Novozymes A/S v Genencor International, Inc - [2013] APO 15

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Novozymes A/S v Genencor International, Inc. [2013] APO 15

Patent Application: 2002353178

Title:Proteases producing an altered immunological response and methods of making and using the same

Patent Applicant:  Genencor International, Inc.
Opponent:  Novozymes A/S
Delegate:  Dr B. Akhurst
Decision Date:  30 January 2013
Hearing Date:  7 November 2012
Catchwords:  PATENTS - section 59 – opposition to grant of a patent – novelty – claims to a class of variant polypeptides – ‘mere paper anticipation’ argued – claimed variants not disclosed – inventive step – not a matter of routine to prepare specific mutants – inventive step not established – utility –whether the potential for an adverse reaction to a product makes it not useful for it primary purpose – lack of utility not established – fair basis – submissions relate to the merit of the invention – lack of fair basis not established – clarity – lack of clarity not established – opposition fails on all grounds

Representation: Patent applicant: Dr Nigel Parker and Mr Michael Houlihan of Houlihan²
Opponent: Dr Jacinta Flattery-O’Brien and Dr Keiran Williams of Shelston IP

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2002353178

Title:Proteases producing an altered immunological response and methods of making and using the same

Patent Applicant: Genencor International, Inc.
Date of Decision: 30 January 2013
DECISION
The opposition fails on all grounds. Costs awarded according to Schedule 8 against Novozymes A/S.
REASONS FOR DECISION
Background

Patent application 2002353178 was filed by Genencor International, Inc. (‘Genencor’) on 20 December 2002 via the PCT, claiming priority from US basic document 60/344,657 filed on 31 December 2001. The application was advertised as accepted on 29 May 2008. A notice of opposition to grant of a patent was served by Novozymes A/S (‘Novozymes’) on 1 September 2008, followed by a statement of grounds and particulars on 1 December 2008.

Evidence in support was served on 1 October 2009, consisting of a statutory declaration by:
· Dr. Charles Linton Hardy dated 30 September 2009 (CLH#1) with exhibits CH‑1 to CH‑45.
Genencor proposed amendments to the specification under sec 104 on 22 June 2010. A restricted set of claims was allowed on 24 January 2011, following which evidence in answer was served on 21 February 2011, consisting of a statutory declaration by:
· Ass. Professor Anthony Wayne Purcell dated 17 February 2011 (AWP#1) with exhibits AWP‑1 to AWP-7.
Evidence in reply was completed on 5 December 2011, consisting of a statutory declaration by:
· Dr Charles Linton Hardy dated 1 December 2011 (CLH#2) with exhibits CH‑46 to CH-60.
After an amendment was allowed to the statement of grounds and particulars on 11 December 2012 under regulation 5.9(c), a request for leave to serve further evidence in respect of these exhibits, was granted unopposed on 8 March 2012.
Genencor filed responding evidence on 20 June 2012, consisting of a statutory declaration by:
· Ass. Professor Anthony Wayne Purcell dated 18 June 2012 (AWP#2) with exhibits AWP-8 to AWP-9.

Novozymes opposed grant of the patent on the grounds of manner of manufacture, novelty, inventive step, usefulness, clarity and fair basis.
Standard of proof
The onus of proof in opposition proceedings lies with the opponent, who must establish that it is clear that a valid patent cannot be granted (F.Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [29], [67]; (2001) 50 IPR 305 at 311 [29], 319 [67]; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18], [22]; (2009) 79 IPR 426 at 430 [18], 432 [22]).

The primary facts are to be established on the balance of probabilities, but the ultimate facts - the facts leading directly to a conclusion of a lack of novelty or a conclusion of obviousness - must be proved to the level of practical certainty (Justice Besanko in Aspirating IP Ltd v Vision Systems Ltd [2010] FCA 1061 at [35]; (2010) 88 IPR 52 at 63 [35])
The specification and claims
The title of the specification is “Proteases producing an altered immunological response and methods of making the same”. On page 1, the description teaches that proteins used in industrial, pharmaceutical and commercial applications are becoming increasingly prevalent and important. However, this has led to numerous individuals becoming sensitised to the proteins, resulting in the widespread occurrence of allergic reactions. At page 2, the description identifies a need in the art to identify proteins that produce enhanced and reduced immune responses.
On page 3-4, the invention is broadly summarised as the provision of:
· protein and protease variants with reduced immunogenic responses as compared to the parent protein, the encoding DNA molecules and associated host cells and methods for making proteins less immunogenic than the wild-type protein; and
· methods for identifying B-cell epitopes within a protease. In preferred embodiments, the epitopes are identified using serum from human donors known to be sensitized to the protease of interest.
Claims construction
The principles to be applied in construing a patent specification are well settled in law (Flexible Steel Lacing Company v Beltreco Ltd [2000] FCA 890 at [70] - [81]; (2001) 49 IPR 331 at 347 [70] - [81], Pfizer Overseas Pharmaceuticals v Eli Lilly and Company [2005] FCAFC 224 at [247] - [250]; 68 IPR 1 at 52-54 [247] - [250]). Briefly and most relevantly, the claims, cast in precise language, mark out the legal limits of the monopoly granted by the patent. While the claims are construed in the context of the specification as a whole, it is not legitimate to vary the boundaries of monopoly as fixed by the words of the claim, by adding words or glosses drawn from other parts of the specification. However, if an expression in the claims is unclear or ambiguous, it is permissible to resort to the body of the specification to define or clarify the meaning of words used in the claims (Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461 at 479).

There are 22 claims under consideration. Claim 1 is the only independent claim and is as follows:

1. A variant of a protease of interest comprising a B cell epitope, wherein:
(i) the variant differs from the protease of interest by having an altered B cell epitope whereby the variant exhibits an altered immunologic response from the protease of interest in a human; and
(ii) the B cell epitope of the protease of interest includes at least one amino acid substitution at a residue corresponding to 69, 90, 92, 93, 139, 178 and 179 of Bacillus amyloliquefaciens subtilisin.

