Alethia Biotherapeutics Inc. v Daiichi Sankyo Company, Limited

[2015] APO 59

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Alethia Biotherapeutics Inc. v Daiichi Sankyo Company, Limited [2015] APO 59

Patent Application:                   2008311698

Title:Antibody targeting osteoclast-related protein Siglec-15

Patent Applicant:  Daiichi Sankyo Company, Limited

Opponent:  Alethia Biotherapeutics Inc.

Delegate:  Dr B. Akhurst

Decision Date:  9 September 2015

Hearing Date:  17 June 2015, in Melbourne 

Catchwords:  PATENTS – opposition to grant of a patent - novelty - the prior art does not disclose a relevant antibody with sufficient specificity - inventive step - it would have been a matter of routine to prepare the claimed antibodies and use them as claimed - opposition succeeds

Representation:  Patent applicant:  Ben Fitzpatrick of Counsel, instructed by Mark Roberts and Dr Rachel Stevenson of Davies Collison Cave, Melbourne.

Opponent: Clive Elliott QC, instructed by Steve Gledhill patent attorney of FB Rice.

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application:                   2008311698

Title:Antibody targeting osteoclast-related protein Siglec-15

Patent Applicant:  Daiichi Sankyo Company, Limited

Date of Decision:  9 September 2015

DECISION

Claims 1-15, 17-33 and 35 lack an inventive step.  Daiichi has 2 months from the date of this decision to propose amendments to overcome this deficiency.

Costs awarded according to Schedule 8 against Daiichi Sankyo Company, Limited.

REASONS FOR DECISION

Background

1. Patent application 2008311698 was filed on 8 October 2008, via the PCT, by Daiichi Sankyo Company, Limited (Daiichi) claiming priority from application JP 2007-265420 filed on 11 October 2007.  The application was examined and advertised as accepted on 1 December 2011. 

2. Alethia Biotherapeutics Inc. (Alethia) served a Notice of Opposition and statement of grounds and particulars, and completed evidence in support on 31 October 2012.  After gaining several extensions of time to file evidence in answer, the evidentiary period was stayed pending a request by Daiichi to amend the specification under section 104.  Allowance of the amendments was advertised on 6 March 2014.  Evidence in answer was filed on 18 March 2014 and evidence in reply on 17 June 2014.

3. The matter was heard on 17 June 2015 in Melbourne. 

   The Evidence

4. Evidence in support consisted of a declaration by:

   ·    Colin Dunstan (Dunstan#1) dated 30 October 2012 with Exhibits CD-1 to CD-7

5. Evidence in answer consisted of declarations by:

   ·    Thomas John Martin dated 24 July 2013 (Martin#1) with Exhibits TJM-1 to TJM-3

   ·    Thomas John Martin dated 29 January 2014 (Martin#2) with Exhibit TJM-5

   ·    Charles Reay Mackay dated 8 August 2013 (Mackay#1) with Exhibit CRM-1

   ·    Charles Reay Mackay dated 14 February 2014 (Mackay#2)

6. Evidence in reply consisted of a declaration by:

   ·    Colin Dunstan (Dunstan#2) dated 17 June 2014 with Exhibits CD-8 to CD-11

   Grounds of opposition

7. The grounds of opposition pressed by the opponent were manner of manufacture, novelty, inventive step, fair basis, clarity and usefulness.

   Onus of Proof

8. The request for examination in relation to the patent application was filed on 7 April 2010. As a consequence, the substantive amendments of the Patents Act brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present patent application.  This includes the amendment to subsection 60(3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition has been made out.  Instead, the onus of proof in this opposition lies with the opponent, who must establish that it is clear that a valid patent cannot be granted (F.Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [29], [67]; 50 IPR 305; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18], [22]; 79 IPR 426).

9. For the same reason, the substantive amendments to grounds of opposition that came into effect on 15 April 2013 do not apply to the present opposition.  Instead the law that applies to the grounds of opposition in this case is that which stood immediately prior to 15 April 2013.

