Gliknik, Inc. v CSL Behring Lengnau AG
[2020] APO 46
•12 October 2020
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Gliknik, Inc. v CSL Behring Lengnau AG [2020] APO 46
Patent Application: 2012392760
Title:Immunomodulatory Proteins
Patent Applicant: CSL Behring Lengnau AG
Opponent: Gliknik, Inc
Delegate: Felix White
Decision Date: 12 October 2020
Hearing Date: 8 July 2020, by videoconference
Catchwords: PATENTS – recombinant Fc hexamer as a substitute for intravenous immunoglobulin – section 59 – opposition to grant of a patent – grounds of lack of manner of manufacture, lack of novelty, lack of inventive step, best method, clarity, support, clear and complete enough disclosure – consideration of reg 5.23 – plausibility of methods of treatment and “Swiss” claims - opposition successful on grounds of lack of support and clear and complete enough disclosure but fails on other grounds– opportunity to amend – costs awarded to opponent
Representation: Applicant appeared by written submissions filed on 1 July 2020
Patent attorneys for the applicant: Griffith Hack
Patent attorney for the opponent: Anthony Shaw, Allens
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2012392760
Title:Immunomodulatory Proteins
Patent Applicant: CSL Behring Lengnau AG
Date of Decision: 12 October 2020
DECISION
The opposition succeeds on the grounds of lack of support and clear and complete enough disclosure.
The applicant is given a period of two (2) months to file amendments under s104.
Costs according to Schedule 8 are awarded against CSL Behring Lengnau AG
REASONS FOR DECISION
Background
1. Patent application 2012392760 (the application) is the Australian national phase entry of PCT/GB2012/052561 filed in the name of the Liverpool School of Tropical Medicine. The application enjoys the international filing date of 17 October 2012 and does not claim any earlier priority. The application was subsequently assigned to CSL Behring Lengnau AG (the applicant) which assignment was recorded at IP Australia on 1 November 2019.
2. The application was examined and advertised as accepted on 28 June 2018 after two adverse examination reports. The complete specification at issue is AU 2012392760 B2 (the specification).
3. Gliknik Inc. (the Opponent) filed a notice of opposition under s 59[1] on 28 September 2018.
[1] References to legislation and regulations are to the Patents Act 1990 (“the Act”) and the Patents Regulations 1991 (“the Regulations”) unless indicated otherwise.
4. The statement of grounds and particulars (SG&P) was filed on 8 January 2019. An amendment to the SG&P to add two additional citations (D14 and D15) was allowed on 4 December 2019.
Evidence
5. The parties relied upon evidence as set out in the table below.
Evidence Declarant Date of Declaration Reference Exhibits In support Dr. Anthony Shaw 2 April 2019 Shaw #1 ALS-1 to ALS-17[2] In answer Dr. Beate Peter 3 July 2019 Peter BP1 to BP9[3] Sarah Cox 3 July 2019 Cox SC1 In reply Dr Anthony Shaw 4 September 2019 Shaw #2 ALS-18 to ALS-19 [2] The Opponent’s exhibits included a number of citations that are referred to with D numbers as follows:
D1 (WO2011/073692) ALS-5 D2 (WO2008/151088) ALS-6 D3 (Sorensen et al) ALS-7 D4 (WO2012/016073) ALS-8 D5 (Jain et al) ALS-9 D6 (White et al) ALS-16 D7 (Mekhail et al) ALS-10 D8 (Siragram et al) ALS-11 D9 (Salfield et al) ALS-12 D10 (Samuelsson et al) ALS-13 D11 (Smith et al) ALS-14 D12 (Yoo et al) ALS-15 D13 (Czajkowsky et al) ALS-17 D14 (Teeling et al) ALS-18 D15 (Angerer et al) ALS-19 [3] Exhibit BP2 includes a declaration from the present inventor (“Pleass declaration”) filed with the European Patent Office, which I note was also filed with IP Australia in response to the second adverse examination report.
6. The Opponent’s representative commented at the hearing that this case was unusual in that all the declaration evidence filed was from both parties’ patent counsel and many of the exhibits refer to the prosecution of the related European patent EP2908914 B. While the lack of evidence from researchers in the field might be said to make the task of assessing common general knowledge, inventive step and sufficiency more difficult, I will nevertheless approach this task in the usual way, referring to the evidence on file and assigning weight as appropriate.
Reg. 5.23 considerations
7. Both parties filed additional documents for consideration under the provisions of Reg. 5.23; the Applicant on 30 October 2019 and the Opponent on 7 July 2020. For the following reasons, I have not taken any of these documents into consideration in this decision.
8. The Applicant submitted on 30 October 2019 that the Opponent’s evidence in reply was not proper evidence in reply, and in the alternative that a second declaration from Dr. Peter and four additional exhibits should be considered. The documents submitted by the Opponent on the day before the hearing were said to support the Opponent’s proposition that Fc aggregates and multimers were known to be important to the mode of action of IVIG. In my view these documents add little information compared to those already in evidence, and as such I have disregarded them.
9. Regarding the question of evidence in reply, I am satisfied that the Opponent’s evidence is properly in reply as it is presented as a direct response to points made in the Peter declaration paragraph 32.
10. The documents filed with the second Peter declaration (all published after the filing date) were submitted to support the Applicant’s proposition that Fc multimers for the treatment of autoimmune disease were an “emerging field” at the filing date, in support of the inventive step of the present claims. As will be seen from the consideration of inventive step below, I have not found that the Opponent has made out its case for lack of inventive step. The Applicant’s Reg. 5.23 submission is therefore moot.
The opposition
Grounds of opposition
11. The grounds of opposition pressed by the opponent were:
Lack of manner of manufacture,
lack of novelty,
lack of inventive step,lack of best method,
lack of clarity,
lack of sufficiency, and
lack of support.
Onus
12. Examination of the application was requested after 15 April 2013. Consequently, the present opposition is governed by the Act and Regulations as amended by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Raising the Bar Act). Amendments to s 7, 40 and 60(3A) of the Act apply to the present case as a consequence of Schedule 1, items 55(1)(d) and 55(4)(a), and Schedule 6, item 133(7)(d) of the Raising the Bar Act.
13. The standard of proof that applies in the present case is the balance of probabilities. Under s 60(3A), if I am satisfied, on the balance of probabilities, that a ground of opposition to the grant of a patent exists, I may refuse the application.
14. The Applicant submitted that the Opponent carries the onus of proof.[4] Bearing in mind the general provisions of s 60(3A) and s 60(3) which allow the Commissioner to take into account grounds that were not relied upon by the Opponent, provided that both parties have had a reasonable opportunity to be heard,[5] I will make my decision on the basis of the submissions on file, available evidence and the balance of probabilities.
[4] Applicant’s submissions (AS) [16]
[5] s 60(2)
Field of the application
15. The application is titled “Immunomodulatory Polypeptides”
16. The field of the invention relates to engineered proteins intended for use as replacements of intravenous immunoglobulin (“IVIG”).[6]
The person skilled in the art[6] Description at p. 1 l. 7-8. Unless indicated otherwise, all page and line number references are to the description as accepted.
17. It is well established that many of the issues in an opposition are answered by reference to the person skilled in the art:
“He 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.”[7]
[7]Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70].
18. The hypothetical skilled person works in the field with which the invention is connected and is a non-inventive person or team likely to have a practical interest in the subject matter of the invention.[8]
[8]ibid
19. Given the field of the invention above, the notional skilled team would have a practical interest in, and understanding of, immunology and in particular the role of immunoglobulins.