As noted by Novozymes, the description on pages 10-22 provides a dictionary for a number of terms used in the specification, including the following:
·A “protease of interest” refers to a protease that is being analysed, identified and/or modified (page 12 lines 27-28).
·An “altered B cell epitope” refers to an epitope amino acid sequence which differs from the precursor (“parent”) peptide or peptide of interest, such that the variant peptide of interest produces different (i.e. altered) immunogenic responses in a human or other animal e.g. altered allergenicity, including either increased or decreased overall immunogenic response. The alteration may be a substitution and/or deletion of an amino acid within the epitope, or addition of one or more residues in the epitope. (page 11, lines 13-21)
·An “altered immunogenic response” means an increased or decreased T-cell and/or B cell response to the variant, and is not limited to altered allergenicity (page 11, lines 16-17; page 12, lines 12-20). This is consistent with the meaning given by the expert declarants to the similar term “altered immunologic response” used in the claims (CLH#1 at [73] – [74]); AWP#1 at [H73]; AWP#2 at [CLH86]). I conclude that in the context of the specification, the terms “immunologic response” and “immunogenic response” are synonymous.
·The numbers used in the specification to define the position of amino acid residues are those assigned to the amino acids in the mature wild-type B. amyloliquefaciens subtilisin (BPN’), presented in Figure 1 of the specification (page 14, lines 3-4).
·The term “corresponding to [specified residues] of Bacillus amyloliquefaciens subtilisin” means:
“a residue at the enumerated position in a protein or peptide, or a residue that is analogous, homologous, or equivalent to an enumerated residue in a protein or peptide.” (page 14, para 3)
In their submissions, Novozymes construed the terms “analogous”, “homologous” and “equivalent” using the definitions provided in the specification for amino acid sequences and proteins. However, the meaning of these terms in the context of a single amino acid residue is unclear. Resort to the description at page 28, lines 17-21 reveals that, for an amino acid in a precursor protease:
·an “equivalent” residue is a residue that is homologous or analogous to a specific residue or portion of that residue in B. amyloliquefaciens subtilisin;
·a “homologous” residue corresponds in position in either the primary or tertiary structure to a specific residue or portion of that residue in B. amyloliquefaciens subtilisin;
·an “analogous” residue has the same or similar functional capacity to combine, react, or interact chemically, as does a specific residue or portion of that residue in B. amyloliquefaciens subtilisin.
The first line of claim 1 raises the question of whether the protease of interest, the variant, or both, comprises a B cell epitope. Given the reference to “the B cell epitope of the protease of interest” in part (ii) of the claim, the protease of interest must comprise a B cell epitope. As to the variant, Dr Hardy understands the specification to disclose a need in the art to modify an epitope to reduce or preferably neutralise (eliminate) the ability of the B cell to identify that epitope (CLH#1 at [62]). His statement reflects the aspect of the invention described at page 4 lines 5-7 of the description. Dr Purcell does not dispute this construction. The words “neutralising” and “eliminating” a B cell response to an epitope indicates that a reduced immunologic response encompasses no response. Logically, where the parental B cell epitope is neutralised (eliminated), the “altered B cell epitope” in the variant of claim 1 no longer acts as a B cell epitope. It follows that while the protease of interest must contain a B cell epitope, the variant may not.
Novozymes submitted that there are two possible constructions of claim 1, due to the phrase in part (ii) of the claim “the B cell epitope of the protease of interest includes…”. One construction being that the epitope in the protease of interest has the specified substitution(s), the other that the variant differs from the protease of interest by including one or more of the specified substitutions.
I consider the second construction to be correct. Claim 1 defines “A variant of a protease of interest … wherein:” features (i) and (ii) must be present. The reference to a B cell epitope in the preamble provides antecedent basis for “the B cell epitope of the protease of interest” in part (ii). One or more of the amino acids in the parental epitope are substituted in the variant. Even if I am wrong and the claim is ambiguous, resort to the body of the specification establishes that it is the claimed variant that contains the substituted residues relative to the corresponding residues in B. amyloliquefaciens subtilisin (see for example the description at page 4, para 2; page 22, lines 18-23 and page 24, lines 2-15).
Dr Hardy confirms that at the priority date it was well understood there are a number of conserved residues between subtilisin-like proteases which provide a framework that enables alignment of the protease sequences, making it possible to identify a mutation site in a subtilisin, by reference to the corresponding site in subtilisin BPN’ (CH#1 at [46]).
I agree with Novozymes, that the “variant” of claim 1 is not restricted to variants of B. amyloliquefaciens subtilisin BPN’. However, claim 1 defines the amino acid substitutions in terms of the amino acid position numbers in BPN’. It follows that there must be a degree of “correspondence” between the sequence of the protease of interest and that of BPN’ (as determined by alignment of the amino acid sequences or the atomic co-ordinates in the tertiary structure of the proteins), in order that the substituted residues could be considered to “correspond” to residues of B. amyloliquefaciens subtilisin, as required by claim 1. This construction is supported by Dr Hardy’s evidence (CLH#1 at [46]; CLH#2 at [30]) which is not disputed by Dr Purcell. I further agree with Novozymes that claim 1 does not require the variant to be a subtilisin, particularly in view of dependent claim 4 which specifies the protease of interest as a subtilisin.
The parties disagreed on whether the variant of claim 1 is required to have protease activity. Genencor submitted that the claims defined a protease per se, and Novozymes that there was no requirement for the variant of claim 1 to have protease activity. Claim 2 explicitly requires the variant to exhibit protease activity, a feature that would be redundant if this activity was required in claim 1. The description refers to the use of the variants as vaccines and in immunoassays, neither of which would require protease activity. Therefore, although it is derived from a protease, I agree with Novozymes that claim 1 does not require the variant to have protease activity.
In summary, claim 1 defines a variant of a protease of interest, wherein the protease of interest comprises a B cell epitope. The variant differs from the parent protease in that the parent B cell epitope is altered in the variant. As a consequence, the variant exhibits an increased or decreased B cell response (not limited to altered allergenicity) and/or T-cell response in a human. The altered B cell epitope includes one or more amino acid substitutions at a residue which, in the parent, was homologous (corresponds in position in either the primary or tertiary structure), or analogous (has the same or similar functional capacity to combine, react, or interact chemically), to amino acids 69, 90, 92, 93, 139, 178 and 179 of B. amyloliquefaciens subtilisin BPN’.
Regarding the dependent claims, claim 2 is as follows:
2. A variant of Claim 1 further comprising a mutation selected from:
(a) at least one amino acid substitution in a B cell epitope of the protease of interest corresponding to residues 46-60 and 86-100 of Bacillus amyloliquefaciens subtilisin; and
(b) at least one amino acid substitution at anyone or more amino acid residues corresponding to 3, 31, 40, 41, 50, 76, 79, 107, 111, 122, 147, 206, 217, 218 and 238 of Bacillus amyloliquefaciens subtilisin; and
(c) at least one amino acid substitution corresponding to: S3T, I31L, P40Q, D41A, N76D, I79A, I79T, I111V, I122A, V147P, V147I, Q206L, Y217L, N218S and H238Y; and
(d) a multiple substitution consisting of any one of: 179A-I122A-Y217L, N76D-I122A-Y217L, and N76D-I79A-I122A-Y217L;
whereby the variant has an altered B cell epitope and exhibits an altered immunologic response from the subtilisin in human; and wherein the variant exhibits protease activity.
Claim 3 is to the variant of Claim 1 or 2, further comprising at least one amino acid substitution at a residue corresponding to amino acids 46-67, 69-75, 86-100, 126-140, 166-169, 172, 174-180, 206-212, 214-225, 246‑258 and 259 of Bacillus amyloliquefaciens subtilisin.
Claim 4 specifies that the variant of the earlier claims is a subtilisin.
Claim 5 limits the immunological response of claims 1-4 to being less than that produced by the protease of interest. Dependent claims 6 and 7 require that the immunological response is an in vivo, or in vitro reduction in allergenicity, respectively.
Claim 8 defines a nucleic acid encoding the variant of any one of claims 1-7. Claims 9 and 10 define an expression vector comprising the nucleic acid of claim 8, and a host cell transformed with the vector, respectively.
Claim 11 defines a cleaning composition, personal care product or pharmaceutical product comprising the variants of claims 1-7. Dependent claim 12 specifies that the pharmaceutical product further comprises a pharmaceutically acceptable carrier.
Claim 13 defines a skin care composition comprising the variant of any one of claims 1-7; dependent claim 14 adds a cosmetically acceptable carrier. Claim 15 specifies the carrier. Claim 16 requires that the skin care composition of claims 13-15 further comprise a skin care active, and claims 17-18 specify the active. Claim 19 requires that the skin care composition of claims 17 or 18 further comprise glycerin.
Claim 20 is to a skin care composition comprising:
a) from about 0.00001% to about 1%, by weight, of the variant of any one of Claims 1 to 7;
b) from about 0.01% to about 20%, by weight, of a humectant;
c) from about 0.1% to about 20%, by weight, of a skin care active;
d) from about 0.05% to about 15%, by weight, of a surfactant; and
e) from about 0.1% to about 20%, by weight, of silicone.
Claims 21 and 22 are omnibus claims defining the variant of any one of claims 1-7, or the skin care composition of any one of claims 13 to 20, respectively, by reference to the disclosure of the specification. Since the omnibus claims do not restrict the scope of the earlier claims to any specific embodiments, the scope of claims 21-22 is the same as that of the claims to which they are appended.
Novelty
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 Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19 at [20]; (1977) 137 CLR 228 at 235:
“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.”
This test is satisfied if the alleged anticipation discloses all of the essential features of the invention as claimed (Nicaro Holdings Pty Ltd v Martin Engineering Co [1990] FCA 40 at [19]; (1990) 16 IPR 545 at 549). To meet this requirement, the prior art must contain “clear and unmistakable directions to do what the patentee claims to have invented” (The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 486; (1971) 1A IPR 121 at 138).
The citations
The prior art base is defined in Schedule 1 of the Act. Genencor’s priority claim of 31 December 2001 is not in dispute. Novozymes relied on the following documents to establish lack of novelty:
WO 2001/083559 (Novozymes A/S) 8 November 2001
WO 2003/006602 (Novozymes A/S) 23 January 2003
WO 2001/083559 (WO’559) is in evidence as CH-58. It was published before the priority date and is part of the prior art base for novelty and inventive step. WO 2003/006602 (WO’602) (Australian application 2002316816) is in evidence as CH-59. This document is a “whole of contents” citation, published after the priority date of the opposed claims, but having an earlier priority date than the opposed claims. WO’602 is prior art for novelty purposes only.

