the in-house work done by Dr Nordgren on a bivalent M. hyo/PCV-2 combination vaccine, the choices made by his research team and the reasons for those choices, and the success or failure of that work may well have had a role in the formation of the opinions which Dr Nordgren was being asked to give when addressing the development of a new or improved bivalent M. hyo/PCV-2 vaccine.

    Not representative of non-inventive person skilled in the art

43. During the concurrent session, Dr Nordgren agreed that he is “inventive” in relation to M. hyo/PCV-2 combinations, and that he “knew more than most” people who participate in project teams associated with vaccines.

44. Dr Nordgren is named as an inventor on a number of patents and patent applications. Several examples were tendered during the hearing. That Dr Nordgren is listed as an inventor on patents and patent applications is not apparent from his first affidavit (or subsequent affidavits) as he did not annexe a curriculum vitae (CV) listing the patents and patent applications on which he is listed as an inventor.

45. Boehringer submits that Dr Nordgren’s CV was omitted from his affidavits simply because the information in his CV was already summarised at paragraphs 6 to 20 of his first affidavit, and that no inference can be drawn from his failure to do so as the Expert Evidence Practice Note does not require an expert to annexe a CV. Whilst that may be correct, the inference is not sought to be drawn from the absence of a CV per se, rather from the absence of detailed information that would usually be found in a CV, such as inventorship on patents and published papers.

46. Being listed as an inventor on a patent itself is unsurprising in an expert witness in a patent case. However, it is relevant when assessing the evidence of an expert, for the purpose of determining by reference to the non-inventive person skilled in the art whether an invention as claimed involves an inventive step, to know whether the expert is listed as an inventor on one or multiple patents and patent applications. It will also be relevant if the invention claimed in the patent or patent application is in the same or a related field to the patent in suit.

1. Potency information in the Applications is given by reference to a reference vaccine for which no absolute measurements of the antigen content are given and does not assist with reproducing an IVP of similar potency. Potency information given as a percentage of an antigen lot is also unclear and does not assist with reproducing an IVP of similar potency.

2. L1211RK15 and L0912RK08 are two of the 10 pleaded IVPs upon which Boehringer focussed in submissions.

   (a)Serial L1211RK15, a bivalent (M. hyo and PCV-2) IVP, is the subject of Examples 12 and 13 of the 537 Application (and used as a reference vaccine in Table 14 of Example 12 of the 535 Application and 540 Applications and Table 25 of the 537 Application).

   (b)Serial L0912RK08, a bivalent (M. hyo and PCV-2) IVP, is the subject of Example 14 of the 540 Application (which also appears in Table 14 of the 535 and Table 25 of the 537 Application).

   Boehringer submits that these two IVPs are good candidates for reflecting the best method known to Zoetis at the time of filing, and that the M. hyo and PCV-2 antigen concentration or content were not disclosed for both IVPs in the Applications.

3. As at the filing date, Zoetis knew the concentration of antigens in its preferred M. hyo and PCV-2 reference and qualifying sample; L1211RK15 (certainly on Day 0). Thus, Boehringer submits that the relative potencies in the Applications were relative to a sample with known concentration, making the relative potency meaningful only to a skilled person with the knowledge of the concentration of the reference sample.

4. The Applications do not provide sufficient information to the skilled addressee to make a formulation with the potency of L1211RK15. The 537 Application describes L1211RK15 by way of a percentage of “antigen lot” (or antigen stock preparation) that was included in the overall IVP, but does not provide any information about the antigen content of the antigen lot that was used to make L1211RK15 (or L1211RK09). The relative potency of L1211RK15 is also given relative to itself, which does not assist. The information in the 537 Application is not sufficient to enable a skilled person to know the amount of M. hyo or PCV-2 antigens included in L1211RK15, and a skilled person would be unable to replicate that formulation.

5. Boehringer also submits that the 540 Application does not provide any information about the potency of L1211RK15. Further, no information about M. hyo potency is provided in the 535 Application for L1211RK15, and the limited information about PCV-2 potency in the 535 Application does not assist.

