Isconova AB and Erasmus University Rotterdam Medical Center v CSL Limited
[2017] APO 48
•29 September 2017
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Isconova AB and Erasmus University Rotterdam Medical Center v CSL Limited 2017 APO 48
Patent Application: 2011280259
Title:Influenza vaccine
Patent Applicant: Isconova AB and Erasmus University Rotterdam Medical Center
Opponent: CSL Limited
Delegate: Sophina Calanni
Decision Date: 29 September 2017
Hearing Date: 25 May 2017, in Canberra
Catchwords: PATENTS - opposition to the grant of a patent – construction of the term ectodomain – clarity – fair basis – novelty – the citations do not disclose use of a neuraminidase ectodomain in the vaccine – inventive step considered – it was not common general knowledge to substitute the full antigen with the hemagglutinin or neuraminidase ectodomain – use of an immunostimulating complex (ISCOM) is not common general knowledge or obvious – opposition fails on all grounds
Representation: Counsel for the applicant: Ms Sophie Goddard
Patent attorney for the applicant: Dr Simon Potter, Spruson & Ferguson
Patent attorneys for the opponent: Dr Bill Pickering and Dr Tania Uren of Davies Collison Cave
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2011280259
Title:Influenza vaccine
Patent Applicant: Isconova AB and Erasmus University Rotterdam Medical Center
Date of Decision: 29 September 2017
DECISION
The opposition is unsuccessful on the grounds argued at the hearing by the opponent CSL Limited. Claim 16 found to lack clarity. The Applicant is given 2 months from the date of this decision to propose amendments to address this issue. Costs according to Schedule 8 awarded against CSL Limited.
REASONS FO R DECISION
Background
Application 2011280259 was filed by Isconova AB and Erasmus University Rotterdam Medical Center (Isconova) on 25 July 2011. The application claims priority from US 61/366,983, which was filed on 23 July 2010.
Following examination, the application was advertised accepted on 22 May 2014. A Notice of Opposition was filed by CSL Limited (CSL) on 22 August 2014, followed by the statement of grounds and particulars on 21 November 2014.
After the filing of evidence in support of the opposition, the applicant sought amendment of the complete specification. These amendments were allowed on 17 December 2015 without opposition.
The evidentiary stages of the opposition were finalised on 21 March 2016 and the opposition was set for hearing on 31 August 2016. An amendment to the statement of grounds and particulars (SG&P) was filed on 30 June 2016 and subsequently allowed. Two additional requests to amend the SG&P were filed on 17 and 24 August 2016. The applicant objected to these further requests and the hearing for the substantive opposition was deferred to allow the Commissioner to consider the amendments to the SG&P.
With respect to the amendment of the SG&P, the Deputy Commissioner refused the amendment of the SG&P filed 17 August 2016, but allowed the amendments in the request filed 24 August 2016.
Grounds of opposition
The statement of grounds and particulars sets out the following grounds of opposition: entitlement, novelty, inventive step, patentable invention, manner of manufacture, full description, clarity and fair basis. At the hearing, CSL pressed the grounds of novelty, inventive step, clarity and fair basis.
Onus
The request for examination in relation to the patent application was received on 13 March 2013. As a consequence, the substantive amendments of the Patents Act (the Act) brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present patent application. This includes the amendment to subsection 60(3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition has been made out.
The onus of proof in this opposition proceeding lies with the opponent, who must establish that it is clear that a valid patent cannot be granted.
Evidence
The parties relied upon evidence by several declarants as set out in the table below.
| Evidence | Declarant | Date of Declaration | Reference | Exhibits |
| In Support | Adriana Baz Morelli | 17 February 2015 | Morelli #1 | ABM1 to ABM9 |
| Steven Rockman | 17 February 2015 | Rockman #1 | SR1 to SR18 | |
| In Answer | Mohammed Alsharifi | 14 January 2016 | Alsharifi #1 | MA1 to MA17 |
| In Reply | Adrian Baz Morelli | 17 March 2016 | Morelli #2 | ABM10 to ABM 12 |
| Steven Rockman | 17 March 2016 | Rockman #2 | SR19 to SR30 | |
| Regulation 5.23 | Mohammed Alsharifi | 16 August 2016 | Alsharifi #2 | MA18, MA19, MA20 (in part) |
10. Regarding the additional evidence filed on 8 September 2016 pursuant to Regulation 5.23, the exhibits listed in the table above identify only those exhibits that can be relied upon. For exhibit MA20 I have only had regard to pages 5, 25, 26, 11, 181, 212, 287-291 as set out in a letter from the Commissioner’s delegate dated 15 September 2016.