Genencor submitted that both documents are mere paper anticipations of the opposed claims, and that in the absence of clear and unmistakable directions to carry out the invention claimed in the opposed specification, neither document anticipates the opposed claims.
Novelty in light of WO 2001/083559
The WO’559 specification is titled “Protein variants having modified immunogenicity”. On page 1, the invention is said to provide: a method of selecting a protein variant having modified immunogenicity as compared to a parent protein; a protein variant and use thereof; and a method for producing said protein variant. On page 2, the document addresses a need in the art for methods to identify epitopes on proteins that can trigger unwanted allergic reactions in susceptible individuals, and the need to alter such epitopes to modify the immunogenicity of proteins in a targeted manner. The method is said to have at least four useful purposes, including, most relevantly, reducing the allergenicity of a commercial protein using protein engineering.

To establish lack of novelty, Novozymes relied on claim 80 of WO’559 as dependent on claims 23, 26, 27, 29 and 75-76. These claims are as follows:
23. A protein variant, wherein the amino acid sequence of the protein variant differs from the amino acid sequence of the parent protein with respect to at least one epitope area of the parent protein.
26. The protein variant according to claims 22 or 23, wherein the epitope areas correspond to antibody binding peptide sequences reactive to antibodies raised against the parent protein.
27. The protein variant according to claims 22-26, wherein the epitope pattern is a IgE epitope pattern.
[At page 36 of WO’559, the term “epitope pattern” used in claim 27 means a consensus sequence found in antibody binding peptides. This definition is consistent with the Dr Hardy’s understanding of the term (apparent at CLH#2 at [21] and [35]).
T cells, via T cell receptors on the cell surface, recognise a complex of fragments of protein (peptides) in combination with an MHC molecule on the surface of certain cells. In contrast, B cells use cell surface or secreted antibodies (immunoglobulins, abbreviated to Ig) to recognise 3‑dimensional epitopes on the surface of a macromolecule. One type of antibody, IgE, is involved in allergic reactions. (CLH#1 at [13] - [16], AWP#1 at [H13] – [H16]) Since claim 27 specifies an IgE epitope pattern, I conclude that claim 27 restricts the claims to a B cell epitope.]
29. The protein variant according to claims 22-28, wherein the allergenicity of the protein variant is below 75%, preferable below 50%, more preferably below 25% of the allergenicity of the parent protein.
75. The protein variant according to claims 22-29, wherein the protein variant is an enzyme.
76. The protein variant according to claims 75, wherein the enzyme is a protease, … [or one of three other specified types of enzymes].
80. The protein variant according to claim 76, wherein the protease is a subtilisin comprising one or more of the following substitutions corresponding to any of the following substitutions in SEQ ID NO: 10 [identified in the sequence listing as that of B. amyloliquefaciens subtilis subtilisin BPN’]:
[there follows a list of 60 alternative numbered amino acid positions with specified substitutions, relevantly including]
Position 92 to G, A, V, L, I, W, P, M, F, N, Q, Y, S, T, D, E, R, K, H;
Position 93 to G, A, V, L, I, W, P, M, F, N, Q, Y, S, T, D, E, R, K, H;
Position 179 to G, A, V, L, I, W, P, M, F, N, Q, Y, S, T, D, E, R, K, H;
The submissions
Novozymes submitted that WO’559 discloses protease variants with substitutions at positions corresponding to positions 92, 93 and 179 of B. amyloliquefaciens subtilisin having decreased antibody-mediated immunogenicity, and provides detailed instructions for producing the peptide variants presently claimed. Novozymes contended that WO’559 plants a flag at the invention of opposed claim 1.
To support its “mere paper disclosure” submission, Genencor contended that WO’559 teaches so many different variants, that it provides no clear and unmistakable directions to the specific variants presently claimed in the opposed application. Furthermore, it contains no teaching that would lead the skilled addressee to choose the specifically claimed amino acid residues for substitution. In particular, Genencor asserted that WO’559 does not disclose the features of modifying a B cell epitope in the parent protease of interest; or that the altered B cell epitope elicits an altered immunologic response in a human.
Enabling disclosure
There was no argument, and the expert evidence confirms, that the skilled addressee at the priority date would have been able to produce the variants disclosed by WO’559 (CLH#1 at [87]; CLH#2 at [68], [79]; AWP#2 at [CLH68]).
“Mere paper anticipation”
The protease variants claimed in the opposed application represent a class of polypeptides. The structure of each variant encompassed by the claims is derived from a protease of interest with a degree of correspondence with BPN’, such that the positions of the substituted residues can be considered, prior to the substitution, to have corresponded to positions in B. amyloliquefaciens subtilisin BPN’.
The class of polypeptides can be considered analogous to a class of classical chemical compounds. Whether a specific member of the class is disclosed in an earlier document can be determined by applying the principles applicable for chemical compounds.
Justice Bennett in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at [173], in considering the novelty of claims to a chemical compound, provided a number of general principles. Most relevant to this opposition is:
“Where the prior disclosure is to a broad chemical claim encompassing many compounds, there may not be anticipation in the absence of the skilled addressee understanding or perceiving a specific compound in the disclosure (Imperial Chemicals Industries Pty Ltd v Commissioner of Patents (2005) 213 ALR 399 at [64]-[65]). That is, there is no actual description of the particular compound to the skilled addressee; there is no relevant disclosure. There may be a distinction, albeit fine, between a “fleeting” or “paper” disclosure or the “intellectual content” of a disclosure on the one hand and a “disclosure for novelty purposes” or “enabling disclosure” on the other (Imperial Chemicals at [68]; University of Georgia Research Foundation v Biochem Pharma Inc (2000) 51 IPR 222, a decision of Dr Barker of the Patent Office described by Crennan J in Imperial Chemicals as a ‘sound account of the relevant distinctions between a “paper disclosure” and an “enabling disclosure” in the field of chemistry’ (at 412)). It depends on what the skilled reader would understand.”
At [190]-[191], Justice Bennett continued:
“… the Court, armed with the evidence of the skilled addressee as to terms of art and the nature and extent of the disclosure in the prior art document, must determine whether the prior disclosure is sufficient to enable the skilled addressee to perceive, understand and, where appropriate, apply the prior disclosure necessarily to obtain the invention.”
In Imperial Chemicals at [66], Justice Crennan had highlighted “the danger of applying the ‘reverse infringement’ test to broad chemical claims by reference to whether a description of a broad class of compounds encompasses a specific compound later disclosed”. She continued:
“It is possible to imagine many cases where asking the question ‘does a prior claim encompass a later disclosure?’ will give the same practical result as asking the Meyers Taylor question which is ‘would a prior claim constitute an infringement of a later disclosure (if a patent therefor were valid)?’ However, with a claim to a broad class of chemical compounds, such an approach will not always or necessarily dispose of the question of what is taught to a skilled addressee; while no trope should be overworked in the law, on one view, adopting such an approach where the alleged anticipation contains a very broad claim to a whole class of chemical compounds, could lead to a finding of a want of novelty based on the disclosure of a whole flag locker without any teaching (i.e. disclosure for novelty purposes) of a particular flag. ”
As noted above, the WO’559 specification is directed to variants of proteins, including proteases, having altered immunogenicity as compared to the parent protein. Proteases taught by WO’559 include serine proteases such as subtilases, including subtilisin and savinase-like subtilisin (pages 86-89 of the specification and CLH#2 at [26]). BPN’ subtilisin from B. amyloliquefaciens is explicitly identified as a relevant subtilisin, and in much of the document, homologous positions in subtilisin proteases are defined in terms of BPN’ numbering (CLH#2 at [26], [30] - [32]).
Claim 80 appears to be the clearest disclosure of the class most relevant to the opposed application. Claim 80, as dependent on claims 23, 26, 27, 29 and 75-76 in combination, defines a variant of a subtilisin protease with reduced allergenicity (below 75% of the parent protease). The variant differs from the parent protease in having an altered B cell epitope. The variant comprises a specified substitution in any one or more of 60 amino acids positions each defined in terms of the corresponding position in B. amyloliquefaciens subtilisin BPN’. The potentially substituted amino acids include position numbers 93, 93 and 179.