20. The Opponent criticised the evidence of Dr Peter as not being grounded in practical experience, and as being self-serving and not independent, given that she is employed as patent counsel by the Applicant which has an active interest in the field.[9]
[9] OS [95]
21. Nevertheless, a declarant’s evidence can be used to inform me about what the hypothetical skilled worker (“a pale shadow of a real person – a tool of analysis”)[10] would know or do, bearing in mind that that the role of the Delegate in considering evidence is to look at the substance of the opinion expressed in evidence and the reasons behind it.[11]
[10] AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30 at [23]; 89 ALJR 798.
[11] Cf. Ocean Marine Mutual Insurance Association (Europe) OV v Jetopay Pty Ltd [2000] FCA 1463 at [21]–[23]
22. Dr. Peter’s CV includes working as research assistant on antibody production[12] and postgraduate work as a cell biologist and bioinformatician.[13] After gaining a patent attorney qualification and joining the Applicant as senior patent counsel in 2010 her role involved working closely with the Applicant’s immunoglobulin project team[14] which included literature review and attending relevant scientific conferences.[15] I am therefore satisfied that Dr Peter would have been aware of common general knowledge in the field of the invention[16] in the period leading up to the filing date and is able to provide evidence relevant to what the hypothetical skilled worker would know and do.
[12] Peter [5]
[13] Peter [7]
[14] Peter [10],[14], [29]
[15] Peter [29]
[16] Peter [14]
23. With respect to the other declarants, Dr. Shaw and Ms. Cox do not purport to provide evidence as to what the skilled worker would know or do.[17] Dr. Pleass, whose declaration is found in BP2, is the inventor of the present application and I will weigh his evidence with that in mind.
[17] Paragraphs [5]-[7] of Shaw #2 refer to statements made to him by the Opponent in response to the Peter declaration, but these are not made with any reference to the skilled worker or common general knowledge.
Common general knowledge
24. Common general knowledge is the background knowledge and experience available to all those working in the relevant art:
"The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.”[18]
[18] Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; 144 CLR 253 at 292
25. Guidance on this consideration was provided in British Acoustic Films Ld v Nettlefold Productions (1936) RPC 221 at 250:
“In my judgement it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or a series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less merely because it is widely circulated. Such a piece of knowledge only becomes common general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art.”
26. To summarise, if it can be demonstrated by evidence that something is generally accepted by the hypothetical skilled worker, then this can be treated as common general knowledge. Scientific papers can be used to support such evidence but they do not themselves constitute common general knowledge.
27. The Opponent made the following submissions on common general knowledge: that it was “generally known that the mechanism of action of IVIG in the treatment of ITP[19] involved activation of Fcγ receptors (see for example, D8 and D10)”;[20] that “it was generally known at or before the priority date of the Opposed Application that IgG1 Fc multimers were capable of selectively binding to Fcγ receptors and that IgG1 Fc multimers could be used as a replacement for IVIG (See for example, D2 at paragraphs [00125]-[00132] and [00258]; D4 at paragraphs [0047], [0073], [00168], and [0236]-[00239]; and D7, abstract)”;[21] “[i]t was also generally known, that IgG Fc multimers were being investigated as replacement for IVIG for the treatment of ITP (See for example, D5 at page 1; D2 at paragraphs [00307] – [00311]; and D4 at paragraphs [00229]-[00230])”;[22] and “D3 establishes that it was generally known that IgM and IgA tailpieces can induce multimerization of IgG and that this multimerization is enhanced by mutating the Ig to have a cysteine at position 309”.[23]
[19] Idiopathic Thrombocytopenic Purpura
[20] OS at [99]
[21] OS at [100]
[22] OS at [101], see also OS [107]
[23] OS at [102]
28. The Applicant did not make any particular submissions on common general knowledge except to argue that “Dr Peter and Dr Pleass have backgrounds that enable them to understand the specification and provide evidence as to what the PSA knew or would have done at the priority date, including the CGK of the PSA.”[24] I have found above that Dr. Peter’s evidence is relevant to what the skilled worker would know or do. As for Dr Pleass, given that he is the inventor of the present application, I will weigh his evidence from the perspective that his level of expertise and ingenuity is somewhat higher than the notional uninventive person skilled in the art.
[24] AS at [44]
29. The relevant portion of the Peter declaration is “At 17 October 2012, the use of recombinant Fc multimeric proteins for therapeutic value was still an emerging field. There was little evidence for the activity for such recombinant Fc multimers, and what might be required for them to function as IVIG replacement in the treatment of autoimmune or inflammatory diseases”.[25] The Pleass declaration does not explicitly discuss common general knowledge but it contains the statement that comments made by the inventor and the co-authors of D7 relating to use of polymeric IgG1-Fc molecules without effect function as a replacements for IVIG therapy were entirely speculative.[26]
[25] Peter at [32]
[26] Pleass declaration (in BP2) at [20]
30. I am not satisfied on the balance of the available evidence that any of the Opponent’s submissions constituted common general knowledge. Such submissions are based on several scientific papers and patent documents that can be used to support evidence relating to common general knowledge but have little weight on their own in this regard. On the other hand, Dr. Peter’s evidence supports the proposition that the activity of recombinant Fc multimers and their ability to function as IVIG replacements was not “generally known and accepted without question” in the sense of British Acoustic Films.
Background of the invention
31. Before construing the specification, I note the comments of Middleton J in Eli Lilly and Company Limited v Apotex Pty Ltd.[27]
“It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date.”
[27][2013] FCA 214;100 IPR 451 at [139].
32. The specification describes that IVIG was first used to treat immune deficiency, but is now predominantly used to treat autoimmune or inflammatory conditions. IVIG is an immunoglobulin preparation of predominantly IgG manufactured from pooled plasma, which can cause unpredictability in terms of sterility, presence of impurities such as IgA, and lot to lot variation. The specification describes there is a need for defined replacements for IVIG.[28]
[28] p. 1 l. 14-29
33. The specification admits that the mechanism of action of IVIG remain unclear.[29] The specification does provide a survey of literature relating to the mode of action of IVIG. The most salient points appear to be:
·Fc receptors have been demonstrated to be involved in the disease ITP;[30]
·Interaction of sialylated Fc with DC-SIGN on dendritic cells has been implicated in anti-inflammatory effects in a mouse model of arthritis;[31] and
·Other mechanisms of action not necessarily related to Fc receptors or glycan receptors have been proposed.[32]
[29] p. 1 l. 31 and following discussion
[30] p. 2 1. 1-4
[31] p. 2 l. 10-12, and which is consistent with effects described in exhibit ALS-9 (D5)
[32] p. 2 l. 29- p. 3 l. 5
34. The specification also describes that recombinant compounds based on IgG Fc (constant region) domains had been suggested in earlier patent documents as replacements for IVIG[33] and concludes that there is a need for “compounds of defined structure which effectively target appropriate mechanisms underlying the biological activity of IVIG, for treating autoimmune and inflammatory diseases.”[34]
[33] p. 3 l. 7-8 and following discussion
[34] p. 4 l. 30-32
The invention as described
35. The specification then describes the structure of an artificial polymeric protein made of Fc receptor binding monomers comprising two IgG heavy chain constant regions,[35] and provides further definition relating to how these polymers can be structured and made. As I will refer to the respective parts of that description while construing the claims in due course, I will not restate it here. I will however note that this part of the description provides several pages[36] of information relating to the properties of different classes of Fcγ receptor. Although this includes statements such as “FcγRs are involved in regulating innate and adaptive immune responses, which makes them attractive targets for the development of novel immunotherapeutic approaches”[37] this passage does not provide any information directly linking Fcγ receptor binding with any particular therapeutic indication.
