CSL Limited v Baxter International Inc and Baxter Healthcare S.A

Case •

[2016] APO 9

•

18 February 2016

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

CSL Limited v Baxter International Inc and Baxter Healthcare S.A. [2016] APO 9

Patent Application:                   2008345135

Title:Recombinant VWF formulations

Patent Applicant:  Baxter International Inc. and Baxter Healthcare S.A.

Opponent:  CSL Limited

Delegate:  Sophina Calanni

Decision Date:  18 February 2016

Hearing Date:  26 November 2015 in Canberra

Catchwords:  PATENTS - section 59 – opposition to grant of a patent – opposed on the basis of novelty, inventive step, clarity, fair basis and utility – novelty – whether feature inherent in the citation– inventive step – whether the claimed invention is obvious in light of common general knowledge alone – whether the document cited would be ascertained, understood and regarded as relevant – opposition unsuccessful

Representation:  Patent applicant:  Mr Chris Burgess of counsel assisted by Gary Cox and Dr Linda Kennaugh of Wrays.

Opponent:Dr Bill Pickering, patent attorney, assisted by Dr Tania Uren of Davies Collison Cave

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application:                   2008345135

Title:Recombinant VWF Formulations

Patent Applicant:  Baxter International Inc. and Baxter Healthcare S.A.

Date of Decision:  18 February 2016

DECISION

The opposition fails on all grounds.

Subject to appeal, I direct that the application proceed to grant.

I award costs in accordance with Schedule 8 against CSL.

REASONS FOR DECISION

Background

  1. Patent application 2008345135 (the application) was filed by Baxalta Incorporated and Baxalta GmbH (Baxalta) on 23 December 2008. 

  2. The application was examined and advertised accepted on 13 February 2014.  A notice of opposition was filed on 13 May 2014, followed by a statement of grounds and particulars on 6 August 2014.  A request to amend the notice of opposition was filed on 7 January 2015 to change the party opposing the application to CSL Limited (CSL).  An amended statement of grounds and particular was also filed on 23 September 2015 and subsequently allowed on 16 October 2015.

  3. Baxalta filed Section 104 amendments on 22 December 2014, after the evidence in support had been completed.  The amendments were advertised allowed on 30 April 2015.

  4. The request for examination in relation to the application was filed on 29 March 2012.  Consequently, substantive amendments of the Patents Act 1990 brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present 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. It is further noted that any subsequent references to sections of the Patents Act relate to the Patents Act 1990 prior to amendment by the Raising the Bar Act.

    The evidence

  5. The evidence in support consists of the declaration of Dr Richard Shalders (Shalders) and exhibits RS1 RS14, filed on 5 November 2014.

  6. The evidence in answer consisting of the declarations and exhibits listed below was filed on 7 May 2015.

    ·Dr Thomas Exner (Exner), exhibits TE1-TE7

    ·Dr Emmanuel Favaloro (Favaloro), exhibits EF1-EF8

  7. The evidence in reply consists of the declaration of Dr Jeffrey Hey (Hey) and exhibits JH1-JH4, filed on 13 July 2015.

  8. A hearing was held in Canberra on 26 November 2015. 

    Grounds of opposition

  9. The opponent relied on the following grounds of opposition as identified in the amended statement of grounds and particulars allowed on 16 October 2015:

    ·manner of manufacture

    ·novelty

    ·inventive step

    ·utility

    ·section 40 issues of clarity, fair basis and full description.

  10. I note that CSL did not provide written submissions with respect to the absence of a manner of manufacture, nor did they press that ground at the hearing.  As such, I will not consider manner of manufacture in this decision.

    Standard of proof

  11. The onus of proof in this opposition proceeding rests with the opponent, who must demonstrate that it is “clearly shown” or  “practically certain” that the claims are invalid  (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

  12. The specification relates to the preparation of stable, liquid pharmaceutical formulations of recombinant von Willebrand Factor (VWF).

  13. VWF is a large, multimeric glycoprotein circulating in plasma as a series of multimers ranging in size from 500 to 20,000 kD.

  14. VWF is synthesised in endothelial cells and megakaryocytes as a primary translation product of 2813 amino acids.  VWF undergoes considerable processing, including dimerisation and multimerisation to very large forms.  A bleeding disorder called von Willebrand disease (VWD) occurs when VWF is deficient or defective.

