SmithKline Beecham Biologicals (S.A.) v Novartis Vaccines and Diagnostics Inc - [2006] APO 37

ABSTRACTS OF DECISIONS

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Application : No.709406 in the name of SmithKline Beecham Biologicals (S.A.)

Title: Combined Vaccines Comprising Hepatitis B Surface Antigen and Other Antigens

Action: Opposition under s.59 of the Patents Act 1990 by Novartis Vaccines and Diagnostics Inc.

Decision: Issued 12 December 2006
Abstract

The specification is directed to a multivalent vaccine composition comprising hepatitis B surface antigen (HBsAg) and two or more other antigens selected from diphtheria (D), tetanus (T), pertussis (Pw), polio (P), Haemophilus influenzae b (Hib) and hepatitis A (HA). A multivalent vaccine has the advantage of providing immunisation against a number of pathogens through a single injection

The opposition was partially successful on the grounds of novelty and inventive step but was unsuccessful on all other grounds.

Claims 1 to 7, 12 to 14, 20 to 23 and 28 to 31 lack novelty in light of the Choi thesis. The citation discloses HBsAg-DTPw vaccine formulations adjuvanted with AP and use of these vaccines to prevent hepatitis B infection.

Claims 1 to 17, 20 to 25 and 27 to 34 lack an inventive step in light of EP168234 in combination with common general knowledge in the art. EP168234 discloses superior properties for AP as adjuvant in monovalent HBsAg vaccines in comparison to AH as adjuvant.

However, it was not established that the prior art or common general knowledge discloses or teaches toward vaccines in which HBsAg is adjuvanted with AP and other antigens with AH. As such there was no evidence to deprive claims 18, 19 and 26 of novelty or an inventive step.

Given that there is clearly patentable subject matter remaining in the application I give the applicant 60 days to provide amendments to resolve the lack of novelty for claims 1 to 7, 12 to 14, 20 to 23 and 28 to 31 and the lack of inventive step for claims 11 to 17, 20 to 25 and 27 to 34.

PATENTS ACT 1990

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Re:Patent Application No.709406 by SmithKline Beecham Biologicals (S.A.); opposition under s.59 of the Patents Act 1990, by Novartis Vaccines and Diagnostics Inc.

BACKGROUND

SmithKline Beecham Biologicals (S.A.) (the applicant) filed patent application 709406 (16480/97) on 4 March 1997. Following examination, 709406 was advertised as accepted on 26 August 1999.
Novartis Vaccines and Diagnostics Inc.(the opponent) opposed the application on 25 November 1999 and served its statement under regulation 5.4 of the Patent Regulations on 28 February 2000. Service of evidence in support was concluded on 2 October 2000. The applicant completed service of evidence in answer on 27 June 2001. Evidence in reply was completed on 29 October 2001.
On 1 March 2001, prior to completion of evidence in answer, the applicant filed a request to amend the specification under section 104. The opponent filed a notice of opposition to the amendments on 17 October 2002. The opposition was withdrawn on 13 February 2004 and the amendments allowed on 1 March 2004.
On 29 October 2001 the opponent filed a first request to amend the statement of grounds and particulars to add six extra documents. Service of this further evidence was completed on 6 November 2002. A second request to serve further evidence was filed on 24 February 2004. The applicant objected to service of this further evidence and the matter was heard on 12 May 2004. Leave to serve only part of the further evidence, a Korean Master’s thesis, was granted on 6 July 2004. The applicant’s response to the Korean thesis was served on 6 December 2004.
On 16 February 2005 the opponent filed a third request to serve further evidence together with that evidence. The evidence consisted of two statutory declarations addressing enablement of the Korean thesis. The applicant objected to the service of this further evidence and the matter was heard on 14 April 2005. Leave to serve both declarations was granted on 27 April 2005 and the applicant was given two months from the date of the decision to file a response to this evidence. The applicant’s evidence in response was served on 27 June 2005.
On 14 October 2005 the opponent filed a fourth request to serve further evidence, together with that evidence. The evidence consisted of a further declaration addressing enablement of the Korean thesis and a declaration providing details of various pending oppositions on foreign equivalents of 709406. The applicant objected to the service of this further evidence and the matter was heard on 10 December 2005. Leave to serve this further evidence was not granted.
On 6 December 2005 the opponent served a fifth request to file further evidence. The evidence consisted of a further declaration addressing enablement of the Korean thesis. The applicant formally objected to the fifth request to serve further evidence on 10 January 2006 and the matter was heard in Canberra on 10 February 2006. Leave to serve this further evidence was not granted.
The substantive hearing was held in Melbourne on 2 November 2006. The applicant was represented by Mr Bruce Caine of Counsel, assisted by Ms Helen Rofe of Counsel, Mr John Slattery of Davies Collison Cave and Dr Richard Easeman of Glaxo SmithKline. The opponent was represented by Mr Ben Fitzpatrick of Counsel, assisted by Dr Ian Rourke and Mr Tony Davis of FB Rice & Co. and Mr Cameron Marshall of Carpmaels and Ransford of London.