6. Similarly, none of the Applications provide sufficient information to the skilled addressee to make a formulation with the potency of L0912RK08: only the 540 Application mentions it, and the information provided is insufficient. For example, Table 14 of the 540 Application describes the potency of L0912RK08 relative to L1211RK15, however, as submitted, the 540 Application does not provide any information about the potency of L1211RK15.

7. Finally, Boehringer notes that none of the Applications describe a “qualifying serial” for the purposes of a monovalent M. hyo vaccine. This is no doubt because each of the Applications is directed towards a multivalent immunogenic composition comprising at least M. hyo and PCV-2 antigens, and in the case of the 540 Application, at least M. hyo, PCV-2 and PRRS virus antigens.

8. Boehringer then addressed a third pleaded IVP: L0712RK33, which was the subject of Example 15 of the 540 Application (which is not present in the 535 or 537 Applications). L0712RK33 is a bivalent (M. hyo and PCV-2) IVP used as the diluent for a hydrophilised PRRS vaccine. Boehringer submits that L0712RK33 is the IVP which has a relative potency that most closely resembles the target relative potency of Zoetis’ commercial product (which had been determined by the filing date). According to Boehringer, insufficient information is provided in the 540 Application for the skilled addressee to reproduce an IVP of the same or similar potency as L0712RK33. This is because the 540 Application provides no details regarding the reference vaccine against which the relative potency of the M. hyo or PCV-2 components of L0712RK33 was measured.

9. Boehringer submits that Zoetis’ documents indicate that the M. hyo and PCV-2 of L0712RK33 were set and tested relative to L1211RK15. However, that fact is not disclosed in the 540 Application: that is, L1211RK15 is not identified as the reference or comparator for the relative units used. Further, even if the 540 Application did disclose that the M. hyo and PCV-2 potencies of L0712RK33 were relative to L1211RK15, Boehringer submits that this would not have assisted the skilled person because the 540 Application does not provide any information about the potency of L1211RK15.

10. Boehringer observes that L0712RK33 is not disclosed at all in the 535 Application or the 537 Application, so those Applications also do not provide any information to the skilled addressee to reproduce a formulation with the potency of L0712RK33.

11. In a table annexed to its submissions, Boehringer gave details as to the remainder of its pleaded IVPs. L100211J was the sole M. hyo-only IVP. It is described in Table 4 of the 535 Application as having an M. hyo antigen content of 452 units (unspecified) per dose, and in Table 5 the target/observed relative potency is given as 13/12.1. No details of the reference vaccine used to calculate the relative potency is provided.

12. In response to Boehringer’s submissions as to the absence of any concentration information, particularly of the reference serial, Zoetis points to the ranges of concentration given in the specifications and says that those provide a sufficient disclosure of the absolute concentration for M. hyo p46 antigen and PCV-2 antigen in each Application. Zoetis submits that the absolute concentration range combined with the relative potencies provided in the examples is a disclosure of the best method of performing the invention known to the patent applicant.

13. Zoetis submits that the absolute concentration of p46 M. hyo antigen or PCV-2 antigen is not material having regard to the nature of the invention described and claimed in the Applications. Even if the absolute concentration was held to be material, Zoetis submits that Boehringer has not shown that Zoetis’ disclosure of the ranges of absolute concentrations is a deficient disclosure. Dr Nordgren was not asked to conduct a study similar to those reported in the Applications or to make a commercial product. Nor was he asked how he would go about using the ranges in the specification or the information about relative potency to make a composition for any particular purpose.

14. Zoetis observes that the “preferred” range of about 2 µg/mL to about 6 µg/mL aligns almost exactly with the range of values recorded in a document tendered by Zoetis, for L1211RK09 and L1211RK15. Zoetis observed that all the 10 pleaded IVPs fall within the preferred range.

15. Finally, Zoetis attacks Boehringer’s pleaded best method case, asserting that there was no challenge pleaded as to the combination of absolute M. hyo p46 and PCV-2 antigen levels in any particular IVP or otherwise.

