Statens Serum Institut v Octapharma AG
[2007] APO 10
•6 March 2007
ABSTRACTS OF DECISIONS
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Application : No. 753468 in the name of Statens Serum Institut
Title: Process for Producing Immunoglobulins for Intravenous Administration and other Immunoglobulin Products
Action: Opposition by Octapharma AG under Section 59 of the Patents Act 1990
Decision: Issued 06 March 2007.
Abstract
The invention is an immunoglobulin G (IgG) product and a process for its preparation wherein the product demonstrates increased purity and stability such that adverse clinical affects caused by impurities following intravenous administration of IgG (IVIG) are reduced or obviated and the addition of stabilisers to a liquid formulation is not required.
The opponent argued that the use of the term “comprising” indicated that the order of the process steps as claimed was not set, however the delegate concluded that the specific wording of the claim did not support this construction.
The opponent argued that the claimed product and process lacked novelty and inventive step in the light of cited documents. None of these documents, however, disclosed a product having the claimed properties or a process specifying process steps of the same type in the same order. Furthermore the opponent did not establish that the common general knowledge would have led the person skilled in the art to modify the disclosed product or the process in the manner claimed as a matter of routine. The invention as claimed is both novel and contains an inventive step.
The opponent also argued that the invention was not a manner of manufacture because it failed the “threshold test” for newness, however, the delegate found that, in the light of its novelty and inventiveness, this was not established.
The opponent submitted that the Claims 14 and 15 lacked fair basis due to the use of the term “obtainable”, however the delegate considered that the product is effectively limited to that of the process defined due to the exhaustive and extended nature of the process defined in Claims 1 to 13. The delegate found that the claims are clear and fairly based.
The opposition is therefore unsuccessful on all grounds.
PATENTS ACT 1990
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Re:Patent Application No. 753468 by Statens Serum Institut and Opposition thereto by Octapharma AG under Section 59 of the Patents Act 1990
BACKGROUND
Patent 721477 was filed in the name of Statens Serum Institut (hereafter referred to as “SSI”) as PCT/DK/00312 under the Patent Cooperation Treaty on 9 June 1999 claiming priority from EP 98201909 dated 9 June 1998 and US Application 60/102,055 dated 28 September 1998. The application entered the National Phase in Australia under application number 42572/99 and was advertised accepted on 17 October 2002. A Notice of Opposition under Section 59 was filed on 17 January 2003 by Octapharma AG (hereafter referred to as “Octapharma”)and a Statement of Grounds and Particulars followed on 17 April 2003.
In letters dated 8 November 2004 and 24 November 2004, Statens requested that the Commissioner direct that Document D10 cannot be relied upon by the Opponent in the prosecution of the opposition due to lack of certainty of its publication date. On 16 November 2004 the Delegate of the Commissioner decided that the issuing of a direction as requested was not appropriate in the circumstances and deferred all further consideration of D10 to the substantive opposition. This was confirmed in a further letter by a delegate of the Commissioner dated 4 January 2005.
The Statement of Grounds and Particulars was amended under Reg 5.9 on 9 November 2005. The grounds of opposition were manner of manufacture, novelty, inventive step and section 40.
The evidentiary stages were completed by 17 March 2006.
The matter was heard in Canberra on 23 June 2006. Statens Serum Institut was represented by Rachel Butler and Paul Whenman of FB Rice, Sydney. Octapharma AG was represented by Mark Roberts of Davies Collison Cave, Melbourne.
EVIDENCE
The evidence in support consists of Statutory Declarations by
Mark Kemball Roberts, dated 17 October 2003, with annexures MKR-1 to MKR-7,
Neil Howard Goss, dated 12 November 2003 (NHG1) with annexures NHG-1 to NHG-5,
Neil Howard Goss, dated 13 October 2004 (NHG2), with annexures NHG-6 to NHG-9,
Mark Kemball Roberts, dated 15 October 2004 (MKR2) with annexure MKR-12
The evidence in answer consists of the following:
Documents dated 11 April 2005:
oStatutory Declaration and Verification of Translation by Gunnar Houen with exhibits GH1 to GH6
oStatutory Declaration by Birgitte Espersen with exhibit BE-1
oStatutory Declaration by Inga Laursen with exhibits IL1 to IL6
oVerification of Translation by Birte Marie Melgaard
Documents dated 14 July 2005:
oStatutory Declaration by Anna Johnston with annexure AJ-1
oStatutory Declaration by Anna Johnston with annexure AJ-2
oStatutory Declaration by John Sullivan with annexures JSS-1 to JSS-3
The evidence in reply consists of a Statutory Declaration by Neil Howard Goss, dated 14 October 2005 (NHG3) with exhibits NHG-13 to NHG-14.