   The specification

10. In construing the specification I note what Justice Middleton said in Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214, 100 IPR 451 at [139]:

    “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.”

11. The opposed specification is titled “Antibody targeting osteoclast-related protein Siglec-15”.  On page 1, the technical field of the invention relates to a substance useful as a therapeutic and/or preventive agent for abnormal bone metabolism, a method of screening for such substances, a method of detecting abnormal bone metabolism and a method of treating and/or preventing abnormal bone metabolism.

12. On pages 1-5, the specification describes the background to the invention.  In summary, bone is a dynamic organ which is continuously remodelled.  Healthy bone maintains an equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts, in order to maintain a constant bone mass.  When the equilibrium between bone formation and resorption is lost, abnormal bone metabolism disorders such as osteoporosis occur.  Many systemic hormones and local cytokines have been reported to regulate bone metabolism and these factors act together to maintain bone mass.  There are many factors involved in age-related osteoporosis, and advancement of basic research into the mechanisms that regulate bone formation and resorption is essential to elucidate the mechanism of its occurrence and to develop a therapeutic agent therefor. 

13. On pages 4-5 the specification summarises the published information regarding the sialic-acid-binding immunoglobulin-like lectins (siglecs), which are a family of type I membrane proteins that recognise and bind sialylated glycans.  While many siglecs are expressed on the cell membrane of immune cells and are considered to be involved in the immune response (Nature Reviews Immunology (2007) 7: 255-266), there are a lot of siglec molecules whose physiological functions have not been elucidated yet (page 4).  The newly identified Siglec-15 (Glycobiology (2007) 17: 838-846), is identical to a molecule called CD33 molecule-like 3 (CD33L3) which is highly conserved from fish to humans and has been found to be strongly expressed in dendritic cells and/or macrophages of human spleen and lymph nodes (page 4).  Human Siglec-15 binds to Neu5Aca2-6GalNAc; mouse Siglec-15 binds to Neu5Aca2-3Galbl-4Glc and Neu5Aca2-6GalNAc (Glycobiology (2007) 17: 838-846).  On page 5, the opposed specification refers Alethia’s patent application WO 2007/093042 which is cited in this opposition, and acknowledges that it reports that the expression of Siglec-15 increases with the differentiation and maturation of osteoclasts, and the differentiation of osteoclasts is inhibited by decreasing the expression of Siglec-15 by RNA interference.  The opposed specification notes however, that “the effect of an anti-Siglec-15 antibody on osteoclast differentiation has not been elucidated yet”.     

14. On page 5 of the opposed specification, under the heading “Disclosure of the Invention”:

    “An aspect of the invention is to provide: a gene which is specifically expressed in various forms of abnormal bone metabolism such as bone destruction which are seen in osteoporosis, rheumatoid arthritis, cancer metastasis to bone or the like; a substance which inhibits the differentiation and maturation of osteoclasts and the activity thereof; a novel method for screening a therapeutic and/or preventative agent for abnormal bone metabolism; a substance which inhibits the differentiation and maturation of osteoclasts and the activity thereof; and a therapeutic and/or preventive agent for abnormal bone metabolism.”

15. On page 6, under the heading “Means for solving the problem”, the specification states:

    “The present inventors studied to elucidate the mechanism of osteoclast differentiation, maturation and activation in order to find a substance having a therapeutic and/or preventive effect on abnormal bone metabolism. As a result, they found that the expression of the Siglec-15 gene increases with the differentiation and maturation of osteoclasts and also found that the differentiation of osteoclasts is inhibited by an antibody which specifically binds to Siglec-15, and thus, the invention has been completed.”