In its novelty submissions, Novozymes noted the statement by Dr Hardy, which was not disputed by Dr Purcell, that the amino acid positions disclosed in the examples and claims of WO’559 have been identified as candidate positions for changing in order to produce variants with modified immunogenicity (CLH#2 at [63]). However, the claims are to specific variants. To anticipate these claims, a prior document must contain clear and unmistakeable directions to the specific variants claimed.
Is there any evidence that these variants were made? When commenting on the disclosure of these particular variants, Dr Hardy states at CLH#2 [67] and [79]:
“67. Variants with mutations at positions 92, 93 and 179 of B. amyloliquefaciens subtilisin are specifically mentioned in [WO’559] in claims 17, 18, 27, 29, 80 and 81 in the context of having decreased antibody-mediated immunogenicity.”
“79. As discussed in points 66 and 67 of this statutory declaration, substitutions at positions 69, 90, 92, 93, 178 and 179 corresponding to subtilisin BPN' had either been previously made (CH-59 [WO’602]) or specifically mentioned in the context of reducing antibody-mediated immunogenicity (CH-58 [WO’559]) at the priority date of the Opposed Application.”
Dr Hardy’s evidence establishes that variants with substitutions corresponding to positions 92, 93 and 179 of B. amyloliquefaciens subtilisin are within the broad disclosure of WO’559. However, it is clear that he does not understand WO’559 to disclose the production of these particular variants. This is consistent with Dr Purcell’s evidence that the document does not clearly show that the specific variants had been made (AWP#2 at [CLH79, 82-86]).
Is there any evidence that the variants with substitutions corresponding to positions 92, 93 and 179 of B. amyloliquefaciens subtilisin are disclosed by WO’599 as preferred embodiments? A review of the claims dependent on claim 80 does not support a view that variants with substitutions at positions 92, 93 and 179 of B. amyloliquefaciens subtilisin are a preferred subset of the broad disclosure of claim 80.

Example 11 of WO’599 determines potential epitope sequences for a number of BPN’-like proteases, using surface scanning and homology modelling (AWP#2 at [CLH12-51]; CLH#2 at [39]). However, only the epitopes located in BPN’ itself are identified in BPN’ numbering. Fifty‑one epitopes were found for BPN’ (pages 256-260); none include the amino acids at positions 92, 93 or 179. Novozymes has provided no evidence that establishes that epitopes of the alternative subtilisins disclosed in Example 11 include amino acids at positions corresponding to those as presently claimed, or that the person skilled in the art would understand the disclosure to include substituting the amino acids at these particular positions. Consequently, I have no basis on which to conclude that the variants of claim 1 are disclosed as preferred embodiments in WO’559.
I have no other evidence before me that establishes that WO’599 discloses the specific protease variants with substitutions corresponding to positions 92, 93 and 179 of BPN’ with sufficient particularity that these could be considered to form part of the technical disclosure of WO’599.
I find claim 1 and dependent claims are novel in light of WO’559. While not necessary for this decision, I will deal with some other issues briefly.
“… an altered B cell epitope …”
Genencor asserted that WO’559 does not disclose or even suggest that the sites to be mutated are actually B cell epitopes. However, given my construction of claim 27 at WO’559 at [30] above, I find that claim 80, as dependent on claim 27, defines a variant with an altered B cell epitope.
“an altered immunologic response ... in a human”
Genencor submitted that the strategy used in the opposed application identifies epitopes using antibodies in sera obtained from humans sensitised to the protease of interest. In contrast, the methodology described in WO’559 relied on antibodies generated in rodents and rabbits, which less closely resembles a real-life model.
A significant amount of the expert evidence addressed the relative merits of the use of human versus animal sera to identify epitopes on proteins of interest, and the effect that different presentation of antigen has on the immune response. Both Dr Hardy and Dr Purcell agree that while rodents can be good models for predicting B cell epitopes in humans, the rodent antibody response will not always exactly mirror the response in humans (AWP#1 at [18]; CLH#2 at [P18]; AWP#2 at [P18]).
It is clear from the evidence that the person skilled in the art would understand that a B cell epitope predicted in a rodent model will not in every instance constitute a B cell epitope in a human. If a B cell epitope predicted in a rodent model is not recognised by the human immune system, substituting its amino acids to make it less immunogenic will have no effect on the immunologic response that the variant epitope elicits in a human. It logically follows that the person skilled in the art would understand that variants generated on the basis of a B cell epitope predicted by a rodent model, will not necessarily produce an altered immunologic response in humans.
Dr Hardy noted a discrepancy between the information in Example 1 of WO’559 and the results presented in Tables 2-3 (CLH#2 at 36]). Example 1, “Identification of epitope sequences and epitope patterns”, discloses screening for epitopes using antibodies generated in rodents. However, Tables 2-3 which include results for two BPN’-like proteases, indicate that while mainly rodent antibodies were used, in some instances human serum was used in the screening procedure.
No relevant variants were tested in WO’559 for altered immunogenicity in humans. However, it is clear from the specification that the disclosure is directed towards modifying the immunogenicity of proteins used in commercial applications for humans such as personal care products, food and pharmaceuticals (see for example, page 1, para 2 and page 6, para 2).
It is questionable whether each variant in WO’599 would in fact exhibit an altered immunologic response in a human. However, given my conclusion at [46] above, that WO’559 does not provide an adequate disclosure of the specific variants to anticipate the opposed claims, it is not necessary to decide the question of the immunologic effect any specific variant of WO’559 would have in a human.
Novelty in light of WO 2003/006602
Novozymes submitted that WO’602 discloses variants of the protease B. lentis subtilisin with mutations at positions corresponding to amino acids 69, 90 and 178 of B. amyloliquefaciens subtilisin. Novozymes asserted that variants that would infringe claim 1 of the opposed application are disclosed as having been made, and consequently, the document contains an enabling disclosure of such variants.
In response, Genencor submitted that the document is directed to mutants that alter subtilase enzyme activity rather than their immunogenicity. Genencor argued that the document contains no mention of the effect any mutation might have on the immune-reactivity of the enzyme, and no mention of changing amino acids to reduce immunogenicity in the enzyme.
Dr Hardy confirms that WO’602 relates to subtilisin variants having improved properties relative to the native protease with regards to cleaning performance, thermal stability, enzyme stability or catalytic activity (CLH#2 at 52). He further describes the document as exemplifying site-directed mutagenesis of subtilase 309 (Savinase®) and production of the variant enzyme containing a substitution, deletion or insertion of an amino acid at, relevantly, the positions corresponding to 69, 90 and 178 of subtilisin BPN’.
Both claim 1 and Example 1 of WO’602 include references to subtilase variants comprising a substituted amino acid at position numbers 69, 90 or 178, or a deletion or insertion of amino acids at these positions. Claim 1 of WO’602 defines a subtilase variant comprising an alteration (specified substitutions, deletion or insertion) at one or more of 52 amino acid positions. The amino acid positions are defined in BPN’ numbering. Example 1 “Construction and expression of enzyme variants” lists 45 amino acid positions and specifies substitute amino acids and/or insertion or deletion of the amino acid at each position and provides directions for site-directed mutagenesis.
Example 2 “Purification of enzyme variants” lists 3 BPN’ and 27 Savinase® variants and explicitly states that these variants had been produced and purified. These variants have one or more alterations (substitutions, 1 deletion) compared to the parent protein. Six have substituted amino acids at relevant positions: position 90 in BPN’ variants; and, in Savinase® variants, the position corresponding to position 139 of BPN’.
The disclosure of WO’602 is not directed to altering the immunologic response of a protease, and does not refer to this feature. Dr Purcell notes that none of these variants were tested for immunogenicity (AWP#2 at [CLH52-62]). Novozymes has presented no evidence that the substituted variants taught by the document would necessarily elicit an altered immunological response in a human. Consequently, the document does not disclose all of the essential features of opposed claim 1 or its dependent claims.