The specification
The field and background of the invention
11. The field of the invention relates to influenza virus vaccines.
12. The specification states that currently licensed influenza virus vaccines are composed of the viral envelope glycoproteins hemagglutinin (HA) and neuraminidase (NA)[1]. Antibodies elicited by each of these proteins display distinct properties in providing immunity against the virus.
[1] Specification page 1 lines 25-26.
13. Antibodies to HA neutralise viral infectivity by interfering with virus binding to receptors on target cells and preventing fusion of the viral and cellular membranes. In contrast, antibodies to NA disable release of progeny virus from infected cells, reducing virus shedding and spread into the environment[2].
[2] Ibid lines 28-37.
14. Effective protection of the population from seasonal and pandemic influenza can be challenging because the influenza virus evades host immunity by generating antigenic variants. Given the threat of future influenza pandemics, the specification indicates that there is a need for vaccines that induce broadly protective immunity[3].
[3] Specification page 2 lines 18-24.
The description of the invention
15. The specification states that the invention is a composition comprising at least one immune stimulating complex (ISCOM) and at least one ectodomain from at least one HA domain and at least one ectodomain from at least one NA domain from an influenza virus, wherein the ectodomains represent ectodomains isolated from the influenza virus[4].
[4] Specification page 5 lines 9-12.
16. The specification contemplates several embodiments of the invention, including the use of a full ectodomain or a part thereof having the same enzymatic and/or antigenic activity, an isolated or synthetically produced ectodomain, a soluble ectodomain or head domain and hybrid proteins[5].
[5] Ibid lines 13-30.
17. The invention described uses ISCOM and/or ISCOM matrix complexes as adjuvants and immune modulating agents, and may comprise one or more antigens other than the ectodomain antigens[6].
[6] Specification page 6 line 34- page 7 line 28.
18. The description ends with three examples describing the preparation, expression and purification of HA and NA antigens (Examples 1, 2) and investigation of immunisation and infection in an animal model (Example 3).
19. The specification includes 28 claims. Each of the claims relate to compositions and their use in the preparation of a medicament for immune stimulation or modulation.
20. The compositions claimed are directed to two main embodiments as represented by claims 1 and 2 of the application and reproduced below.
Composition comprising at least one ISCOM matrix and at least one ectodomain from at least one influenza virus hemagglutinin domain and at least one ectodomain from at least one influenza virus neuraminidase domain, wherein:
the ectodomains represent ectodomains isolated from the influenza virus,
the ectodomains are recombinant ectodomains, and
the ectodomains do not contain a streptavidin tag.Composition comprising at least one ISCOM complex, at least one influenza virus hemagglutinin ectodomain and at least one influenza virus neuraminidase ectodomain, wherein the ectodomains represent ectodomains isolated from influenza virus, and the ectodomains are present in the composition at a ratio of neuraminidase ectodomain(s) to hemagglutinin ectodomain(s) that is greater than that of wide type influenza viruses.
21. I note that on 16 August 2016 Isconova filed a statement of proposed amendments to the specification. The parties were advised on 19 August 2016 that the amendments were not directed to overcoming the issues in the opposition and would not be considered by an examiner until after the opposition has been decided. Consequently those amendments do not form part of the specification, and I have not had regard to them in my decision.
Construction
22. The principles applicable to construction of patent claims are well established. As discussed by Bennett J in H Lundbeck A/S v Alphpharm Pty Ltd[7]
“...the words in a claim should be read through the eyes of the skilled addressee in the context in which they appear. Words used in a specification are to be given the meaning which the person skilled in the art would attach to then, having regard to his or her own general knowledge and to what is disclosed in the body of the specification...
