CSL Limited v Grifols S.A - [2015] APO 8

IP AUSTRALIA
.
AUSTRALIAN PATENT OFFICE
CSL Limited v Grifols S.A. [2015] APO 8

Patent Application: 2008255137

Title:Process for obtaining a concentrate of Von Willebrand Factor or a complex of factor VIII/Von Willebrand Factor and use of the same

Patent Applicant:  Grifols S.A.
Opponent:  CSL Limited
Delegate:  Dr B. Akhurst
Decision Date:  3 March 2015
Hearing Date:  10 December 2014, in Canberra
Catchwords:  PATENTS - section 59 - manner of manufacture – claimed subject matter is not obvious on the face of the specification – novelty – parameteritis – features have been chosen to have a technical effect - lack of novelty not established – inventive step – not established – utility – a claim encompasses subject matter that would not achieve the promise of the invention – full description – not established – fair basis – not established

Representation: Patent applicant: Ms Shanaz Irani of Spruson & Ferguson, Sydney.
Opponent:Dr Bill Pickering and Dr Tania Uren of Davies Collison Cave, Melbourne.

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2008255137

Title:Process for obtaining a concentrate of Von Willebrand Factor or a complex of factor VIII/Von Willebrand Factor and use of the same

Patent Applicant: Grifols, S.A.
Date of Decision: 3 March 2015
DECISION
The opposition is successful. Claim 11 is not useful.
Grifols has 2 months from the date of this decision to propose amendments to overcome the deficiency.
Costs are awarded against Grifols.
REASONS FOR DECISION
Background

Patent application 2008255137 was filed by Grifols, S.A. (Grifols) on 4 December 2008, claiming priority from basic application ES 200800021 filed on 8 January 2008. The application was examined and advertised as accepted on 7 April 2011.
CSL Limited (CSL) served a notice of opposition to grant of a patent on 12 July 2011, followed by a statement of grounds and particulars on 7 October 2011. Evidence in support was completed on 7 June 2012, evidence in answer on 26 June 2013 and evidence in reply on 25 September 2013. A subsequent request by Grifols to file further evidence was allowed, and the evidence filed on 9 January 2014. CSL filed responding evidence on 7 March 2014. A request by CSL to adduce a document referred to in the responding evidence, but omitted from the exhibits, was allowed as further evidence on 15 October 2014. A request to amend the statement of grounds and particulars was allowed on 22 October 2014.
The matter was heard on 10 December 2014 in Canberra. CSL filed its summary of submissions on 1 December 2014. Grifols’ summary was received on 8 December 2014.
The Evidence
Evidence in support consisted of a declaration by:
· Dr David Eakins (Eakins) dated 6 June 2012 with Exhibits DE-1 to DE-9
Evidence in answer consisted of declarations by:
· Dr Neil Howard Goss (Goss#1) dated 8 May 2013 with Exhibits NHG-1 to NHG-5
· Dr Mark Patrick Smith (Smith#1) dated 21 June 2013 with Exhibits MPS-1 and MPS-2
Evidence in reply consisted of declarations by:
·     Dr Hung Pham (Pham#1) dated 20 September 2013 with Exhibits HP-1 to HP-5
·     Dr Albrecht Gröner (Gröner) dated 24 September 2013 with Exhibits AG-1 to AG-7
·     Dr Darryl William Maher (Maher) dated 25 September 2013 with Exhibit DM-1
Grifols’ further evidence consisted of declarations by:
· Dr Mark Patrick Smith (Smith#2) dated 20 December 2013
· Dr Neil Howard Goss (Goss#2) dated 12 December 2013
CSL’s responding evidence consisted of a declaration by:
· Dr Hung Pham (Pham#2) dated 7 March 2014 with Exhibits HP-6 to HP-8
CSL’s further evidence consisted of a declaration by:
· Dr Hung Pham dated 6 October 2014 with Exhibit HP-9
Grounds of opposition
The grounds of opposition pressed by the opponent were manner of manufacture, novelty and inventive step, utility, full description, clarity and fair basis.
Onus of Proof
The request for examination in relation to the patent application was filed on 29 April 2009. As a consequence, substantive amendments of the Patents 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 exists. Instead, 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 (F.Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [29], [67]; 50 IPR 305; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18], [22]; 79 IPR 426).
The specification
The complete specification is not to be read in the abstract. It must be construed through the eyes of the person skilled in the art, in the light of the common general knowledge and the art before the priority date (Kimberley Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 at [24]; 207 CLR 1 at 16). Further 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).
The specification is titled “Process for obtaining a concentrate of Von Willebrand Factor or a complex of factor VIII/Von Willebrand Factor and use of the same”. Grifols’ experts and Dr Maher have provided a summary of the role of Von Willebrand Factor (VWF) and Factor VIII (FVIII) which I have relied on for the following background summary.
Von Willebrand’s Factor and FVIII are blood plasma proteins that, together with small blood cells known as platelets, are necessary for blood coagulation (clotting). Blood coagulation is important to stop blood loss from a damaged blood vessel, a process known as haemostasis. The haemostatic process involves formation of a platelet plug at the site of the wound (primary haemostasis). In addition, and almost concurrently, clotting factors, including VWF and FVIII, respond in a complex cascade to form fibrin strands which strengthen the platelet plug (secondary haemostasis).
Von Willebrand Factor is the largest known soluble protein, ranging in size from a monomeric 260 kDa subunit to multimeric complexes of more than 20,000 kDa. The higher molecular weight forms of VWF are essential to primary haemostasis, and act by binding to the damaged surface of the blood vessel and facilitating platelet adhesion. In addition, VWF acts as a carrier protein for FVIII, which circulates in the blood in an inactive form non-covalently bound to VWF. Deficiencies in functional VWF or FVIII leads to the bleeding disorders Von Willebrand’s disease (VWD) and Haemophilia A (HA), respectively. Von Willebrand’s disease may be mild or severe depending on the nature of the defect. With no recombinant form available, severe VWD can only be treated with VWF derived from human plasma.
On page 1 of the opposed specification, the invention relates to a therapeutic concentrate of VWF or a FVIII/VWF complex and a process for producing a medicinal compound indicated for the treatment of VWD and HA, which has been nanofiltered through a pore size of less than 35 nm, through which virus contamination can effectively be eliminated.
On page 4, filtration through membrane pores in the nanometre range has been shown to be effective in the removal of enveloped and non-enveloped viruses and other infectious particles such as prions. On page 6, prior to the application, there was no therapeutic concentrate indicated for the treatment of VWD that had been filtered though a 20 nm membrane, and filtration of high molecule weight VWF through 20 nm pores was not thought possible. On pages 9-10, the inventors have surprisingly demonstrated that a solution containing VWF or FVIII/VWF complex can be filtered under certain conditions to obtain a high-purity medication suitable for the treatment of VWD and HA.
The claims
The correct approach to the construction of claims was discussed by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70, 81 IPR 228 at [118] – [120]:
“… 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 them, having regard to his or her own general knowledge and to what is disclosed in the body of the specification …
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 …”
The specification contains 13 claims, reproduced below. Claims 1 and 12 are independent. ‘Omnibus’ claim 12 defines the process of claim 1 by reference to the Examples.
Claim 1
1.A process for obtaining a concentrate of Von Willebrand Factor or a complex of Factor VIII/Von Willebrand Factor of human or recombinant origin, characterised by:
a) preparation of a solution of Von Willebrand Factor or a complex of Factor VIII/Von Willebrand which contains VWF in a concentration of up to 12 IU VWF:RCo/ml and a proportion between Von Willebrand Factor/Factor VIII of 0.4 or more,
b) nanofiltration of the solution prepared in a) through a filter having a pore size of 20 nanometers, at a maximum pressure of less than or equal to 0.5 bar, in the presence of calcium ion and at a pH greater than 5.5.
Claim 1 part a) defines a solution to be filtered and part b) provides the filtration conditions.