Novozymes has not established that the opposed claims lack novelty in light of WO ‘602.
Inventive step
Under the provisions of subsections 7(2) and 7(3) of the Patents Act 1990, an invention is taken to involve an inventive step when compared with the prior art base unless it would have been obvious to a person skilled in the art. The invention must be obvious in the light of the common general knowledge as it existed in the patent area before the priority date, either on its own or together with information in a document, or combination of documents, that the person skilled in the art could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant and, where necessary, combined.

“Obvious” means “very plain” (Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21 at [51]; (2007) 72 IPR 447 at 461 [51]).

The test for obviousness is whether it would have been a matter of routine to proceed to the claimed invention.
“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.” (Aicken J in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12 at [45]; (1981) 148 CLR 262 at 286)
More recently, the High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59 at [51] - [53]; 212 CLR 411 at [51] - [53] approved the approach taken in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at 187 in which Graham J had posed the 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 claimed invention] in the expectation that it might well produce a useful [desired result]?”
The usual approach to obviousness is the problem-solution approach. Once the problem has been formulated, and the common general knowledge and the prior art base have been determined, the question of whether the claimed solution is obvious must be addressed.
The problem
Novozymes, referring to Dr Hardy’s first declaration at [61] - [62], submitted that the problem addressed by the opposed application is that the use of proteins in industrial, pharmaceutical and commercial applications has resulted in the sensitisation of numerous individuals to these proteins, resulting in the widespread occurrence of allergic reactions to these proteins. Accordingly, there was a need in the art to identify proteins that produce enhanced and reduced immune responses.

Genencor disagrees, arguing that the opponent has not fully appreciated the invention of the opposed specification. Genencor submits that the opponent does not acknowledge the importance and relevance of using human sera to identify clinically relevant epitopes on the protease of interest. By “clinically relevant” epitopes, I understand Genencor to mean those most relevant to the development of hypersensitivity and allergy in humans.
In this case, there is no suggestion in the specification that the inventive step was the discovery of the true nature of the problem. To the contrary, the specification identifies a problem that the invention addresses. On pages 9-10 under the heading “Description of the invention”, the description summarises prior methods of reducing the allergenicity of proteins. While various strategies have been reported:
“… due to the large number of variants disclosed, one of skilled in the art is presented with a problem with respect to identifying an optimal protease product with reduced immunogenic potential suitable for use in personal care and/or other applications.”
Notwithstanding that the claims are drafted to encompass variants exhibiting both reduced and enhanced immunological responses, given the explicit statement of the problem in the specification, I consider the problem addressed by the opposed application is to identify the most clinically relevant epitopes in a protease of interest in order that these epitopes can be modified to produce optimal protease products with altered immunogenic potential.
The solution
Novozymes, relying on Dr Hardy’s evidence and passages from the description, identified the solution as to identify B cell epitopes within a protease and modify these so as to reduce or preferably neutralise (eliminate) the ability of the B cell to identify that epitope.

I have found the problem to relate to identification of the most clinically relevant epitopes, in order to produce optimal variants with altered immunogenic potential. Therefore, I agree with Genencor’s submission that the solution in this case is to use sera from sensitised human individuals to identify the clinically relevant epitopes on a protease of interest. Dr Purcell’s evidence supports this conclusion (AWP#1 at [17]; AWP#2 at [CLH8 P16]).
The person skilled in the art
Consistent with the parties submissions, the person skilled in the art in this case is a person or team who, at the priority date, had expertise in molecular biology and protein engineering with a knowledge of immunology and in particular allergy.

There was no argument that Dr Purcell was a person skilled in the art at the priority date.
Regarding Dr Hardy, Genencor acknowledged his experience in immunology, but submitted that it was not clear where he was employed on 31 December 2001 and consequently, whether he could be considered a relevant person skilled in the art. In particular, Genencor noted that before the priority date, Dr Hardy had worked on the role of various molecules in viral clearance as well as T cell proliferation and migration and his publication immediately before this date related to T cells.
Dr Hardy’s curriculum vitae records his current position as Senior Research Officer attached to the Department of Immunology at Monash University and The Department of Immunology & Respiratory Medicine at The Alfred Hospital. Under the heading “Previous positions” Dr Hardy held postdoctoral research positions between August 1995 and February 2000. From the details provided, Dr Hardy’s work in each of these positions before the priority date is clearly in the field of immunology.
At paragraphs 10 and 11 of his first declaration, Dr Hardy’s description of his practice in comparison to that of his colleagues in the same research area (allergy research), confirms that his immunology experience extended to the allergy field at the priority date of the application.
“10. I have been asked to comment on what was commonly known in the field of allergy research as at 31 December 2001. … Unless specifically indicated to the contrary, the comments in this section of my declaration (paragraphs 13 to 31) relate to what I knew and to what, in my opinion, was generally known in the allergy research community at the priority date.
11. As was common practice among those working in the field of allergy research at the priority date, I regularly carried out literature searches (approximately weekly). I regularly reviewed articles in the journals mentioned below at the priority date and I believe my colleagues working in the same research area would also have done so.”

I find that Dr Hardy was a person skilled in the relevant art at the priority date of the application.
The prior art base
Novozymes submitted that the invention of opposed claim 1 lacks an inventive step in light of the common general knowledge in the art alone, and in combination with any one of three published patent documents as follows:
WO 2001/083559 (Novozymes A/S) 8 November 2001
WO 1992/010755 (Novo Nordisk A/S) 25 June 1992
WO 2001/007575 (The Procter & Gamble Company) 1 February 2001
WO 2001/083559 is in evidence as CH-58, WO 1992/010755 as CH-28, and WO 2001/007575 as CH-29. In all cases, publication occurred before the priority date of the opposed application, and consequently the documents are part of the prior art base for the consideration of inventive step.
Inventive step when compared with the common general knowledge in the art
The experts were substantially in agreement as to the common general knowledge in the art at the at the priority date (CLH#1 at [10] – [32]; AWP#1 at [21]).
In its submissions, Novozymes summarised the common general knowledge as follows:
· methods to identify B cell epitopes were well known at the filing date of the opposed application (CLH#1 at [18]; AWP#2 at [CLH8 P16] and [CLH88-89]); and
· modification of allergens by mutation or deletion of amino acids in B cell epitopes in order to modify/decrease allergenicity were well known at the filing date of the opposed application (CLH#1 at [31]).
Novozymes submitted that, as discussed in the first Hardy declaration at [32], in order to alter the allergenicity of a protein, the skilled addressee, at the priority date of the present application, would identify the B cell epitope, mutate amino acids within the B-cell epitope and test (a) for allergenicity, and (b) for protein function efficacy. Novozymes argued that given Dr Hardy’s evidence, which includes the option to identify B cell epitopes using sera from among other sources, allergic patients, that the subject matter of the claims:
·     is an option that the person skilled in the art would have considered in solving the identified problem at the priority date;
·     the option would at once suggest itself to the person skilled in the art;
·     there was no practical difficulty in implementing the particular solution claimed (as acknowledged by Dr Purcell in his second declaration at [CLH74-75]; and
·     the common general knowledge does not teach away from the claimed solution.
Novozymes contended that the skilled addressee would be led directly as a matter of course by the common general knowledge discussed above to produce a variant of a protease of interest with at least one substitution at a position corresponding to the B-cell epitope in the expectation that it might well produce a protease with an altered immunological response in humans.