The claims are part of the specification...While the claims define the monopoly claimed in the words of the patentee's choosing, the specification should be read as a whole...Those who attempt to elevate the "purposive construction" utilised by Lord Diplock in Catnic Components Limited v Hill & Smith limited...should understand the application of that approach to construction as explained by Lord Hoffman in Kirin-Amgen...
It is not permissible to read into a claim an additional integer or limitation to vary or qualify the claim by reference to the body of the specification. However, terms in the claim which are unclear may be defined or clarified by reference to the body of the specification. ”
[7] H Lundbeck A/S v Alphpharm Pty Ltd [2009] FCAFC 70, [118]-[120].
23. The primary point of difference between the parties in respect of the construction of the claims related to the term “ectodomain”.
24. CSL submitted that the term should be construed by reference to the specification, specifically referring to page 5 of the specification[8],
“the ectodomain may be the full ectodomain or a part thereof having the same enzymatic activity and/or antigenic activity. According to one embodiment the part of the ectodomain may be the head domain thereof.”
[8] Specification, page 5 lines 19-23.
25. Thus, having regard to the specification as a whole, CSL submitted that “ectodomain as recited in the claims includes ectodomains having just the globular head... It is not limited to ectodomains having both a stalk and globular head. ” [9]
[9] Rockman #2, [22].
26. Isconova submitted that the interpretation of the term “ectodomain” put forward by CSL contradicts the understanding of the term as set out in the application, which clearly refers to the extracellular portion of HA and NA, including both the stalk and globular head. As stated by Dr Baz Morelli:[10]
“...I understand the term "ectodomain" to mean the extracellular portion of HA or NA, i.e. not including the transmembrane domain and cytoplasmic tail. ”
[10] Morelli #1, [26].
27. I note that Dr Alsharifi's understanding of the term aligns with that of Dr Baz Morelli, and that, in his first declaration, Dr Rockman clearly demonstrated his understanding that an ectodomain contains both a globular head region and a stalk region[11].
[11] Rockman #1 [12], [13].
28. It is apparent that each of the declarants understands the plain meaning of the term “ectodomain” as it relates to HA and NA to be the extracellular portion of a membrane protein, incorporating the globular head and stalk regions of the protein. Whilst the invention described in the specification includes embodiments where only a part of the ectodomain is used in the vaccine composition, to modify the plain meaning of the term “ectodomain” based on these further embodiments would be adding glosses from other parts of the specification which is not legitimate[12].
[12] Decor Corp v Dart Industries 13 IPR 385 at 400.
29. I therefore construe the term “ectodomain” as the extracellular portion of a membrane protein, incorporating the globular head and stalk regions of the protein.
Clarity
30. Subsection 40(3) requires that the claims must be clear. A claim will lack clarity if a third party could not ascertain whether a proposed action would fall within the ambit of the claim[13].
[13] Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59.
31. In respect of claims 23, 24, 26 and 27, CSL submitted that the term “e.g.” is unclear since it is unclear whether the exemplary limitations are actually limiting.
32. Isconova submitted that in relation to claims 23, 24, 26 and 27, the term “e.g.” is commonly known to mean “example”. A specific element in the claim presented as an example is considered to be non-limiting.
33. I consider that the use of the term “e.g.” within the stated claims is used to merely exemplify representative instances of the broader concept. The term does not provide a limitation on the scope of the claims. Claims 23, 24, 26 and 27 are clear.
34. CSL also submitted that Claim 22 is unclear because there is no reference to the term “additives” in the description.
35. Isconova submitted that the term “additives” in the context of a vaccine composition would be clear to a person skilled in the art.
36. Although the specification does not explicitly define the term “additive”, the term is commonly used in the art. There is no evidence from any of the declarants that they did not understand the term. In the context of pharmaceutical or vaccine compositions, the person skilled in the art could readily resolve that any constituent other than the principal active ingredients could be considered an additive, and therefore claim 22 is clear.