    Aim of the invention

  15. The specification states (paragraphs [0006]-[0007]):

    “US. Pat. Nos. 6,531,577, 7,166,709, and European Patent Application No. 04380188.5, describe plasma-derived VWF formulations. However, in addition to quantity and purity issues with plasma-derived VWF, there is also a risk of blood-born pathogens (e.g., viruses and Variant Creutzfeldt-Jakob disease (vCJD).

    Thus there exists a need in the art to develop a stable pharmaceutical formulation comprising recombinant VWF.”

    Detailed Description of the invention

  16. At paragraph [0008] of the opposed application the invention provides formulations useful for compositions comprising recombinant VWF, resulting in a highly stable pharmaceutical composition.

  17. The specification indicates that recombinant VWF (rVWF) can be produced by any method known in the art ([0040]), said methods generally including the steps of providing a molecule that contains the nucleic acid sequence encoding VWF, introducing the molecule into a host cell, cultivating the host cell and isolating the protein([0040]-[0045]).

  18. At pages 12-20 of the specification describes a range of excipients that may be used in pharmaceutical formulations.  The specification (page 12, paragraph [0060]-[0061] indicates that:

    “For protein drugs, the choice of excipients is particularly important because they can affect both efficacy and immunogenicity of the drug. Hence, protein formulations need to be developed with appropriate selection of excipients that afford suitable stability, safety, and marketability.

    The principal challenge in developing formulations for therapeutic proteins is stabilizing the product against the stresses of manufacturing, shipping and storage. The role of formulation excipients is to provide stabilization against these stresses.”

  19. The specification then goes on to briefly describe the different types of excipients and their mode of stabilisation.  Excipient classes described include buffers, salts, stabilisers and bulking agents, surfactants, amino acids, antioxidants, metal ions and preservatives.

    The specification also provides a general discussion of other factors important for pharmaceutical formulations such as methods of preparation, administration and dosage regimes.

  20. The description ends with 3 examples that describing a range of experiments carried out to assess the activity or recombinant VWF exposed to different conditions.  Example 1 examines precipitation of rVWF …, Example 2 assesses the stability of rVWF based on the activity level of the recombinant protein in various formulations.  Example 4 examines protein unfolding and degradation  in various formulations.

    Person skilled in the art

  21. It is well established that many of the issues in an opposition are answered by reference to the person skilled in the art.  As stated in Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; 49 IPR 225 at [70], the person skilled in the art:

    "...is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious."

  22. CSL submitted that the skilled addressee in the present application is clearly a formulation chemist.  At the hearing CSL noted that the area of expertise of both expert witnesses for Baxalta was not formulation chemistry and suggested that as a consequence careful consideration should be given to evidence adduced by those experts.

  23. Baxalta submitted that while Dr Exner and Dr Favaloro are not formulation chemists, they have extensive research, clinical and diagnostic experience in field of blood clotting factors, including VWF.  The evidence shows that Dr Favaloro has working knowledge of VWF formulations, as well as an understanding of the approaches and difficulties in developing formulations containing VWF (see Favaloro [26],[82]).  Similarly, Dr Exner has technical and research and development experience with blood clotting factors, including protein reagents in liquid and lyophilised forms (see Exner [25],[33]).

  24. In the present case the art is the formulation of recombinant blood clotting factor compositions, in particular recombinant VWF compositions. The person skilled in the art must have an understanding of the production of recombinant blood clotting factors and knowledge of the formulation of such compositions, with a particular emphasis on developing a stable pharmaceutical formulations.  I consider that a range of  persons could provide useful evidence as to the characteristics of the skilled addressee, including formulation chemists, clinical haematologists and scientists with experience in the production of recombinant proteins.  As such, I will have regard to the evidence of all declarants. Where there is conflict in their evidence, I will resolve that conflict in the normal way.

    Claim construction

  25. The specification contains 22 claims.  Claims 1 and 15 are independent. Omnibus claim 22 defines a stable liquid formulation as defined in claim 1 or claim 15 by reference to the examples.