    Nature of the invention in each Application

16. First, and most importantly, it is necessary to ascertain the nature of the invention, being the embodiment which is described by the specification as a whole and around which the claims are drawn (cf the invention so far as claimed in any claim): Sandvik at [94] (per Greenwood, Rares and Moshinsky JJ).

17. The invention in the 535 Application and around which the claims are drawn may be described as an improved immunogenic composition or vaccine to elicit a protective response in pigs against the disease caused by M. hyo, utilising an M. hyo soluble preparation which can also be used as a base or platform for a combination vaccine with at least one additional antigen protective against selected microorganisms (other than PCV-2, as there are no claims to an M. hyo/PCV-2 combination).

18. Whilst claims 1 to 6 are to an immunogenic composition, a close reading of the whole of the specification shows that the invention is concerned with eliciting a protective immune response to protect pigs from disease caused by M. hyo, (ie a vaccine) which is within the specification’s definition of an immunogenic composition. The later claims are to methods of eliciting a protective response, and immunising a pig utilising the immunogenic composition (ie vaccines). The title of the 535 Application is “Mycoplasma hyopneumoniae vaccine” and the field of the invention relates to a vaccine. The 535 Application states that what is needed is an improved vaccine, and that it would be highly desirable to provide a ready-to-use, single dose M. hyo/PCV-2 combination vaccine. The prior art discussed in the specification are vaccines.

19. The invention described in the 537 Application and around which the claims are drawn may be described as an improved vaccine to protect pigs against the diseases caused by M. hyo and PCV-2, utilising an M. hyo soluble preparation as a base or platform for a combination vaccine with PCV-2 antigen and potentially at least one additional antigen protective against selected microorganisms (other than PRRS, as there are no claims to an M. hyo/PCV-2/PRRS combination).

20. Again, whilst the early claims of the 537 are to a multivalent immunogenic composition, a close reading of the whole of the discussion in the specification shows that the invention is concerned with the protection of pigs from mycoplasmal pneumonia and Post-weaning Multisystemic Wasting Syndrome caused by the microorganisms M. hyo and PVC-2 respectively (ie a combination vaccine against M. hyo and PCV-2). The title “PCV/Mycoplasma hyopneumoniae combination vaccine” to the field of the invention, the background of the invention, the summary of the invention, the detailed description and the examples all support the invention being an improved vaccine to protect pigs against the diseases caused by M. hyo and PCV-2.

21. The benefits said to accrue to the 537 Application invention are the same as for the 535 Application. Although given that PCV-2 is ubiquitous, more so than PRRS, the removal of the serum derived antibodies, likely to be PCV-2 and potentially others, is more important in the M. hyo/PCV-2 combination vaccine.

22. The invention described in the 540 Application and around which the claims are drawn may be described as an improved trivalent vaccine to protect pigs against the diseases caused by M. hyo, PCV-2, and PRRS, utilising an M. hyo soluble preparation as a base or platform for the combination vaccine with PCV-2 and PRRS antigens.     

23. Again, whilst the early claims of the 540 Application are to a trivalent immunogenic composition, a close reading of the whole of the discussion in the specification shows that the invention is concerned with the protection of pigs from mycoplasmal pneumonia, Post-weaning Multisystemic Wasting Syndrome and PRRS virus caused by the microorganisms M. hyo, PVC-2 and PRRS respectively (ie a combination vaccine against M. hyo, PCV-2 and PRRS). The title “PCV/Mycoplasma hyopneumoniae/PRRS combination vaccine” to the field of the invention, the background of the invention, the summary of the invention, the detailed description and the examples all support the invention being an improved vaccine to protect pigs against the diseases caused by M. hyo, PCV-2 and PRRS.

24. The question is whether each of the Applications describe the best method known to Zoetis of performing each of the inventions at their time of filing.