EVIDENCE

The opponent filed the following evidence as evidence in support, evidence in reply and as part of various rounds of further evidence.

Evidence in support

·    Statutory Declaration of Ian Jeffrey Rourke, patent attorney of FB Rice & Co., made 29 May 2000, with exhibits IJR-1 to 28 (Rourke#1);
·    Statutory Declaration of Ngaire Ann Pettit-Young, senior librarian at the University of New South Wales Library, made 18 May 2000;
·    Statutory Declaration of John Cooper Cox, Consultant Scientist and previously Principal Scientist with CSL made 28 August 2000, with exhibits JCC-1 to 2 (Cox#1);
·    Statutory Declaration of Ian Jeffrey Rourke made 28 September 2000 (Rourke#2);
·    Statutory Declaration of Yvonne Cossart, Bosch Professor of Infectious Disease, University of Sydney, made 28 September 2000, with exhibits YC-1 to 3.

Evidence in reply and further evidence (1)

· Statutory Declaration of John Cooper Cox made 29 October 2001, with exhibits JCC-3 to 10 (Cox#2).

Further evidence (2)

·    Statutory Declaration of Ian Jeffrey Rourke made 24 February 2004, with exhibit IJR 29 (Rourke#3);
·    Statutory Declaration of Ian Jeffrey Rourke made 7 May 2004, with exhibit IJR-30 (Rourke#4);
·    Statutory Declaration of Ian Jeffrey Rourke made 15 June 2004, with exhibit IJR-32 (Rourke#5);
·    Statutory Declaration of John Cooper Cox made 5 May 2004, with exhibits JCC-11 and 12 (Cox#3);
·    Statutory Declaration of John Cooper Cox made 15 June 2004, with exhibit JCC-13 (Cox#4).

Further evidence (3)

· Statutory Declaration of Jean Petre, consultant for vaccines and biologicals, previously scientist with Chiron Vaccines and SmithKline Beecham, made 2 February 2005, with exhibits JP-1 to 3;
· Statutory Declaration of Mario Contorni, scient in the Drug Formulation Technical Development group at Chiron Vaccines, made 7 February 2005, with exhibits MC-1 to 3.

The applicant filed the following evidence in answer and in response to the further particulars and evidence.

Evidence in answer

·    Statutory Declaration of Martin Friede, Director of Rigil Kent Ltd, a pharmaceutical company and previously Senior Scientist at SmithKlineBeecham Biologicals S.A., made 4 April 2001, with exhibit MF-1 (Friede#1);
·    Statutory Declaration of Peter Dodd Cooper, consultant in vaccine technology to AnuTech Pty Ltd, made 26 June 2001, with exhibits PDC-1 to 4 (Cooper#1);
·    Statutory Declaration of Martin Friede made 21 August 2001 (Friede#2).

Evidence in response to further particulars

·    Statutory Declaration of David Finlay Herd, Head of Regulatory Affairs of GlaxoSmithKline Australia, made 30 August 2002, with exhibits DH-1 and;
·    Statutory Declaration of Peter Dodd Cooper made 2 September 2002, with exhibit PDC-5 (Cooper#2);
·    Statutory Declaration of John Michael Slattery made 30 August 2002, with exhibit JMS-A (Slattery#1);
·    Statutory Declaration of John Michael Slattery made 30 August 2002, with exhibits JMS-B and C (Slattery#2)
·    Statutory Declaration of Terence Michael Nolan, Professor and Head, School of Population Health and Department of Public Health, University of Melbourne, made 1 November 2002, with exhibits TN-1 to 5.

Evidence in response to further evidence (2)

· Statutory Declaration of Nathalie Garçon, Research Director with GlaxoSmithKline S.A, made 3 December 2004, with annexures I-IV (Garçon#1).

Evidence in response to further evidence (3)

· Statutory Declaration of Nathalie Garçon made 23 June 2005 (Garçon#2).

SPECIFICATION

The specification is directed to a multivalent vaccine composition comprising hepatitis B surface antigen (HBsAg) and two or more other antigens selected from diphtheria (D), tetanus (T), pertussis (Pw), polio (P), Haemophilus influenzae b (Hib) and hepatitis A (HA). A multivalent vaccine has the advantage of providing immunisation against a number of pathogens through a single injection.
The specification explains that past attempts to produce a multivalent hepatitis B vaccine have encountered problems with stability and immunogenicity of HBsAg when in a multivalent format. The applicant has overcome this problem by adsorbing the hepatitis B antigen to aluminium phosphate (AP) and the other antigens to AP or aluminium hydroxide (AH). This format maintains immunogenicity and stability similar to that seen for monovalent HBsAg, and greater than that seen for previous attempts to formulate a multivalent HBsAg using AH.
The specification contains 5 examples describing formulation of vaccines containing HBsAg adsorbed to AP, and DT and DTPw adsorbed to AH. The examples include the results of comparative vaccination trials in which the immunogenicity and stability of HBsAg monovalent, divalent and multivalent vaccine formulations are compared. The results demonstrate strong immunogenicity and stability for the AP adsorbed multivalent HBsAg in contrast to a multivalent vaccine where HBsAg is adsorbed to AH.