37. Whilst the opponent did not object to the clarity of claim 16, I note that at the hearing the applicant submitted that they would remove claim 16. The claim refers to the composition of claims 1-15 wherein one or more of the ectodomains from at least one HA domain and one or more of the ectodomains from at least one NA domain are a head domain. As I have discussed above, the ectodomain, as it relates to HA and NA, incorporates both the head and the stalk regions of the protein. The head domain merely represents part of the ectodomain of the protein. As a result of the inconsistency, claim 16 lacks clarity. Given the applicant’s submission that they will introduce amendments to remove claim 16, I will not decide any further matters with respect to this claim.
Fair Basis and Priority
38. CSL submitted that claim 1 lacks fair basis and is not entitled to the application’s earliest claimed priority date. They submitted that the priority date of claim 1 should be deferred to the date when the post-acceptance amendments to claim 1 were filed, namely 22 May 2015.
39. In considering fair basis, the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd[14] approved the words of Gummow J in Rehm Pty Ltd v Websters Security System (International) Pty Ltd:
“the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification.”
[14] Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58 at 69.
40. CSL referred to Example 1 of the application, noting that it describes the preparation of recombinant HA and NA ectodomains for incorporation into ISCOM particles. In the recombinant constructs described, the HA and NA genes are expressed as hybrid proteins containing a Strep-tag[15].
[15] Specification, paragraph bridging pages 16-17.
41. Turning to the remainder of the opposed specification, CSL submitted that there is no guidance of the presence or use of tag sequences, in particular a streptavidin tag. CSL submitted that, instead, “the description provides only a very brief and general overview of the nature and production of HA and NA ectodomains on pages 5 and 6 of the specification.”[16] That is, the specification is either silent with respect to the inclusion of a streptavidin tag fused to the ectodomain, or explicitly teaches that a tag can be used. There is no suggestion that the streptavidin tags should not be used.
[16] Opponent's written submissions dated 11 May 2017 (OWS), [48].
42. On this basis, CSL asserted that the facts of the present case could be considered analogous to the facts in AstraZeneca v Apotex[17](AstraZeneca), where it was held that the specification prior to amendment did not contain a real and reasonably clear disclosure of the claimed subject matter after amendment because the claimed composition was inconsistent with the specification[18].
[17] AstraZeneca v Apotex [2014] FCAFC 99.
[18] OWS, [51]-[52].
43. Isconova stated that the critical distinction between AstraZeneca and the present application is that, beyond the information provided in the Examples, the present application provides no suggestion, expressly or by implication in any of the references to HA or NA ectodomains made throughout the application, that a streptavidin tag is required or preferred.
44. The specification as a whole only briefly describes the HA and NA ectodomains comprised within the compositions claimed. These ectodomains may be isolated from the influenza virus or synthetically produced[19], and, when they are recombinantly produced, eukaryotic expression systems, both mammalian and insect, are preferred platforms in view of their better preservation of the antigenic structure[20]. I consider that, having regard to the specification as a whole, the HA and NA ectodomains are described in a general sense without a specific requirement for a streptavidin tag. I therefore consider there is real and reasonably clear disclosure of recombinant HA and NA ectodomains, including those without a streptavidin tag. Therefore, claim 1 is fairly based on the description as filed.
[19] Specification, page 5 lines 21-24.
[20] Specification, paragraph bridging pages 5 and 6.
45. CSL submitted that, in accordance with Section 114 of the Act and Regulation 3.14 of the Patent Regulations 1991, the priority date for claim 1 and claims appended thereto should be the date on which the amendments to claim 1 were filed. I have found that claim 1 is fairly based, it therefore follows that s114 is not enlivened.
46. CSL also submitted that claim 22 is not fairly based on the description because there is no real and reasonably clear disclosure of a composition further comprising additives because there is no reference to additives in the description.
47. As discussed above in [36], any constituent of the vaccine composition other than the principal active ingredients (HA and NA ectodomains and ISCOM matrix and/or complex) could be considered an additive. The specification describes the inclusion of a range of additional constituents in the compositions of the invention, including for example pharmaceutically acceptable excipients, carriers or diluents and further adjuvants or antigens[21] and, hence, there is a real and reasonable clear disclosure of compositions that further comprise additives.
[21] Specificationion, page 14 lines 12-13, 32-35 and page 15 lines 1-10.
48. Therefore claim 22 is fairly based on the description.
Novelty
49. It is well established that the general test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aicken J:[22]
“The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement.”