    Consideration

25. Boehringer makes no best method challenge in relation to the invention claimed in claims 1 and 2 of the 535 Application: the M. hyo platform. Boehringer alleges that the 537 and 540 Applications do not disclose a best method of performing the invention claimed in each of the claims of those Applications.

26. An M. hyo/PCV-2 combination immunogenic composition which is suitable for use in a vaccine is central to the invention in both the 537 and 540 Applications. The Applications describe preferred forms of such a composition by setting out certain details in the examples of specific experimental vaccines or IVPs. The concentration or content of M. hyo and PCV-2 antigen in the IVPs is critical to their performance, and thus the performance of the invention.

27. As at the filing date of each of the Applications, the Zoetis team was using the bivalent (M. hyo/PCV-2) IVP, L1211RK15 as the reference sample against which the relative potency of other IVPs was being tested. L1211RK15 had been chosen following a minimum immunising dose clinical study in pigs. At that time, the Zoetis team knew the composition of L1211RK15, including the absolute concentration of the M. hyo and PCV-2 antigens in that IVP.

28. Zoetis chose to keep the absolute concentration of the M. hyo and PCV-2 antigens in L1211RK15 — the key to unlocking the IVPs in the examples — to itself, disclosing only the relativities of other IVPs to the reference sample in the Applications.

29. Rather than providing the key, the Applications instead refer to a broad range of the antigen concentrations, expressed as absolute concentrations (in µg antigen/ml), within which the concentration preferably lies. Dr Nordgren described the range as being so broad as to be meaningless.

30. The Applications either specify the potencies of the IVPs in the examples in relative units, without defining the relevant reference or comparator, or in certain cases, do not describe the preferred compositions at all. The examples describe particular IVPs and evaluate their performance by comparing them against each other. Various passages in the specifications indicate that some IVPs performed better than others, for example in terms of efficacy. There are also references to the need to “balance” the antigens, which the experts confirm as being important.

31. The three Applications claim to have developed an immunogenic composition that provides protective efficacy after a single dose. The experts understood single dose efficacy to be an important aspect of the invention. The potency of, and balance between, the antigens in such a composition is critical to its ability to meet that objective. Similarly, it is relevant that the Applications claim to have solved the problem of interference, including not only interference by serum-derived antibodies, but also antigen-antigen interference. Again, the potency of, and balance between, the antigens in such a composition is critical.

32. The Applications do not provide sufficient information to the skilled addressee to make a formulation with the potency of L1211RK15 (or any other of the IVPs). The 537 Application describes L1211RK15 by way of a percentage of “antigen lot” (or antigen stock preparation) that was included in the overall IVP, but does not provide any information about the antigen content of the antigen lot that was used to make L1211RK15 (or L1211RK09). The relative potency of L1211RK15 is also given relative to itself, which does not assist. The information in the 537 Application is not sufficient to enable a skilled person to know the amount of M. hyo or PCV-2 antigens included in L1211RK15, and a skilled person would be unable to replicate that formulation. The 540 Application does not provide any information about the potency of L1211RK15.

33. Even though the 535 Application does not claim an M. hyo/PCV-2 combination, it still uses L1211RK15 as the reference vaccine against which other IVPs are compared. See for example, Example 12.

34. Zoetis was not obliged to identify the best method as such in the Applications. I am prepared to assume that Zoetis considers that including IVPs in the examples in the Applications, in combination with the disclosed ranges, satisfy its obligation to include the best method known to it at the time of filing.

35. However, I consider that Zoetis has chosen to hide the best method in plain sight in each of the Applications. At first glance it appears that details, including concentration, are provided for the IVPs discussed in the examples. It is only when the skilled reader goes looking for the concentration information for the reference sample against which all the relative concentrations are given that it is apparent that information — the key to the relative concentrations — is not provided anywhere in the Applications.

36. Keeping the key to itself is contrary to the obligation of good faith which, as the authorities emphasise, is fundamental to the best method requirement.