THE CLAIMS

The specification ends with 34 claims, with the following 2 independent claims.
1. "A vaccine composition comprising a hepatitis B surface antigen (HBsAg) adsorbed to aluminium phosphate (AP) and two or more other antigens adsorbed to aluminium hydroxide (AH) or AP and selected from diptheria (D), tetanus (T), pertussis (Pw), polio, Haemophilus influenzae b, and hepatitis A."
28. "Use of aluminium phosphate (AP) as an adjuvant for adsorbing HBsAg, characterised in that the use is for the purpose of formulating a stable and effective combined vaccine comprising a HBsAg component adsorbed to aluminium phosphate and two or more other antigens adsorbed on aluminium hydroxide or aluminium phosphate and selected from antigens that provide immunity against diptheria, tetanus, pertussis, polio, Haemophilus influenzae b, and hepatitis A, whereby the stability and/or immunogenicity of the HBsAg component is greater than in a corresponding combined vaccine in which the HBsAg component is adsorbed on AH."
The remaining claims 1-7, 8 to 27 and 29 to 34 recite various antigens, specific vaccine formulations, levels of stability and immunogenicity and methods of preparation and use.

NOVELTY

At the hearing the opponent chose to restrict their submissions to two citations:
- A Korean Masters Thesis entitled “Studies on the Interaction of Hepatitis B Vaccine and other Vaccines, publicly available since July 1998 (Choi); and
- Korean Patent Application No. 90-13356 (Korean Green Cross Ltd), published 27 March 1992 (KR 90-13356).
I too have restricted my consideration to these two citations as none of the other documents listed in the statement of grounds and particulars clearly disclose a multivalent HBsAg vaccine in which the HBsAg has been adsorbed to AP as adjuvant.

The law of novelty

The basic test for novelty is the “reverse infringement” test as stated in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd, (1972) RPC 457 at pages 485, 486.:
“If carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim”.
In applying this test regard must be given to the level of disclosure in the prior publication. As stated in Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR at 517:
“It is well accepted that the prior art must disclose all features of the invention embodied in the patent in suit and must do so in clear, unequivocal and unmistakeable terms. The prior art must enable the notionally skilled addressee at once to perceive and understand and be able practically to apply the discovery without the necessity of making further experiments. Whatever is essential to the invention must be read out of or gleaned from the prior publication.”
In Nicaro Holdings, Gummow J also referred to the speech of Lord Reid in C. Van Der Lely N.V. v Bamfords Limited (1963) RPC 61 and 71-72 where Lord Reid reaffirmed the principle set down by Lord Westbury in Hills v Evans [1862] 4 De G, F & J 288; 45 ER 1195 in relation to the level of disclosure necessary to anticipate a claimed invention:
"a person of ordinary knowledge of the subject would at once perceive and understand and be able practically to apply the discovery without the necessity of making further experiments".
Accordingly the alleged anticipation must not only disclose all of the integers of the claim it must also provide sufficient detail to enable the skilled addressee to combine those integers to produce the invention without the need for further experimentation.

The Korean Master’s thesis (Choi)