[22] Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19;137 CLR 228 at 235.
50. This test is satisfied if the alleged anticipation discloses all of the essential features of the invention as claimed[23]. To meet this requirement, the prior art must contain “clear and unmistakable directions to do what the patentee claims to have invented… A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.”[24]
[23] Nicaro Holdings Pty Ltd v Martin Engineering Co [1990] FCA 40 at[19]
[24] The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 485-486
51. At the hearing, CSL indicated that the documents pressed with respect to novelty are:
WO 2011/126370, University Utrecht Holding B.V. et al, (D1) as a “whole of contents” novelty citation
Bosch et al (2010) Journal of Virology 84:10366-10374 (Bosch)
D1
52. CSL submitted that claims 2-6 and 13, and claims 7-12, 14-15, 17-24 and 26-28 insofar as they are dependent from claim 2 lack novelty over D1. As affirmed by CSL at the hearing, the relevance of this document with respect to novelty falls on the interpretation of the term “ectodomain”.
53. In paragraphs [22]-[29] I have considered the submissions and evidence referred to by both parties and determined that the term “ectodomain” is to be construed as the extracellular portion of a membrane protein, incorporating the globular head and stalk regions of the protein.
54. For the purposes of the novelty consideration, the relevant disclosure of WO 2011/126370 is Example 2, which describes the preparation of an influenza vaccine. One of the vaccine formulations described comprises the HA ectodomain and the NA head domain in ISCOM Matrix-M. The vaccine does not comprise the NA ectodomain (as I have construed that term), and therefore does not disclose all of the essential features of claim 2.
55. I note that I have not determined whether D1 is part of the prior art base as the opponent has not introduced the priority documents for the present application or D1 into evidence. I am therefore unable to establish whether the claimed priority dates are valid. However, I note that given the disclosure provided in D1, it is not necessary for me to determine whether the documents are entitled to their earliest claimed priority date.
Bosch
56. CSL submitted that Bosch anticipates claims 1, 7-12, 16-21, 23, 24, 26 and 27.
57. In a similar manner to D1 above, the relevance of Bosch falls on the interpretation of the term “ectodomain”. The influenza vaccine disclosed in Bosch comprises a HA ectodomain and a NA head domain, and therefore does not disclose all of the essential features of claim 1 (or appended claims 7-12, 17-21, 23, 24, 26 and 27).
Conclusion on novelty
58. It has not been established that any of the claims lack novelty.
Inventive step
59. An invention is taken to involve an inventive step unless it would have been obvious to the person skilled in the art in light of the common general knowledge, either considered alone or together with the prior art. The prior art is information the skilled person could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant.[25].
[25] Subsections 7(2) and 7(3) of the Act
60. The test for whether an invention is obvious is to ask whether it would have been a matter of routine to proceed to the claimed invention. In Wellcome Foundation Ltd v V.R. Laboratories (Aust.) Pty Ltd[26]Aickin J stated:
“The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not. ”
[26] Wellcome Foundation Ltd v V.R. Laboratories (Aust.) Pty Ltd [1981] HCA 12 at[45],148 CLR 262 at 286
61. The High Court in Aktiebolaget Hassle v Alphapharm Pty Ltd (Alphapharm)[27] approved this approach, and also endorsed the Cripps question:
“Would the notional research group at the relevant date, in all the circumstances ... directly be led as a matter of course to try [the invention claimed] ... in the expectation that it might well produce a useful [product or process]?”
[27] Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59, 212 CLR 411
62. In addition, where the invention lies in a combination of features as in the present application, Alphapharm indicated that the question is whether the combination, not each individual feature, is obvious when compared to the prior art base[28]:
“The claim is for a combination, the interaction between the integers of which is the essential requirement for the presence of an inventive step. It is the selection of the integers out of "perhaps many possibilities" which must be shown … to be obvious, bearing in mind that the selection of the integers in which the invention lies can be expected to be a process necessarily involving rejection of other possible integers. ”
[28] Alphapharm (supra) at [41]
63. Another important consideration when assessing inventive step is the misuse of hindsight. As noted by the Court in Alphapharm[29]
“The danger of such misuse will be particularly acute where what is claimed is a new and inventive combination for the interaction of integers, some or all of which are known.”