An ambiguity arises in claim 1 regarding the measurements used to calculate the VWF/FVIII proportion, because both proteins can be quantified in terms of concentration or their activities. A further ambiguity arises as to whether the proportional requirement in part a) applies only to solutions containing both proteins, or also to solutions of VWF alone. In order to resolve an ambiguity it is permissible to resort to the body of the specification to define or clarify the meaning of words used in the claim without infringing the rule that clear and unambiguous words in the claim cannot be varied or qualified by reference to the body of the specification (Interlego AG v Toltoys Pty Ltd [1973] HCA 1 at [14]; (1973) 130 CLR 461 at 479. Relevantly, the description on page 10 states:
“The solution which has to be filtered is characterised in that it has a VWF:RCo/FVIII activity ratio which is greater than or equal to 0.4 and typically between 1 and 3, and is therefore equally applicable to solutions of VWF without FVIII and solutions of the FVIII/VWF complex, given that VWF, being the multimer molecule of larger size, is the one which limits the process.”
It is clear from that statement, that the requirement for a VWF/FVIII proportion of ³0.4 applies to all VWF-containing solutions, regardless of whether they contain FVIII. This is logically sound because where FVIII activity approaches zero or is absent, the VWF/FVIII proportion is necessarily greater than 0.4 (consistent with Smith#2 at [2.6]). The statement above also clarifies that the VWF/FVIII proportion in claim 1 is calculated using the relative activities of each protein in the solution. A dictionary in the description states the activity of VWF is based on its role as a cofactor for the antibiotic Ristocetin in platelet aggregation (abbreviated as VWF:RCo) and expressed as International Units (IU) VWF:RCo (page 7, lines 17-20). The coagulating activity of FVIII is expressed as IU FVIII:C (page 7, lines 22-25).
Claim 1 defines the VWF concentration in the solution in terms of its RCo activity. In its plain meaning the solution is required to contain an amount of VWF protein that has an activity of no more than 12 IU VWF:RCo/ml.
Claims 2-13
2. A process according to claim 1, characterised in that the concentration of calcium ion in the solution undergoing nanofiltration varies between 0.05 and 0.2 M.
3. A nanofiltration process according to claim 1 or 2, characterised in that the Von Willebrand Factor recovered after nanofiltration maintains a multimer structure which includes multimers of the order of 11 or more.
4. A nanofiltration process according to any one of claims 1 to 3, characterised in that the recovery of Von Willebrand Factor after nanofiltration is 60% or more.
5. A nanofiltration process according to any one of claims 1 to 4, characterised in that the recovery of Factor VIII after nanofiltration is 70% or more.
Claims 4 and 5 are ambiguous regarding how the ‘recovery’ of FVIII or VWF should be construed, i.e. in terms of the amount of protein or its activity, or both. Resort to the description on page 10 provides clarification:
“Under the conditions specified it is possible to filter up to 120 litres of solution per m² of filtering surface area, obtaining a recovery of FVIII activity of more than 70% and a recovery of VWF activity of more than 60%, with a preserved VWF multimer structure (more than 11 multimers) and a VWF:RCo/FVIII ratio which is at least 80% of that of the material used.”
This paragraph is consistent with claims 4 and 5 in terms of percentage recoveries and it explicitly refers to recovery in terms of the active proteins. Construction of claims 4 and 5 to require recovery of active protein is consistent with claim 1 which specifies the VWF concentration in the starting materials in terms of its activity. It is also consistent with claims 10 and 11 that refer to methods of treatment, which would require active protein. For these reasons I construe claims 4 and 5 as referring to the percentage recovery of active protein.
6. A nanofiltration process according to any one of claims 1 to 5, characterised in that a loading ratio of up to 50 IU of Von Willebrand Factor per cm² of filtering surface area is used.
7. A nanofiltration process according to any one of claims 1 to 6, characterised in that the maximum concentration of the solution being filtered is 0.6 AU (OD₂₈₀).
8. A nanofiltration process according to any one of claims 1 to 7, characterised in that the nanofiltration is carried out at a pressure of between 0.2 and 0.4 bar.
9. A nanofiltration process according to any one of claims 1 to 8, characterised in that the standard nanofiltration flow is between 10 and 20 litres/hour/m².
10.Use of the concentrate obtained in the process according to any one of claims 1 to 9 for the preparation of a medicinal compound for use in the treatment of Haemophilia A or Von Willebrand’s disease.
11. A method for the treatment of Haemophilia A or Von Willebrand’s disease, comprising administering to a patient in need thereof a concentrate obtained in the process according to any one of claims 1 to 9.
12.A process for obtaining a concentrate of Von Willebrand Factor or a complex of Factor VIII/Von Willebrand Factor of human or recombinant origin, characterised by:
a) preparation of a solution of Von Willebrand Factor or a complex of Factor VIII/Von Willebrand which contains VWF in a concentration of up to 12 IU VWF:RCo/ml and a proportion between Von Willebrand Factor/Factor VIII of 0.4 or more,
b) nanofiltration of the solution prepared in a) through a filter having a pore size of 20 nanometers, at a maximum pressure of less than or equal to 0.5 bar, in the presence of calcium ion and at a pH greater than 5.5,
and substantially as herein before described with reference to any one of the Examples.
13. A concentrate of Von Willebrand Factor or a complexity of Factor VIII/Von Willebrand Factor of human or recombinant origin obtained according to the process of any one of claims 1 to 9.
The reference in claim 13 to a “complexity” of FVIII/VWF is ambiguous. However, it is clear from the description on at least page 1, lines 26-28, that this term should be understood to refer to a complex of FVIII/VWF. Consistent with my construction, two experts understood “complexity” be a typographical error, and construed the claim accordingly (Goss#1 at 1.86; Smith#1 at 1.81).
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. The threshold requirement for a patentable invention will not be satisfied if it is apparent on the face of the specification that the quality of inventiveness necessary for there to be a proper subject of letters patent under the Statute of Monopolies is absent (NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15 at [9]; (1995) 183 CLR 655).
CSL’s submissions under this ground are essentially that the specification acknowledges that some features in claim 1 were known in the art and the additional features are without inventive merit. Responding, Grifols submitted that claim 1 defines a new process involving a combination of features for obtaining a concentrate of VWF or FVIII/VWF complex and it is not apparent on the face of the specification that this process was known for this purpose.
To establish that the claimed process is obvious on the face of the opposed specification, CSL relied on the references on pages 5-6 to patent application WO 2005/040214 (WO’214) and its commercial embodiment Factane®. Specifically, on page 5, the opposed specification acknowledges that WO’214 discloses a VWF-containing FVIII composition filtered through a sieve of pore size between 13-25 nm in the presence of calcium ion, and that lower molecular weight multimers VWF can, in specified circumstances, be filtered through 20 nm pores.
To establish that a relevant pH and pressure was known in the prior art, CSL relied on the disclosure of WO’214 itself. However, these features in the WO’214 process are not reproduced in the opposed specification, nor has the content of WO’214 been explicitly incorporated by reference. Therefore, I cannot conclude on the face of the specification that the combination of filtration conditions in claim 1 were known in the art and thereby obvious.
Furthermore, Grifols drew my attention to page 6 of the opposed specification, which at lines 15‑21 distinguishes the prior art, including WO’214, in that the earlier documents do not disclose that VWF can be successfully filtered through <35 nm pores and retain the activity required to treat VWD and HA.
CSL has not established that the subject matter of claim 1 is not a manner of manufacture.
Novelty
CSL submitted that claims 1-3, 5, 8 and 10-11 lack novelty in light of one or more of the following prior art documents:
·     WO 2005/040214 A1 (Laboratoire Francais Du Fractionnement et des Biotechnologies) 6 May 2005 (WO’214)
·     Chtourou, S. et al. (2007) Vox Sanguinis 92: 327-337 (Chtourou)
·     Furuya, K. et al. (2006) Vox Sanguinus 91: 119-125 (Furuya)
The publications WO’214 and Chtourou are related insofar as they both relate to a product which in its commercial embodiment is marketed as Factane®.
It is well established that the general test for anticipation, or lack of novelty, is the reverse infringement test. The classic formulation of this test is that given by Aicken 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) 91 ALR 513 at 517). To meet this requirement, the prior art must contain “clear and unmistakable directions” to the claimed invention. However, “if in carrying out the directions contained in a prior inventor’s publication will inevitably result in something being made or done which, if the claim of the opposed specification were a claim of a valid patent, would constitute an infringement of that claim, then that claim would have been anticipated.” (Novozymes A/S v Danisco A/S [2013] FCAFC 6 at [145] referring to General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (1971) 1A IPR 121 at 138).