[35] p. 8 l. 31-35
[36] p. 13 l. 18 – p. 16 l. 24
[37] p. 15 l. 7-9
36. The specification ends with six examples.
37. Example 1 describes the production of a recombinant polymeric Fc protein in CHO cells using a commercially available expression vector[38] which encodes the Fc domain of human IgG1, which was modified to form pFUSE-hIgG1-Fc2-TP-LH309/310CL. This encodes a human IgG domain including a Cysteine at position 309 and a Leucine at position 310 and an IgM tailpiece. Example 1 also describes expression of polymeric IgG1 Fc fragments from pFUSE-hIgG1-Fc2-TPLH309/310CL in which the expressed polymeric Fc fragments were “about 90% hexameric versus 10% dimeric”[39]
[38] pFUSE-hIgG1-Fc2, p. 38, l. 32-34
[39] p. 41, l. 6
38. Example 2 describes the characterisation of the expressed polymeric IgG1 Fc fragments by atomic force microscopy and in silico modelling. It observes that “oligomerization required the Cys309 mutation” and concludes from this observation that the polymeric IgG1 Fc fragments form hexamers via disulphide bridges. In silico modelling concludes that the polymeric structures were more likely to be barrel-shaped than star-shaped.
39. Example 3 provides in vitro measurements of binding of the polymeric IgG1 Fc fragments of Example 1 to various receptors.
40. Example 3.1 shows binding to the human Fc receptors FcγRI, FcγRIIA and FcγRIIB and mouse Fc receptors FcγRI and FcγRIIB. FcγRIIA and FcγRIIB are said to be involved in protecting from ITP. The polymeric IgG1 fragments were also predicted by in silico modelling to bind FcγRIII which is also thought to be involved in ITP.
41. Example 3.2 shows that the polymers of Example 1 are sialylated in a lectin binding assay, and predicts by in silico modelling that these would be able to bind DC-SIGN.
42. Example 3.3. shows binding of the polymeric IgG1 Fc fragments to FcRL5 on the surface of human B cells.
43. Example 3.4 discloses how the polymeric IgG1 Fc fragments do not interact with human FcRn, which “may play a role in hexameric-Fc mediated control of more chronic autoimmune disease” but suggests that “minor modifications to the existing construct e.g. reversion of Leu310 to His310 may reinstate binding to human FcRn.”[40]
[40] p. 45, l. 33-34
44. Example 3.5 discloses the polymeric IgG1 Fc fragments do not activate complement.
45. Example 4 discloses administration of the polymeric IgG1 Fc fragments can reduce platelet depletion (p<0.05 compared to control) in a mouse model of ITP.
46. Example 5 is a prophetic example describing how the polymeric IgG1 Fc fragments could be used to treat ITP in humans in the same way as IVIG.
47. Example 6 involves an in silico comparison of the polymeric IgG1 Fc fragments of Example 1 and immunoglobulin based molecules of US2010/0239633 (a US Patent Publication corresponding to D2).
The claimed invention
48. The opposed application ends with 8 claims, of which claims 1 and 8 are independent.
Claim construction
49. The principles of construction have been well traversed by the courts, and a number of principles have been set down in various decisions. Principles most relevant to this particular case were summarised by the Full Court of the Federal Court in Kinabalu Investments Pty Ltd v Barron Rawson Pty Ltd.[41]
“When determining the nature and extent of the monopoly claimed, the specification must be read as a whole. But as a whole it is made up of several parts which have different functions. The claims mark out the legal limits of the monopoly granted. The specification describes how to carry out the process claimed and the best method known to the patentee of doing that. Although the claims are construed in the context of the specification as a whole, it is not legitimate to narrow or expand the boundaries of monopoly as fixed by the words of a claim, by adding to those words glosses drawn from other parts of the specification. If a claim is clear and unambiguous, it is not to be varied, qualified or made obscure by statements found in other parts of the document. It is legitimate, however, to refer to the rest of the specification to explain the background of the claims, to ascertain the meaning of technical terms and resolve ambiguities in the construction of the claims. See Flexible Steel Lacing Co vBeltreco Ltd (2000) 49 IPR 331 at [73] – [75] (Hely J).
[41] [2008] FCAFC 178 at [44] – [45]:
50. Other more specific principles of construction collected in Flexible Steel[42] at [81] are:
[42] Flexible Steel Lacing Co vBeltreco Ltd (2000) 49 IPR 331 (cited supra)
·a specification should be given a purposive construction rather than a purely literal one;
·the hypothetical addressee of the specification is the non-inventive person skilled in the art before the priority date;
·the words used in a specification are to be given the meaning the hypothetical addressee would attach to them, both in the light of the addressee’s own general knowledge and in the light of what is disclosed in the body of the specification;
·as a general rule, the terms of the specification should be according their ordinary English meaning;
·evidence can be given by experts on the meaning those skilled in the art would give to technical or scientific terms and phrases, and on unusual or special meanings given by such persons to words which might otherwise bear their ordinary meaning;
·however, the construction of the specification is for the court, not for the expert. In so far as a view expressed by an expert depends upon a reading of the patent, it cannot carry the day unless the court reads the patent in the same way.
51. I will focus the construction analysis on the independent claims. I will refer to the dependent claims as necessary bearing in mind the presumption that each claim is of differing scope and, where possible, claims should be construed accordingly.[43]
[43] Parkinson v Simon (1894) 11 RPC 493
Claim 1
52. Claim 1 reads as follows (spacing and emphases have been added for ease of reference):
A polymeric protein consisting of six polypeptide monomer units
when used in a method of treating an autoimmune or inflammatory disease in a mammalian subject,
wherein the method comprises administering to the mammalian subject an effective amount of the polymeric protein;
wherein each polypeptide monomer unit consists of an Fc receptor binding portion consisting of two immunoglobulin G heavy chain constant regions;
wherein each immunoglobulin G heavy chain constant region comprises a cysteine residue which is linked via a disulfide bond to a cysteine residue of an immunoglobulin G heavy chain constant region of an adjacent polypeptide monomer unit;
and wherein a tailpiece region is fused to each of the two immunoglobulin G heavy chain constant regions,
wherein the tailpiece regions facilitate the assembly of the monomer units into a polymer.
53. The claim is directed to a polymeric protein when used in a method of treatment. That is, the claim is in substance a treatment method claim. However for clarity I will address the structure of the protein before considering the treatment method aspect.
“Consisting of”
54. The term “consisting of” is not defined in the specification, however it is commonly understood in patent law to be a “closed” or exclusionary term; an integer “consisting of” specified elements is made of those elements and none other. This is consistent with the Macquarie dictionary definition provided in evidence by Dr. Peter.[44] It is also consistent with the claims originally filed in PCT/GB2012/052561 (published as WO2014/060712 A1). Claims 13 and 14 of that WO publication are both directed to polymeric proteins but the former is written in “comprising” language whereas the latter is defined by “consisting of” language similar to the structure of the opposed claims. This is evidence of the drafter’s intention to differentiate closed “consisting of” language from open “comprising” language.
[44] Peter [27] and Exhibit BP8.
Six polypeptide monomer units
55. The polymeric protein referred to in the claim must therefore be made of exactly six monomer units as defined below. Notably, I am construing this to exclude complexes which also contain different monomer units.
Polypeptide monomer units
56. The polypeptide monomer units themselves consist of a single Fc receptor binding portion which in turn consists of two IgG heavy chain constant regions. This could be summarised as each monomer consists of an IgG heavy chain constant region dimer[45] which can either be two monomeric heavy chain constant regions linked by disulfide bonds[46] (as in the Examples) or can be a single chain Fc (as in claim 7).
[45] Monomeric Fc does not bind to Fc receptors.
[46] See also p. 9 lines 7-9 and lines 17-19
IgG heavy chain constant regions
57. The specification defines a heavy chain constant region as potentially including the entire IgG heavy chain[47] but can also be shorter fragments, typically (but not limited to) the Fc fragment. Nevertheless this region must be capable of binding Fc receptors which puts an implicit lower limit on the size of the fragments.
[47] See p. 9 lines 1-2 and lines 33-35 which imply that the VH domain could be present.