  26. Claim 1 recites:

    "A stable liquid pharmaceutical formulation of a recombinant von Willebrand Factor (rVWF) comprising: (a) a rVWF; (b) a buffering agent; (c) one or more salts;

    wherein said rVWF in pharmaceutical formulation causes agglutination of stabilised platelets in the presence of ristocetin, is stable for at least 26 weeks at 4oC and comprises a polypeptide that has a molecular weight of approximately 250kDa selected from the group consisting of:

    (a)the amino acid sequence set out in SEQ ID NO:3;

    (b)a biologically active analog or variant of (a);

    (c)a polypeptide encoded by the polynucleotide set out in SEQ ID NO:1;

    (d)a biologically active analog or variant of C;

    (e)a polypeptide encoded by a polynucleotide that hybridises to the polynucleotide set out in SEQ ID NO:1 under moderately strident hybridisation conditions;

    wherein said buffering agent is citrate at a concentration of about 0.1 mM to about 500mM;
    wherein the pH is in a range of about 3.0 to about 9.0; and
    wherein the salt is at concentration of about 0.5 mM to 500mM."

  27. With regard to claim 1, the components of the liquid pharmaceutical formulation are all known and there is no dispute with regard to their meaning. However, the parties are in dispute regarding the properties of the formulation, specifically the requirement that the rVWF is stable for at least 26 weeks at 4oC.

  28. CSL submitted that meaning of the term 'stable' was unclear.  They indicated that in the opposed application stability of the rVWF formulations is measured in terms of either antigen content or platelet agglutinating activity, and it is unclear which measure is being referred to in the claims (written submissions [64]; Hey [46]).

  29. Baxalta submitted that the meaning of the word stable in the context of the claims refers to the preservation of the ability of the recombinant VWF to agglutinate platelets on the presence of ristocetin after 26 weeks at 4oC (written submissions [49[).

  30. 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 ...”

  31. I note that the examples in the present application describe experiments testing the chemical stability (agglutinating activity) and physical stability (precipitation and unfolding) of a rVWF in the tested formulations.  Furthermore, exhibits RS3 and JH4 adduced in the opponent's evidence clearly indicate that in the art both chemical and physical stability are commonly measured to assess the overall stability of a protein formulation (see for example RS3 page 804, left column, paragraph 3; JH4 page 180 and page 186, paragraph 2).  Thus, in my view, reading the specification as a whole, the skilled addressee, having regard of their general knowledge and what is disclosed in the body of the specification, would understand that the term "stable" relates to both the chemical and physical stability of the formulation. 

  32. I therefore consider the claim to be directed to a stable pharmaceutical formulation that must

    (1) contain the following components:

    ·rVWF (selected from the polypeptides listed in parts (a) to (e)),

    ·a citrate buffering agent (at a concentration of between 0.1mM to 500 mM), and

    ·one or more salts (at a concentration of 0.5mM to 500mM); and

    (2) have the following properties:

    ·is a liquid formulation,

    ·has a pH in a range of about 3.0 to 9.0,

    ·causes agglutination of stabilised platelets in the presence of ristocetin, and

    ·is chemically and physically stable for at least 26 weeks at 4°C.

  33. Claims 2-14 and 22 are dependent on claim 1 and relate to specific embodiments of the individual components and formulation. 

  34. The second independent claim, Claim 15, defines the best method of performance of the invention. The formulation defined must contain the components listed below and also have the four properties described above at paragraph [32].

    ·rVWF (selected from the polypeptides listed in parts (a) to (e)),

    ·a citrate buffering agent (at a concentration of about 15mM), and

    ·sodium chloride at a concentration of about 100mM, and

    ·calcium chloride at a cocentration of about 10mM; and

  35. Claims 16-22 are dependent on claim 15 and relate to specific embodiments of the individual components and the formulation.

    NOVELTY                

  36. Subsection 7(1) of the Patents Act states that an invention is taken to be novel unless it is not novel in light of the prior art. A citation is part of the prior art base for the purposes of novelty if it was published before the priority date.

    It is well established that the general test for lack of novelty is the reverse infringement test as given by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19 at [20]; [1977] HCA 19; 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”.

  37. The only document relied on by the opponent in relation to the ground of novelty was US 6,005,077 (Schwarz et al.) 21 December 1999 (“D1”).  This document was  published before the priority date of the claim, and is therefore part of the prior art base. 

  38. The opponent submitted that claims 1-7, 10-12 and 16-20 lack novelty based on the disclosure of D1.

  39. The most relevant parts of the document are Examples 1 and 7 which describe recombinant VWF formulations.

    Example 1

  40. Example 1 discloses the production of recombinant VWF in CHO cells.  Following purification, the recombinant VWF was rebuffered in a buffer of pH 7.0 containing the following:

    5g/ml Na3citrate.2H2O
    2g/l NaCl
    5g/l glycine
    5g/l L-lysine.HCl
    0.62 g/l CaCl2.2H2O

    The preparation was characterised by 36.4U/ml VWF antigen as measured in a commercial VWF ELISA, and by a VWF activity of 13.8 U/ml, measured using a ristocetin mediated platelet aggregation assay.