THE SPECIFICATION
The invention disclosed in this application is an immunoglobulin G (IgG) product and a process for its preparation. The applicant asserts that the product demonstrates increased purity and stability such that adverse clinical affects caused by impurities following intravenous administration of IgG (IVIG) are reduced or obviated. The SSI IVIG is thus described as a “third generation” ready-to-use liquid product which is stable, of high purity, has a largely normal distribution of IgG subclasses with low IgA and IgM content. It contains essentially no polymeric aggregates of immunoglobulins and/or other plasma proteins higher than dimers, has low anti-complimentary activity and a high content of IgG monomers and dimers. Although the presence of stabilisers is permitted as an option, there is no specific exemplification of such an embodiment and the description specifically teaches that an advantage of the product is that, due its purity, “the addition of stabilizers such as non-ionic detergent, PEG or albumin is not necessary in order to avoid aggregation of IgG during storage of the IVIG as a liquid product” (page 4, line 14ff).
10. It is also stated that the product can be freeze-dried, however the advantages of the invention are clearly identified throughout the specification as arising from the liquid IVIG product and all embodiments are formulated as a liquid.
11. The applicant indicated that prior art IVIG products differed from that claimed in that they lacked the combination of high purity, low concentration of non-IgG immunoglobulin, and stability with high clinical efficacy and reduced adverse drug reactions.
12. The purification process by which this product is prepared, the disclosure of which makes up the bulk of the description, is a thirteen step procedure involving both precipitation and ion exchange removal of non-IgG proteins and two virus inactivation steps.
13. The claims of the specification as accepted are as follows:
Claim 1 is a process claim as follows to which Claims 2 to 13 are appended
A process for purifying immunoglobulin G (IgG), from a crude immunoglobulin-containing plasma protein fraction, which process comprises the steps of:
(a) preparing an aqueous suspension of the crude immunoglobulin containing plasma protein fraction;
(b) adding a water soluble, substantially non-denaturating protein precipitant to the said suspension of step (a) in an amount sufficient to cause precipitation of a high proportion of non-immunoglobulin G proteins, aggregated immunoglobulins and particles including potentially infectious particles such as virus particles, without causing substantial precipitation of monomeric immunoglobulin G, thereby forming a mixture of a solid precipitate and a liquid supernatant;
(c) recovering a clarified immunoglobulin G-containing supernatant from the mixture of (b);
(d) applying the clarified immunoglobulin G-containing supernatant of step
(c) to an anion exchange resin and subsequently a cation exchange resin, wherein the anion exchange resin and the cation exchange resin are connected in series and wherein the buffer used for the anion exchange chromatography
and the cation exchange chromatography is the same buffer, the pH of said same buffer is below 6.0.(e) washing out protein contaminants and the protein precipitant from the cation exchange resin of step (d) with a buffer having a pH and ionic strength sufficient to remove the contaminants from the resin without causing substantial
elution of immunoglobulin G;(f) eluting immunoglobulin G from the cation exchange resin of step (e) with a substantially non-denaturating buffer having a pH and ionic strength sufficient to cause efficient elution of the immunoglobulin G, thereby recovering an immunoglobulin G-containing eluate;
(g) performing a dia/ultrafiltration on the immunoglobulin G-containing eluate to concentrate and/or dialyse the eluate, and optionally adding a stabilizing agent;
(h) adding a virucidal amount of virus-inactivating agent to the immunoglobulin G-containing dia/ultrafiltrated and optionally stabilized fraction of step (g) resulting in a substantially virus-safe immunoglobulin G-containing solution;
(i) applying the immunoglobulin G-containing solution of step (h) to an anion exchange resin and subsequently to a cation exchange resin;
(j) washing the cation exchange resin with a buffer having a pH and ionic strength sufficient to wash out the protein contaminants and the virus-inactivating agent from the resin without causing substantial elution of immunoglobulin G;
(k) eluting immunoglobulin G from the cation exchange resin of step (j) with a substantially non-denaturating buffer having a pH and ionic strength sufficient to cause efficient elution of the immunoglobulin G, thereby recovering an immunoglobulin G-containing eluate; and
(l) subjecting the immunoglobulin G-containing eluate of step (k) to dia/ultrafiltration to lower the ionic strength and concentrate in immunoglobulin G of the solution, and adjusting the osmolality by adding a saccharide..
14. Claim 14 and 15 are directed to an immunoglobulin product obtainable from one of the preceding process claims.
15. Claim 16 is directed to an immunoglobulin product per se defined according to specific properties:
An immunoglobulin product having the following characteristics:
a) A purity of more than 98%,
b) A content of IgG monomers and dimers of more than 98.5%,
c) A content of IgA less than 4 mg of IgA/I, and
d) A content of IgG1, IgG2, IgG3 and IgG4.
16. Claims 17 to 23 are also directed to an immunoglobulin product and are appended to Claim 16.
17. Claims 24 and 25 are Swiss-style claims appended to Claims 16-23
DECISION
Construction Issues
18. A key construction issue in this case is whether the process steps set out in Claim 1 must be carried out in the order in which they are recited or the order of the steps may be altered and whether or not additional steps may be inserted between the recited steps.
19. The opponent argues that the use of the term “comprises” in Claim 1 should be construed as indicating that the steps of the process defined by the claim make up a non-exhaustive list and that the wording of the claim permits the insertion of additional undefined steps within the process and the re-arrangement of the recited steps in any order. The applicant contends that the order is fixed.