Linkage to adjacent monomer
58. Each constant region is defined as comprising a cysteine which forms a disulfide bond with a cysteine of a constant region of neighbouring monomer unit. That is each monomer unit comprises two disulfide bonds, each to a neighbouring monomer. In theory, this could accommodate two configurations: one where each monomer bonds to both its neighbours for form a ring or barrel, and an alternative where each monomer has two bonds to a single neighbour. The latter construction, while technically consistent with the language of the claim and specification, is nevertheless inconsistent with the technical teaching of the description; it is not at all clear if such a configuration could even exist and it is certainly not supported by the specification. I will therefore use common sense and reject the latter construction as inconsistent with the specification as a whole.
59. The location of the cysteine is not specified, but it clearly must be in a position that enables disulfide bonding between neighbouring monomer units. The description at p. 10 lines 5-19 discusses modification of parts of the IgG sequence to make them more like IgM or IgA which are naturally polymeric, in particular modifying position 309 to a cysteine which corresponds to Cys 414 in IgM and Cys 309 in IgA. This particular embodiment is recited in dependent claim 4, which gives a clear implication that claim 1 encompasses other disulfide bond positions.
Tailpiece region
60. The claims specify that a tailpiece is fused to each heavy chain constant region. The tailpiece must be functional to facilitate assembly of the monomers into a polymer. Although the claim does not explicitly state that the tailpiece must be able to facilitate assembly into a hexamer, this is the only reading consistent with the claim as a whole. Tailpieces are defined at p. 11 lines 5-20. The term “tailpiece” appears to be a commonly used term[48] referring to an 18 amino acid C-terminal extension found in IgM and IgA. However the specification explicitly contemplates that synthetic sequences which can facilitate assembly can also be used.[49] This broader construction is consistent with claim 2 which limits the tailpiece to one derived from IgM or IgA.
[48] See D3 which references the term “tailpiece” to the seminal Kabat et al textbook on antibody structure at ref. 2
[49] p. 11 lines 16-17.
Fused
61. The description indicates that fused sequences may be fused directly to the region indicated or may be fused via an intervening amino acid sequence, such as a linker sequence. Typical linker sequences are said to be up to 20 amino acids in length.[50] Although this language could be construed to include the possibility of a longer intervening amino acid sequence such as an entire additional domain, that interpretation seems at odds with the way “fused” is used in the specification as a whole. I will therefore construe “fused” to mean that there are no more than 20 amino acids between the IgG heavy chain constant region and the tailpiece.
[50] p. 10 l 29 – p. 11 l.3
Crosslinked IgG heavy chain hexamer barrel structure
62. Taken together, the structural elements of the claim require: a hexameric protein, each monomer made of two IgG heavy chain constant regions fused via a ≤ 20 AA linker to a tailpiece (which is structurally undefined but must be capable of inducing hexamerisation), and each monomer is bound to two neighbours by disulfide bonds from each constant region, thus forming a “barrel” structure.
When used in a method of treating an autoimmune or inflammatory disease
63. As indicated above, this claim is equivalent to a treatment method.[51] The method involves administering an effective amount the hexameric protein as defined above to a mammalian subject. It is implicit that the subject must be suffering from the disease. The term “effective amount” also implies that the treatment must be capable of being effective.[52] The disease to be treated can be any autoimmune or inflammatory disease. Autoimmune diseases are defined on p. 27 of the description as being any disease in which the immune system attacks the body’s one tissues. Inflammatory diseases are defined as any disease characterised by destructive inflammation not associated with normal tissue repair. An extensive though non-exhaustive list of diseases to be treated is found at p. 27-29.
[51] As per the obiter of the High Court in Wellcome v Commissioner of Patents 1A IPR 261 at 266: "there is no distinction between the claim to the process and the claim to the substance when the substance claim is limited to its use in the process".
[52] “Treatment” is not defined in the description but this is consistent with the construction of the term “method of treating” in AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99 as importing some degree of safety and efficacy. See that decision at [91] and [96].
64. Dependent claim 6 limits the scope of protection to a defined group of diseases to be treated which roughly[53] corresponds to those diseases which the description asserts are treatable with IVIG at p. 27 lines 22-34.
[53] Two diseases present in claim 6 not apparently asserted in the description to be treatable by IVIG are Stevens-Johnson syndrome and Alzheimer’s disease.
Claim 8
65. Claim 8 is written as a “Swiss-type” claim which otherwise has the same structural and functional limitations as claim 1. Swiss claims, which has been recently reviewed by the Full Federal Court in Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd (Mylan),[54] derive from requirements from the European Patent convention that have never been part of the Australian legal landscape. However patentees still have sought Swiss protection, perhaps to provide an alternative avenue to indirect infringement when suing to restrain supply of pharmaceuticals.[55]
[54] [2020] FCAFC 116
[55] Mylan at [194]
66. Swiss claims are method of manufacture claims. They are not product claims[56] nor are they method of treatment claims – the monopoly only extends to the point that the medicament is made.[57]
[56] Mylan at [193]
[57] Mylan at [195]
67. Nevertheless they are limited to the specified therapeutic purpose, which supports their novelty vis a vis the same method of manufacture for an existing purpose. The specification of therapeutic purpose is an essential feature of the invention claimed.[58]
[58] Mylan at [196]-[198]
68. The Full Federal Court in Mylan held that therapeutic purpose does not impart a separate essential feature of “intention”,[59] although evidence of intention can be used as part of the process of determining whether the therapeutic purpose is present. The Full Court also pointed out that therapeutic purpose, when construed under common law principles in Australian courts, does not require that the therapeutic effect must be achieved.[60]
[59] Mylan at [222]
[60] Mylan at [111]
69. Therefore the scope of the “Swiss-type” claim, which is directed to a method of manufacture with an essential purpose but no essential therapeutic effect, is somewhat different from that of a method of treatment which does have a requirement for a therapeutic effect. However as will be seen below, this difference in scope does not have an effect on determination of plausibility of the claims under s 40.
Best method
70. The Opponent submits[61] that the present application fails the best method requirement of s 40(2)(aa) because it does not provide any details of guidance in relation to treating a disease.
[61] OS [179]
71. The best method requirement is a distinct one from the support and sufficiency requirements of s 40. It is a requirement that the patentee disclose the best method known to them at the time. In Expo-Net Danmark A/S v Buono-Net Australia Pty Ltd (No 2) [2011] FCA 710, Bennett J adopted a test from analogous South African jurisprudence as follows:[62]
[62] Expo-net at [16], referenced with approval in Les Laboratoires Servier v Apotex Pty Ltd [2016] FCAFC 27; 247 FCR 61; 117 IPR 415
“an applicant for revocation must show that:(a) the method which the patentee failed to disclose is a method of performing the invention;
(b) the method is in fact a better method of performing the invention than the method disclosed in the specification;
(c) the method was known to the patentee at the time when the application for the patent was lodged at the Patent Office;
(d) the method is not disclosed in the specification; and
(e) the patentee knew that the method was better than the method(s) described in the specification.
That analysis is, with respect, useful.”
72. This analysis requires evidence of a better method known to the applicant at the time of filing in order to proceed. I note that D7 and D13 constitute evidence of the applicant’s knowledge of the invention prior to the earliest priority date (which is the filing date). However these documents do not disclose any better method of performing the invention than in the specification as filed. I have no other evidence as to the applicant’s knowledge prior to the earliest priority date. This ground therefore fails.
Clarity
73. The Opponent submits that the claims lack clarity as it is not clear whether the disulfide bonds recited in the claim refer to bonds between monomers or within monomers, due to the mention in the specification that Fc portions comprise two heavy chains linked together by disulfide bonds.[63] As pointed out by the Applicant[64] it is well known that Fc portions comprise disulfide bonds both within and between the heavy chains in the dimer. As per my construction above, the claim specifically refers to additional disulfide bonds between monomer units. There is no lack of clarity in the claims.