Choi relates to preparing multivalent HBsAg vaccines suitable for vaccination of children in developing countries. The “materials and methods” discloses preparation of HBsAg, diphtheria, whole cell pertussis, tetanus, measles, mumps, rubella and Japanese encephalitis virus (JE) antigens; adsorption of these antigens to AP and preparation and administration of vaccine formulations comprising various combination of these antigens. The “results and discussion” then discloses anti-HBsAg antibody titres and viral challenge in guinea pigs and mice immunised with monovalent HBsAg, multivalent HBsAg-DTPw, multivalent MMR and divalent HBsAg-JE vaccines. These results confirm strong antibody titres to HBsAg and good immunity against hepatitis B infection.
Choi prima facie deprives many of the claims of novelty. It discloses the preparation and testing of an effective multivalent HBsAg vaccine formulated with AP as adjuvant, thereby disclosing the features of vaccines and methods as claimed.
However, the applicant argued that the skilled addressee could not produce an effective vaccine by following the Choi protocol and that thus Choi was not enabling.
The applicant based their arguments on work done by their expert witness Dr Nathalie Garçon. Dr Garçon attempted to repeat the experiments described in Choi, however she could only produce a cloudy aggregated formulation with limited immunogenicity in vaccinated guinea pigs. From this she concluded:
“Thus, in my view, it is not possible to follow the teaching in the Choi thesis to make vaccine composition contain HBsAg adsorbed to AP in combination with DTPw”.
However the Garçon experiments differed from the Choi experiments in that Dr Garçon did not use the same source of pertussis, diptheria or tetanus antigens as Choi.
The opponent argued that these differences are likely to have a substantial impact on success or failure of the vaccine. In support of this, another expert witness Dr Petre described his experience with “jellyfish” aggregates produced when using particular pertussis preparations. Problems with particular DTPw preparations in multivalent vaccines are also disclosed in the WHO publication (JMS-A) and by the applicant’s expert Dr Nolan (see para 9). Both documents describe circumstances in which certain DTPw preparations have produced aggregates. Thus I am satisfied that the opponent has established that different antigen sources may have an impact on vaccine formulation.
The applicant did not provide any counter evidence to explain why Dr Garçon’s sources of antigen would not affect vaccine stability, nor did they suggest that the specific antigens used by Choi would be unavailable to the skilled addressee. As such the applicant has not provided any substantial evidence to support their claim that the Choi methodology cannot be followed, or does not enable preparation of a stable and effective multivalent HBsAg vaccine.
Given this I am satisfied that Choi deprives the following claims of novelty:
·    Claims 1 to 7. These claims recite multivalent vaccines comprising at least 3 antigens, and more specifically comprising diphtheria, pertussis and tetanus antigens. Choi discloses an HBsAg-DTPw vaccine.
·    Claim 12. This claim recites stability on storage at 37⁰C for one week. Both the disclosure in the specification and expert evidence suggest that using AP as adjuvant confers this level of stability on HBsAg in a multivalent vaccine. As such it is to be expected that the Choi vaccine inherently provides this level of stability.
·    Claims 13 and 14. These claims recite immunogenicity sufficient to produce a geometric mean titre of at least 200 mIU/ml, and more specifically greater than 300 mIU/ml. Table 6 of Choi discloses a geometric mean titre for the HBsAg-DTPw vaccine of 375 mIU/ml.
·    Claim 20. This claim recites vaccines where at least one antigen other than HBsAg is adsorbed to AP. All antigens in the Choi vaccine are adsorbed to AP.
·    Claims 21to 23. These claims recite vaccines suitable for use in medicine, methods of using vaccines to prevent hepatitis B and methods of preparing vaccines for the prophylaxis of hepatitis B. The abstract and introduction in Choi explain that experiments in Choi are directed at producing vaccines for vaccination of children in developing countries.
·    Claims 28 to 31. These claims recite a method of using AP as an adjuvant for adsorbing HBsAg in multivalent vaccines, and more particularly a method where the resultant vaccine has stability at 37⁰C for one week and immunogenicity sufficient to produce a mean geometric titre of greater than 200 mIU/ml. Choi discloses the use of AP as adjuvant, a titre of 375 and as discussed above a vaccine that is more likely than not to inherently provide the claimed stability.
Choi does not disclose antigens other than D, T and Pw or the specific dosages and methods recited in claims 8 to 11, 15 to 17, 24 to 26, 27 and 32 to 34. As such Choi does not deprive these claims of novelty.
In particular Choi does not disclose or suggest using both AP and AH as adjuvant, with AP as adjuvant for HBsAg and AH as adjuvant for the remaining antigens. As such Choi does not disclose the vaccine or methods exemplified in the specification and claimed in claims 18, 19 and 26.
In summary, I am satisfied that Choi deprives claims 1 to 7, 12 to 14, 20 to 23 and 28 to 31 of novelty. However, Choi does not deprive the remaining claims of novelty.

Korean Patent Application KR 90-13356

The opponent submitted that KR 90-13356 teaches preparation of a multivalent HBsAg vaccine in which HBsAg is adsorbed to AP. KR 90-13356 relates to the preparation of multivalent HBsAg-DTPw vaccines. It discloses preparation of HBsAg, D, P and T antigens, absorption of antigen to adjuvant and vaccine formulation.
However KR 90-13356 only teaches aluminium as adjuvant for D and T. When disclosing HBsAg KR 90-13356 teaches that there are problems with adsorption of HBsAg to aluminium adjuvants and that better immunogenicity is obtained when HBsAg is adsorbed to pertussis.

Given this I do not believe that the opponent has established that there are clear and unmistakeable directions to adsorb HBsAg to AP. As a consequence, I do not believe that KR 90-13356 deprives the claims of novelty.

INVENTIVE STEP

Although the statement of grounds and particulars contained an extensive list of documents, the opponent confined their submissions at the hearing to common general knowledge alone and common general knowledge in combination with each of only five documents: EP168234; Hinman et al (1988) in Vaccines, pages 587-661; the CSL Medical Handbook (1979); EP339667; and a 1992 WHO report.
I too will confine my discussion to these areas, and to Choi and KR 90-13356, the two documents discussed under novelty. These documents represent the closest prior art.

The law of inventive step

The High Court in Aktiebolaget Hassle v Alphapharm Pty Limited [2002] HCA 59 at 53 affirmed the test set out by Graham J in Olin Mathieson v Biorex [1970] RPC 157 at page 187:
“Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of the relevant prior art [.......] directly be led as a matter of course to try [a particular thing] in the expectation that it might well produce a useful result?”
The Court in Alphapharm also noted with approval the test set out in Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd (1979-80) 144 CLR 253, at page:
“In the case of a combination patent the invention will lie in the selection of integers, a process which will necessarily involve rejection of other possible integers. The prior existence of publications revealing those integers, as separate items, and other possible integers does not itself make an alleged invention obvious. It is the selection of integers out of, perhaps many possibilities, which must be shown to be obvious.”
Accordingly there must be a motivation for the skilled person to apply what is disclosed in a relevant prior art document or what is common knowledge in the art in such a way as to achieve the claimed invention.
In the current circumstances there must be motivation for a worker in the field of human vaccine development to try AP as adjuvant when seeking to develop a stable and effective combined vaccine against hepatitis B and other common childhood diseases such as diphtheria, tetanus and whooping cough.