Arbitrary features and parameteritis

Regarding claim 1, CSL submitted that the features of the solution to be filtered in part a) of the claim are arbitrary and therefore inessential to the process of claim 1. However, prima facie, the limitations these features impose on claim 1 renders them essential to the claimed process (Catnic Components v Hill and Smith Ltd [1982] RPC 183 at 228). Nevertheless, CSL argued that there is no evidence that the VWF concentration or VWF/FVIII proportion are in any way part of the invention, and their inclusion in the claims is simply “a case of parameteritis” within the meaning of Williams Advanced Materials Inc v Target Technology CoLLC (Williams) [2004] FCA 1405; 63 IPR 645.
The hearing officer in Euroceltique S.A. v Sandoz Pty Ltd (Euroceltique) [2009] APO 21 reviewed and applied the relevant caselaw regarding parameteritis in a claim, including Williams. I agree with the hearing officer’s reasoning in that case, and since the situation in Euroceltique is relevant to the present circumstances, I adopt his approach at [112] that in a case of potential parametritis, the question to be asked is whether the parameters in a claim “have been chosen to achieve a technical effect, or whether they are an arbitrary convenience?”.
CSL relied on its expert evidence to establish that the VWF concentration of up to 12 IU VWF:RCo/ml and VWF/FVIII proportion of 0.4 or more in the solution to be filtered are arbitrary.
VWF concentration of up to 12 IU VWF:RCo/ml
Regarding the VWF concentration expressed in terms of IU VWF:RCo/ml, as this is a measurement of VWF activity in the solution, Dr Pham believes it would have only an indirect effect on filtration performance (Pham#1 [11]). Dr Pham notes that it is well known in the art that protein concentration and protein load are very important, particularly for nanofiltration (Pham#1 at [12]). In this context, Dr Pham understands the VWF activity measurement is used as a de facto limitation of protein concentration, which he considers “relatively arbitrary” since it is clear that other proteins may be included in the solution to be filtered (Pham#1 at [11]). Similarly, Dr Gröner at [41] understands claim 1 to be expressing “a maximum VWF activity per volume of material to be filtered which will be related in some manner to the protein concentration of the material to be filtered”. As such, Dr Gröner concludes the particular concentration in claim 1 is an arbitrary selection based on an example that shows that only a slightly higher protein concentration clogged the filter (Gröner at [41]).
CSL’s experts clearly accept that the VWF activity is to some extent related to the protein concentration in the solution. In this regard, Grifols relied on statements in the specification that relate the VWF activity measurement to the protein concentration in the solution. The first is on page 9 of the description:
“The solution which is to be nanofiltered has a maximum concentration of 0.6 Absorbance Units (AU₂₈₀), equivalent to not more than 12 IU VWF: RCo/ml”.
The spectrophotometric determination of the absorbance of a solution at 280 nm (AU₂₈₀) is a crude estimate of total protein concentration in that solution. The second statement is in Example 6, which is titled “Effect of the concentration of the material used on nanofiltration of the FVIII/VWF complex” and relevantly concludes that:
“… the viable concentration range for the nanofiltration of FVIII/VWF solution having a specific activity of approximately 10 IU FVIII/AU_280nm is ≤0.6 AU, approximately equivalent to … ≤12 IU/ml of VWF:RCo”
The disclosure of specification and the expert evidence discussed above supports a conclusion that a VWF concentration of ≤12 IU VWF:RCo/ml bears some relationship, albeit indirectly, to the total protein concentration in the solution to be filtered. The expert evidence establishes that the protein concentration of the solution should be optimised to below a particular level (Eakins at [13]; Goss#1 at [1.77]; Smith#1 at [1.69]; Pham#1 at [12]; Gröner at [31], [34]).
VWF/FVIII proportion of 0.4 or more
Dr Pham and Dr Gröner considered the VWF/FVIII ratio of ³0.4 to be arbitrary, on the basis that no ratio can exist where there is no FVIII (Pham#1 at [11]; Gröner at [41]). However, I have construed the claims otherwise and consequently this evidence is moot.
Are the VWF concentration and VWF/FVIII proportion arbitrary features?
Responding to CSL’s submissions, Grifols stressed that the VWF:RCo and FVIII:C activity measurements are crucial. It submitted that the requirement for up to 12 IU VWF:RCo/ml and a VWF/FVIII ratio of 0.4 or more ensures a preserved VWF multimer structure containing the high molecular weight multimers in the solution to be filtered, which is necessary to ensure functionality in the final product filtered in accordance the conditions in part b) of claim 1. Furthermore, at a VWF/FVIII ratio below 0.4, there will be too much FVIII co-administered which will induce thrombogenesis (i.e. hypercoagulation, with the potential for obstructive clotting).
Not inconsistent with Grifol’s submission, CSL accepted that a VWF/FVIII value of 0.4 or more is “related to producing a product that could ultimately be processed further for use in the treatment of VWD or Hemophilia” insofar as “the value merely indicates that some amount of VWF must be present in the solution”. Furthermore, Dr Maher at [8] confirms that the VWF/FVIII activity ratio in products indicated for use in VWD is relevant to minimising the risk of thrombosis.
Overall, I am satisfied that the VWF concentration of up to 12 IU VWF:RCo/ml and proportion between VWF/FVIII of 0.4 or more have been chosen for a purpose, and have a technical effect on the process as claimed. It follows that these features are not simply arbitrary, and for the claimed process to be anticipated, they must be present in the prior disclosure.
WO’214
CSL opposed claims 1-3, 5, 8 and 10-11 for lack of novelty in light of WO’214, which is in evidence as DE-9. Parts of the submissions and evidence refer instead to the disclosure of equivalent Australian application AU 2001283931. The parties agreed at the hearing that the opposition should proceed on the basis of the document in evidence and therefore I have taken any references to AU 2001283931 in the evidence and submissions to refer to WO 2005/040214.
WO’214 is titled “Virally-safe Factor VIII with a low content of higher multimers”. On page 1, the invention relates to a plasma-derived virally-safe FVIII compositions obtained after nanofiltration in which the VWF content is 15% or less decamers and higher multimers. On page 3, the inventors had found that the reduction of high molecular weight VWF multimers in the FVIII filtrates correlates with the efficacy of virus retention by the filter.
It was not in dispute that WO’214 discloses filtration of a solution containing FVIII and VWF of human origin under the conditions set out in part b) of claim 1. The question is whether WO’214 also discloses the VWF/FVIII proportion of ³0.4 and VWF concentration of ≤12 IU VWF:RCo/ml in the solution to be filtered?
Accepting that WO’214 does not explicitly disclose the VWF/FVIII proportion of ³0.4, CSL submitted that this is an inherent property of the relevant solution in WO’214.
Dr Gröner understands the VWF/FVIII ratio of the solution to be filtered in WO’214 “is likely to be around 1” based on the FVIII binding activity of the VWF (at [21]). I have construed the VWF/FVIII proportion in claim 1 as requiring a measurement VWF:RCo activity, rather than FVIII-binding activity. Grifol’s experts are both of the opinion that a measurement of VWF’s FVIII-binding activity does not necessarily equate to its haemostatic activity as measured by VWF:RCo, because all forms of VWF have FVIII-binding activity, while its haemostatic function lies predominantly with the higher molecular weight forms that are reduced in the process taught by WO’214 (Smith#2 at [2.29]; Goss#2 at [2.15]). Taken together, this evidence does not support a conclusion that the VWF/FVIII proportion is necessarily, as a matter of fact, around 1.
Both Dr Gröner and Dr Pham expect the solution to be filtered in WO’214 to have a VWF/FVIII ratio around 1, because the material is directly extracted from human plasma and the ratio is not adjusted by process set out in WO’214 (Gröner at [40]-[42]; Pham#2 at [42]). Grifol’s experts, noting that WO’214 does not disclose an activity ratio in the starting material, do not agree that the required proportion is necessarily present in the solution to be filtered (Smith#2 at [2.42]; Goss #2 at [2.26]). Dr Goss at [2.24] would expect the non-covalently-associated VWF and FVIII proteins to dissociate to some extent even under the mildest purification conditions, which would alter the VWF/FVIII proportion from the conventionally-assigned ratio of 1 in the plasma extracts. Furthermore, Dr Goss understands from Examples 2 and 3 of WO’214 that the amount of high molecular weight multimers is low in the solution prior to filtration (Goss#1 at [1.118]), a view not expressly disputed by CSL’s experts. As a matter of logic, a reduction in levels of the most haemostatically active VWF multimers would be expected to reduce the VWF:RCo activity and, it follows, the calculated VWF/FVIII proportion.