[63] OS [183]
[64] AS [63]
Sufficiency (clear enough and complete enough disclosure)
74. Sufficiency post-Raising the Bar was surveyed in Evolva SA [2017] APO 57 (“Evolva”) The approach adopted by the Deputy Commissioner in that case was:
What is the scope of the invention as claimed?
What does the specification disclose to the skilled person?
Does the specification provide an enabling disclosure of all the things that fall within the scope of the claims, and in particular:
(a) Is it plausible that the invention can be worked across the full scope of the claim?(b) Can the invention be performed across the full scope of the claim without undue burden?[65][65] Evolva at [45]
75. Having already construed the claims and specification, I will turn to the question of the plausibility of therapeutic effectiveness (for method claims) or therapeutic purpose (for Swiss-style claims), which has not been considered in Australian jurisprudence post-Raising the Bar.
76. However the plausibility requirements for Swiss-type claims in view of the corresponding provisions in the UK Patents Act 1977 have been recently considered by the UK Supreme Court in Warner-Lambert Company LLC v Generics (UK) Ltd [2018] UKSC 56 “Warner”. The Explanatory Memorandum to the Raising the Bar Act at item 8 points specifically[66] to the intent that the Australian provisions should be interpreted in a similar way to the UK.
[66] “The item is intended to modify the wording of paragraph 40(2)(a) of the Act so as to require enablement across the full width of the claims, while adopting language that is consistent with that used in other jurisdictions. The wording in the amendment is similar to s 14(3) of the UK patents legislation, which has been interpreted as imposing this requirement.” (Citations omitted)
77. In the majority decision of the Supreme Court, in which Swiss-type claims were under consideration, Sumption LJ set out seven principles:
First, the proposition that a product is efficacious for the treatment of a given condition must be plausible.
Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion …
[T]hird, the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, …
Fourth, although the disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true.
Fifth, that reasonable prospect must be based on … a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se.
Sixth, … the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. …
Seventh, sufficiency is a characteristic of the disclosure, and these matters must appear from the patent. The disclosure may be supplemented or explained by the common general knowledge of the skilled person. But it is not enough that the patentee can prove that the product can reasonably be expected to work in the designated use, if the skilled person would not derive this from the teaching of the patent[67][67] Warner at [37] – reformatted for clarity with some supporting reasoning omitted.
78. The dissenting judgements took some issue with the fifth point of this analysis, arguing that the metabolic mechanism aspect was too high a bar for plausibility, but both the dissenting judgements agreed that the bar of plausibility was not so low as to enable speculative “armchair claiming”. Manse LJ understood the plausibility requirement “to attach some limit to the Swiss-form claims for manufacture of compounds for uses which could otherwise be presented on a purely speculative basis”[68] whereas Hodge LJ provided a simpler five-point test:
[68] Warner at [192]
(a) … that the therapeutic effect of the medication appears plausible from the data in the patent interpreted in the light of the common general knowledge,
(b) [the test does] not require that the patent discloses experimental evidence to demonstrate that plausibility unless there is an allegation, supported by sufficient evidence, that the invention does not work, but
(c) allow the plausibility to be reinforced by considering evidence which post-dates the patent (although later-published data are not admissible if they alone render the therapeutic effect plausible),
(d) take account of the ease with which the therapeutic effect can be ascertained using straightforward tests which are known in the prior art, and
(e) where the data in the specification have made the claimed therapeutic effect plausible, [there is a] burden on an objector to substantiate doubt that the desired effect can be achieved.[69][69] Warner at [181]
79. Notably, both the majority decision[70] and Hodge LJ[71] considered that there was no onus on an objector to substantiate doubt if the asserted effect is not prima facie supported by the specification.[72]
[70] Warner at [33]
[71] Warner at [179]
[72] This is also consistent with the statement at item 8 of the Explanatory Memorandum to the Raising the Bar Bill: “If, on its face, the specification would appear to the skilled person to lack sufficient disclosure, the onus of establishing that the invention is described in enough detail lies with the applicant”
80. I note at this point that the discussion in Warner related to plausibility of efficacy, which as I have found earlier is a precondition of method claims whereas the only precondition of Swiss claims under the Australian construction is plausibility of purpose. Nevertheless if the efficacy of a product is not plausible then it would follow that an intention to treat would not be plausible. Therefore it does not seem that substituting the word “purpose” for “efficacy” in the frameworks of either Sumption LJ or Hodge LJ would provide any substantial difference to the plausibility analysis.
81. I conclude from the foregoing that that the disclosure of the specification (supplemented by common general knowledge) must make the effect or purpose plausible, and a mere speculative assertion is not sufficient.
82. Turning to the last of the Evolva questions, factors indicative of undue burden include the need for the skilled addressee to undertake a “research programme” to carry out the invention across the full scope,[73] whereas factors indicative of sufficient disclosure include the presence of a “principle of general application” such that the person skilled in the art would reasonably expect the invention to work with anything that falls within the general term.[74]
[73] Evolva at [33], [36], [44]
[74] Evolva at [37], [38], [43], OS at [193]
Points of contention
83. The Opponent challenged that a principle of general application did not exist in the following areas: the location of the crosslinking cysteine; and the use of the hexamer to treat any and all mammalian autoimmune or inflammatory diseases.
Position of the disulfide bond
84. With respect to the disulfide bond, the Opponent pointed out that the only demonstration of hexamer formation in the specification was with the specific C309 mutation in the CH2 domain.[75] The Opponent further submitted that the four naturally occurring cysteines in the CH2 and CH3 domains are already involved in intramonomer disulfide bonds and are not available to bond to adjacent monomers.[76] The Opponent finally pointed to paragraph 55 of the Peter declaration which states that in this emerging field, treatment effects from one Fc multimer cannot be extended to other configurations of Fc multimer.[77]
[75] OS at [196]
[76] OS at [198]
[77] OS at [200]
85. The Applicant’s submissions did not directly address whether the position of the C309 mutation was a principle of general application or not.
86. The evidence available to me from the specification indicates that the sequence of IgG is modified to make it more like IgA or IgE (see paragraph 59 above). The specification also provides a predicted crystal structure showing the location of C309 cross links in the constant region and C360 crosslinks in the tailpiece (Fig 1A) which shows which parts of the heavy chain constant regions abut the neighbouring monomers.
87. I have no evidence as to the difficulty or otherwise of locating other possible disulfide bond positions. On the balance of the available evidence I am satisfied that the concept of “disulfide bonds between adjacent monomers” would a principle of general application: such that if the skilled worker could make alternative mutations that produced intermonomer disulfide bonds they would be expected to behave in the same way, i.e. stabilise the hexamer barrel structure.
88. Therefore on the balance of probabilities I am not satisfied that lack of sufficiency has been made out on this ground.
89. Although the Opponent did not explicitly press lack of sufficiency with regard to the scope of the tailpiece region, which as claimed is not limited to the IgE tailpiece exemplified, I consider that similar considerations apply to the tailpiece region. The presence of the structural model would enable the skilled worker to use appropriate alternative hexamerisation domains that would behave in the same way.