    The claims

16. The principles to be applied in construing the claims are well settled in law and were summarised by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70, 81 IPR 228 at [118]-[120]. Most relevantly, the words in a claim should be read through the eyes of the skilled addressee in the context in which they appear. Words used in a specification, including the claims, are to be given the meaning which the person skilled in the art would attach to them, having regard to his or her own general knowledge and to what is disclosed in the body of the specification. While the claims define the monopoly claimed in the words of the patentee’s choosing, the specification should be read as a whole. It is not permissible to read into a claim an additional integer or limitation to vary or qualify the claim by reference to the body of the specification. However, terms in the claims which are unclear may be defined or clarified by reference to the body of the specification. The construction of a specification, including the claims, is ultimately a question of law for the Court.

17. The claims under consideration in this opposition proceeding are those filed on 23 October 2013 and allowed on 19 February 2014, which are reproduced in Annex A to this decision.  There are three independent claims.  Independent claims 1 and 2 each define a class of antibodies or functional fragments thereof having specified binding and functional activities.  Independent claim 34 defines two hybridoma cell lines deposited under the Budapest Treaty.

18. The dependent claims further define the antibody or fragment by way of: its functional activity (claims 3-10); the method by which it is obtained (claims 11-12); the nature of the antibody or fragment (claims 13, 17-22); its binding activity (claims 14-15); deposited hybridomas that produce the antibody (claim 16); pharmaceutical compositions comprising the antibody or fragment (claims 23-28); and its therapeutic use and associated Swiss-style claim (claims 29-33).  Claim 35 defines the subject matter of the earlier claims by reference to the Example and/or Figures. 

19. In view of the context in which it was provided, the expert evidence provides little assistance on the proper construction of the opposed claims.  Associate Professor Dunstan was provided with a copy of the opposed specification, but he states that the content of then claims 1-34 “was explained to” him by the attorneys seeking his opinion on novelty and inventive step (Dunstan#1 at [30]).  Daiichi’s experts were not shown the opposed specification nor were they informed of the application number (Martin#2 at [5]; Mackay#2 at [5]).  Instead, Professors Martin and Mackay were asked to review the prior art with a view to describing its disclosure on the basis of advice that:

    “.., the claims of the patent application under opposition are directed to an antibody or functional fragment thereof, that specifically recognizes Siglec-15 protein or a region thereof, and which is effective to inhibit osteoclast formation [for Professor Mackay only: “and/or osteoclastic bone resorption”] and/or which is useful in the treatment of abnormal bone metabolism” (Martin#2 at [4]; Mackay#2 at [3])

    Inhibitory and therapeutic antibodies

20. Much of the expert evidence refers to “therapeutic” antibodies, whereas independent claims 1 and 2 define antibodies with “inhibitory” activity.  There was no dispute, and the evidence confirms, that there is a difference in scope between these terms (Dunstan#1 at [36], [37]; Martin#1 at [23], [27]-[28]; Mackay#1 at [29]).  The requirement in the claims for an inhibitory effect limits the claimed antibodies to those that exhibit inhibitory activity in vitro or in vivo. 

21. Claims 24-28 and Swiss claim 30 relate to pharmaceutical compositions with a specified in vivo activity.   Similarly, the therapeutic and/or preventative methods of claims 29 and 31-33 to require the specified effect in vivo. Construed against redundancy in light of claim 24, the pharmaceutical composition of claim 23 is not required to have a therapeutic or preventative activity for abnormal bone metabolism.

    Claim 1

22. Independent claim 1 defines an antibody, or functional fragment of the antibody, which:

    ·specifically recognises one or more polypeptides defined in parts (a) to (i) of the claim; and

    ·inhibits osteoclast formation and/or osteoclastic bone resorption. 

23. Parts (a)-(d) and (e)-(h) of claim 1 specify the amino acid sequence by reference to the full length sequence or specified partial sequences of SEQ ID NOs: 2 or 4 in the sequence listing.  The nature of these sequences is disclosed on pages 28 and 48-49 of the opposed specification, and is summarised below:

    In part (a) of claim 1, SEQ ID NO: 2 represents the human Siglec-15 polypeptide (328 amino acid residues in total).  The partial sequences referred to in parts (b)-(d) are as follows:

    (b)Amino acid residues 21-328 of SEQ ID NO: 2 represent the mature polypeptide lacking the signal sequence,

    (c)Amino acid residues 1-260 of SEQ ID NO: 2 represent the signal sequence and extracellular domain,

    (d)Amino acid residues 21-260 of SEQ ID NO: 2 represent the extracellular domain without the signal sequence.