  41. Both parties submitted that the concentration of Na3citrate in Example 1 contained a typographical error (Shalders [23], Exner [107], Hey [51]), and should refer to “g/l” rather than “g/ml”. In their submissions [24] CSL referred to the Patent Manual of Practice and Procedure at 2.4.5.2.4 indicating that where there is an error in a citation, that error is not to be given a literal interpretation.  Instead if the skilled addressee would have recognised the error, but knew how to correct it, then the corrected version is disclosed.

  42. Accordingly, the example describes a formulation containing recombinant VWF in a buffer comprising:

    17mM Na3citrate.2H20
    34mM NaCl
    67mM glycine
    27mM L-lysine.HCl
    4.2mM CaCl2.2H2O

  43. Baxalta suggested that the preparation of Example 1 is not a formulation but merely describes the production of recombinant VWF.  However, the components of the preparation of VWF (after rebuffering) include the typical excipients found in a formulation, namely a buffer and salts, and the preparation has a physiological pH.  While Dr Favaloro contends that the gel filtration buffer of example 1 does not necessarily provide a therapeutic formulation, I note that example 7 of D1 contains the same components and is regarded as a formulation (Favaloro [159]-[160]).  As such, I consider the preparation described in example 1 is also a formulation.  

  44. The formulation of example 1 clearly meets requirements that it be a liquid formulation, with a pH of 3.0 to 9.0 and causes agglutination of stabilised platelets in the presence of ristocetin.  Therefore, the only required property that is not explicitly disclosed relates to chemical and physical stability of the formulation for at least 26 weeks at 4°C.

  45. CSL submitted that although D1 does not explicitly discuss the stability of the recombinant VWF formulation, the formulation must be stable if the teachings of the opposed application are accurate (CSL's submissions paragraph [26]).  Dr Hey stated at [47]:

    “As there has been no alteration to the rVWF in producing the formulation, this level of stability of rVWF is either a natural property of rVWF or the rVWF is stable in the environment provided by the other elements making up the formulation.”

  46. The basis for the CSL's submission is the principle set out in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd,[1972] RPC 457 at 485-486:

    “If carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated."

  47. Baxalta in their submissions pointed to the further principle set out in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd supra at 486:

    "If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented: Flour Oxidizing Co. Ltd. v. Carr & Co. Ltd.(1908) 25 R.P.C. 428 at 457, line 34, approved in B.T.H. Co. Ltd. v. Metropolitan Vickers Electrical Co. Ltd.(1928) 45 R.P.C. 1 at 24, line 1). A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee."

  1. The critical question to consider when assessing if D1 anticipates the present claims is whether a person following the directions of the citation would have inevitably produced a formulation that is chemically and physically stable for at least 26 weeks at 4oC.  I observe that the onus is on the opponent to establish its case and in order to fulfil that onus the situation would appear to require persuasive expert evidence.

  2. Of the opponent's declarants, only Dr Hey provides evidence which clearly supports the opponent's position. He states at [52]:

    “Although there is no specific indication of the stability of rVWF in the formulation in Example 1 of US6005077, I do not believe there is any reason to believe the formulation would not be stable.  Indeed given that this formulation in terms of ingredients is the same as that set out in most of the claims of the opposed application I would be surprised if the formulation was not stable.  If the rVWF formulation described in Example 1 of US6005077 is not stable, then it seems to me that claim 1 of the opposed application must be missing something (such as more precise concentrations of excipients and/or additional excipients) that itself or in conjunction with the other excipients is necessary for stability.”

    Further, at [54] Dr Hey stated:

    “To summarise, it appears to me that the rVWF formulation of Example 1 (when read to correct the obvious error) and Example 7 of US6005077 has a pH of 7.0 and includes citrate and salts at concentrations within the ranges specified in claims 1-7 and 10-12 of the opposed application, and has platelet agglutinating activity.  Based on what is described in the opposed application, I have no reason to believe that the rVWF formulation of Examples 1 and 7 of US6005077 would not be “stable” at 4oC for 26 weeks.  Therefore, claims 1-7 and 10-12 of the opposed application do not appear to be describing anything which had not already been described in US605077.”