Plausibility of therapeutic use
90. With respect to the breadth of the claims in terms of therapeutic use, the Opponent submitted:
… the specification of the Opposed Application fails to plausibly or credibly provide that the invention will work across the scope of each of the Opposed claims (Regeneron Pharmaceuticals Inc., Bayer Pharma AG v Genentech Inc. [2013] R.P.C. 28 at [101]). In this regard, the Opposed Application claims the use of a very large number of hexameric proteins for treating any and all autoimmune or inflammatory diseases. The Opposed claims therefore include a vast number of discrete methods and it is incumbent upon the applicant to enable the invention to be performed in respect of each of them (Biogen Inc. v Medeva plc [1997] R.P.C. 1, 48-49; Kirin-Amgen Inc v Hoechst Marion Roussel [2004] UKHL 46, and of Kitchin LJ in Regeneron Pharmaceuticals Inc and Bayer Pharma AG v Genentech Inc [2013] EWCA Civ 93, as cited with approval in Evolva SA [2017] APO 57).[78]
[78] OS at [204]
91. The authorities cited by the Opponent in this passage were reviewed in Warner and I am satisfied that the Warner plausibility principles are not inconsistent with them. I will therefore address the plausibility from the Warner perspective: does the disclosure of the specification make it plausible that the Fc hexamer as claimed could treat any and all autoimmune inflammatory disease, or does it contain merely speculative assertions?
92. The Applicant’s submissions on therapeutic use were as follows:
… to limit the claims to the treatment of ITP as discussed at [OS 68b] is an unfair limitation compared with the contribution made by the applicant. The specification details and exemplifies the effective treatment of ITP in mice at Example 4, however the entire specification provides vast detail on how the polymers can be used as a replacement for IVIG without limitation as to the specific conditions which may be treated. Since IVIG is known as a treatment for a great number of autoimmune or inflammatory disease (See for example D8 and D10), it is allowable to claim beyond the disclosed examples ie: that the claimed. polymers are used for the treatment of other autoimmune or inflammatory disease, rather than limiting to ITP. Further, the skilled person understands that ITP is a well-established example for autoimmune and inflammatory disease (Gliknik themselves have relied on ITP as support for autoimmune disease in general, e.g. in D4.). The PSA would consider it plausible from the data provided in the specification that the claimed polymers could be used for the treatment of autoimmune or inflammatory diseases beyond ITP.[79]
[79] AS at [70] – footnotes integrated into the text.
93. The evidence available to me is as follows:
· The Fc hexamer as claimed is structurally defined and as such is not the same as IVIG.
· The specification itself admits that the mechanism of action of IVIG is unclear.
· Dr. Peter’s opinion is that at the priority date there was little evidence of what might be required for recombinant Fc multimers to function as IVIG replacements.[80]
· Two diseases with mechanisms of protection described in the specification are ITP (via Fc receptors) and a mouse model of arthritis (via DC-SIGN).
· Other autoimmune and inflammatory diseases are listed in the present specification as being amenable to treatment with IVIG but no rationale or mechanism for this is disclosed.[81]
· Dr. Pleass’s opinion is that his own comments regarding the use of Fc multimers as a replacement for IVIG therapy were “entirely speculative”.[82]
· The examples in the specification demonstrate binding of the Fc hexamers to various Fc receptors and lectins including prediction of binding to DC-SIGN, and demonstrate some protective efficacy in a mouse model of ITP.[83]
· Scientific publications on their own do not constitute common general knowledge – in any event D8 and D10 referenced by the applicant only use mouse models of ITP.[84]
· Other patent documents (such as D4) make broad claims based on data on ITP as an experimental model. This is no evidence of common general knowledge or plausibility of the instant specification.
[80] Peter at [32]
[81] p. 27 l 22 et seq
[82] Pleass declaration at 20
[83] Examples, summarised supra
[84] D8, abstract; D10, sentence bridging p. 484-485
94. From the balance of the available evidence, I consider it is plausible on the face of the opposed specification that the Fc hexamer could be used as a treatment for ITP and arthritis, but that there is no more than speculative assertion that it could be an effective treatment for other autoimmune and inflammatory diseases.
95. Since none of the instant claims are limited to these diseases, all claims encompass subject matter that fails the plausibility test of s 40(2)(a).[85]
[85] For completeness, I am satisfied that once plausibility has been established, treatment of ITP and arthritis could be carried out without undue experimentation; there is no evidence that a further research program would be required to do so.
Support (s 40(3))
96. To determine whether the requirements of support are satisfied post-Raising the Bar, the following steps were set out in CSR:[86]
i. construe the claims to determine the scope of the invention as claimed,
ii. construe the description to determine the technical contribution to the art, and
iii. decide whether the claims are supported by the technical contribution to the art.[87]
[86] CSR Building Products Ltd v United States Gypsum Co (“CSR”), [2015] APO 72
[87] CSR at [95]
97. The Opponent’s position on support is essentially the same as that on sufficiency – that the technical contribution is limited to a specific Fc multimer (with a mutation at position at 309) tested on a mouse model of ITP[88] and does not support the use of these polymeric proteins to treat any or all autoimmune or inflammatory diseases.[89]
[88] OS at [217]
[89] OS at [218-219]
98. The Applicant’s position on support on the other hand is that limitation to one particular sequence on the one hand and treatment of ITP on the other hand would be unfair in view of the contribution of the invention which is “vast detail on how the polymers can be used as a replacement for IVIG”.[90]
[90] AS at [69-70]
99. I do not fully accept either of these positions. I am not convinced that the technical contribution of the present description relies on the position of the cysteine mutation at position 309, as there is no evidence that shows that this position is important, and indeed the different stradomer structures cited by the Opponent do appear to have comparable activities.
100. Put another way, the position of the disulfide bond is somewhat unrelated from the technical contribution of the application, which is not the IgG barrel structure itself but rather its characterisation.
101. However (for similar reasons as provided in relation to plausibility) I am not convinced that the description establishes that these Fc hexamers can be used as a replacement for IVIG for all possible applications of IVIG.
102. Rather it appears to me that the technical contribution of the description is the characterisation of the claimed polymers in the Examples, i.e. in terms of their ability to bind Fc and lectin, and their effect in a mouse model of ITP.
103. Due to the lack of understanding of the mode of action of IVIG in the treatment of diseases other than ITP or arthritis, I therefore come to the same conclusion as to plausibility, in that the claims are only supported in so far as they apply to treatment of ITP or arthritis.
Manner of Manufacture
104. The Opponent submitted that the claims recite use of a known material for a purpose of which their known properties make them suitable, citing Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232. Although I am satisfied that the hexameric Fc barrel was not a novel material (see discussion of D1 at paragraph 111 below) I am not satisfied that it was known that the Fc binding properties of this hexamer would have made it suitable for treatment of autoimmune or inflammatory diseases because the identical protein was only disclosed as an “empty cassette” or synthetic intermediate. Furthermore I am not satisfied that the Fc binding properties of IVIG were common general knowledge such that the skilled worker would have read D1 with those in mind (see discussion of CGK at paragraph 30 above).
105. The principles advanced in Microcell are more relevant to the situation where an improved material such as stainless steel[91] is claimed for the same uses the previous materials had already been used for. However there Microcell acknowledged a variety of situations where this principle will not apply:
[91] Microcell at [10] quoted an earlier submission from Superintending Examiner Oates in Re L. &G.'s Application (1940) 58 RPC 21: “I submit it would be almost in restraint of trade if a man could come along and say: "Because no one else has mentioned such and such an article I am going to make it of stainless steel and get a patent for it" … The suggestion that he could seems, not unnaturally, to have almost horrified Mr. Oates.”
“a change or variation in the construction of the apparatus is rendered necessary by reason of the use of a particular kind of material not previously used for that purpose;
… the use for a particular apparatus of a known material not previously used for that purpose is due to a hitherto unknown or unsuspected property of the material;
… the adaptation of the known material to the particular piece of apparatus leads to a new departure in the technique of the production of the apparatus”[92][92] Microcell at [10], citations omitted
106. Notwithstanding the lack of evidence that the hexamer was “known to be suitable” for the claimed methods, the situation of the present case can also be distinguished from Microcell merely in that the hexamer is formulated for treatment, which is a “change or variation” from its use in D1 as a synthetic intermediate.