Common general knowledge alone

The crux of the opponent’s argument was that, at the priority date, it would have been obvious for the skilled person to combine or test pre-existing vaccine combinations to produce a multivalent HBsAg vaccine. The opponent submitted that a multivalent HBsAg was widely acknowledged as a desirable goal and one that was likely to be achieved through combining pre-existing antigen-AP combinations.
I am satisfied that, in the case of HBsAg, a multivalent HBsAg was a well known and desirable goal. Both parties’ experts agreed on this. Their assertions were supported by a number of the documents, including a 1992 WHO publication (‘WHO’ JMS-A), described by both parties’ experts as indicative of the state of the art at the priority date of the application. WHO discusses the benefits of a multivalent HBsAg vaccine and suggests testing combinations of pre-existing monovalent HBsAg vaccines and other vaccines, such as polyvalent DTPw vaccines, to develop a multivalent HBsAg vaccine. It explains that a multivalent vaccine would reduce the cost and effort currently involved in vaccinating against common childhood diseases such as hepatitis A, diphtheria, whooping cough and tetanus.
I am also satisfied that each of the antigens was well known in Australia at the priority date. Both parties’ experts agree that the skilled person would have been well aware of adjuvanted HBsAg, D, P and T antigens, particularly in the context of monovalent HBsAg vaccines and bivalent and trivalent D, P and T vaccines commercially available in Australia at the priority date. The applicant pointed to two HBsAg vaccines sold in Australia at the priority date, both of which were adjuvanted with AH, and the opponent identified various D, P and T sold by CSL and adjuvanted with AP.
The opponent also made the point that AP and AH were the only two adjuvants routinely used for human vaccines at the priority date. As such the skilled person was only required to make a choice between AP and AH as adjuvants.
I am also satisfied that a preferred approach to multivalent vaccine formulation was to use pre-existing successful antigen-adjuvant combinations as the building blocks for a multivalent vaccine. This is an important point because it means that the skilled person would give preference to pre-existing adjuvant-antigen combinations, such as the commercially available HBsAg and DTPw vaccines discussed above, as the starting point for a multivalent HBsAg vaccine.
This preference arises in part as a consequence of difficulties in predicting which adjuvant will be best for any specific antigen. Adsorption of antigen to adjuvant is facilitated by opposing surface charge on antigen and adjuvant. In the absence of knowledge of the surface charge of an antigen, which will be the case for complex antigens such as HBsAg, D, P and T, a range of adjuvant-antigen combinations must be tested. This introduces extra costs and delays in the vaccine formulation process.
The combination approach is also supported by the WHO publication, which promotes testing combinations of pre-existing vaccine formulations as a means of identifying an effective multivalent vaccine.
The WHO publication cautions against mixing untested pre-existing vaccines immediately prior to vaccination and teaches conducting preliminary experiments to test different combinations to identify compatible DTPw and HB combinations and optimise performance parameters.
The document states:
“Since both the inactivation and absorption procedures used for the production of DPT and HB vaccines are similar and because there are no other basic incompatibilities between DPT and HB vaccines that would prevent their being combined into a quadrivalent product which would be safe, effective, and stable, the commercial development of DTP-HB should be entirely possible. However because of the differences in composition of DTPs from different manufacturers, it is to be anticipated that not all DPTs will be easily combinable with HB vaccine and that optimization of the performance parameters of specific quadrivalent products will be the result of continuing trial and error at the product research level.”
It is also important to note that it is standard to use the same adjuvant for all adjuvanted antigens in a vaccine formulation. For example, if starting with AP, it would be preferable to adsorb all antigens with AP.
These factors taken together paint a picture of an art where a multivalent HBsAg was a desired goal and the skilled person would be motivated to work toward this goal by testing combinations of pre-existing antigens adjuvanted with AP or AH.
The opponent argued that, against this backdrop, there was no invention in simply choosing to focus on AP as one of two equally preferred adjuvants. In support of equal preference for AP and AH the opponent referred to the WHO publication and Hinman et al (IJR-19), each of which discloses both AP and AH as adjuvants for antigens to be used in a multivalent HBsAg vaccine, and neither of which discloses a preference for one adjuvant over the other.
However the applicant did not agree with this assessment. Both Friede and Cooper asserted that, at the priority date there was a perception in the art that AH enhanced the immune response to a greater extent than AP (Friede II at para 10 and Cooper II, para 7). AH’s superiority as an adjuvant is also suggested in a 1992 review article authored by the opponent’s expert Cox (IJR-21). In this article Cox states that AH has been observed to be twice as active at adsorbing antigens as AP at pH 6 and that the “continued use of AlPO₄ is also perplexing”.
Friede and Cooper also explained that AH had advantages because it could be obtained as a preformed gel “Alhydrogel^tm”. Use of a preformed gel simplified the adsorption process and use of a quality controlled commercial product with consistent particle size and adsorptive properties ensured consistency between batches of adsorbed antigen. In contrast AP was not available as a preformed gel and had to be prepared each time by back titration of soluble aluminium salt. As a consequence aluminium phosphate precipitates often exhibited variable particle size and adsorptive properties.
Although this perception would change if it was common general knowledge that there were problems with adsorbing AH to any of the specific antigens used in the multivalent HBsAg vaccine, or that AP was a better adjuvant than AH for the selection of antigens to be used in the vaccine, I have no such evidence.
Thus I am left with the evidence of Friede and Cooper and with the Cox review article (IJR-21) which support a preference for AH, and nothing from the opponent to refute or counter this. Given this the opponent has failed to establish that the claimed invention lacks an inventive step in light of common general knowledge in the art alone.