  3. However, as Baxalta submitted at the hearing, it is not correct to state that the ingredients are the same as that set out in the claims.  There are material differences between the claimed formulations and the formulation described in Example 1.  More particularly, Baxalta contends that examples 1 and 7 of D1 are dual buffer systems that contain significant concentrations of both sodium citrate and glycine in the formulation.  In addition, the concentration of each salt in the preferred formulation of the application is over twice that of Examples 1 of D1 (written submissions [87]-[88], Exner [113], Favaloro [159]).

  4. In view of the differences in the formulations, it is difficult to accept the assertion of Dr Hey that he has "no reason to believe that the rVWF formulation of Examples 1 and 7 of US6005077 would not be stable at 4oC for 26 weeks." (Hey [54]).  In fact, the evidence adduced by the opponent themselves clearly supports the notion that variations in the substances added to a preparation may have significant effects on protein stability (see for example RS3, page 803, right column, paragraph 2 and page 804, right column, Drug Stability and  JH4, page 184, paragraph 2).  I therefore consider the statements of Dr Hey to be speculative and as a consequence CSL has not established that the inevitable result of following Example 1 of D1 is the production of a stable liquid formulation that is chemically and physically stable for at least 26 weeks at 4°C.

    Example 7

  5. As noted earlier, the formulation of Example 7 of D1 contains the same components as the formulation in Example 1.  In addition, the formulation described comprises only the low molecular weight VWF and as a consequence will not cause agglutination of stabilised platelets in the presence of ristocetin.  Thus for the same reasons as discussed above in paragraph [51], CSL has not established that the inevitable result of following example 7 would be a stable liquid formulation as defined in claim 1.

  6. Therefore I am not satisfied that D1 contains clear and unmistakeable directions to produce a stable liquid formulation comprising rVWF that is chemically and physically stable for at least 26 weeks at 4oC.

  7. All of the claims incorporate the feature of stability for at least 26 weeks at 4oC, therefore CSL has not established that the claims lack novelty in light of US 6,005,077.

    INVENTIVE STEP

  8. CSL opposed all claims under this ground, submitting that the claimed invention was obvious on the basis of the common general knowledge alone, and the common general knowledge in combination with US 6,005,077 (D1).  I note that in the written submissions the opponent had sought to rely on the product information pamphlets as prior art documents under s7(3)(b) (see [35]).  However, at the hearing CSL stated that they were relying on product information pamphlets as evidence of prior use of the products in the context that the person skilled in the art would consider commercially available products common general knowledge in the art.  In the event that the earlier rVWF products do not form part of the common general knowledge CSL submitted the documents could be used in combination with common general knowledge to demonstrate that the claimed invention was obvious.

  9. 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] HCA 21; (2007) 72 IPR 447 at 461 [51] - [52]). Obviousness in the light of the common general knowledge is assessed 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.

  10. The test for obviousness was provided by Aicken J 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.”

  11. The High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd (Alphapharm) [2002] HCA 59 at [51]- [53]; [2002] HCA 59; 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]?”

  12. 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] HCA 9; (1980) 144 CLR 253 at 293).

  13. 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

  14. The problem faced by the inventors was the development of a stable liquid pharmaceutical formulation of rVWF.

    Common General Knowledge

  15. The common general knowledge that is relevant is that in Australia. The state of the common general knowledge is a question of fact relating to what was known by skilled workers in the field. It must be determined on the basis of evidence from suitably qualified experts.

  16. All experts agreed that:

    • pharmaceutical formulations of VWF for treating Von Willebrands disease (VWD) must contain VWF molecules having platelet agglutinating activity
    • there were a number of commercially available VWF formulations at the priority date, these products were provided in lyophilised form and reconstituted prior to administration
    • stable liquid formulations of therapeutic proteins are generally desirable
    • there was no commercially available liquid formulation of VWF
    • a range of buffers were typically used in preparing pharmaceutical preparations including citrate, phosphate, carbonate, Tris histidine, succinate and glycinate buffers
    • pharmaceutical formulations also typically contain a tonicity agent
    • experimental methods were used to vary excipients in a systematic manner when preparing pharmaceutical formulations.

    Commercially available VWF products

  17. A significant aspect of CSL's case for inventive step relies on an understanding of the VWF formulations that were commercially available before the priority date of the application.  As stated in Aktiebolaget Hassle v Alphapharm Pty Ltd [2000] FCA 1303;51 IPR 375 at 391 the common general knowledge is not restricted to information that might be retained in the mind of the skilled person, but extends to material that is routinely consulted by such a person in the field.