107. Therefore the ground of lack of manner of manufacture has not been made out.
Novelty
108. The legal standard for novelty is well recognised to be the reverse infringement test cited by both parties in their submissions.[93] Reverse infringement occurs if the prior publication discloses each and every element of the claimed invention[94] bearing in mind that a partial disclosure may anticipate a claim if the missing integers would have been understood to be present or would have been inevitable results.[95] However it is often said that anticipation requires the accuracy of a sniper[96], and alleged anticipatory citations must be read with the caution of General Tire &Rubber Co v Firestone Tyre & Rubber Co Ltd [1972] RPC 457 at p. 486:
“If ... 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 be as likely to be carried out in a way that would not do so, the patentee's claim will not be anticipated”
[93] Myers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19 at [20], OS [55], AS [17]
[94] AS [17] citing Rodi and Wienenberger AG v Henry Showell Ltd (1969) RPC 367 at 391
[95] OS [59] citing Danisco A/S v Novozymes A/S (No 2) [2011] FCA 282
[96] Gyles J in Apotex Pty Ltd v Sanofi-Aventis [2008] FCA 1194
Cited prior art
109. The opponent pressed its case for lack of novelty based on the following citations: D1, D2, D4, D7, and D13[97]. I will address each in turn.
[97] OS at [61]
D1 – WO2011/073692 A1
110. D1 is an earlier patent publication from the present inventor. D1 is directed to polymeric antigen fusion proteins which bind to Fc receptors as a means for delivering antigens to antigen-presenting cells.[98] D1 uses apparently the same polymeric IgG Fc-structure as in the present invention[99], but as a scaffold for delivery of antigens to the immune system. This is disclosed in D1 as being heptameric on the basis of molecular weight[100] however given that the monomer structure is the same as that of the present application, I consider on the balance of probabilities that this would have in fact been hexameric.[101]
[98] D1 e.g. p. 3 lines 11-12
[99] D1 e.g. p. 46 line 51- p. 47 line 2 which discloses constructs identical to those in the examples of the opposed application, except for the presence of a Plasmodium falciparum antigen at the N-terminus.
[100] See Figs 1-2 of D1 and the respective figure legends at p. 38.
[101] A conclusion consistent with the inventor’s later publications in D7 (see Fig 1) and D13 (see Figs 1 and 2). Although D7 and D13 are not in consideration as prior art (see para 119 below), I am content to use them as confirmatory evidence as to inherent properties of the construct of D1.
111. At the hearing the Opponent pointed out that the construct hIgG1-Fc-TP-LH309-310CL disclosed at p. 38 lines 33 and Fig 2(b) right panel of D1 (and implicitly disclosed at p. 42 lines 25-34) lacked the Plasmodium antigen and therefore was structurally identical to the hexameric protein as claimed.
112. However I am not convinced that D1 discloses that this construct should be used in the treatment of inflammatory diseases. The Opponent’s submissions refer to claims 1-19, pages 4-6 and 31-34 of D1.[102] Pages 4-6 set out general descriptions of the invention of D1, where in all cases the fusion protein comprises at least one functional factor which is an antigen or other therapeutic molecule.[103] The claims of D1 say the same thing. The disclosures of p. 31-34 are generic descriptions of pharmaceutical formulations which can only be read in combination with the teaching of the rest of the document as a whole, i.e. the therapeutic molecule of D1 is a fusion which does not satisfy the closed “consisting” language of the Opposed claims.
[102] SG&P at p. 3 3rd last paragraph, OS at [65]
[103] D1 p. 4 line 29 p. 5 line 8
113. I consider that D1 discloses hIgG1-Fc-TP-LH309-310CL only in the context of a synthetic intermediate and not its use in the treatment of autoimmune diseases as claimed.
D2 - WO 2008/151088 A9 and D4 - WO 2012/016073 A2
114. D2 and D4 both disclose “stradomers” which are multimeric forms of immunoglobulin Fc[104] and are intended as therapeutic replacement for IVIG.[105] The structure of stradomers in both documents is an IgG constant region (made up of CH2 and CH3 domains) and a multimerization domain (which can be in an IgG hinge[106] or a different multimerization domain such as GPP or isoleucine zipper[107]). These constructs dimerise to form constant region dimers that resemble the “monomers” as recited in the Opposed claims. D2 further discloses “serial” stradomers which have additional copies of the hinge-constant region[108] and “core” stradomers in which multiple serial stradomers with IgM CH4 domains are associated together via a J protein which binds the CH4 domain to simulate an IgM structure[109] or “cluster” stradomers which multimerise via a multimersation domain[110] that could correspond to the “tailpiece” recited in the Opposed claims.
[104] D4, abstract
[105] D2, abstract
[106] D4 Fig 1a
[107] D2, Fig 23D D4 Fig 1e, 1g
[108] D2, Fig 4
[109] D2, Fig 10B
[110] D2, Fig 23D
115. Nevertheless it is difficult to see how D2 or D4 disclose the exact structure of the protein recited in the Opposed claims with the accuracy of a sniper, particularly bearing in mind the protein is defined in closed “consisting” language. The Opponent’s submissions point to various points in D2 and D4 which are said to correspond to elements of the claims. Although as set out above I can consider that some elements of the Opposed claims correspond to features in D2 and D4, for the purpose of this analysis I will concentrate on the feature of the intermonomer disulfide bonds required by the Opposed claims.
116. The Opponent’s submissions pointed to paragraph [00122] of D2 as disclosing that “cysteine bridges may be used to connect individual stradomer units to form a core stradomer”[111] and likewise pointed to [0070] of D4[112]. The embodiment discussed in [00122] cannot be said to correspond to the structure in the Opposed claims as it requires a J chain to be used as a core moiety, which is excluded by the closed “consisting” language. I note that elsewhere in D2, disulfide bonds are mentioned as “inter-stradomer monomer linkages [which] serve to join the two individual stradomer monomers of the stradomer.”[113] However this corresponds to disulfide bonds within constant region dimers, not between them as required by the Opposed claims. Paragraph [0070] of D4 likewise is directed to inter-stradomer monomer linkages.
[111] OS at [67]
[112] OS at [74]
[113] D2 paragraph [116]
117. At the hearing, the Opponent’s representative submitted that the inter-stradomer monomer linkages would be anticipatory if the Opposed claims encompass intra-monomer disulfide bonds. However as I have found that the claims require disulfide bonds between hexamers to form a barrel structure, I am not satisfied that the claimed structure is disclosed by D2 or D4.
Grace period – D7 and D13
118. Section 24(1) provides that for the purposes of deciding whether an invention is novel or involves an inventive step, any information made publicly available by, with or without the consent of the nominated person or the patentee, or their predecessor in title (in particular including the inventor), within 12 months before the filing date of a complete application, must be disregarded.
119. D7 was published on 19 October 2011.[114] D13 was published online on 26 July 2012. Both of these dates are within the period of 12 months before the filing date of the instant application (17 October 2012). The sole named inventor Richard Pleass is listed as last author on both of these publications.
[114] The Cox declaration and exhibit SC-1 draw attention to this information which is evident from the front page of D7. I note that the Applicant did not make a similar submission with respect to D13 but the facts relating to D13 are the same.
120. I am satisfied that D7 and D13 were published with the consent of the inventor. Therefore I must disregard both D7 and D13 for the purposes of consideration of novelty and inventive step.
121. None of the asserted prior art documents have been shown to take away novelty of claim 1 or 8. This ground therefore fails.
Inventive step
122. The most commonly used approach to inventive step is the so-called “Modified Cripps Question” adopted by the High Court in Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59:
“Would the notional research group at the relevant date in all the circumstances which includes a knowledge of all the relevant prior art and of the facts of the nature and success of [compound], directly be led as a matter of course to try [the claimed invention] in the expectation that it might well produce [the desired result]?”