In summary, Dr Pham and Dr Gröner expect the solution to be filtered in WO’214 to meet the proportional requirement in claim 1a) (Gröner at [21]; Pham#2 at [42]). In contrast, Dr Goss and Dr Smith are in agreement that WO’214 does not explicitly disclose a VWF/FVIII activity ratio of 0.4 or more in the solutions to be virus filtered and that this ratio would necessarily be present (Smith#2 at [2.30], [2.42]; Goss#2 at [2.26]). Taken together, this evidence does not establish that WO’214 discloses a solution to be filtered that necessarily, as a matter of fact, contains a proportion between VWF/FVIII of 0.4 or more.
Since it does not disclose the VWF/FVIII proportion, I do not need to decide whether WO’214 discloses a VWF concentration of ≤12 IU VWF:RCo/ml in the solution to be filtered.
CSL has not established that WO’214 provides clear and unmistakeable directions to the invention of claim 1 or, it follows, claims 2-3, 5, 8 or 10-11.
Chtourou
CSL opposed claims 1-3, 8 and 10-11 for lack of novelty in light of Chtourou, which is in evidence as DE-6.
Chtourou is titled “A solvent/detergent-treated and 15-nm filtered factor VIII: a new safety standard for plasma-derived coagulation factor concentrates”. The document discloses sequential filtration of a VWF/FVIII-containing solution through 35 nm then 15 nm pores, to remove viruses and the factors involved in transmission of transmissible spongiform encephalopathy.
While acknowledging that Chtourou does not explicitly disclose filtration through a filter with 20 nm pores, CSL submitted that the disclosure of filtration through 15 nm pores is a demonstration of filtration through a 20 nm pore filter; the technical details being equivalent to the claims of the opposed application.
The expert evidence does not support a conclusion that Chtourou provides clear and unmistakable directions to a relevant process involving filtration through 20 nm pores. Dr Eakins acknowledges the difference in pore size and identifies two effects this difference may have on the product of the process, as follows:
“15. Chtourou et al describes the 15 nm filtration of a plasma derived FVIII solution Factane®. …
20. The process described in Chtourou et al appears to differ from the process of claim 1 of the opposed application primarily in relation to the pore size of the filter. In Chtourou et al, the filter had a pore size of 15 nanometres whilst the filter in the process claimed in the opposed application has a pore size of 20 nanometres. I can see no reason why replacing the 15 nanometre filter of Chtourou et al with a 20 nanometre filter would make any difference to way the process of Chtourou et al. operates other than to perhaps be less efficient in viral removal. Increasing the pore size would also be expected to achieve high yields of the FVIII and vWF.”
The evidence of the other experts strongly supports a conclusion that they distinguish 15 nm filtration from filtration through a 20 nm filter:
“As noted by Mr Eakins at [20], Chtourou et al does not describe filtration through a 20 nm filter. Instead it describes sequential filtration through a 35 nm and a 15 nm filter”. (Goss#1 at [1.109]).
“At paragraph 20 Mr Eakins states that the only difference between the process described in Chtourou et al. and the opposed application is the pore size of the filter with Chtourou et al. using a 15 nm filter and the process in the opposed application using a 20 nm filter. I do not agree that the difference in filter size is the only difference …” (Smith#1 at [1.101])
“[Chtourou] discloses a comparable process but with an even smaller pore size (15 nm filter)” (Gröner at [37])
“The process disclosed in Chtourou et al. is the same as the process of claim 1 of the opposed application with the exception of the size of the nanofilter” (Pham#2 at [32]).
Grifols submitted that the Chtourou disclosure is deficient in other aspects. However, in the absence of any explicit or implicit disclosure of filtration through 20 nm pores, I do not need to consider the matter further. Chtourou does not provide clear and unmistakable directions to the invention as presently claimed.
Furuya
CSL opposed claims 1, 3, 10 and 11 for lack of novelty in light of Furuya (exhibit DE-7) on the basis that the VWF/FVIII proportion of ≥0.4 is not an essential feature of the claimed process.
I have found above that the VWF/FVIII proportion is an essential feature of the claims. Therefore, for the claims to lack novelty, Furuya must explicitly or implicitly disclose a relevant process including this feature. It was not in dispute that Furuya does not explicitly disclose the required VWF/FVIII proportion. Furthermore, in the context of inventive step, I have found the VWF/FVIII proportion of ≥0.4 is not an inherent feature of the process disclosed by Furuya. It follows that the disclosure of Furuya does not anticipate the subject matter of claim 1 or any dependent claim.
Conclusion on novelty
CSL has not discharged the onus of establishing that the claimed subject matter is not novel.
Inventive step
CSL opposed claims 1-13 for lack of inventive step in light of the common general knowledge in the art alone and in combination with prior art documents.
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. ‘Obvious’ means ‘very plain’ (Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21 at [51] - [52]; (2007) 72 IPR 447 at 461 [51] - [52]). 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.
The test for obviousness was provided by Justice Aicken in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12 at [45]; 148 CLR 262 at 286 as follows:
“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.”
The High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd (Alphapharm) [2002] HCA 59 at [51]- [53]; 212 CLR 411 at [51]-[53] approved that approach, in addition to the similar approach taken by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at 187 in which he posed a reformulated “Cripp’s question” as follows:
“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 [result or alternative]?”
Where the invention lies in a combination of features, the question is whether the combination, not each individual feature, is obvious when compared to the prior art base (Alphapharm at [41]; Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9 at [116]; (1980) 144 CLR 253 at 293).
The usual approach to determining inventive step is the problem-solution approach. Once the problem has been formulated and the common general knowledge and the prior art base has been determined, the question of whether the claimed solution is obvious must be addressed.
The problem
Von Willebrand’s disease was before the priority date (and still is) exclusively treated using plasma-derived VWF concentrates as no recombinant VWF was available for humans (Goss#1 at [1.33]; Smith#1 at [1.27]). In this context, CSL identified the problem addressed by the application as the removal of viruses from a solution containing VWF/FVIII or VWF, while retaining active VWF.
Grifols agreed that there was a long felt need for safe therapeutics, but it relied on the following statement on page 7 of the specification to pose the problem more narrowly, as the need to prepare a FVIII/VWF concentrate nanofiltered through 20 nm pores and suitable for the treatment of VWD:
“The preparation of a FVIII/VWF concentrate nanofiltered through 20 nm with proportions between the two components of the FVIII and VWF macromolecular complex which are more similar to those normally encountered in human plasma (1 unit of VWF for every 1 unit of FVIII), which still has all the advantages of the native FVIII/VWF complex and is suitable for the treatment of VWD and Haemophilia A, is still an unresolved problem.”
Other passages of the description support a broader view of the problem that nevertheless relates to nanofiltration. The specification states on page 3 that 35 nm filtration is not effective against non-enveloped viruses, but FVIII filtered through pore sizes less than 35 nm (eg. 15 or 20 nm) either have no VWF content, or contain VWF lacking the high molecule weight multimers required for the treatment of VWD. On page 4, although nanofilters were available with pores less than 35 nm it was thought they would only allow filtration of smaller proteins.
Turning to the expert evidence, only Drs Goss and Smith discuss the state of the art before reading the specification. Their evidence is broadly that in preparing plasma-derived proteins as therapeutic agents before the priority date it was a known requirement to inactivate and/or remove contaminating infectious agents, in particular viruses, to minimise the risk of transmission to recipients (Goss#1 [1.40]; Smith#1 at [1.31]-[1.32]). Viral inactivation could be affected by pasteurisation or treatment with dry heat, solvent/detergent or low pH (Goss#1 at [1.44]-[1.48]; Smith#1 at [1.31]-[1.32]). Before the priority date, both experts were aware of nanofiltration being used to remove infectious agents, including viruses, from low molecular weight plasma products (Smith#1 at [1.34]; Goss#1 at [1.48]-[1.49]). At that time, Dr Goss was familiar with commercially available 15 and 35 nm pore filters being used for the low molecular weight blood plasma products (Goss#1 at [1.49]). Neither Dr Goss nor Dr Smith identify a problem involving specifically 20 nm filtration.