20. The term “comprises”, on its conventional construction, is understood to be non-exhaustive, requiring at least the presence of the items to which the term refers but not limited thereto. I note that in the present case the description provides no dictionary specifying a different interpretation. However, Claim 1 as drafted states, in respect of each of the recited process steps (b) to (l), that the action to be carried out in that step is performed on the product of the preceding process step. Although this does not preclude the presence of additional steps, it does indicate that the order in which the recited steps are performed is significant in the process as a whole and cannot be changed. This view accords with the submissions of the applicant and the comments of its experts.
21. In my view therefore the process defined in Claim 1 requires the inclusion of the specific steps (a) to (l) in the order in which they are recited, but also permits the inclusion of additional purification steps.
22. A second key construction issue is the interpretation of the term “connected in series” used to describe the nature of the connection of the anion and cation exchange resins in step (d). The plain meaning of the term implies a consecutive connection between the two resins however it is not clear whether the resins are directly connected such that the eluate of the anion resin passes directly onto the cation resin without collection and/or whether intervening processes are encompassed. It is therefore legitimate to refer to the description to resolve this ambiguity. At page 9, line 31 the description states that “in the present context the term ‘connected in series’, when used in connection with the ion exchange resins, means that the proteins passing through the anion exchange resin are loaded directly onto the cation exchange resin with no change in buffer or other conditions”. Notably, while the preferred embodiment recited at pages 10 and 11 indicates that the ion exchange process is conducted by passage through two physically connected columns, this is not a requirement of the “in-series” relationship in its broadest aspect. I thus consider that the “in-series” ion exchange process defined may include two separate ion exchange procedures conducted in separate containers wherein the product of the first resin is collected and placed onto the second resin but requiring the use of the same buffer at the same pH i.e. less than 6.0, in respect of each resin. This view generally accords with that expressed by both Dr Goss for the opponent and Dr Johnston for the applicant.
23. The opponent also argued that the addition of a “virus-inactivating agent” specified in step (h) should be interpreted in line with the definition in the specification at page 15, paragraph 2 as merely requiring the application of a treatment that inactivates the virus particles present in the filtrate produced in step (g) and rather than being limited to the addition of an “agent”. I note, however, that step (j) refers to the addition of a buffer having “sufficient ionic strength to wash out the protein contaminants and the virus inactivating agent from the resin” indicating that a virus inactivating agent rather than a physical treatment is proposed. This is supported by the text at page 16, line 10ff of the specification where it states that “After virus-inactivation and preferably filtration, ion exchange chromatography is performed in order to remove the virus-inactivating agent and protein contaminants.” Moreover at page 16, line 24ff the specification discusses a range of methods that may be used to remove the virus-inactivating agent depending upon the specific agent employed. In the light of this I interpret the term “agent” to refer to a chemical treatment involving the addition of an agent which is then removed via ion exchange.
24. Referring to Merk v Sankyo [1991] APO 27, the opponent argued that the use of the term “obtainable by” does not limit the product of Claims 14 and 15 to one produced by the process claimed, but encompasses an immunological product that may be produced by any process, only limited to being capable of production by the process recited claimed. I agree with this conclusion, however, note that in practical terms the operation of the 13 step purification process claimed gives rise to an IgG product with quite specific purity and stability characteristics as discussed in the specification. Consequently, while the term does not restrict the process to that disclosed, the product is effectively limited to that of the process defined.
25. Claims 22 and 23 use the phrasing “for…” and thus do not impart any restriction upon the claim other than suitability for the purpose stated.
26. Claims 24 and 25 are in the Swiss style and refer to the preparation of a medicament intended for the treatment of specified conditions in mammals (24) or humans (25).
Section 40
27. The opponent argued that Claims 14 and 15 are not fairly based on the description because, as a result of the use of the term “obtainable”, they are not limited to immunoglobulin products prepared according to the method of the invention nor are they limited by properties associated with the product of the process of the invention.
28. The recent High Court decision of Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2004) 62 IPR 461 ruled that the test for fair basis requires an analysis of the specification to determine whether the invention as claimed is consistent with the invention as described in the specification (as properly construed). This proposition is consistent with the tests applied in Rehm Pty Ltd v Western Security Systems (International) Pty Ltd (1988) 81 ALR 79 and CCOM Pty Ltd v Jiejing Pty Ltd (1994) 122 ALR 417 which require a " real and reasonably clear" disclosure of the claimed invention in the priority document.
29. In the present case, the specification states that the invention comprises in a first aspect, an immunoglobulin purification process, and in a second aspect, an immunoglobulin product which combines the advantages of purity, lack of adverse clinical reactions and interactions and stability arising from the levels of purity achieved. The specification explicitly refers to the product in a number of locations in the description as that “obtainable” by the process of the invention.
30. Thus, although much of the specification is directed to the process and conditions that the applicant used to prepare the IgG product, the specification also provides clear statements that the invention is not limited to the product when produced by the disclosed process. It also includes an IgG per se, defined either explicitly by specific properties (as in Claim 16) or implicitly, by reference to the described process which will inherently result in an IgG having these properties. Consequently I consider that Claims 1 to 13 are fairly based on the invention described.