The notional research group, as discussed at paragraph 19 above, would have an understanding of immunology in general and immunoglobulins in particular.
Inventive step in view of prior art citations
123. Lack of inventive step can arise in view of a single document when read in view of the common general knowledge (s 7(2) and s 7(3)(a)) or in view of multiple documents that could be reasonable expected to be combined (s 7(3)(b)).
124. As submitted by the Opponent[115] “While not the sole test for determining inventive step, a useful approach for determining inventive step is the problem-solution approach. In determining the problem, consideration should be given to the common general knowledge and the prior art information. If the problem itself is common general knowledge, or if knowledge of the problem is part of the prior art information, then that knowledge or information may be used in assessing inventive step (AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99 at [202]-[203])”. I concur with that submission.
[115] OS at [84]
125. The Opponent further submitted[116]
“The problem addressed by the Opposed Application, and as suggested by the Opposed Application at page 4, lines 30-32, is not the creation of hexameric IgG1 Fc compounds, as that concept was already previously disclosed multiple times (see for example D2, D4), but rather the provision of hexameric IgG1 Fc fragments as compounds which target the Fc receptors underlying the biological activity of IVIG and which act as an alternative to IVIG for the treatment of ITP.
In Paragraph 33 of the declaration of Dr. Beate Peter made on 2 July 2019 (the First Peter Declaration) Dr. Peter considers that the inventors recognized and showed that the hexameric proteins exemplified in the Opposed Application are useful in methods of treatment of autoimmune or inflammatory diseases and characterizes the invention as the use of the hexameric structures, rather than the structures themselves.”
[116] OS at [85]-[86]
126. I agree with this to some extent. I have found that the hexameric structure recited in the claim was first disclosed in D1 (although not D2 or D4) so I agree that the problem is not the creation of the structure itself. Notwithstanding my findings as to sufficiency and support above, the claims as accepted are not limited to the treatment of ITP and hence the problem should not be limited to the treatment of ITP. I conclude that the problem addressed by the Opposed application is treatment of autoimmune and inflammatory diseases using IVIG mimetics. The claimed solution is treatment using the hexameric structures as claimed.
127. The Opponent’s submissions on inventive step appear to have been cruelled to the extent that the majority of their submissions are from the perspective that the stradomers of D2 and D4 correspond to the structural features of the hexamer in the present claims. As I have found with respect to novelty, this is not the case. Furthermore, an inventive step case cannot be mounted based on D7 and D13 as these have been excluded from the prior art base under the grace period provisions.
128. Given my construction of the claims and D2/D4, there appear to be three residual points in the Opponent’s submissions:
·Lack of inventive step by combination of features within D2, D4 and D5;[117]
·Modification of the “cluster stradomer” embodiment in D2 to include disulfide bonds as used in D3;[118] and
·Use of the hexameric intermediate of D1 as an IVIG replacement in therapy e.g. as taught by D14 or D15.[119]
[117] OS at [137] et seq
[118] OS at [102] and reference to Fig 23D of D2 made in the oral hearing
[119] Not specifically pressed in the opponent’s submissions but implicit from [162] and [43]
129. Starting with the combination of features within D2, D4 and D5, the Opponent refers to the disclosure of “inter-stradomer monomer linkages” in D2 in paragraph [00116][120]. I have previously found that this embodiment refers to intra-monomer disulfide bonds in the sense of the present claims, and as such I do not find that it could directly lead the skilled worker to introduce crosslinks between monomers without impermissible hindsight.
[120] OS [142]
130. The Opponent engages with Dr. Peter’s opinion that combining features from across D2, D4 and D5 is an exercise in picking and choosing[121] and would not result in a functional structure[122] by submitting that the functionality of the claimed invention is limited to the C309 mutation.[123] This is essentially a restatement of the Opponent’s position on support with respect to the C309 mutation. Although not explicitly stated in their submissions, the Opponent appears to be either attempting to reduce the weight of Dr. Peter’s evidence or to submit that the problem is not solved for alternative crosslink positions..
[121] Peter at [42]
[122] Peter at [43-44]
[123] OS [146]
131. However I have found that the hexameric structure used in the claim is a crosslinked barrel structure as shown in Fig 1 even if the crosslink is not limited to C309, and I have no evidence to establish that the problem is not solved in terms of the position of the crosslink. Although these documents are related to similar subject matter (“stradomers”) and would reasonably be read together by the skilled worker, Dr. Peter’s evidence supports the case that the exercise of finding features across D2, D4 and D5 was a “pick and choose” exercise in hindsight.
132. Turning to the combination of D2 and D3, I have already found that D3 is not representative of common general knowledge but it nevertheless forms part of the prior art base. A threshold question for inventive step is whether the skilled worker would have been directly led to introduce a C309 mutation described in D3 into the cluster stradomers disclosed in Figure 23D of D2, in the context of the problem of providing an IVIG mimetic. Although D2 is directed to the questions of IVIG mimetics, D3 is not – rather it is a theoretical study of the polymerisation behaviour of different Ig chains. The passage discussing introduction of C309 into IgG at p. 2862-2863 is presented in the context of making IgG more like IgM or IgA. Therefore I consider that the uninventive skilled worker would only read D2 and D3 together in the context of making a stradomer more like IgM or IgA. The only motivation within D2 to do this is in the context of the “core” stradomer embodiment discussed at [00122] and Fig 10 of D2, which requires IgM CH4 domains and an additional J chain. Therefore I find that the uninventive skilled worker, even reading D2 and D3 in combination, would only be directly led to introduce C309 crosslinks into a “core” stradomer with an additional subunit and therefore not arrive at the claimed invention.
133. Finally, turning to use of the hexameric intermediate of D1 as an IVIG replacement, the Opponent engaged with Dr. Peter’s opinion that as of the priority date recombinant Fc was an “emerging field” with reference to D14 and D15.[124] I have already found that D14 and D15 cannot establish common general knowledge by themselves, however they nevertheless form part of the prior art base. The Opponent then submitted that “the hexameric Fc multimer described in the Opposed Application and its claimed use in the treatment of autoimmune and inflammatory disorders is simply one example of the various Fc multimers that have been extensively described in, for example, D2, D4, and D5.”[125] D2, D4 and D5 do not disclose the hexameric structure as claimed; however an identical hexamer structure had been disclosed in D1 as established earlier, in the context of a design intermediate. The question then is whether, in view of D1, D14 and/or D15, the skilled worker would have been directly led to use the intermediate of D1 with a reasonable expectation of success as an IVIG replacement.
[124] OS [162]
[125] ibid
134. The only evidence I have to answer this question is found in the declaration of the present inventor and also the author of D1: “At the time I did not know whether such polymeric IgG1-Fc molecules did in fact have potential as a replacement for IVIG.”[126] This statement was made with respect to D7, which discloses the same construct as the intermediate of D1. Further, it was made with respect to the “speculative” comments[127] in D7 as to therapeutic effectiveness of the construct. The Opponent does not submit[128] that D1 itself contains any suggestion of therapeutic activity residing merely in the IgG Fc regions.
[126] Pleass declaration at [20]
[127] Dr. Pleass’s words, from ibid
[128] Cf OS at [109]
135. Therefore the balance of the evidence available to me is that there would have been no expectation of success in providing an IVIG replacement even if the skilled worker were to read D1, D14 and D15 in combination.
136. None of the grounds for lack of inventive step have been made out.
Conclusion
137. The opposition succeeds on the grounds of lack of sufficiency and lack of support. As the grounds in this decision appear amenable to resolution by amendment, I allow the Applicant a period of two (2) months from the date of this decision to file amendments under s104.
Costs:
138. It is conventional that costs follow the event. I therefore award costs according to Schedule 8 against the Applicant.
Felix White
Delegate of the Commissioner of Patents
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