[29] Alphapharm (supra) at [21]
What is the problem addressed by the application?
64. As discussed earlier, the present specification lies in the field of influenza virus vaccines. More particularly, the specification is concerned with the provision of improved or alternative vaccines against influenza.
65. The applicant has indicated in their written submissions that the Cripps question for the present case can be formulated as below[30]. I agree that the asserted representation is appropriate for the present application.
[30] Applicant’s written submissions dated 18 May 2017 (AWS), [173].
“Would the notional addressee (including a research group) at 23 July 2010, in all the circumstances, which include a knowledge of all relevant prior art [insofar as it is CGK or available under s7(3)] and of the facts of the nature and success of the existing influenza vaccine, directly be led as a matter of course to try a vaccine,
(a) with the features of claim 1, a composition comprising ISCOM matrix and recombinant HA and NA ectodomains, without the inclusion of a streptavidin tag; or(b) with the features of claim 2, a composition comprising ISCOM complex and HA and NA ectodomains with a ratio of NA:HA which is greater than that of wild type influenza viruses,
in the expectation that it might well produce a useful alternative to or a better vaccine that the existing vaccine?”
66. As noted by both parties, the reference to the expectation in this formulation of the test for inventive step means a reasonable expectation of success[31].
[31] OWS, [83]; AWS, [174]
The common general knowledge
67. Common general knowledge was defined by Aickin J inMinnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd[32]:
“The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.”
[32] Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; 144 CLR 253at 292.
68. As observed by Beach J in GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No. 2) Limited v Apotex Pty Ltd[33]
“Information cannot be treated as part of the common general knowledge unless there is evidence of its general acceptance and assimilation by persons skilled in the art. Information does not constitute common general knowledge merely because it might be found, say, in a journal, even if widely read by such persons.”
[33] GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No. 2) Limited v Apotex [2016] FCA 608 at [872].
69. On the basis of the evidence provided I am satisfied that the following matters represent the common general knowledge in the art.
Commercially available influenza vaccines at the priority date were inactivated virus vaccines.[34]
HA and NA are the two main surface glycoproteins of an influenza virus. These proteins are each immunogenic and are the main targets of the host immune response against influenza.[35]
Commercial influenza virus vaccines in Australia contained both HA and NA.[36]
A vaccine may include an adjuvant to improve its immunogenicity and effectiveness. A range of adjuvants were available for use including for example alum, oil-based adjuvants, lipopeptides or adjuvant active bacterial toxins[37].
ISCOMs and ISCOM-complex are known adjuvants.
[34] Morelli #1, [18], consistent with for example Rockman#1, [20]; Specification, page 2 lines 7-9.
[35] Morelli #1, [22], consistent with for example Rockman #1 [11]- [14].
[36] Morelli #1, [21], consistent with for example Rockman #1, [20]; Alsharifi #1, [32].
[37] Specification, page 8 line 27 – page 9 line 8.
70. CSL asserted a number of additional matters they considered were common general knowledge[38]. The most significant in the context of the present consideration are discussed below.
Other matters relevant to the inventive step consideration
[38] OWS, [91].
HA and NA ectodomains
71. CSL submitted that it is well known that the surface glycoporoteins HA and NA are the major contributors to a protective immune response. As such, the use of the ectodomains in the vaccine was an obvious variation since the ectodomain is the antigenic portion and that is all that is needed to induce an immune response. The evidence of Dr Rockman was said to support this submission.
72. Dr Rockman stated[39]:
“The preparations of HA ectodomain were commonly formulated with an adjuvant such as Freund’s complete adjuvant, and used to immunise sheep and other animals to obtain anti-HA sera for use as reagents. Examples of this practice date back to the 1970s (see for example, Oxford et al;, attached hereto and marked Exhibit “SR8”). This is something that we regularly did at bioCSL and something that I knew others in the field regularly did to obtain anti-HA antibodies. Thus, the idea of using the HA ectodomain with an adjuvant as an immunogen has been around since the 1970s.