With the benefit of hindsight, Dr Gröner at [38] nevertheless considers the problem addressed by the application as the need to increase the virus safety of a product used to treat HA or VWD by virus filtration.

Overall, I believe a reasonable formulation of the problem addressed by the application is the provision of a means to remove viruses from a solution containing VWF/FVIII or VWF, while retaining active VWF.
The person skilled in the art
It was not in dispute that the person skilled in the art is a person or team of people with expertise in working with plasma proteins such as VWF and FVIII and the preparation of plasma proteins for therapeutic use.
Dr Eakins, Dr Pham and Dr Maher are all CSL employees working at CSL Limited, or CSL Behring (Australia) Pty Ltd, in Victoria. Dr Eakins has 10 years research and development experience relating to plasma-derived therapeutics, including viral removal and inactivation (Eakins at [2]). Dr Pham is a biochemist involved in evaluating new technologies for the manufacture of plasma proteins for human therapy, including a FVIII/VWF product (Pham#1 at [3]). Dr Maher has had extensive experience in the production and use of clotting factors derived from human plasma, in particular VWF and FVIII (Maher at [2]).
Dr Gröner is a virologist working for CSL Behring GmbH in Germany who since 1988 has worked in the field of pathogen safety of relevantly plasma-derived therapeutic products (Gröner at [2]). There was no dispute that Dr Gröner’s common general knowledge would reflect that of the person skilled in the art in Australia.
Dr Goss has worked in the field of biochemistry since 1983 and specifically plasma protein biotechnology since 1987. He is currently the Director of a plasma fractionation and biotechnology consultancy firm (Goss#1 at [1.1]-[1.2]). Dr Smith is a New Zealand-based haematologist who has worked in the area of coagulation disorders and haemophilia both there and in Europe since 1995 (Smith#1 at [1.2]-[1.6]).
Although the primary focus of their expertise differs somewhat, I am satisfied that each of the declarants is a relevant person skilled in the art for the purposes of this opposition.
The common general knowledge in the art
There was no dispute that:
·    nanofiltration of some smaller plasma-derived proteins to remove viruses was common general knowledge in the art before the priority date;
·    that the filtration conditions could be optimised by adjusting parameters such as pH, temperature, pressure and protein concentration, or
·    that decreasing the concentration of the solution to be filtered would increase yield.
Was the invention obvious in the light of the common general knowledge in the art?
CSL submitted at the hearing that claim 1 lacks an inventive step being an obvious application of the common general knowledge in the art. Specifically, CSL argued that the requirement for viral safety in plasma products is common general knowledge in the art, as is the need to preserve the function of the filtered product. CSL submitted that the evidence establishes that it was common general knowledge that small enveloped viruses could be removed using a 20 nm pore-size filter. Regarding the filtration criteria, CSL submitted that the pressure and protein concentration were parameters the person skilled in the art would seek to adjust in optimising a filtration process.
At best, CSL’s submissions are that the person skilled in the art could have arrived at the invention specified in the claims. However, critically, I have no submissions or evidence that establishes that faced with the problem I have identified above, and without the benefit of hindsight, the person skilled in the art would (rather than could) directly be led as a matter of course to try the combination of features as presently claimed in the expectation that it might well produce a useful result. It follows that CSL has not established that any claim lacks an inventive step in light of the common general knowledge in the art.
The prior art
The documents relied on to establish inventive step are the same as those for novelty i.e. WO’214, Chtourou and Furuya.
Ascertained, understood and regarded as relevant
CSL submitted that these documents could reasonably be expected to have been ascertained, understood and regarded as relevant by the person skilled in the art. This conclusion was disputed by Grifols.
Ascertained
Chtourou and Furuya were both published in the journal Vox Sanguinis. Three of the experts regularly consulted or reviewed this journal (Pham#1 at [8]; Goss#1 at [1.21]; Gröner at [11]), and Dr Smith would read articles of interest in it when they came to his attention (Smith#1 at [1.18]). I am satisfied that the person skilled in the art could ascertain documents published in this journal.
Regarding patent literature, Dr Gröner regularly reviewed it in his area of interest (at [11]). When researching a new project, Dr Goss would extensively review all available published literature, but he did not routinely search the patent literature and did not read patent applications unless required specifically to do so (at [1.23]). Although Dr Goss may not routinely search patent databases, a number of databases accessed by computer-based literature searches do include patent literature, which is consistent with his statement that he would review “all available published literature”. Dr Smith, a haematologist, did not read the patent literature (Smith#1 at [1.20]).
I accept CSL’s submission at the hearing, that the person skilled in the art who was actively involved in plasma fractionation and the preparation of therapeutic products was more likely to have read the patent literature, since it is consistent with the expert evidence summarised above.
On the basis of this evidence, I consider it reasonable to conclude that the average person skilled in the art could reasonably be expected to have ascertained patent documents. I am satisfied that each of the cited documents would have been ascertained.
Understood
The three documents CSL relies on are in English and none of the experts had difficulty understanding them. I conclude that having been ascertained, they would have been understood.
Regarded as relevant
WO’214
WO’214 is titled “Virally-safe Factor VIII with a low content of higher multimers”. The Abstract describes the invention as relating to a composition of plasma-derived virally-safe FVIII obtained after nanometric filtration, the composition comprising VWF at a rate of 15% or less of decamers or higher multimers. These compositions are said to have a reduction in virus titre by more than 4 log and are thus suitable for treating haemophilia.
Grifols submitted that WO’214 would not have been considered relevant because it is directed to the preparation of a FVIII composition rather than a solution containing VWF or a FVIII/VWF complex. Consistent with this, Dr Goss and Dr Smith do not consider WO’214 relevant because it describes the preparation of a Factor VIII composition containing low levels of higher molecular weight VWF multimers which, in their view, could not be used to treat VWD (Goss#1 at [1.118]; Smith#1 at [1.110]).
I understand from their evidence that Drs Eakins, Pham and Gröner considered WO’214 relevant to the problem insofar as it described nanofiltration of VWF (Eakins at [28]; Pham#1 at [26]-[27]; Gröner at [20]-[22]).
WO’214, on its face, relates to the virus filtration of VWF-containing solutions. Three experts considered the document relevant, two did not. On balance, I find that the person skilled in the art could reasonably be expected to have regarded WO’214 as relevant.
Chtourou
Chtourou is titled “A solvent/detergent-treated and 15-nm filtered factor FVIII: a new safety standard for plasma-derived coagulation factor concentrates”. As noted by Grifols, the abstract mainly focusses on FVIII, but states that after nanofiltration, copurified VWF was reduced but VWF/FVIII binding properties were unaffected. The abstract concludes that nanofiltration of FVIII at 15 nm is feasible despite the large molecular weight of FVIII and VWF.
Given the reference to filtered VWF, Dr Eakins, Dr Pham and Dr Gröner each considered Chtourou relevant (Eakins at [15]; Pham#1 at [27]; Gröner at [37]).
Grifols submitted that Chtourou would not have been considered relevant because it describes the preparation of a FVIII concentrate for the treatment of HA, not VWD. To establish this point, Grifols relied on a statement on page 8 of the 11 page document from which Dr Goss at [1.103] and Dr Smith at [1.96] conclude that the document was not relevant. However, the threshold question of whether the person skilled in the art would consider a document relevant in the context of the problem does not, in my view, require a detailed consideration of the document. In this art, a person researching a problem is likely to perform a literature search using suitable keywords, and review the documents identified by the search on the basis of the title and abstract. This strategy would identify a document’s prima facie relevance. Whether it is in fact sufficiently relevant for a finding of obviousness is to be determined by applying the applicable law.
Given the evidence as a whole, I find the person skilled in the art could reasonably be expected to have regarded Chtourou as relevant.
Furuya
Furuya is titled “Implementation of a 20-nm pore-size filter in the plasma-derived Factor VIII manufacturing process”. The abstract indicates that in order to improve the viral safety of its FVIII product, the authors attempted to replace the 35 nm pore-size filter with a 20 nm filter. Under the heading “Results”, the abstract states that no differences were observed in the biochemical properties of the FVIII products including, among other things, the contents and multimeric structure of VWF.