  18. The evidence introduced by each of the expert witness with regard to the VWF products available before the priority date is largely disparate, however a list of available products can be determined considering their evidence as a whole.

  19. Dr Shalders introduced the” Registry of Clotting Factor Concentrates from 2012” (RS2) into evidence.  This document is published after the priority date and does not contain any information that allows me to determine which of the listed VWF products were sold prior to December 2007. 

  20. I note that Dr Shalders also stated at [25]:

    "Each of Immunate, Advate, Alphanate, Wilate, Wilfactin, Haemate-P and Biostate are VWF containing products, a number of which were sold prior to December 2007."

  21. At best Dr Shalders' declaration confirms that one or more of the identified VWF products were available for sale prior to December 2007.  Turning to the supporting evidence introduced with regard to pharmaceutical products, only the information in RS7 for Biostate was published before the priority date.  Therefore based on Dr Shalders evidence I can establish that Biostate was commercially available before the priority date.

  22. Dr Exner does not provide any specific evidence in relation to commercially available products other than to review RS2 and note that it was published after the priority date of the present application.

  23. Dr Favaloro identifies one FVIII/VWF preparation available at the priority date was Haemate P (produced by CSL Behring).  Based on this evidence I am satisfied that Haemate P was available before the priority date. 

  24. Dr Hey provided as evidence "The Registry of Clotting Factor Concentrates 2006" [JH5] which confirms the availability of Wilfactin, Alphanate, Fanhdi and Wilate before the priority date (see Tables 2, 3 and 7).  I consider the skilled person working in the field of blood clotting factors would routinely consult the Registry of Clotting Factor Concentrates, and as such I am satisfied that the evidence shows that Wilfactin, Alphanate, Fanhdi and Wilate were commercially available before the priority date.

  25. As such, considering all of the evidence on this matter I am satisfied that Biostate, Haemate P, Wilfactin, Alphanate, Fanhdi and Wilate were commercially available before the priority date and were part of the common general knowledge in the art.

  26. As the VWF products listed above in [73] were found to form part of the common general knowledge I will not consider obviousness based on the use of the product information pamphlets (as 7(3) documents) in combination with common general knowledge.  However, for completeness I note that a number of these documents (Humate (RS6), Wilate (RS8), Willfact (RS10), Immunate (RS11)) were published after the priority date, or a publication date could not be determined.  As a consequence these documents could not be taken into consideration when assessing obviousness under subsection 7(3).

    Was the invention obvious in the light of the common general knowledge in the art?

  27. CSL submitted at the hearing that claim 1 lacks an inventive step being an obvious application of the common general knowledge in the art.  CSL argued that in looking to develop of stable liquid formulation of rVWF, the person skilled in the art would have given consideration to the rVWF used in the formulation, the pH of the formulation, and the excipients used in the formulation, selecting these to meet not only the stability requirement but also the requirements imposed by the intended use of the formulation (written submissions [41]).  More specifically, the person skilled in the art would look to prepare a formulation that includes a buffer, tonicity agents and stabilizing agents (Hey [28]), and having regard to the product information pamphlets for VWF formulations on the market would have selected citrate as the buffer and NaCl and/or CaCl2 as the tonicity agent (Hey [29]-[30]) and then adjusted the concentrations of excipients in a systematic manner until a stable liquid rVWF formulation was identified. (Hey [32]).

  28. I accept that at the priority date of the application, a well established goal in the art was to move away from plasma derived blood clotting factors to recombinant clotting factors.  I further accept that as set out in [0060]-[0098] the present application it was routine to use excipients such as buffers and stabilisers in protein formulations.  However, it was also well understood that protein stability in such formulations was unpredictable and that combinations of excipients could have profound and unexpected effects on protein stability (see for example Favaloro [71]-[76]; JH4, page 184, second paragraph and RS3 p 804, right column, Compatability of drug with potential formulation additives).

  29. The evidence shows that each of the witnesses would look to commercially available formulations with an aim to develop a liquid formulation.  Specifically, Drs Shalders, Exner and Favaloro each submit that they would use such formulations as a starting point for a stable liquid formulation (Shalders [26], Exner [85], Favaloro [133]).  Dr Hey differs from the other experts in his submission.  He considers that having regard to the product information pamphlets for VWF formulations on the market he would have selected citrate as the buffer and NaCl and/or CaCl2 as the tonicity agent (Hey [29]-[30]) and then adjusted the concentrations of excipients in a systematic manner until a stable liquid rVWF formulation was identified. (Hey [32]).