EP168234

The opponent submitted that EP168234 deprived the claims of an inventive step because the citation would motivate the skilled person to use AP adjuvanted HBsAg when exploring formulation of a multivalent HBsAg vaccine.
For this to be the case it must first be established that EP168234 could, before the priority date of the application be reasonably expected to have been ascertained, understood and regarded as relevant.
EP168234 is a patent document published in 1986. It relates to the purification of HBsAg and preparation of monovalent HBsAg vaccines. In particular it discloses testing of HBsAg vaccines adjuvanted with AP and AH and demonstrates that AP adjuvanted HBsAg has superior potency to AH adjuvanted HBsAg in vaccination studies with mice.
I am satisfied that the skilled person would regard the document as relevant. As explained by the opponent’s experts and borne out by the WHO document, combining or building on pre-existing vaccines was a preferred route to multivalent vaccines at the priority date. Thus the skilled person seeking to develop a multivalent HBsAg vaccine would appreciate the relevance and value of a document disclosing successful formulation of a core component of the desired vaccine.
I am also satisfied that, as a relevant patent document EP168234 would have been ascertained by the skilled person. The field of vaccine development is a highly technical and commercially competitive field where practitioners routinely consult scientific and technical documents relevant to the art. The opponent’s expert Cox states in his first and second declarations that scientists in the art would regularly review patent literature and that he personally had found patent literature to be a valuable source of information.
Thus I believe that EP168234 could have been ascertained, understood and regarded as relevant by the skilled person at the priority date of the application.
The teaching in EP168234 would also overcome any bias against AP as adjuvant for HBsAg. Page 12 of the citation explicitly describes AP as a superior adjuvant for HBsAg.
“It has been found that the aluminium phosphate adjuvant vaccine has superior antigenic properties compared to those of the aluminium hydroxide adjuvant vaccine and that both of these have superior properties to that of a commercial serum-based vaccine, Heptavax B, based on intraperitoneal injection of mice.”
This assertion is then backed up in table 1, where relative potencies of 3.8, 1.6 and 1.0 are disclosed for AP, AH and Heptavax respectively. Thus, EP168234 would motivate the skilled person to select AP adjuvanted HBsAg for testing with pre-existing DTPw formulations such as those sold by CSL at the priority date, or as the basis for addition of further antigens such as various combinations of D, T, P, hepatitis A and other antigens of childhood diseases.
Given this I am satisfied that the claims 1 to 7,12 to 14, 20 to 25 and 28 to 31 lack an inventive step in light of EP168234 in combination with common general knowledge in the art. Claims 1 to 7, 12 to 14 and 20 to 23 include within their scope stable effective DTPw-HBsAg-AP vaccines and methods of using these vaccines to prevent hepatitis B. Claim 24 and 25 include within their scope a method of preparing a vaccine by combining, testing and optimising pre-existing DTPw-AP and HBsAg-AP vaccines. Claims 28 to 31 include within their scope a method of using AP as an adjuvant to prepare a DTPw-HBsAg-AP vaccine.
I am also satisfied that the citation also deprives claims 8 to 11, 15, 27 and 32 to 34 of an inventive step. These claims recite additional antigens such as Meninigicoccal, Haemophilus, Hepatitis A and polio antigens, and acellular pertussis. However, citations such as the Hinman et al (1988) disclose incorporation of additional antigens such as these in combination vaccines. As such I am satisfied that incorporation of these antigens in multivalent vaccines was also a well understood goal in the art at the priority date of the application.
I am also satisfied that the specific embodiments disclosed in claims 16 and 17 lack an inventive step. The claims define specific amounts of each antigen in a single vaccine dose. However, these amounts fall within the amounts used in commercial vaccines such as those described in the CSL handbook and in Hinman et al. They are also consistent with amounts determined through the routine testing that is described by both parties’ experts as standard practice in the art. This is supported by the opponent’s expert Cox who described the specific embodiments as “mere design choices which could readily by (sic) derived from routine experiments”. Given this, I believe that claims 16 and 17 also lack an inventive step.
However, the opponent has failed to show that claims 18, 19 and 26, which define adjuvanting HBsAg with AP and other antigens with AH, lack an inventive step. To the contrary, the opponent’s experts suggest that there was a preference for using the same adjuvant for all antigens and there was a bias against combining different adjuvants in the same vaccine. Given this, I have no evidence that claims 18, 19 and 26 lack an inventive step.
In summary, I am satisfied that claims 1 to 17, 20 to 25 and 27 to 34 lack an inventive step in light of EP168234 in combination with common general knowledge in the art.