Three experts appear to consider Furuya relevant in that it discloses virus filtration of VWF (Eakins at [22]; Pham# at [7]; Gröner at [37]). Drs Goss and Smith do not directly address the relevance of the document.
I conclude that Furuya would have been regarded as relevant.
Was the invention obvious in light of the cited prior art?
CSL’s submissions on obviousness were the same for all the cited documents, and it is convenient to present them here. CSL considered the requirement for a VWF/FVIII proportion of ≥0.4 to lack inventive ingenuity. Regarding the VWF concentration of ≤12 IU VWF:RCo/ml, CSL submitted that it was known that protein concentration affects nanofiltration efficiency, and it was routine and typical to keep the protein concentration low so as not to clog the filter. CSL continued:
“The particular values recited in the claims are merely workshop variations from a known field, resulting from routine optimization performed with the expectation of successfully developing a process to remove viruses from a solution containing VWF or VWF/Factor VIII while retaining active VWF. As noted in Elconnex Pty Ltd v Gerard Industries Pty Ltd (1992) 25 IPR 173 at 180:
“this is not a case of a new combination, although of old integers, but of an old combination which has been, at most, subjected to slight variations. The question must be whether those variations are other than obvious.”
We submit that the variations are obvious and that if there is anything inventive in the opposed application, it is certainly not defined using the specific values recited in any one of claims 1 to 13.
I have no clear evidence before me that establishes that the VWF/FVIII proportion or VWF concentration, as these appear in the claims, had been recognised as important integers of earlier filtration processes, such that the presently claimed combination could be considered ‘slight variations’ in the parameters used to carry out the earlier processes. However, I will consider the obviousness of the claims in light of each of the cited documents.
WO’214
WO’214 describes a process in which a virally-safe FVIII composition for the treatment of HA is obtained after filtration of a solution under conditions that result in a low residual content of high molecular weight VWF multimers (WO’214, page 1 para 1, page 4 para 1; Goss#1 at [1.118]; Smith#1 at [1.110]).
As indicated above, it was not in dispute that WO’214 discloses a process involving the filtration conditions of part b) of claim 1. I have found above WO’214 does not disclose the VWF/FVIII proportion in part a), but made no finding regarding the VWF concentration.
For claim 1 to lack an inventive step the light of WO’214 it must be shown that on the basis of this disclosure, the person skilled in the art seeking to solve the problem would, as a matter of routine, have prepared a solution of VWF or VWF/FVIII complex which contains a VWF concentration of up to 12 IU VWF:RCo/ml, and a proportion between VWF/FVIII of 0.4 or more.
Grifols submitted that WO’214 teaches away from the invention presently claimed, because it describes the preparation of a FVIII concentrate for the treatment of HA not VWD, and specifically aims to show the removal of high molecular weight VWF multimers. Consistent with this, Dr Goss and Dr Smith consider the product of the WO’214 process unsuitable for the treatment of VWD, even with further processing (Goss#1 at [1.118]; Smith#2 at [2.32]). Both experts understand the process steps to be directed to reducing the high molecular weight forms of VWF that account for the majority of VWF’s haemostatic activity (Goss#1 at [1.118]; Smith#1 at [1.110]). Both state that even if concentrated to a therapeutic VWD dose, the FVIII activity in the solution would be too high for administration (Goss#2 at [2.32], [2.45]; Smith#2 at [2.18], [2.27]). I conclude that if they were faced with the problem identified above, neither expert would try to optimise the process of WO’214 expecting it to produce a useful result.
Dr Eakins at [29] states that WO’214 does not mention the concentrations of the VWF/FVIII solutions to be filtered, but he considers it is “widely known that greater yields of protein in nanofiltration are obtained by using dilute protein solutions prior to filtration”.
At [30], Dr Eakins explains it is routine to adjust process parameters to optimise a nanofiltration process and in particular, protein concentrations, flow rates, loading rates, and ionic concentrations. He provides no further information on how he would adapt the process taught by WO’214. Critically, Dr Eakins’ evidence does not establish that, in seeking to solve the problem, he would routinely try to optimise either the VWF concentration in the solution to be filtered on the basis of its RCo activity or the VWF/FVIII activity ratio.
Dr Gröner at [42] expects the starting material for virus filtration in WO’214 to have a ratio between VWF and FVIII of ≥0.4. Regarding the VWF concentration of ≤12 IU VWF:RCo/ml, he understands this to depend on the upstream manufacturing process ([41]). Consistent with Dr Eakins, Dr Gröner states that it is well known in virus filtration that there is a clear advantage to filtering a dilute solution, but he considers the selection of the particular VWF concentration in claim 1 to be an arbitrary limitation (Gröner at [41]). Dr Gröner’s evidence establishes that he would routinely optimise the protein concentration in a solution to be filtered. It does not establish that, faced with the problem, Dr Gröner would routinely optimise that protein concentration on the basis of a VWF concentration expressed in terms of RCo activity.
Dr Pham considers the VWF/FVIII proportion and VWF concentration in claim 1 to be arbitrary parameters (Pham#1 [11], [15]). He considers the protein concentration in the starting material critical in filtration processes using nanofilters (Pham#1 at [12]; Pham#2 at [7]), but he believes the concentration of VWF in terms of its activity to be at best a de facto limitation on protein concentration (Pham#1 [11]-[12]; Pham#2 at [7]). Although Dr Pham states that the requirement for VWF/FVIII activities of ≥0.4 in the solution to be filtered would be a simple matter to achieve (Pham#1 at [13]-[14]), I conclude from his evidence as a whole, that in seeking to solve the problem, and without the benefit of hindsight, he would not routinely set out to optimise the WO’214 process in this manner, or to specify the protein concentration in the starting material on the basis of its VWF:RCo activity.
In summary, the evidence does not establish that a filtration process with the combination of the features set out in claim 1 is obvious in light of WO’214.
Chtourou
To establish that the claimed process is obvious in light of Chtourou, it must at least be established that the person skilled in the art seeking to solve the problem would, as a matter of routine, adjust the process taught by Chtourou to use a 20 nm filter, and additionally prepare a solution having the features set out in part a) of claim 1.
Dr Goss and Dr Smith understand Chtourou to disclose a process to purify FVIII for the treatment of haemophilia, not a process for filtering VWF or VWF/FVIII complex while retaining sufficient VWF activity to treat VWD (Goss#1 at [1.109]; Smith#1 at [1.96]). Dr Goss’ evidence is essentially that the document provides no relevant information on how to purify a VWF or VWF/FVIII concentrate while retaining sufficient activity for the treatment of VWD (Goss#1 at [1.103]). Dr Smith states that, at the priority date, he would not have expected that replacing a 15 nm filter with a 20 nm filter would provide a therapeutically effective concentrate for the treatment of VWD, and he questions whether increasing the pore size would achieve higher yields of VWF (Smith#1 at [1.101]). I conclude from their evidence that neither Dr Goss nor Dr Smith would pursue the filtration process of Chtourou with any expectation that, if optimised in any manner, it could solve the problem.
In comparing the disclosure of Chtourou with the opposed claims, Dr Eakins at [20] noted the discrepancy in filter pore size, but he states:
“I can see no reason why replacing the replacing the 15 nanometre filter of Chtourou et al. with a 20 nanometre filter would make any difference to the way the process of Chtourou et al. operates other than to perhaps be less efficient in viral removal. Increasing the pore size would also be expected to achieve high yields of the FVIII and vWF”.
Given the context in which Dr Eakins evidence was given and the ambivalent nature of his comment, I am not satisfied that, that in seeking to solve the problem and without the benefit of hindsight, he would routinely alter the Chtourou process to change the filter pore size.
Dr Pham understands Chtourou to teach that FVIII/VWF can be passed through a 15 nm filter albeit with some reduction in HMW multimers of VWF. Starting from this filtered material he says it would be routine to produce a product that could be used to treat VWD (Pham#1 at [27]). Dr Pham exemplifies this by noting that it is simple to separate VWD from FVIII, and once dissociated they can be separated based on their size after which the VWF obtained could be concentrated to the required level (at [27]). Dr Gröner also considers it a simple task to take the virus-filtered product of Chtourou and increase the concentration of VWF, if necessary, to provide a suitable protein to treat VWD (Gröner at [43]). The routine steps that Dr Pham and Dr Gröner would take to solve the problem, are not those specified in claim 1.