31. The opponent also raised a number of fair basis issues in relation to the lack of specificity of the claims with respect to the pH of the buffers used in the ion exchange chromatography step (c) and diafiltration and the exclusion of detergent, PEG or albumin as stabiliser from the IgG product. I consider, however, that these features are disclosed broadly in the specification as preferments and the claims are therefore fairly based in respect of these issues.
32. The opponent asserted that the claims of the specification are unclear due to the use of indefinite terminology, for example the phrase “such as” in Claims 1, 5 and 11, and the use of non-limiting constructions “for” and “for use” in Claims 22 and 23. I disagree. The interpretation of these terms is well established. The words “such as” indicate preferments that are non-limiting on claims in which they occur and the “for” or “for use” constructions indicate a requirement for suitability. Therefore the scope of the claims in question can be clearly determined regardless of the presence of these terms.
The Person Skilled in the Art
33. I consider that the person-skilled-in-the-art (PSA) is a skilled but uninventive person concerned with the problem of developing improved processes for purification of immunoglobulins and is therefore familiar with the chemistry and biochemical action of immunoglobulins and common techniques for their production and purification. Given the nature of the field and the prior art, I agree with the opponent that the PSA would have knowledge and experience in plasma fractionation, especially in relation to immunoglobulins
34. Referring to the decision in Minnesota Mining & Manufacturing Company v Tyko Electronics Pty Ltd [2002] FCAFC 315 at 45, the opponent argued that while Mr Goss satisfied the requirements of an impartial PSA, Dr Johnson and Dr Sullivan did not because they had been provided with copies of the patent in suit, as reflected in their evidence, and Dr Johnson lacked relevant experience in plasma fractionation of purification of IgG. Consequently the opponent argued that their evidence should be disregarded or given little weight.
35. The applicant, however, argued that Mr Goss was also poorly qualified to be an impartial PSA. SSI presented evidence that Mr Goss had attended two meetings representing CSL as Director of Plasma Products R&D in 1999 and 2000 during which SSI’s IVIG invention had been presented to him by representatives of SSI. From the evidence of Houen and Laursen it appears that Mr Goss had been briefed in some detail of the SSI IVIG process, product and the work done at that stage in the apparent hope of collaborating with CSL on the SSI IVIG product and that he was furthermore provided with a copy of the application now in suit. Although Mr Goss responds in his third declaration that he has limited if any recollection of the meetings and that the purpose of the meetings was to negotiate the development of CSL intellectual property rather than the SSI IVIG, it is evident that he had at least some knowledge of the process and the properties of the envisaged product.
36. Consequently it is apparent to me that the witnesses for both the applicant and the opponent had some knowledge of the SSI IVIG invention prior to the preparation of their declarations and that this may have compromised their impartiality in assessing the common general knowledge and activities that they consider “routine” for the PSA. I will therefore give the evidence provided by both sets of experts a reduced weighting in my considerations of inventive step, although I consider that, in view of the above their evidence is of equal weight.
Novelty
37. In determining the question of novelty, the test to be applied is the " reverse infringement test" as set out in Meyers Taylor Pty Ltd v Vicarr Industries Ltd, (1977) CLR 228 at page 235, where Aickin J stated:
"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."
38. This test was quoted with approval in the recent cases of Pfizer Overseas Pharmaceuticals v Eli Lilly and Company [2005] FCAFC 224 (see paragraphs 311 et seq) and Bristol-Myers Squibb Company v FH Faulding & Co Limited (2000) 97 FCR 524.
39. Such an infringement of a claim occurs where "each and every one of the essential integers" of that claim has been taken. (Rodi and Wienenberger AG v Henry Showell Ltd, (1969) RPC 367 at page 391; Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 16 IPR 545 at page 549)).
40. However, as noted in Pfizer [supra], it is not sufficient for a citation to contain all the essential features of the claim, there must be "clear and unmistakable" directions to the claimed invention. In addition, the citation has to "enable" the skilled worker to produce the invention from the written disclosure. The basic principle is explained in Hill v Evans (1862) 4 De G F & J 288; 45 ER 1195be where the court noted:
"the antecedent statement must be such that a person of ordinary knowledge in the subject would at once perceive, understand, and be practically able to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful. If something remains to be ascertained which is necessary for the useful application of the discovery that affords sufficient room for another valid patent."
41. I also note that the directions contained in the novelty destroying disclosure may be implicit as discussed in Bristol-Myers Squibb Company v FH Faulding & Co Ltd [2000] FCA 316; 46 IPR 553 at 576:
“What all authorities contemplate, in our view, is that a prior publication, if it is to destroy novelty, must give a direction or make a recommendation or suggestion which will result, if the skilled reader follows it, in the claimed invention. A direction, recommendation or suggestion may often, of course, be implicit in what is described and commonly the only question may be whether the publication describes with sufficient clarity the claimed invention or, in the case of a combination, each integer of it.”