EP339667

The opponent submitted that EP339677, in combination with common general knowledge in the art would motivate the skilled person to try AP as an adjuvant for HBsAg when formulating a multivalent HBsAg vaccine. However, for this to be the case EP339677 must provide a formulation that the skilled person would regard as suitable for a combination vaccine and overcome any bias in the art to use AH in favour of AP.
EP339677 is a European patent application published on 2 November 1989. The application teaches combining HBsAg, hepatitis A and an aluminium adjuvant to prepare a divalent vaccine. This approach overcomes previous problems with reduced immunogenicity when pre-existing monovalent vaccines are combined. As such the citation teaches a process suitable for the preparation of at least divalent hepatitis vaccines.
In their submissions the opponent also asserted that the citation taught that AH and AP were equally suitable as antigens. At page 3 the citation states:
“The adjuvant which can be used in the present invention is not critical. It must only be capable of enhancing the immune activity to a desired extent and may not cause any side effects. Aluminium gel can be suitably used in the present invention as adjuvant, in particular aluminium hydroxide gel and aluminium phosphate gel.”
However, all of the examples in the citation use AH as adjuvant rather than AP. When this information is viewed in the context of applicant’s experts’ assertions that there was a preference for AH over AP in Australia at the priority date, the citation teaches to maintain that preference for AH as adjuvant. As such, I am not satisfied that the citation provides motivation for the skilled person to use both AP and AH, or use AP in preference to AH, when formulating a mulitivalent HBsAg vaccine. Thus I do not believe that the citation deprives the claims of an inventive step.

Hinman et al (1988) in Vaccines, pages 587-661, the CSL Medical Handbook (1979), 1992 WHO report

As discussed under common general knowledge, at the priority date there was a preference for AH. The WHO report does not provide any motivation to set aside this preference, or to try both AP and AH with an equal expectation of success. As such I do not believe that the WHO report deprives the claims of inventive step.
Similarly Hinman et al does not teach of any advantages for AP over AH. Hinman et al provides a general description of various vaccines used for child immunisation, including DTPw and HBsAg vaccines. It also discusses the advantages of combination vaccines. However it does not reveal a preference for AP as adjuvant. As such I do not believe that Hinman et al overcomes the bias against AP or deprives the claims of an inventive step.
The CSL Handbook also does not teach of the advantages of AP over AH, particularly in the context of multivalent HBsAg vaccines. The handbook pages disclose that aluminium phosphate and aluminium hydroxide may be used as adjuvants and provides the details of 7 CSL vaccines containing combinations of D, P and T, 4 of which are adjuvanted with AP. However, there is no comparison of AP and AH, or suggestion that AP may be more suitable as an adjuvant for a HBsAg vaccine. Thus, I am not satisfied that the handbook provides information that would overcome the bias against AP. As a consequence I do not believe that the CSL handbook deprives the claims of an inventive step.

Choi

Choi is a Master’s thesis written in the Korean language and obtained from a Korean university. It first appeared in the opposition proceeding some time after completion of evidence in answer and it appears that it was only located as part of opposition proceedings in Korea or Europe.
The applicant provided brief submissions on Choi in which they asserted that the skilled person could not be reasonably expected to have ascertained Choi before the priority date of the opposed application. On the basis of this and the lack of any contrary evidence from the opponent I am not satisfied that Choi falls within the definition of a prior art document for the purposes of inventive step.

KR 90-13356

As discussed under novelty, KR 90 13356 teaches of problems when absorbing HBsAg with AP. The solution to this problem is to adsorb HBsAg to pertussis toxin and then combine the pertussis adsorbed HBsAg with AP adsorbed DTPw. As such the citation teaches away from the solution claimed by the applicant. Thus I do not believe that KR 90-13356 deprives the claims of an inventive step.

MANNER OF MANUFACTURE

The law of manner of manufacture

In Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232, at 249, the Court stated:
“Many valid patents are for new uses of old things. But it is not an inventive idea for which a monopoly can be claimed to take a substance which is known and used for making various articles, and make out if it an article for which its known properties make it suitable, although it has not in fact been used to make that article before.”
It was also stated in British Celanese Ltd v Courtaulds Ltd 52 RPC 171, at pages 193-194:
“It is accepted as sound law that a mere placing side by side of old integers so that each performs its own proper function independently of any of the others is not a patentable combination, but that where the old integers when placed together have some working inter-relation producing a new or improved result then there is patentable subject-matter in the idea of the working inter-relation brought about by the collocation of the integers.”