In summary, the evidence does not establish that a filtration process with the combination of the features set out in claim 1 is obvious in light of Chtourou.
Furuya
Furuya is titled “Implementation of a 20-nm pore-size filter in the plasma-derived Factor VIII manufacturing process”. The abstract states that virus inactivation/removal from the FVIII product ‘Cross Eight®’ by solvent-detergent treatment, two chromatography steps and virus filtration with a 35 nm pore-size filter did not adequately clear the smaller, non-enveloped, viruses. To resolve this problem the authors replaced the 35 nm filter with a 20 nm filter, a strategy said to have markedly increased viral clearance without variation in the biochemical properties of the two products and without a serious loss of FVIII (abstract).

There was no dispute that Furuya discloses the filtration conditions required by claim 1b). Therefore, a relevant question is whether the person skilled in the art seeking to solve the problem would, as a matter of routine, perform the Furuya process in a manner that requires the solution to be filtered to have the VWF concentration and VWF/FVIII proportion specified in part claim 1a)?
Grifols submitted that Furuya teaches away from the claimed subject matter .
Inherency
Furuya does not mention the VWF/FVIII activity ratio or the VWF concentration of the solution to be filtered. Nevertheless, Dr Eakins and Dr Gröner conclude that prior to filtration the solution in Furuya would meet the requirements of claim 1 part a) on the basis of VWF being present in the final Cross Eight® product (Eakins at [23]-[24]; Gröner at [44]). In this regard, Dr Eakins appears to rely on a statement in Furuya that there was no difference in the VWF multimer structure in the 20 nm- and 35nm-filtered solutions, a conclusion based on immunoblots presented in Figure 4 of the document (page 123 of Furuya, Eakins at [24]).
The Figure 4(b) immunoblot in Furuya compares the VWF protein content after 35 nm- or 20 nm-filtration of the affinity-purified solution and demonstrates the presence of VWF multimers greater than decamers in both products. However, the Figure 4 immunoblot provides qualitative information only. Furuya provides no indication of the VWF concentration or VWF:RCo activity in the filtered products or, most relevantly, in the solution prior to filtration (consistent with Goss#1 at [1.112]; Smith#2 at [2.46]-[2.47]).
Furthermore, Dr Goss and Dr Smith disagree with CSL’s experts that the simple presence of VWF multimers in the final product establishes a VWF/FVIII proportion of ≥0.4 in the solution prior to filtration. The production process for the Furuya Cross Eight® product involves affinity purification with FVIII-specific antibodies prior to filtration (Furuya page 120, right column and Figure 1; Eakins at [22]; Goss#1 at [1.111]; Smith#1 at [103]; Pham#1 at [44]; Gröner at [44]). Dr Goss and Dr Smith believe affinity purification would selectively purify FVIII at the expense of other proteins, leading to low levels of VWF in the solution to be nanofiltered (Goss#1 at [1.62]-[1.63]; Smith#1 at [1.29], [1.48], [1.103]). Accordingly, Grifols’ experts do not expect the solution to be filtered in the Furuya process to have a proportion of VWF/FVIII of ≥0.4 (Goss#1 at [1.112]; Smith#2 at [2.46]). To support his conclusion, Dr Goss notes that (i) the Registry of Clotting Factor concentrates states that the Cross Eight® product after filtration has no functional VWF (Goss#1 at [1.61], [1.113]); and (ii) that none of the registered FVIII products manufactured using FVIII-specific affinity chromatography have functional VWF (Goss#2 at [2.28]-[2.29]). On this basis, Dr Goss believes an immunoaffinity chromatography step would remove the vast bulk of the VWF in the feedstock prior to filtration, and he considers it extremely unlikely that the feedstock being nanofiltered in Furuya contained substantial amounts of high molecular weight VWF (Goss#2 at [2.29]).
In the absence of any quantitative information in Furuya regarding the pre- or post filtration solution, Dr Gröner’s conclusion that immunoaffinity chromatography is unlikely to separate (dissociate) complexed VWF/FVIII, which was based on VWF being detected in the final product, appears speculative.
Furuya on page 123 reports that the VWF/FVIII proportion of 0.007-0.015 U VWF/U FVIII:C in the 20 nm-filtered product are ‘similar to those usually found’ (which I understand to be those usually found in the 35 nm-filtered product). However, this disclosure is not determinative of the matter because it is not clear that this proportion is based on VWF:RCo measurements of activity, such that the reported VWF/FVIII ratio can be directly compared to the claimed proportion.
Considered as a whole, the evidence before me does not establish that the solution to be filtered in Furuya et al., necessarily, as a matter of fact, satisfies the requirements of claim 1, part a).
Matter of routine?
I have found above that the VWF/FVIII proportion of ≥0.4 is not an inherent property of the solution to be filtered in Furuya. Therefore, for the claims to lack an inventive step in light of this document, it must be shown that on the basis of its disclosure, the person skilled in the art seeking to solve the problem would, as a matter of routine, have prepared a solution of VWF or VWF/FVIII complex which contains a VWF concentration of ≤12 IU VWF:RCo/ml, and a proportion between VWF/FVIII of ≥0.4.
I conclude from Dr Smith’s and Dr Goss’ evidence discussed above that they would not follow or try to optimise the Fuyura process in any way expecting that it would substantially retain VWF activity in the filtered product.
Dr Eakins’ evidence provides no basis for a conclusion that faced with the problem he would routinely seek to optimise the Furuya process with respect to the VWF/FVIII activity ratio in the solution to be filtered, or that he would routinely set out to prepare that solution with a VWF/FVIII ratio of ≥0.4 and VWF concentration of ≤12 IU VWF:RCo/ml.
Dr Gröner states that whether the citations meet the requirement of a VWF concentration of ≤12 IU VWF:RCo/ml depends on the manufacturing process (at [41]). He considers that there are clear advantages to filtering a dilute solution but the selection of this particular concentration is arbitrary (at [41]). Dr Gröner’s evidence does not support a conclusion that in seeking to solve the problem he would, as a matter of routine, try to optimise the Furuya process on the basis of a VWF concentration expressed in activity terms.
Dr Pham considers the VWF concentration expressed in terms of activity to be arbitrary, with the typical approach being to ensure that the protein concentration is at a low level (Pham#1 at [11]-[12]; Pham#2 at [7]-[8]). He considers the proportion of VWF/FVIII of ≥0.4 to make little sense (Pham#2 at [8]).
The evidence does not establish that the person skilled in the art in seeking to solve the problem would, as a matter of routine, seek to optimise the Furuya process with respect to the parameters set out in part a) of claim 1, or that they would arrive at the specific requirements as presently claimed.
Conclusion – inventive step
The evidence does not establish that the person skilled in the art seeking to remove viruses from a solution containing VWF/FVIII or VWF, while retaining active VWF, would, as a matter of routine, take deliberate steps to prepare a solution for filtration having a VWF concentration of up to 12 IU VWF:RCo/ml and a proportion of VWF/FVIII of 0.4 or more. It follows that I cannot find that claim 1 or any other claim lacks an inventive step over the cited prior art.
Useful
CSL opposed claims 5 and 11 under this ground.
The principles for determining whether a claimed invention is useful for the purposes of s. 18(1)(c) are 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]; 77 IPR 449 at [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 [81], [217]; 81 IPR 228)
“In construing the claims for the purposes of utility, the claims must, moreover, 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 [2011] FCA 452 at [293]; (2011) 92 IPR 46 at [293])
Claim 5
Claim 5 is dependent on claims 1-4 and requires the nanofiltration process to achieve 70% or more recovery of FVIII. CSL’s case for inutility in claim 5 is that it is appended to claim 1 which encompasses nanofiltration with low calcium ion concentrations that would not achieve 70% recovery. However, on a proper construction, claim 5 defines only that subset of processes in the earlier claims that do achieve 70% or more recovery of FVIII. It is not relevant to the utility of claim 5 that the earlier claims encompass processes that would not do so.
CSL has adduced no evidence that the process of claim 5 is otherwise not useful and consequently this aspect of the opposition fails.