37. Zoetis’ response, that the concentration ranges provided in the Applications are sufficient, is not an answer. The person skilled in the art seeking to make the invention at the expiry of the patents granted on the Applications would be forced to expend time and money embarking on a program of work to find the best starting point in that range – information that was known to the patentee when the Applications were filed, and information which it kept to itself.  

38. Zoetis’ focus on the precision of the pleadings and requiring Boehringer to nominate its IVP choice as the “best” as its answer to the best method challenge is at odds with the obligation of good faith. By doing so, the best method case became more akin to a game of battleship, wherein the challenger, not blessed with the patent applicant’s full knowledge of the in-house research and development work and context leading to the choice of the commercial product, is forced to nominate IVP’s as the “best method” known to the Patent Applicant. Ultimately, this was irrelevant as, whichever of the IVPs nominated, absolute concentration details were not provided for any of the antigens in them.

39. Zoetis’ demand that Boehringer define “best” was also not in keeping with its good faith requirement. When it filed the Applications, Zoetis knew the “key”, the absolute concentration of the reference IVP, and chose to keep it to itself.

40. I consider that Boehringer’s no absolute concentration best method challenge was adequately pleaded. There was no surprise to Zoetis in the case that was put in relation to the absence of any absolute concentration for the M. hyo and PCV-2 antigens. Boehringer made it abundantly clear in its opening and closing that its primary best method case was based on the absence of any absolute antigen concentration of M. hyo and/or PCV-2 antigens.

41. In GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No 2) Ltd v Generic Partners Pty Ltd (2018) 2131 IPR 384 at [106] (per Middleton, Nicholas and Burley JJ), the missing information as to the grade of HPMC was tailored to optimising the commercial process on the patent applicant’s manufacturing machinery/process. The concentration details (particularly of the reference IVP) are fundamental to the working of the invention, not the optimisation of the commercial product in the specific circumstances of the patent applicant’s own lab.

42. The disclosure of the best method known to the patentee tells the skilled worker, seeking to make the invention on the expiry of the patent, the methodology to achieve the form of the invention that obtains the result (including touted benefits) which constitutes the invention, and relieves them from having to confront the blind alleys and pitfalls (ie undertake the routine trial and experiments and animal studies otherwise involved in making the invention,) and already overcome by the patentee by the time the Application was filed.

43. By keeping to itself the concentration of M. hyo and PCV-2 antigens in its selected reference sample L1211RK15, Zoetis has denied the person skilled in the art the best method of performing the invention claimed in claims 3, 7–8 and 11 of the 535 Application, claims 1 to 24 of the 537 Application and claims 1 to 25 of the 540 Application.

    MANNER OF MANUFACTURE

44. Boehringer alleges that certain of claims of the Applications are claims to “mere collocations” of integers rather than a combination, and as such are not patentable subject matter pursuant to s 18(1) of the Act.

1. Both parties dealt with the ground of manner of manufacture only briefly in their oral and written submissions.

2. Where a claimed “combination” consists only of integers which do not interact with each other to produce a new result or product, it is not a manner of manufacture. Rather, it is a “mere collocation of separate parts”, each performing its own separate function, which is unpatentable; Firebelt at [21] (per Spender, Drummond and Mansfield JJ); Smith & Nephew Pty Ltd vWake Forest University Health Sciences (2002) 82 IPR 467 at [16] (per Finn, Bennett and Middleton JJ).

3. The actual claim under consideration in Wake Forest, claim 49, was as follows:

   An apparatus for applying negative pressure to a wound beneath a fluid-impermeable seal comprising:

   a screen means for positioning beneath said seal for preventing overgrowth of tissue in the wound, …;

   a flexible tube having an inlet and inserted into said open cell polymer foam section and an outlet end for extending from beneath said seal and for supplying said negative pressure; and

   wherein said apparatus is in an aseptic package.

   (Emphasis added.)

4. The aseptic package was held by the Full Court to not be a patentable combination.

5. The patentee in Wake Forest referred to Pugh v Riley Cycle Co Ltd (1914) 31 RPC 266 to submit that the only effect of including the additional integer, the aseptic packaging, was to limit the claim, without affecting the invention in the claimed combination.