Accordingly, where there is a combination of known integers the integers must influence each other, or work together in some new way to move beyond being a mere collocation of integers.
The opponent asserted that the vaccine was nothing more than use of a combination of known adjuvanted antigens in a way that took advantage of the known properties of each antigen. However this ignores the known problems with HBsAg in multivalent vaccines. As stated in the specification at page 1A and in the WHO publication, HBsAg was known to have reduced immunogenicity when combined with other antigens. Thus the known properties of HBsAg in a multivalent vaccine were a reduced immunogenicity. The applicant’s invention overcomes this problem by improving the immunogenicity of HBsAg in this environment, thereby producing a new and improved result. Although the prior art may have suggested that this problem might be overcome through routine trial and error, this is a matter for inventive step rather than manner of manufacture.
Given this, I am satisfied that the claimed invention meets the requirements of manner of manufacture.

SECTION 40

The opponent made submissions on each of the following grounds: lack of clarity, lack of fair basis and lack of full description. Although each of these is a separate and distinct ground, much of the opponent’s argument on each ground focused on the brevity of description in the specification. Particularly the lack of exemplification of anything more than HBsAg adjuvanted with AP and the remaining antigens adjuvanted with AH.
With respect to fair basis, the thrust of the opponent’s argument was that there was only experimental evidence of formulations comprising HBsAg-AP and DTPw-AH and this was at odds with the claims, which recited HBsAg-AP in combination with a range of other antigens adjuvanted with AP or AH. However, there is no requirement that the claims be limited to examples if the invention as claimed is consistent with the invention as described in the body of the specification. The opposed specification clearly states that the crux of the invention is in the use of AP as adjuvant for HBsAg. The specification explains that it is this feature that confers stability on HBsAg and maintains its immunogenicity when combined with other antigens. As such I am satisfied that there is consistency between the claims and the body of the specification and the claims are fairly based. Furthermore, the opponent provided no evidence to suggest that further formulations falling within the scope of the claims were beyond the skill of an ordinary worker in the field of the invention.
The opponent put forward similar arguments with respect to lack of full description. They asserted that the art of vaccine formulation is an unpredictable art and that the description of a single HBsAg-AP/DTPw-AH vaccine was insufficient to enable the skilled person to formulate further vaccines with different choices of antigen and adjuvant. However, disclosure of this single example meets the requirement that the specification enable the skilled addressee to produce something within each claim.
Given this I have no evidence before me to suggest that the specification fails to full describe the invention.
The opponent also suggested that various claims lacked clarity because the claims did not clearly define how qualities such as immunogenicity and stability were to be determined and did not clearly define which antigens-adjuvant combinations fell within the scope of the claims. However, neither party’s experts demonstrated difficulties in understanding the scope of the claims or appreciating terms used in the claims. As such I am not satisfied that there are significant clarity issues with the claims.

CONCLUSION

The opposition was partially successful on the grounds of novelty and inventive step but was unsuccessful on all other grounds.

86. Claims 1 to 7, 12 to 14, 20 to 23 and 28 to 31 lack novelty in light of the Choi thesis. The citation discloses HBsAg-DTPw vaccine formulations adjuvanted with AP and use of these vaccines to prevent hepatitis B infection.

87. However, Choi does not disclose antigens other than HBsAg and DTPw, the specific embodiments claimed in the opposed application, or HBsAg adjuvanted with AP and DTPw adjuvanted with AH. As such, I am not satisfied that Choi deprives claims 8 to 11, 15 to 19, 24 to 27 and 32 to 34 of novelty.

88. Claims 1 to 17, 20 to 25 and 27 to 34 lack an inventive step in light of EP168234 in combination with common general knowledge in the art. EP168234 discloses superior properties for AP as adjuvant in monovalent HBsAg vaccines in comparison to AH as adjuvant. I am satisfied that the skilled person would be led to combine this information with common general knowledge in the art to formulate a multivalent HBsAg vaccine adjuvanted with AP.

89. However, neither EP168234 nor the prior art suggest formulating vaccines in which HBsAg is adjuvanted with AP and other antigens with AH. As such I am not satisfied that EP168234 deprives claims 18, 19 and 26 of an inventive step.

90. The opponent also provided submissions on manner of manufacture, clarity, fair basis and full description. However they were unable to provide me with clear evidence that the opposed specification failed to meet the requirements for any of these grounds.

91. Given that there is clearly patentable subject matter remaining in the application I give the applicant 60 days to provide amendments to resolve the lack of novelty for claims 1 to 7, 12 to 14, 20 to 23 and 28 to 31 and the lack of inventive step for claims 11 to 17, 20 to 25 and 27 to 34.

COSTS

92. The normal practice is that costs follow the event. In the current circumstances I see no reason to deviate from this practice and I believe that it is appropriate to award costs against the applicant.

TERRY MOORE

Delegate of the Commissioner of Patents

Patent attorneys for the applicant : Davies Collison Cave, Melbourne
Patent attorneys for the opponent : FB Rice & Co., Melbourne