Novozymes provided no submissions and led no evidence to establish that the person skilled in the art would proceed from the common general knowledge (which included the use of sensitised rodent sera) to the particular variants of claim 1 as a matter of routine. Consequently, it has not been established that opposed claim 1 and dependent claims lack an inventive step in light of the common general knowledge in the art.
Ascertained, understood and regarded as relevant
Section 7(3) provides that a document is prior art for the purposes of inventive step if the person skilled in the art could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded as relevant. “Ascertained” means found or discovered (Commissioner of Patents v Emperor Sports Pty Ltd [2006] FCAFC 26 at [29]-[30]; (2006) 67 IPR 488 at [29]-[30]).

Genencor, relying on Dr Purcell’s evidence, submitted that any patent literature should be disregarded for inventive step purposes, because it would not have been ascertained by the skilled addressee at the priority date as a matter of routine. In particular, Genencor argued that only an inventive worker in the field would be inclined to search the patent literature.

Dr Purcell’s evidence on this point is as follows:
“I was aware, in December 2001, that patent literature could be searched and had searched this literature with the assistance of an experienced patent attorney, but only when considering potential intellectual property generated by my laboratory or in the preparation of provisional patent applications based on my research. Searches of the patent literature did not form a part of my regular literature searches in December 2001.” (AWP#1 at [H33])
Dr Hardy’s evidence is:
“In December 2001 I was aware of, and had a growing interest in the patent literature and the protection of intellectual property via patents. While I cannot be certain of the date on which I personally started to search the patent literature, I believe it would have been around the time of the priority date. At any rate, at the priority date, I knew patent searches could be carried out and was aware that experts e.g., patent attorneys, could be engaged to do so.” (CLH#1 at [33])
“I am aware that, at the priority date of the Opposed Application, many of my colleagues working in the field of allergy research were also familiar with the concept of patent literature searching and were conducting searches either alone or with the assistance of a patent attorney.” (CLH#2 at [PH33])

The expert evidence establishes that at the priority date the person skilled in the art was aware that the patent literature could be searched. Some searched the patent literature at this date, and some only searched it in relation to their own intellectual property matters.

Since some people did consult the patent literature, it is reasonable to conclude that an average skilled person could be reasonably expected to consult the patent literature. Each of the documents cited by Novozymes for inventive step purposes provides methods for identifying relevant B cell epitopes in a protein, in order that these can be altered to reduce the immunogenicity of the protein. Each document is directed to a similar problem. Consequently, I am satisfied that the skilled person searching the patent literature seeking to solve the problem would have ascertained these documents.
There was no argument that the person skilled in the art would not have understood and regarded each of these documents as relevant.
Inventive step in light of WO 2001/083559
The disclosure of WO’559 has been summarised above at [29] - [30]. Briefly and most relevantly, the document addresses a need in the art for methods to identify epitopes on proteins that can trigger unwanted allergic reactions in susceptible individuals, and provides a method of selecting a protein variant having modified immunogenicity as compared to a parent protein. The method described used peptides or protein fragments to detect binding by antibodies from rodents and rabbits. However it is apparent from the results presented that rodent and human antibodies were used. (CLH#2 at [34], AWP#2 at [CLH12-51])
The clearest disclosure of variants relevant to this opposition is contained within WO’559 at claim 80 of WO’559, as dependent on claims 23, 26, 27, 29 and 75-76 in combination.
Genencor submitted that given that WO’559 identifies a large number of sites that could be altered either individually or in combination with at least 8 alternative residues in each case, there would be an enormous amount of experimentation involved in arriving at the presently claimed invention. Furthermore, that in the absence of any indication in the document of an acknowledgement of the limitations of the method used, the claims of the opposed application must involve an inventive step.
As I have found above, the solution to the problem addressed by the opposed application was to use sera from sensitised humans to identify clinically relevant epitopes in a protease of interest, in order that these could be altered to produce an optimal variant with altered immunogenicity.
Therefore, the question to be answered is whether, at the priority date, it would have been a matter of routine for the person skilled in the art to substitute human for rodent sera in the method taught by WO’559 in order to identify the most relevant epitope sequences and patterns in the broad disclosure of the document. If the answer to this question is yes, a second question is whether this would this lead to the variants as presently claimed.
Matter of routine – rodent to human sera
In his first declaration at [18], Dr Hardy describes the processes involved in the identification of B cell epitopes by detecting the binding of specific antibodies. At [32], without knowledge of the application or cited documents, Dr Hardy relevantly states that at 31 December 2001, in order to identify B cell epitopes he would have mapped them in the protease of interest using sera from “allergic patients, sensitised mice, etc”.
Regarding the use of sera from pre-sensitised humans (e.g. allergic patients), Dr Hardy, having conducted a trial search of the database PubMed, concludes that the idea of mapping B cell allergen epitopes via antibody binding with human sera was well established and disclosed in the literature at the priority date (CLH#2 at [P16]).