42. In respect of the priority date applicable to determining issues of novelty and inventive step, the opponent submitted that Claims 1, 16, 19, 24 and 25 and the claims appended thereto are not entitled to the earliest priority date of the priority document (9 June 1998) because the feature “below pH 6.0” (Claim 1), “a content of IgG1, IgG2, IgG3 and IgG4” (Claim 16, 19) and some of the specified disease states (Claim 24, 25) were not referred to in the corresponding priority documents. I note as pointed out by the applicant, however, that the pH restriction is referred to at Claims 6 and 7 and the IgG sub-type content is indicated at page 30 of the earliest priority document respectively. In respect of these features I consider that the opponent has failed to establish that the application is not entitled to its claimed priority date of 9 June 1998. I accept, however, that some of the disease states are not referred to in the earliest priority document and a later date would apply.
43. The opponent argued that the Claims of the specification lack novelty in the light of the following documents:
44. Australian Patent 747893 (D6) - published 19 July 1999; priority date 24 December 1997
Relevant to process Claims 1 to 15.
45. Although D6 was published after the earliest priority date of the application, it has an earlier priority date and is still in force. It therefore may be considered for whole of contents novelty.
46. Although D6 is directed to a process for the purification and production of an IgG product suitable for intravenous administration, the process differs in a number of respects from that claimed in Claims 1 to 15. The claimed process at step (b) requires the addition of a non-denaturing protein precipitant, however the precipitant present in D6 is 20% alcohol, which the evidence of the applicant identifies as a denaturant and therefore not suitable as a protein precipitant in the claimed process. Furthermore there is no teaching that alcohol is added in an amount such that precipitation of non-IgG would be effected while that of monomeric IgG would be avoided.
47. D6 also lacks a clear teaching of an anion exchange process followed “in-series” (i.e. with no intervening processing) by a cation exchange process carried out at the same pH (below 6.0) and with the same buffer, as required in step (d) of the claimed process. D6 teaches that the corresponding anion exchange step is followed by a “solvent detergent viral inactivation” step that precedes the cation exchange process involving the addition of a solvent such as a trialkyl phosphate optionally in combination with a detergent or surfactant. Although the citation discusses an option of conducting an anion exchange process after the solvent-detergent treatment, there is no disclosure of an associated in-series cation exchange process nor does D6 explicitly teach that the same buffer is used.
48. D6 does not disclose a virus inactivation treatment conducted on the product of the cation exchange process as required by step (h) of the claimed process. The opponent appeared to argue that this step was encompassed by the filtration of the cation exchange product through “sterilized bacterial retentive filters”, however, there is no suggestion in the citation that this step is intended to inactivate virus particles or that this is achieved. In fact D6 specifically discloses virus inactivation but this requires (i) a heat treatment prior to anion exchange and (ii) a solvent detergent treatment prior to the cation exchange treatment.
49. D6 does not provide an explicit disclosure of the matter claimed in steps (i) to (l) but merely indicates that “further purification procedures, specifically those involving the use of ionic exchange resins, can be carried out prior to and/or following the solvent-detergent treatment”. This general statement of optional additional treatments does not clearly disclose a cation exchange step followed by a virus inactivation step and then a further anion exchange – cation exchange step, as required in the claimed process.
50. In the light of the foregoing analysis I do not consider that document D6 contains clear and unmistakeable directions to carry out the process as recited in Claims 1 to 13 of the SSI specification. Neither does it provide clear and unmistakeable directions that the product of the process described would be “obtainable” from the process claimed in the SSI application and hence does not deprive Claims 1 to 15 of novelty.
51. WO 94/29334 (D7), published 22 December 1994
Relevant to product-obtainable-by-process Claims 14, 15, product Claims 16 to 23 and the use Claims 24, 25.
52. This document is directed to the preparation of an IgG concentrate for therapeutic use involving desalting size exclusion chromatography at pH 7.8, anion and cation exchange chromatography and solvent-detergent virus inactivation but does not disclose the process steps of the SSI specification. In particular it does not include an in-series anion - cation ion exchange regime conducted at below pH 6.0. In terms of the product prepared, the document does not provide a clear and explicit statement of the purity levels of the product, but merely indicates that the product obtained after the anion exchange step is “nearly 100% pure”. There is, however, no statement as to the numeric value of the term “nearly”. Similarly the product is disclosed as being “devoid of aggregated immunoglobulins G, of immunoglobulins E as well as IgA”, however there is no statement as to whether “devoid” is intended to denote a total absence or the presence of a low level. On this point I note that additional purification steps are subsequently performed to remove solvent-detergent and other contaminants, indicating that some level of impurity is in fact contemplated although the level is not discussed. In addition D7 makes no reference to the presence of the four IgG sub-types or to the proportion of IgG monomers and dimers. Although I note that Dr Goss states that he considers that “it is reasonable to assume that in view of the process adopted” the IgG sub-types would be present, I do not consider that this level of disclosure can be considered to be either explicit or implicit “clear and unmistakeable directions”.