Claim 11
CSL submitted that claim 11, insofar as it encompasses a method for treating VWD or HA, lacks utility because without further processing, a concentrate obtained by the process of claims 1-9 is too dilute to be administered to treat these conditions. This is consistent with the expert evidence (Gröner at [9]; Goss#2 at [2.9]; Maher at [10]) and was not disputed by Grifols.
I accept Grifols’ submission, that claim 11 does not preclude further processing steps which would provide a therapeutically-effective concentrate suitable for administration. However, claim 11 does not require further processing steps.
Dr Maher at [7] explains that the majority of products with a VWD registered indication contain VWF/FVIII activity ratios of ≥1, to ensure that when administering sufficient VWF to a VWD patient during a bleed, that the level of FVIII activity in the patient’s blood does not become excessively high with an associated risk of thrombosis. He notes the maximum VWF activity of the product of the earlier claims is at best 12 IU VWF:RCo/mL (i.e. no more than the maximum activity of the solution prior to filtration) and using it directly would require an impractical infusion volume of at least 500 mL for an average dose of 6000 IU VWF (Maher at [10]). This conclusion was not disputed by Grifols’ experts, who both understand the filtrate product of the claimed process to be an intermediate solution that would be further processed and concentrated (Smith#2 at [2.3]; Goss#2 at [2.3]).
The promise of the invention is a virally-safe therapeutic concentrate of VWF or VWF/FVIII complex that can be used in the treatment of VWD and HA (see for example page 1, lines 5-10 of the opposed specification). However, insofar as claim 11 encompasses the use of the filtered product of the earlier claims directly in a method of treatment, the evidence establishes that the method would not achieve the promised benefit, without unwanted side effects and difficulty in administration.
I find claim 11 is not useful.
Section 40
Section 40(2) of the Patents Act relevantly requires that a complete specification must (a) describe the invention fully, including the best method known to the applicant of performing the invention and (b) end with a claim or claims defining the invention. Section 40(3) requires that the claim or claims in a patent specification must be clear and succinct and fairly based on the matter described in the specification.
Section 40(2)(a): Full Description
The High Court in Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 at [25]; (2001) 207 CLR 1 at 17 explained the test for full description as:
“The question is, will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty?”
CSL submitted that the invention insofar as it relates to filtration of VWF alone in a solution is not fully described. It argued that the parameters in claim 1 have been selected by the inventors on the basis of experiments using a solution of both FVIII and VWF. The specification fails to adequately teach the maximal applicable concentration for a solution of VWF alone and it would require undue experimentation to determine this value and the parameters required (eg. pH, pressure and calcium ion concentration) following a change in VWF concentration.
The maximum concentration of the solution to be filtered is defined in the independent claims in terms of its VWF activity (up to 12 IU VWF:RCo/ml). Consistent with Grifols submission, CSL has led no evidence that this maximum value for VWF activity would not be applicable to a solution of VWF alone.
CSL has not established that the subject matter of the claims is not fully described.
Section 40(3): Fair Basis
Section 40(3) requires that the claim or claims in a patent specification be fairly based on the matter described in the specification.

As the test for fair basis, the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (Lockwood) [2004] HCA 58 at [69]; (2004) 217 CLR 274 at 300 [69] approved the words of Gummow J in Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 at 95:
“… 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.”
CSL relied on the judgement in Pfizer Overseas Pharmaceuticals v Eli Lilly and Company (Pfizer) [2005] FCAFC 224, to argue that where an essential feature is missing from a claim, that claim is not fairly based. Specifically, CSL submitted the claims omit the essential feature that the product obtained from the filtration process must have a VWF:RCo/FVIII:C ratio that is ≥0.4. It argued that there is no real and reasonably clear disclosure of a product obtained from the filtration process having any other VWF/FVIII ratio. The passage in the description relied on by CSL to establish that the product requirements are an essential feature is on page 9, under the heading “Detailed Description”. It states:
“This invention describes a therapeutic concentrate of Von Willebrand Factor or a complex of Factor VIII/Von Willebrand Factor which has been nanofiltered through a sieve of pore size less than the equivalent to 35 nm in which the product obtained has VWF:RCo/FVIII:C ratio which is greater than or equal to 0.4 and a conserved multimer structure for the VWF which includes the high molecular weight multimers (more than 11 bands) and which is useful for the preparation of a medicinal compound indicated for the treatment of Von Willebrand’s Disease and Haemophilia A, and a process for obtaining it.”
In Pfizer at [268]-[277], the majority of the Full Court found that where a claim defined a class of compounds in terms of their biological activity, but only a specific class of chemical compounds were disclosed that had that activity, the claim travelled beyond the range of compounds disclosed and, as a consequence, lacked fair basis. The principle in Pfizer does not appear relevant to the present situation, where CSL’s submission is in effect that a process claim is not fairly based where the product of the process is not explicitly stated in the claim. More relevantly, in Lockwood at [68] the High Court observed that the comparison called for by s 40(3) is not analogous to that between a claim and an alleged anticipation or infringement. Furthermore, that it is wrong to apply an ‘over meticulous verbal analysis’ or to isolate in the body of the specification essential integers or features of an invention and inquire whether they correspond with the essential integers of a claim.
‘Process’ claims 1-9 and 12 recite a process for obtaining a concentrate of VWF or FVIII/VWF. CSL led no submissions to the effect that the specification contains no real and reasonably clear disclosure of the process as it is claimed. Grifols submitted that claim 1 defines the critical steps that arrive at an intermediate product that, with further processing, will result in a product with therapeutic efficacy. Grifols referred to Example 8 and Table 8 to provide a disclosure of the filtration process of the claims to produce an intermediate product, followed by further processing including post-washing, concentrating and subsequent precipitation of sodium and glycine, to obtain the high purity FVIII/VWF concentrate.
Furthermore, all of the features of process claims 1-9 and 12 are broadly disclosed at least between page 9, line 13 and page 10, line 13, including the filtration conditions, the protein recoveries, the protein concentration before filtration and the VWF/FVIII ratio. On page 10, lines 22-27, the nature of the filtered VWF or FVIII/VWF complex obtained makes it possible to prepare a high purity medication suitable for the treatment of VWD and HA, respectively. This passage provides a real and reasonably clear disclosure of the VWF or FVIII/VWF concentrate obtained according to the processes of claims 1-9 (opposed claim 13), and the use of that concentrate for the preparation of a medicinal compound to treat VWD and HA (opposed claim 10). Given that therapeutic VWF and FVIII compositions are known in the prior art, it also provides a real and reasonably clear disclosure of the therapeutic method of opposed claim 11.
CSL has not established that the claims are not fairly based.
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).
CSL submitted that claim 1 lacks clarity insofar as it requires a proportion between VWF and FVIII of 0.4 or more, but encompasses embodiments in which the solutions contain no VWF. In addition, CSL considered claims 4 and 5 unclear in that they refer to recovery of protein, without indicating whether this is active or total protein.
I have construed claim 1, 4 and 5 above in this regard and have been able to give them a meaning. I therefore find the claims clear in scope.
CONCLUSION
The subject matter of claim 11 is not useful.
It is possible to overcome the deficiency I have identified by amendment of the claims. I therefore allow Grifols 2 months from the date of this decision to propose such amendments.
COSTS
It is normal in actions before the Commissioner that costs should follow the event. However, subregulation 5.20(6) permits the conduct of the parties in filing their summary of submissions to be taken into account in awarding costs. Subregulation 5.20(4) requires the parties to an oral hearing to file summaries of submissions prior to the hearing; the opponent 10 days before, and the applicant 5 days before the hearing.
CSL and Grifols filed submissions 3 and 5 days late, respectively. In providing submissions on costs, the parties explained that the reason for the delay was that they were both busy at the time submissions would normally be due. They had conferred and agreed to a later timeframe for filing their summaries.
Written summaries of submissions are for the benefit of the hearing officer as well as the parties. Therefore, where the parties agree to a different schedule than that set out in reg. 5(20)(4), it is appropriate that they inform the Commissioner accordingly. Nevertheless, the parties agreed that neither was disadvantaged by late filing of submissions and they both submitted that costs should follow the event. In the circumstances of this case, it is appropriate that costs follow the event.
CSL has been successful in this opposition. I award costs according to Schedule 8 against Grifols S.A.
Dr Barbara Akhurst
Delegate of the Commissioner of Patents