6. The Full Court observed at [18] that the patentee did not support a construction of the claim as a limitation of the scope of the claim. Rather, the aseptic bag was contended by the patentee to be a feature of the apparatus in a kit form. As a matter of construction, the contention was that the aseptic package was an essential integer of the combination the subject of the claim, not an optional additional limitation on the scope of the monopoly.

7. The Full Court in Wake Forest observed at [33] that once the aseptic package is said to be an essential integer and part of the invention claimed, it must interact purposefully and functionally with the other integers to produce the negative wound pressure. The Full Court distinguished the case of Pugh on the basis that the aseptic package was not an optional extra merely assisting in the presentation of the apparatus, or limiting or adding to the claim.

8. The claim itself specified the one “desired effect” of the apparatus; to apply negative pressure to a wound. The Full Court contrasted claim 49 with claim 36 which talked in terms of an apparatus for facilitating the healing of wounds. The Full Court observed at [26] that the aseptic package may facilitate the healing of wounds, but it had nothing to do with the application of negative pressure, the function of the apparatus itself. Given that the aseptic package was discarded prior to use, it had no role in achieving the sole desired effect of negative wound pressure specified in the claim. The terms of the claim itself made it clear that the “in an aseptic package” integer was not part of the claimed “apparatus”.

9. The Full Court observed at [33] that the aseptic packaging may be said to have a purpose — to ensure sterility in treating the wound — but it lacked any desirable functional result in the way described by Dixon J in Palmer v Dunlop Perdriau Rubber Co Ltd (1937) 59 CLR 30 and Aickin J in Minnesota Mining: the essential interaction of the integers of the combination to produce a new result.

10. The invention claimed in each of claims 16 and 17 of the 535 Application, claims 21–23 of the 537 Application and claims 19–23 of the 540 Application includes as an integer a bottle (535 and 537 Applications) or bottles (540 Application) containing an immunogenic composition. Further, some of the claims (claim 17 of the 535 Application, claim 22 of the 537 Application and claims 22 and 23 of the 540 Application) also include an instruction manual “containing information to administer the immunogenic composition” with the claimed kit.

11. An example “kit” claim is claim 21 of the 537 Application:

    A kit for use in carrying out the method of claim 14 [a method of immunising a pig against M. hyo and PCV2] comprising: a bottle comprising an immunogenic composition including both a PCV2 antigen and the supernatant of [M. hyo] culture, wherein the supernatant of the M. hyo culture has been separated from insoluble cellular material by centrifugation, filtration, or precipitation and is substantially free of both (i) IgG and (ii) antigen/immunoglobulin immune complexes.

12. Claim 22 of the 537 Application is an example instruction manual claim:

    The kit of claim 21, further including an instruction manual which contains the information to administer the immunogenic composition.

13. Boehringer submits the “kit” claims of the Applications are mere collocations of separate parts and that, as such, none of these claims are directed to a manner of manufacture. Although the bottle may provide a functional purpose (containing the composition) it plays no part in achieving the immunogenicity of the composition. Boehringer submits that the bottle of the kit claims is analogous to the aseptic packaging in claim 49 in Wake Forest.

14. Zoetis submits that unlike the aseptic packaging claims in Wake Forest that played no part in achieving the desired effect, the relevant claims in this case are not to “immunogenic compositions”, rather they are directed to kits for use in a method of immunisation.