53. The invention as disclosed and claimed in Claims 16 and appended claims is clearly indicated as deriving from a specified level of purity of IgG of greater than 98%, the presence of IgG sub-types and less than 4mg IgA/litre. In view of the specificity of these requirements, I do not consider that the disclosure in D7 provides clear and unmistakeable directions to prepare the product claimed or the use thereof as claimed in Claims 24 and 25. In respect of Claims 14 and 15, I note that the process described in D7 lacks disclosure of specific critical steps in the claimed process. I am therefore not satisfied that the product produced by the process described in D7 would have the purity or stability characteristics of the product of the process of Claims 1 to 13. Consequently I am of the view that D7 does not provide “clear and unmistakable directions” to the product of Claims 14 and 15.
54. D10, product description of GAMMAGARD® S/D (referred to henceforth as “Gammagard”) by Baxter Deutchland GmbH providing clinical information about this product.
Relevant to Claims 14 to 25
55. D10 was the subject of some dispute as to its publication date. The document indicates at page 61 that the information disclosed therein is “as of February 1994”. At page 28, however, the document reports the results of a clinical survey performed between February and May 1994. Furthermore several of the references provided in the List of References at the conclusion of the document indicate publication dates substantially later than February 1994.
56. I note that the opponent has filed no additional documents that validate the February 1994 publication date nor that establish the date of public availability of the product or of D10.
57. Dr Goss indicates in his 3rd Declaration that “product information documents of this type produced for the benefit of clinicians are invariably updated with reference to more up to date scientific literature, over time”. He further asserts that “details provided within the document in regard to the physical parameters of the product (such as purity, amounts of stabilisers, the relative amounts of IgG sub-types, the IgA and IgM concentrations and the level of IgG aggregates) would not have changed over time, and would have been included within the publication from when it was first made available to clinicians following the first and only registration of the product by the US FDA in May 1994.” Dr Goss explained that this is because the regulatory requirements do not allow the changing of these physical parameters without re-registration and they would consequently have remained unchanged since May 1994. While I accept this argument as reasonable, it is largely supposition since there is no evidence before me that establishes either the date of FDA registration of Gammagard or the physical parameters of the product as registered.
58. The opponent also filed as evidence a document identified as NHG-13, being a product information insert of a type which would have been included within the product packaging of Gammagard as sold in the United States and carrying an indication that the document was “issued February 1995”. I note, however, that NHG-13 includes a statement to the effect that it is “Sample Instructions Only”, and that it is for “educational purposes only”. Moreover it states that “Directions for use are provided with Hyland products and may be frequently revised”, and that any laboratory or therapeutic use of the product should be based on package inserts supplied with the product as distinct from NHG-13. This clearly indicates that NHG-13 is not an actual product insert but a sample of what such an insert might look like. Consequently it is not clear to me that the NHG-13 was ever publicly available or to what extent the inserts, if produced, carried the same information as NHG-13 or indeed the accuracy of the information contained therein.
59. The applicant questioned whether the product to which NHG-13 relates was the same as that to which D10 relates and directed me to the factual differences between NHG-13 and D10 relating to the concentrations of various stabilizing agents present in a reconstituted sample of the product. Although I accept that the bulk of the information disclosed in D10 and NHG-13 is the same, and that the infusion rates and additives might well be updated in D10, I do not find that this information assists me in identifying the publication date of D10.
60. On the basis of the evidence before me, I consider that the best that can be said in relation to the publication date of D10 is that parts of it, at least, would likely have been published in February 1994, but that other parts were undoubtedly published after that date. I do not consider that the evidence filed provides any real guidance as to which parts were published earlier and which parts were published later, nor does it assist me in identifying the date of any later publication.
61. Consequently, while I accept the relevance of the content of D10 to the issue of novelty of the application, I do not consider that the opponent has established that the date of publication is such that D10 could deprive the claimed invention of either novelty or inventive step.
62. I note that prior to this hearing the applicant made submissions that the opponent should not be permitted to rely on D10 in its prosecution of the case because the publication date had not been clearly established in the opponent’s evidence. It is prime facie evident, however, that D10 contains disclosures relevant to novelty and inventive step and that it contains some disclosures published before the priority date of the claims in dispute. Consequently I agree with the delegate that the dispute as to the date of publication of D10 is properly considered at the substantive hearing.
63. As an aside, even if the date of publication of D10 had been established as appropriate, I consider that it fails to disclose the level of purity required for the product of the process as claimed in Claim 16 i.e. “more than 98%”. In fact D10 provides no exact statement of the level of purity of the Gammagard product but merely indicates that the purity of the medicament is “at least 90%”and does not provide a more precise analysis. Furthermore Dr Sullivan comments that the “% purity of the IgG product cannot be determined from document D10 as the amount of total protein is not provided.” In fact, the only clear disclosure of the purity level for Gammagard is given in the Table at page 26 of the SSI specification as 94.6%, which is well below the 98% minimum required in Claim 16.