  30. Baxalta has submitted that Dr Hey and Dr Shalders were shown the patent application (and therefore the solution) before they prepared their evidence on obviousness (written submissions [160]) and thus their evidence represents a hindsight reconstruction of an asserted pathway prepared with the benefit of knowing the solution provided by the patent application.  I agree with the applicant, particularly with respect to Dr Hey's submissions concerning the excipient selection he would have made having regard to the commercially available VWF products.  Although there was a known range of  preferred excipients available to formulators at the priority date, it was not possible to predict how components might be selected and combined to achieve storage stability.  As noted by Dr Exner, referring to Annexure TE-7, no two prior products have the same combination of excipients (Exner [95]), and there is no evidence (other than Dr Hey's submissions) that establishes it was obvious to select or reject any particular excipient identified in the pamphlets in favour of another.

  31. As such, 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.  In fact, as submitted by the applicant, the fact that all existing VWF formulations were in the lyophilised form suggests that there was an expectation that the protein would not be stable in a liquid formulation.  It follows that CSL has not established that any claim lacks an inventive step in light of the common general knowledge in the art.

    Obviousness in light of the citation

  32. The document relied on to establish inventive step was the same as relied on for novelty, namely US 6, 6,005,077 (D1).

    Ascertained, understood and regarded as relevant

  33. CSL submitted that the document 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 Baxalta.

  34. Neither party adduced evidence about whether the person skilled in the art would have regard to patent literature.  Therefore I do not need to decide this matter.  Instead I will assume the  that the average person skilled in the art could reasonably be expected to have ascertained the document.  I also accept that the document would have been understood by the person skilled in the art.

  35. However, I am not convinced that the skilled worker would have regarded D1 as being particularly relevant to solving the problem of providing a stable liquid formulation of rVWF. 

  36. As submitted by Baxalta, the problem addressed by the present application was to prepare a stable liquid formulation of rVWF.  D1 instead focuses on improving the pharmacokinetics of Factor VIII, teaching that VWF can be used to prolong the biological half-life of preparations of Factor VIII by stabilisation of Factor VIII.  There is no suggestion that the preparations described in D1 would be suitable for long term storage.  As such, I do not believe that the skilled worker would regard the teaching of D1 as relevant to the problem of formulating stable rVWF formulations.  Since D1 would not be regarded relevant by the person skilled in the art, it cannot deprive the claims of an inventive step.

    CLARITY

  37. A claim will lack clarity if a third party could not ascertain whether a proposed action would fall within the ambit of the claim (Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59).

  38. CSL submitted that claims 1 – 22 lack clarity as it is unclear what is meant by the term “stable” and how it is measured.  In my consideration of the construction of the claims above I have found that reading the specification as a whole, the skilled addressee, having regard of their general knowledge and what is disclosed in the body of the specification, would understand that the term "stable" relates to both the chemical and physical stability of the formulation. 

  39. Similarly, with regard to claim 2, I am satisfied the skilled addressee would understand the phrase "rVWF retains at least about 50% agglutinating ability of stabilized platelets in the presence ristcetin compared to the same material measure at commencement of storage".  There can be no question that the phrase relates to agglutinating activity, rather than the alternative (antigen content) proposed in the written submissions ([65]).

  40. Finally, the opponent drew attention to the fact that claim 21, which specifies that the first salt is at a concentration of 30mM and the second salt is at a concentration of 0.56mM, lacks clarity because it is ultimately dependent on, amongst other claims, claims 13, 14 and 15, which specify that the salt is at a concentration of 10mM and the second salt is at a concentration of 100mM.  The issue described arises because claim 21 is appended to “any one of the preceding claims”.  I consider that in construing the claim the skilled addressee would resolve the matter by construing the claim as appended only to those claims do not already define a specific salt concentration, therefore the claim does not lack clarity

    UTILITY

  1. In their submissions CSL has argued that the claim 1-6, 10, 11 and 16-17 lack utility as there is no indication in the opposed application that a stable formulation of rVWF could be achieved over the broad ranges of excipient concentrations and pH. 