Similarly, it was well known that the NA ectodomain could be released from virions by pronase or trypsin digestion, and this has been done routinely since the 1970s to study NA structure and function (this practice is also described in the 1986 review by Ada and Jones referred to above (Exhibit “SR2”). And as with the HA ectodomains, researchers routinely formulated the purified NA ectodomains with Freund’s adjuvant for immunisation of animals to obtain anti-NA sera (such as described in Kendal and Kiley, attached hereto and marked as Exhibit “SR9”) or, as we have done, to generate monoclonal antibodies to NA.”
[39] Rockman #1, [17]-[18].
73. I consider the submission that the use of the HA and NA ectodomain is an obvious variation is made with the benefit of hindsight, which has clearly been warned against by the authorities. As noted by Dr Alsharifi, all commercial vaccines in Australia were split virion or subunit vaccines[40]. Clearly there has been significant research into modifications that can be made to influenza vaccine preparations [41], but commercial vaccines continue to be based on split virion and viral subunit preparations. Dr Rockman has pointed to some evidence that viral antigen preparations that contain the ectodomain can be used to obtain antisera[42]. However, the antisera were merely used to characterise properties of the antigen. The ability of a protein (or protein domain) to induce an antibody response as described in SR8 and SR9 is not necessarily indicative that the protein (or protein domain) will be effective as a vaccine. As such, I do not consider that the evidence establishes that there is any motivation to use the HA and NA ectodomains in a vaccine preparation.
[40] Alsharifi #1, [32].
[41] See for example ABM4 Table 3; ABM5 Table 2; AMB7, Table 1.
[42] Exhibit SR8, page 187, final paragraph; SR9, page 1485, second paragraph.
ISCOMs and ISCOM-complex
74. I am satisfied that the adjuvant properties of both ISCOMs and ISCOM-complex were well known before the priority date. However, it is not clear that the use of ISCOMs and ISCOM-complex had become part of the common general knowledge, particularly with regard to their suitability for use in an influenza vaccine. I consider that the evidence provided by Drs Baz-Morelli and Rockman[43] confirms that ISCOMs and ISCOM-complex were subject to further research regarding their inclusion in a variety of vaccines. In fact Exhibit ABM4 of Morelli #1, which provides a review of ISCOMs, clearly indicates that effectiveness of ISCOMs as an adjuvant is variable[44] and the capacity of ISCOM-delivered antigen to induce a state of long-lived immunological memory has not been established definitively[45].
[43] Morelli #1, [23], Rockman #1, [23].
[44] ABM4, page 17, right column, final paragraph.
[45] ABM4, page 20, left column, final paragraph.
75. I, therefore, do not consider that there has been general acceptance that ISCOMs were especially useful for enhancing the immune response to HA and NA in an influenza vaccine.
Recombinant HA and NA
76. Similarly, the evidence establishes that the recombinantly- expressed antigens were being investigated for their potential use in vaccines.[46] The evidence does not establish that influenza vaccines that comprise recombinant proteins were common general knowledge, only that the use of inactivated viruses represents common general knowledge.
[46] Morelli #1, [24] and [25], Rockman #1, [24].
Is the invention obvious in light of common general knowledge alone?
77. As Isconova asserted in their submissions, claims 1 and 2 of the present application are directed to a combination of features. Accordingly, it is the selection of the integers out of perhaps many possibilities, in combination, which must be shown to be obvious.
78. As discussed above, I do not consider that the evidence establishes that the skilled addressee would be directly led as a matter of course to use the HA and NA ectodomain or an ISCOM or ISCOM complex in an influenza vaccine, let alone a combination of these components. Therefore, the invention is not obvious in light of common general knowledge alone.
Is the invention obvious in light of the prior art documents?
79. Each of the experts has asserted that they would have searched peer-reviewed literature relevant to their research interests, namely influenza, influenza vaccines and vaccine adjuvants. On this basis I am satisfied that the skilled person would have ascertained each of the prior art documents listed below.