Dr Purcell agreed that the general concept of identifying human B cell epitopes using sera was known at or before the priority date (AWP#2 at [3, CLH8 P16]).
“… Whilst I agree that the general concept of identifying human B cell epitopes using sera was known to the field at or before the priority date, I still find that the identification of B cell epitopes in humans sensitised to B. amyloliquefaciens subtilisin, albeit using approaches that represented best practice at that time, to be new and non-obvious. In particular, the combination of using individuals to identify specific B cell epitopes from the allergen allowed immunogenic regions of B. amyloliquefaciens subtilisin to be identified. Several B cell epitope-containing regions were identified; residues 61-75, 86-100, 126-140, 166-180,202-220, 210-225 and 246-260. At the time of the invention these regions were not known to be immunogenic in allergic individuals.”
Important in that statement, is Dr Purcell’s description of the use of sera from sensitised humans to identify B cell epitopes as “best practice at the time”.
As indicated at [49] – [50] above, the person skilled in the art at the priority date was aware of the limitations of using rodent sera to predict B cell epitopes, in that the results achieved would not always exactly mirror the immune response in humans. Having read WO’559, which discloses a rodent model, what would the person skilled in the art have done at the priority date in order to identify the most clinically relevant epitopes from the large number of predicted epitopes disclosed in the document?
I believe it is reasonable to conclude that the person skilled in the art at the relevant date in all the circumstances would directly be led as a matter of course to apply the best practice at the time i.e. to use sera from sensitised humans to screen proteases of interest for B cell epitopes, with a reasonable expectation this strategy would identify the most clinically relevant of those epitopes, in order that these can be modified to produce an optimal protease product.
Matter of routine – from human sera to the claimed variants
Would the person skilled in the art then have taken as a matter of routine the steps that lead to the variants as presently claimed?
An epitope on a protein is a question of fact. While there may be multiple epitopes on a protein, and variation between individuals in their immune responses, this can be overcome by the use of pooled serum samples i.e. sera (plural) obtained from pre-sensitised individuals. By using antibodies in sera from sensitised humans in the place of rodent sera in the method disclosed by WO’559, it is reasonable to expect that the most clinically relevant B cell epitopes will be identified on a protease of interest. However, the opposed claims are not to an epitope per se. The claims specify substitution of an individual amino acid at one or more specific positions in the B cell epitope of the protease of interest.
At the priority date, Dr Hardy’s approach to altering the allergenicity of a protein used in industry would have been to alter the B cell epitope. Having identified a B cell epitope, he would have mutated amino acids within it by site-directed substitution or deletion according to standard molecular biology techniques, and then tested the mutants (variants) for allergenicity and for protein function. (CLH#1 at [32]) Dr Purcell agreed that this was a practical and reasonable approach to alter the allergenicity of a protease (AWP#1 at H32).
Dr Hardy refers to mutation of amino acids in the plural. The production and testing of a number of mutants is consistent with the disclosure of exhibit CH-17 (Ferreira, F. et al (1998) FASEB J 12: 231-242) that Dr Hardy cites to exemplify his strategy, and also with the examples in WO’559 itself (see for Example the results Table in Example 5).
I consider it reasonable to conclude that having identified the relevant B cell epitopes, the person skilled in the art at the priority date would have routinely prepared a number of variants containing either a substitution or deletion of one or more amino acid residues within the epitope, and then tested them for allergenicity and to confirm functionality. However, in this process there were choices to be made. Any given amino acid could be substituted or deleted and I have no evidence that skilled person would have done both. Furthermore, it is not clear that the skilled person would have targeted every position in an epitope. To the contrary, in Ferreira, F. et al. the authors identified 8 positions likely to influence IgE binding, but chose to substitute only 5 of these (Ferreira, F. et al. page 234, right column, para 2).
The evidence does not establish that the person skilled in the art, having read WO’559, would have prepared the specific variants as presently claimed as a matter of routine. Consequently, Novozymes has not established that the opposed claims lack an inventive step in light of this document.
Inventive step in light of WO 1992/010755 and WO 2001/007575
Both parties combined their submissions as to the relevance of WO’755 and WO’575 for inventive step purposes. The issues raised by the documents are very similar. Accordingly, where the issues are the same I will discuss the documents together for convenience, although each document is being considered separately for inventive step purposes.
The submissions
Novozymes submitted that each of WO’755 and WO’575 identifies B cell epitopes in subtilisins, and substitution of at least one amino acid within the identified B cell epitope to produce a variant with an altered immunologic response. In response, Genencor argued that the documents contain no specific disclosure that, at the priority date, would lead the person skilled in the art to substitute the presently claimed residues, alone or in combination with any others.
WO 1992/010755
WO’755 is titled “Proteins with changed epitopes and methods for the production thereof.” The invention is said to relate to methods for modifying proteins used in industry and medicine. The proteins are epitope mapped and their amino acid sequence genetically engineered to make them less immunogenic. (page 1, para 1) The document discloses variants of subtilisin 309, with specific mutations defined in terms of BPN’ numbering (page 9, paras 1-2).

The evidence establishes that WO’755 discloses subtilisin variants with reduced antibody-mediated responses, due to alterations at a B cell epitope. Variants were screened for altered immunogenicity using rodent sera. (CLH#1 at [38], [75]; AWP#1 at [H38-43])
WO 2001/007575
WO’575 is titled “Subtilisin protease variants having amino acid deletions and substitutions in defined epitope regions”. On pages 1-2, the invention relates to genetically engineered subtilisin proteases which evoke a decreased immunological response, which are useful in compositions such as personal care compositions, and laundry and cleaning compositions. The document discloses subtilisin variants, with specific mutations defined in terms of BPN’ numbering (page 2, second full para).

Dr Purcell suggests at [24] of his first declaration that the epitopes taught by WO’575 may be T rather than B cell epitopes. However, it is clear from Dr Purcell’s evidence as a whole that although often distinct, there may be some overlap between T and B cell epitopes (AWP#1 at [20], [H35-7], [H50-6]). Furthermore, I note Dr Purcell’s qualification “even though some antibody measurements were made using the mouse intranasal test” (AWP#2 at [24]). Based on the antibody responses measured in this document, Dr Hardy understands it to disclose modification of B cell epitopes (CLH#1 at [44] – [45]). On balance, it has not been established that WO’575 does not relate to B cell epitopes, albeit that these may also be T cell epitopes.
Consideration
Neither WO’755 nor WO’575 discloses the specific substitutions of opposed claim 1 (Exhibit CH-45, a “novelty table”). Novozymes asserted that the B cell epitope regions identified in each document show some overlap with those identified in the description of the opposed application. However, from Dr Purcell’s evidence (AWP#1 at pages 17-19), none of these overlapping regions relate to the particular amino acid residues in opposed claim 1. Therefore, even if the person skilled in the art had set out to identify the most relevant of these epitopes, it does not appear that it could lead to the variant of opposed claim 1.

However, even if, using sera from pre-sensitised humans, the skilled person had identified additional B cell epitopes in the parent proteins taught by WO’755 or WO’575, for the reasons provided above at [102] – [107], it could not be considered a matter of routine to proceed from these prior documents to the presently claimed variants.
Novozymes has not established that the opposed claims lack an inventive step in light of WO’755 or WO’575.
Manner of Manufacture
Section 18(1)(a) requires that an invention must be a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. Manner of manufacture is assessed by asking whether the claimed invention lacks the necessary quality of inventiveness on the face of the specification (NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15 at [9]; (1995) 183 CLR 655 at 655).

Novozymes submitted that the specification does not satisfy the requirements of section 18(1)(a) because the claimed invention is merely the result of the application of known methods, to achieve “a similar/analogous result” to that obtained in prior art document WO 92/10755 referred to in the opposed specification. This document is in evidence as CH-28.

To establish this ground of opposition, Novozymes relied on a statement in the opposed specification at pages 9-10, that WO’755 describes a method of producing protein variants evoking a reduced immunogenic response in animals. The method involves immunising rats with the proteins of interest (a series of proteases and variants thereof), and determining the reactivity of the antibodies produced, in order to analyse which changes in the protein were likely to neutralise or reduce antibody binding. The opposed specification notes that a conclusion was drawn in WO’755 that changing a number of specified subtilisin 309 residues would result in a change in the immunogenic potential of the enzyme. Novozymes also relied on the reference in Example 3 of the opposed specification to the use of “established protease engineering techniques known in the art” to construct low allergenic stable protease variants.

Genencor submitted that the present invention provides clinically relevant B cell epitopes and the opposed application relates to new and useful epitopes which provide a significant advantage over those taught by WO’755.

WO’755 is not incorporated by reference into the opposed specification and no other matter can be read into the opposed specification from this document other than is explicitly disclosed. At pages 9-10, after briefly referring to the similar disclosure in WO’755 and three other patent documents, the opposed specification states that, due to the large number of variants disclosed, one of skill in the art is presented with a problem with respect to identifying an optimal protease product with reduced immunogenic potential suitable for use in personal care and/or other applications.”