64. The opponent argued that the purity stated in this example had been wrongly calculated as the total protein to which the component of IgG was compared included approximately 6% human serum albumin (HSA), added to the composition as a stabiliser. The opponent submitted that the HSA was not a contaminant protein and should be omitted from the purity calculation. I do not agree with this submission as the purity has been calculated consistently with the method of the present invention in which the advantage achieved is through the high level of purity relative to all other protein present in the composition.
Inventive Step
65. Under section 7(2) of the Patents Act, an invention is taken to have an inventive step unless it would have been obvious to a person skilled in the art in light of the common general knowledge in the patent area before the priority date of the claims. Under sections 7(2) and 7(3) the common general knowledge may be considered either on its own, or together with prior art information which the skilled person could, before the priority date of the claim, be reasonably expected to have ascertained, understood and regarded as relevant.
The High Court in Aktiebolaget Hassle v Alphapharm Pty Limited [2002] HCA 59 at 53 affirmed the test set out by Graham J in Olin Mathieson v Biorex [1970] RPC 157 at page 187:
“Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of the relevant prior art [.......] directly be led as a matter of course to try [a particular thing] in the expectation that it might well produce a useful result?”
The Court in Alphapharm also noted with approval the test set out in Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd (1979-80) 144 CLR 253, at page:
“In the case of a combination patent the invention will lie in the selection of integers, a process which will necessarily involve rejection of other possible integers. The prior existence of publications revealing those integers, as separate items, and other possible integers does not itself make an alleged invention obvious. It is the selection of integers out of, perhaps many possibilities, which must be shown to be obvious.”
Accordingly there must be a motivation for the skilled person to apply what is disclosed in a relevant prior art document or what is common knowledge in the art in such a way as to achieve the claimed invention.
66. Aickin J set out the following test for obviousness in Wellcome Foundation Limited v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 at page 286:
"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."
67. In the present case the problem sought to be addressed was to develop a process which provides a “highly purified, stable and fully native IVIG preparation with higher clinical efficiency and less adverse drug reactions”.
68. The opponent argued that process Claims 1 to 15 lack an inventive step in the light of the common general knowledge alone.
Common General Knowledge
69. The opponent asserted, and the applicant did not dispute, that in the plasma fractionation industry, technical developments are not regularly released into the relevant technical journals. It is therefore commonplace to stay abreast of the developments in the field by reference to patent documents, personal communication, published information from regulatory authorities and competitor information such as product information brochures. The opponent submitted that researchers in the field would, as a matter of routine keep such information in a systematic fashion for reference purposes and suggested that it could be considered to be common general knowledge in this field. Since this view is not in dispute I accept prime facie that in this field common general knowledge may be derived from a variety of documents such as patents and technical product disclosures.
70. The opponent also submitted that all the steps of the process described in the specification and claimed in the process claims are common general knowledge in the art of purification of immunoglobulin preparations and referred to a number of patent documents at the hearing in support of this assertion. Dr Goss discussed a variety of techniques that he considered to be well known in the field such as the use of a variety of agents to precipitate plasma proteins, the use of both anionic and cationic chromatographic approaches, modifications and variations to the buffer and resins, dia and ultrafiltration techniques and virucidal additives. The applicant did not challenge these comments and the specification in a variety of places indicates that the steps and techniques used in the claimed process are known in the art. Given that there is no evidence to the contrary, I accept that the individual process steps are known.
71. The issue is whether there is an inventive step in combining these known steps in the precise manner claimed or whether, as asserted by the opponent, the combination is an arbitrary choice which would be made as a matter of routine by the PSA that gives rise to no inventive characteristics in the product produced.
72. The applicant’s experts submitted that the devising of new purification processes for IgG is not a straightforward task that can be achieved by merely combining or swapping around existing processing steps due to the unpredictability of chromatography, the fragility of immunoglobulins and the complexity of the plasma starting materials. They explained that these difficulties can arise from such matters as the interference of contaminants with binding characteristics of an ion exchange resin, differing competition between contaminating species in a sample for binding on the resin, the presence of detergents or solvents in a sample to be loaded on a column or the presence of lipoproteins in a sample which can cause fouling of resins. Dr Johnston also mentioned subtleties in selection of ion exchange resins and buffers as having a great effect on the efficiency and selectivity of ion exchange processes.
73. Dr Goss makes it clear, however, that the properties of high purity, high stability, low viral load and freedom from non-IgG proteins were well understood before the priority date as desirable goals. He also argues that it was well understood that the known purification techniques could be used to improve each of these properties and their conditions modified to change the degree to which each of the desired outcomes is achieved. Although Dr Goss, states that it was well known prior to June 1998 that “various aspects of the processing conditions could be modified or varied” and that “wide variations in conditions could be adopted”, he does not establish that a PSA would choose to adopt the specific techniques and conditions recited in the claim in the order defined, nor that the achievement of the precise properties of the product as claimed would be a matter of routine choice of these techniques and conditions from amongst the myriad of options that were evidently known at the time.