Johansson, B. E. 1999, Vaccine, 17:2073-2080 (D11)
Sanders, M. T. et al, 2005, Immunology and Cell Biology, 83:119-128 (D22)
Middleton, D et al, 2009, Journal of Virology, 83:7770-7778 (D24)
Barr, I. G. and Mitchell, G. F., 1996, Immunology and Cell Biology, 74: 8-25 (D26)
Drane, D. et al, 2007, Expert Reviews Vaccines, 6:761-772 (D27)
Sun, H-X. et al, 2009, Vaccine, 27:4388-4401 (D28)
D22, D24 and D26-28
80. At the hearing CSL asserted that their primary argument for the lack of an inventive step was based on the documents describing vaccine compositions containing ISCOMs or ISCOM matrix particles formulated with split virion or subunit influenza preparations (D22, D24 and D26-28 listed above).
81. The difference between the disclosure in these documents and the invention defined in claim 1 of the present application resides in the use of recombinant HA and NA ectodomains in place of the split virion or viral subunits. As discussed at [76], the evidence does not establish that there is a clear motivation to use the HA and NA ectodomains instead of the split virion or viral subunits in a vaccine. Furthermore, as discussed at [79], the use of recombinant antigens in a vaccine does not represent common general knowledge, and it has not been established that the skilled addressee would be motivated to use a recombinant antigen in the expectation that it would provide an improved vaccine.
82. Consequently it is has not been established that claim 1 lacks an inventive step.
83. Claim 2 defines a composition comprising at least one ISCOM complex and at least one influenza virus HA and NA ectodomain, wherein the ectodomains are present in the composition at a ratio of NA ectodomain(s) to HA ectodomain(s) that is greater than that of wide type influenza viruses. While the parties have made submissions regarding the ratio or NA to HA, I have not considered these submissions in depth because CSL has not established that it would be obvious to replace the split virion or subunit components of influenza vaccine with the NA or HA ectodomains. Consequently it has not been established that claim 2 lacks an inventive step.
84. Given claims 1 and 2 do not lack an inventive step I do not need to consider any of the remaining claims.
85. I also note that CSL considered that the claims lack an inventive step over the patent document WO 2009/046497 (D23). Whilst the parties did not agree on whether the skilled addressee would search the patent databases for the purpose of identifying patents relevant to their research interest, I note that D23 provides a similar disclosure to D22, D24 and D26-28, and would therefore be unsuccessful at establishing a lack of inventive step for similar reasons to those stated above.
D11
86. D11 is describes an influenza virus vaccine comprising HA and NA produced in insect cell-lines by recombinant baculovirus. The document reports that in a mouse model, a combined vaccine produced from a recombinant baculovirus expression system expressing NA and HA induced a balanced immune response to HA and NA that was superior to that induced by a conventional vaccine.
87. CSL submitted that the skilled person looking to improve this vaccine would have been directly led as a matter of course to include an adjuvant with a reasonable expectation of boosting the immune response to the HA and NA antigens. While I accept that the inclusion of adjuvants to improve vaccine efficiency and immunogencity was common general knowledge in the art, as discussed at [77], the evidence does not establish that ISCOMs or ISCOM-complex was especially useful for enhancing the immune response to HA and NA in an influenza vaccine. Furthermore, as discussed above, it is not considered obvious to replace the full HA and NA molecules with the HA and NA ectodomains.
88. Accordingly, D11 combined with common general knowledge does not defeat the claims on inventive step.
Combination of documents
89. I note that in their submissions CSL also submitted that it would be possible to combine various groups of the prior art documents referred to in their submissions to establish a lack of inventive step.[47] I do not agree. There is no evidence from any person that they would have combined any of the documents, and I can see no reason to do so based on the disclosure of the documents. Therefore I am not satisfied that the opponent has established that the invention lacks an inventive step on this basis.
[47] OWS dated 11 May 2017, pages 32-34.
Conclusion on inventive step
90. It has not been established that any of the claims lack an inventive step.
Conclusion
91. Claim 16 lacks clarity. I consider that this may be overcome by amendment, and allow Isconova 2 months from the date of this decision to propose appropriate amendments to overcome this issue.
92. The opposition argued by CSL is unsuccessful.
Costs
93. It is usual for costs to follow the event and I can see no reason to vary this approach here. The opposition argued by CSL has been unsuccessful. I therefore award costs according to Schedule 8 against CSL.
Sophina Calanni
Delegate of the Commissioner
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8
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