  2. Baxalta  identified the applicable principles as set out in Apotex Pty Ltd v AstraZeneca AB (No 4) (2013) 100 IPR 285 at [352]:

    "Section 18(1)(c) requires that an invention be “useful”. This will be the case if the claimed invention does what it is intended by the patentee to do, in the sense of meeting the object or promise in the specification, and the end result obtained is itself useful [Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC (2008) 77 IPR 449; [2008] FCAFC 82 at[141]]. For this purpose, the claims must be construed from the perspective of a skilled person in a commonsense way, and not in a way that any such addressee would appreciate would lead to an unworkable result [SNF (Australia) Pty Ltd v Ciba Specialty Chemicals Water Treatments Ltd (2011) 92 IPR 46; [2011] FCA 452 at [293]].

    It is not necessary for the description in the specification to spell out matters which the skilled person could supply without the exercise of any inventive faculty in order to achieve the promise of the invention. The patentee is entitled to assume that the reader has a reasonably competent knowledge of what was known before and reasonably competent skill in the practical mode of doing what was then known. A purposeful adoption of an embodiment that would obviously lead to an unworkable or inferior result is not an appropriate way of testing utility. It is also relevant to pay attention to the nature of the alleged “promise” in the specification. See, by way of analogy, Austal Ships Pty Ltd v Stena Rederi Aktiebolag (2005) 66 IPR 420;[[2005] FCA 805] at [254]-[255]. Ultimately, an asserted lack of utility must be established by appropriate evidence, not by mere speculation that the invention will not work or meet the promise set out in the specification."

  3. Notwithstanding the lack of evidence showing that the opposed invention does not work, Baxalta noted that the claim is limited by the feature of stability after 26 weeks at 4oC.  That limiting integer guarantees there is no prospect on inutility because only those formulationss that meet the promise of the invention fall within the scope of the claims (written submissions at [179]).  I agree with this submission, and therefore consider that the opponent has not made out a case for inutility on this basis.

  4. CSL also made submissions regarding the pH of the liquid formulation, stating that a pH other than physiological pH is not a pharmaceutical formulation.  Again I note that CSL has not adduced appropriate evidence to assert this ground.  Even the evidence of their own experts suggests that they would aim for a pH as close to a physiological pH as possible (Shalders [10]; Hey [22] and annexure JH4, page 186, Liquid formulations).  In answer, Baxalta also pointed to the evidence of Dr Exner at [78] where he stated that it is was not necessary to select a pH of 7 when developing a stable formulation for storage, as the pH can be adjusted with additives before injection into the patient.

  5. I therefore consider that the opponent has not made out a case in relation to the ground of utility.

    FAIR BASIS

  6. It is well established that fair basis is assessed by asking whether there is a real and reasonably clear disclosure of the claimed invention in the specification, and do the claims travel beyond the subject matter of the invention described in the specification (Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58, 217 CLR 274).

  7. The opponent at paragraph [63] of their written submissions submitted that claims 1-2 and 4-22 are not fairly based on the specification because they omit the essential feature that the formulation does not include glutathione. CSL pointed to particular paragraphs of the specification ([00123], [00134] and [00137]) that demonstrate rVWF is not stable in formulations containing glutathione. On this basis they considered that there was no real and reasonably clear disclosure of a stable, liquid pharmaceutical formulation of rVWF that contains glutathione.

  8. Baxalta submitted that as indicated in Lockwood Security v Doric Products supra at [68] it is wrong to seek to isolate in the body of the specification "essential features" of invention in the description of a patent and to ask whether they correspond with the essential integers of the claim in question.

  9. Baxalta further submitted the terms of claim 1 are substantially reproduced in a consistory clause as paragraph 9A of the specification, and that the specification also provides real and reasonably clear disclosure of a range of excipients that may or may not be included in the rVWF formulation.  There is no suggestion in the specification that it is mandatory for glutathione to be excluded. 

  10. I find Baxalta’s submissions persuasive noting that the parts of the description upon which the opponent relies relate to the examples and describe optimal conditions in particular buffers, rather than representing the teaching of the specification as a whole.  The specification as a whole  claims are therefore fairly based.

    CONCLUSION

  11. I find that the opposition was unsuccessful on all grounds.

    COSTS

  12. Both parties submitted that costs should follow the event.  

100. I note that the Applicant proposed amendments to the claims after the Evidence in Support was filed.  The amendment introduced the feature of the claims relating to a  rVWF formulation “causing agglutination of stabilized platelets in the presence of ristocetin”.  While this was an important feature of the formulations claimed, the grounds of opposition did not turn on this feature.

101. As such, I see no reason to depart from the principle that costs should follow the event.  I therefore award costs in accordance with Schedule 8 against CSL.

Sophina Calanni
Delegate of the Commissioner of Patents

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