Given that on its face, the opposed specification is directed at producing optimal proteases, rather then simply alternative or analogous proteases, it is not apparent that the claimed matter is obvious on the face of the specification.
It has not been established that the present invention is not a manner of manufacture.
Useful
The requirements for utility in a claimed invention under section 18(1)(c) were provided by the Full Court of the Federal Court as follows:
“If the claimed invention does what it is intended by the patentee to do and the end result obtained is itself useful, the invention is useful within the meaning of s 18(1)(c) … As to the first aspect, the invention as claimed must attain the result promised by the patentee” (Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC [2008] FCAFC 82 at [141]; (2008) 77 IPR 449 at 479 [141])
“A claim is bad if it covers means that will not produce the desired result, even if a skilled person would know which means to avoid. That is to say, everything that is within the scope of a claim must be useful, otherwise the claim will fail for inutility.” H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at 247 [81], 272 [217]; (2009) 81 IPR 228 at [81], [217]
In construing the claims for the purposes of utility, the claims must be construed from the perspective of a skilled addressee in a commonsense way, and not in such a way that any such addressee would appreciate would lead to an unworkable result (SNF (Australia) Pty Ltd v Ciba Speciality Chemicals Water Treatments Limited and Others [2011] FCA 452 at [293]; (2011) 92 IPR 46 at 212 [293], Inverness Medical Switzerland GmbH v MDS Diagnostics Pty Limited [2010] FCA 108 at [117]; (2010) 85 IPR 525 at 551 [117]).
Novozymes submissions under this ground were that not every variant falling within the scope of the claims would produce the desired result of altered immunogenicity. In addition, it was asserted that claims 13-20 defining skin care compositions encompassed those containing variant peptides with increased immunogenicity, which will not allow for “skin care”.

On the first point, by virtue of part (ii) of the claim, the scope of clam 1 does not encompass variants that will not elicit an altered immunogenic response in a human when compared with the parent protease of interest.
With regard to the second point, Novozymes noted in particular that since dependent claims 5-6 specifies a lower immunologic response, it follows that claim 1 and dependent claims 13-20 must necessarily encompass skin care compositions comprising variants with increased allergenicity. In response, Genencor argued that the production of skin care compositions comprising such variants is an absurd result which should be ignored.
While the production of skin care compositions containing allergenic compositions may be undesirable, I agree with Novozymes that properly construed, claims 13-20 encompass compositions comprising variants with increased allergenicity. The use of such compositions would clearly be deleterious if applied to the skin of persons who are sensitised to the allergen or at risk of developing hypersensitivity on exposure. The question is whether, on this basis, such compositions should be considered not useful for the purposes of section 18(1)(c) of the Patents Act?
The term “skin care compositions” is defined in the specification as:
“… products used in topical and topical application for cleaning and/or moisturising skin. Such compositions include, but are not limited to moisturizing body washes, shower gels, body lotions, moisturizing facial creams, make-up removers, and lotions.”
Such compositions, where they contain a highly allergenic protease variant, would be contraindicated for use in sensitised individuals, or those at risk of developing hypersensitivity. In other people its use would produce no adverse effects. The ability of the composition to provide skin care is separate and distinct from its capacity to cause adverse reactions, notwithstanding that both would be evident at the site of application. Therefore, it does not follow that the composition per se is not useful for its primary purpose, i.e. the promised result of providing skin care such as cleaning and/or moisturising.
Other than that an adverse reaction may occur in some people, Novozymes has provided no evidence or argument that the claimed skin care compositions would not achieve the promised result of skin care.
Novozymes has not discharged the onus of establishing that the claimed skin care compositions are not useful for the purposes of section 18(1)(c).
Section 40 issues
Section 40(3): Clarity
A claim is lacking in clarity if a third party could not ascertain whether an act would fall within the scope of the claim (Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59 at 60). However, a claim does not lack clarity because it uses inexact language or is difficult to construe, as long as it provides a “workable standard” suitable to the intended use (Minnesota Mining & Manufacturing Co v Beiersdorf (Aust) Ltd [1980] HCA 9 at [46]; (1980) 144 CLR 253 at 274).

Novozymes submitted that claims 1 and 21-22 lack clarity. Claim 1 because:
(i)the phrase “the B cell epitope of the protease of interest” renders the claim unclear;
(ii)it is unclear if the protease of interest can be any protease having amino acids corresponding to that of B. amyloliquefaciens subtilisin, or if the claims are limited to B. amyloliquefaciens subtilisin; and
(iii)the claim is indeterminate because it encompasses a variant that: (a) is not a protease; (b) is of indeterminate length/sequence; and (c) bears minimal resemblance to the protease of interest or BPN’ subtilisin.

Novozymes contended that omnibus claims 21 and 22 are not clear because the specification contains no description of variants with mutations at the positions indicated in claim 1 which provide an altered immunological response in humans or any examples of any such variants.

I have found that the claims are capable of construction. The scope of the omnibus claims is the same as the claims to which they are appended. Although claim 1 is broad in its scope, I believe that based on a comparison of aligned amino acid sequences or atomic co-ordinates in the tertiary structures, a person skilled in the art could ascertain whether any given protein or peptide would fall within the scope of the claim.
It follows that claims 1 and 21-22 are clear.
Section 40(3):Fair basis

The test for fair basis was given by the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58 at [69]; (2004) 217 CLR 274 at 300 [69] as:
“… 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.”
Novozymes submitted that the opposed specification does not contain a real and reasonably clear disclosure of the claimed variant with reduced allergenicity, because it does not:
(i) identify the specific amino acids involved in forming the B cell epitopes on B. amyloliquefaciens subtilisin or on any other subtilisin or protease of interest; or
(ii) demonstrate that substitution in a protease of interest of at least one amino acid at a residue corresponding to those listing in claim 1 results in a variant with an altered B cell epitope or that such a variant would result in an altered immunologic response in a human.
To support this argument, Novozymes pointed to the evidence of Dr Hardy that the results of mutations cannot be predicted, and that the specification contains no data to support the idea that variants with the mutations of claims 1, 2 and 3 would alter the immunogenicity of the variant with respect to the protease (CLH#2 at 77). Novozymes noted that Dr Purcell’s evidence does not suggest that the specific amino acids involved in forming B cell epitopes on B. amyloliquefaciens subtilisin have been identified in the opposed application.

Novozymes arguments for fair basis appear to address the inventive merit of the claimed subject matter. This is not relevant to the question of fair basis, which requires consistency of the claims with the matter described in the specification. In Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2011] FCAFC 132 at [63], Justice Jagot emphasised that fair basis is concerned with the way the patent is drafted rather than the merit of the claimed subject matter:
“In order to gain the monopoly sought, the patent must satisfy the statutory tests in the Act. Some tests are directed to the way in which the patent is drafted, others to the right of the patentee to the claimed monopoly. A patent that satisfies the drafting requirements, for example where claims are fairly based on the description in the body of the specification, may still be liable for revocation [under other grounds].
…
Section 40(3) of the Act provides that the claims of a patent must be fairly based on the matter described in the specification. … As the High Court emphasised in [Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; 62 IPR 461] section 40(3) does not involve an analysis of the inventor’s rights to the invention but whether, as a matter of drafting, the claims can be said to reflect what is disclosed or stated in the body of the specification.”
In the present case, the matter in the claims appears in the consistory clauses on pages 5-8 of the description and further on page 33, line 17 to page 34, line 23. There is nothing in the specification that is inconsistent with the consistory statements. Although the specification does not provide data to establish that the claimed variants demonstrate altered immunogenicity, this feature is scientifically plausible and may be reasonably inferred from the information provided.

The opposed claims relate to a subset of the variants disclosed and originally claimed in the specification. However, I accept Genencor’s submission that the presently claimed variants do not represent a selection, but rather restriction of the claims to a subset which were not identified in the documents served as evidence in support.

I find the claims are fairly based.
CONCLUSION
The opposition fails on all grounds.
COSTS
Novozymes, in effect, submitted that costs should follow the event. Genencor requested additional costs due based on Novozymes service of further evidence.
After the evidence in support was filed, Genencor amended the claims, significantly narrowing their scope. The further evidence filed by Novozymes related specifically to the matter in the claims as amended. Given the breadth of the accepted claims, and the nature of the amendments, I do not consider Novozymes actions unreasonable. Consequently, I can see no reason to depart from the normal award of costs.
I award costs in accordance with Schedule 8 against Novozymes A/S.
Dr B. Akhurst
Delegate of the Commissioner of Patents