15. Zoetis contends that Boehringer’s assertion that the desired effect of the invention is the “immunogenicity of the composition” does not reflect a fair reading of the Applications, which disclose at least the following additional effects that are material to methods of immunisation and kits for use therein:

    (a)suitability for singe-dose administration;

    (b)an M. hyo vaccine compatible with other porcine antigens, such as PCV-2 and PRRS virus, whether they are given concurrently as separate single vaccines or combined in a ready-to-use vaccine;

    (c)the M. hyo soluble preparation as a “platform” for multivalent vaccines (without interference);

    (d)single dose, ready-to-use, one bottle administration for a combination M. hyo/PCV-2 vaccine, which requires no mixing of separate vaccines, so there is no risk of contamination or additional labour associated with mixing and no requirement to use the mixture within a few hours;

    (e)a one bottle combination vaccine, which cuts waste and refrigerated storage space in half, and eliminates the labour associated with administering a second dose to the animal; and

    (f)a single dose trivalent vaccine, where the M. hyo/PCV-2 component is provided as a ready-to-use in one bottle liquid composition which can be easily combined with the PRRS component in a second bottle or container such that all antigens can be administered to the pig simultaneously.    

16. According to Zoetis, those desired effects in relation to the vaccines are specifically contrasted in the specification (see, eg 535 Application, page 16, line 23 to page 17, line 2) with the prior art combination vaccines, such as Circumvent PCVM (a two-dose ready-to-use vaccine), or a single-dose, 2-bottle vaccine which requires the simultaneous administration of separate vaccines (eg Boehringer’s CircoFLEX and MycoFlex). The prior art M. hyo/PCV-2 combination vaccines are disadvantageous because they either require two dosing occasions, or one dosing occasion with two bottles.

17. Zoetis submits that the “single bottle” or “two bottles” integers of the combinations contribute to the achievement of one or more of these effects because they are the means by which a ready-to-use single composition, or a ready-to-use M. hyo/PCV-2 component, is provided to the user for carrying out the method of immunising a pig by administering the composition/s so provided (and in accordance with instructions, including as a single dose ready-to-use vaccine).

18. I consider that these asserted effects of the one-bottle kit inventions, which are described in the specifications, are akin to the benefits ascribed to the aseptic packaging. In Wake Forest, the aseptic packaging had a purpose: the specification stated that the apparatus was preferably packed in a sterile condition to avoid the need for sterilisation of the apparatus prior to use. That the aseptic packaging fulfilled its purpose and contributed to the achievement of the effect of sterile conditions was not sufficient for it to be found to interact purposefully and functionally with the other integers to produce negative wound pressure.

19. Zoetis further submitted that the storage of the antigens for a combination vaccine in separate bottles prior to administration limited assay interference as potency tests would be conducted on each of the separate bottles. This argument can only apply to the kit claims of the 540 Application, as it is the only Application with claims to a kit with two bottles.

20. Zoetis offered no separate argument in defence of the instruction manual claims.

21. Claim 16 of the 535 Application claims a kit for use in carrying out the method of claim 9. Claim 9 claims a method of immunising a pig against M. hyo via administering a composition of claim 1. The single bottle in this claimed invention has no role other than containing the solution prior to administration. There is no purposeful and functional interaction between the bottle and the immunogenic composition contents to immunise a pig against M. hyo.

22. Claim 21 of the 537 Application is also a claim to a single bottle including a combination vaccine, so there is no avoidance of assay interference via separate bottles for separate antigens in this case. There is no purposeful and functional interaction between the bottle and the immunogenic composition contents needed to immunise a pig against M. hyo and PCV-2.

23. Claims 19 and 20 of the 540 Application claim a kit comprising a first bottle, wherein the first bottle is provided as a ready-to-use liquid composition. Claim 22 makes express reference to the second bottle, wherein the PRRS virus antigen is in the form of a lyophilized composition. I accept that the two bottles may limit interference prior to administration of the trivalent vaccine, and thereby have a functional interaction with the other integers of the claimed invention.

24. The instruction manual claims add nothing but information. The instruction manual does not act purposefully or functionally with the other integers of the claims. The claims to the instruction manual are claims to a mere collocation.  

    CONCLUSION

25. For the reasons set out above, I consider that other than claim 2 of the 535 Application, all of the claims of the Applications are invalid.

I certify that the preceding seven hundred and seventy (770) numbered paragraphs are a true copy of the Reasons for Judgment of the Honourable Justice Rofe.

Associate:

Dated:       21 September 2023