74. Thus, while I accept that the PSA at the priority date was aware of the desirability of preparing an IgG product having the combination of properties taught in the specification, I consider that the opponent has failed to established that the specific combination of techniques and conditions claimed in the steps of the SSI process in the order recited is an obvious combination that a non-inventive PSA would choose as a matter of routine. Consequently I cannot agree that the choice of techniques and conditions is arbitrary based on the common general knowledge.
75. The opponent also argued that Claims 1 to 15 lack an inventive step in the light of the following documents when combined with the common general knowledge:
76. Australian Patent 199870099 (D2) - published on 24 December 1998
This document was published later than the earliest priority date of the claims of the specification and consequently cannot be considered for the purposes of assessing a lack of inventive step.
77. US 5177194 (D3) - published on 5 January 1993
78. This document discloses a process for purifying immune serum globulins from crude plasma protein fractions involving a virus-inactivation step followed by an anion exchange, ultrafiltration and then cation exchange. The disclosed process does not disclose an in-series cation and anion exchange step and the buffers used are not of pH less than 6.0. In addition, cation exchange precedes rather than follows anion exchange and there is no teaching to use two anion-cation exchange steps. Although the opponent suggested that it would be routine for the PSA seeking to optimise this process to add, insert or re-arrange the process steps such that the claimed process was encompassed, there is simply no inducement in either the document itself nor in the common general knowledge to choose the particular modification of the process steps required. Furthermore, given that the document does not disclose the IgG purity, the content of IgG monomers and dimers, the content of IgA or of IgG sub-types there is no reason to believe that the PSA, faced with this document would be led modify this process to achieve the product obtainable from the SSI process.
79. US 5593675 (D4) - published 14 January 1997
80. This document discloses a process for the purification of immunoglobulins from human plasma with the aim of producing an anti-D immunoglobulin G preparation. It discloses performing an acidic cation exchange step, followed by a weakly alkaline (pH greater than 7) anion exchange step. Following this step the product is then subjected to a further cation exchange step. It does not disclose the buffer and pH conditions of this step. The document thus does not disclose an in-series anion cation exchange step using the same buffer and retaining the same pH of less than 6.0. Furthermore, since the purpose of the process is to prepare an anti-D immunoglobulin-G, IgG1 and IgG3 subclasses are specifically concentrated since these are the anti-D antibodies. Thus the document teaches different steps carried out in a different order for a different disclosed purpose. In addition the document is silent with regard to purity, percentage of monomers and dimers or the IgG subclass distribution. Once again, I consider that although the individual steps are well known in this art and that technically their inclusion would present little challenge to the PSA, there is no motivation evident in the material before me that would lead the PSA, as a matter of routine, to modify the process described in the precise way necessary to produce the process as claimed or the product that is prepared by the process.
81. Finally, the opponent argued that Claims 14 to 25 lack an inventive step in the light of the common general knowledge when combined with the following:
82. WO 94/29334 (D7)
83. As discussed under novelty, This document does not include an in-series anion - cation ion exchange regime conducted at below pH 6.0 nor does it include a clear statement of the purity levels of the product, merely stating that the product is “nearly 100% pure”, “devoid of aggregated immunoglobulins G, of immunoglobulins E as well as IgA” and gives no indication as to the IgG sub-type distribution or the proportion of IgG monomers and dimers. As discussed above, I do not consider that this document or the common general knowledge provides any teaching that would lead the PSA to select the precise modifications of the process necessary to ensure the production of a product obtainable by the claimed process steps. In addition I consider that the opponent has not established that the PSA would as a matter of routine recognise how to modify the disclosed process to achieve a product having the characteristics defined in Claim 16 and its appended claims.
84. D10, while raised by the opponent, will not be considered due to the lack of a clearly established publication date, as discussed under novelty.
Manner of Manufacture
85. The opponent further submitted that the invention claimed in the current application is not to a manner of new manufacture because it failed to pass the threshold test for newness and argued that it is clear on the face of the document (Advanced Building Systems Pty Ltd v Ramset Fasteners (Aust) Pty Ltd (1998) 152 ALR 604 at 614) that the claimed process is made up of well known routine process steps and the product resulting from their combination demonstrates no new or surprising result because the resulting immunoglobulin has characteristics of known immunoglobulin products. It argued that the case was analogous to that in Merck & Co Inc v Arrow Pharmaceuticals Limited [2006] FCAFC 91 (15 June 2006).
86. I have found that the claims are both novel and inventive in view of the cited documents. On that basis I consider that the present claims meet the threshold test for inventiveness and this argument cannot be sustained. In addition the invention is clearly advantageous as it provides a more stable product than previously available.
CONCLUSION
82. I consider that the invention as claimed is both novel and contains an inventive step. Furthermore I consider the claims to be clear and fairly based on the matter described in the specification. The opposition is therefore unsuccessful on all grounds.
COSTS
83. As a general principle, costs follow the event. I see no reason to depart from this principle in the present case. Consequently I award costs against the opponent.
Leigh Tristram
Delegate of the Commissioner of Patents
06 March 2007
Patent attorneys for the applicant : FB Rice, Sydney
Patent attorneys for the opponent : Davies, Collison Cave, Melbourne
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