    In part (e) of claim 1, SEQ ID NO: 4 represents the mouse Siglec-15 polypeptide (341 amino acid residues in total).  The partial sequences referred to in parts (f)-(h) are as follows:

    (f)Amino acid residues 21-341 of SEQ ID NO: 4 represent the mature polypeptide lacking the signal sequence,

    (g)Amino acid residues 1-258 of SEQ ID NO: 4 represent the signal sequence and extracellular domain,

    (h) Amino acid residues 21-258 of SEQ ID NO: 4 represent the extracellular domain without the signal sequence.

24. Claim 1 part (i) refers to “an amino acid sequence including substitution, deletion or addition of one or several amino acid residues in the amino acid sequence described in (a) to (h)”, which Alethia construed as encompassing polypeptides bearing no resemblance to Siglec-15. 

25. The word “several” is relevantly defined in the Macquarie Dictionary as meaning “being more than two or three, but not many”.  The amino acid sequences in parts (a)-(h) of claim 1 are all at least 237 amino acids in length, and part (i) encompasses the substitution, deletion or addition of “two or three but not many” amino acids within these substantially longer Siglec-15 sequences.

26. While even a minimally modified polypeptide may lose the function of the original, claim 1 explicitly requires the claimed antibodies to inhibit osteoclast formation and/or osteoclastic bone resorption.  It is reasonable to construe the antibodies of claim 1 as deriving this activity by binding and interfering with the activity of biologically active Siglec-15 polypeptides and variants.  It logically follows that inhibitory antibodies falling within the scope of claim 1 necessarily bind epitope(s) that are relevant to the biological activity of the Siglec-15 polypeptides and variants in osteoclast formation and/or osteoclastic bone resorption.   

    Claim 2

27. Independent claim 2 defines an antibody, or functional fragment of the antibody, which specifically recognises one or more polypeptides comprising an amino acid sequence encoded by a nucleotide sequence specified in parts (j) to (n) of the claim; and inhibits osteoclast formation and/or osteoclastic bone resorption.

28. Parts (j) to (m) of claim 2 define the nucleotide sequences by reference to SEQ ID NOs: 1, 3, 19 and 43 in the sequence listing.  These sequences are described on pages 28 and 49, of the opposed specification as follows:

    (j) SEQ ID NO: 1 represents the cDNA nucleotide sequence of human Siglec-15,

    (k) SEQ ID NO: 3 represents the cDNA nucleotide sequence of mouse Siglec-15,

    (l) SEQ ID NO: 19 represents the nucleotide sequence encoding the extracellular domain of mouse Siglec-15 encoded by SEQ ID NO: 3,

    (m) SEQ ID NO: 43 represents the nucleotide sequence encoding the extracellular domain of human Siglec-15 encoded by SEQ ID NO: 1.

29. Claim 2 part (n) defines the nucleotide sequence as follows:

    “a nucleotide sequence of a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to the nucleotide sequence described in (j) to (m) under stringent conditions wherein the polynucleotide encodes a polypeptide having a biological activity comparable to that of a polypeptide encoded by a nucleotide sequence described in (j) to (m).”

30. Alethia noted that the opposed specification does not describe the biological activity of the Siglec-15 extracellular domain, nor what is meant by the term “comparable to” in part (n).  There is no explicit dictionary for “comparable to” in the specification.  In its plain meaning, “comparable” means “capable of being compared” (Macquarie Dictionary).  In my view, no meaningful comparison can be made of disparate biological activities.  Consequently, I construe the reference claim 2 part (n) to “a biological activity comparable to that of the polypeptides encoded by the nucleotides of parts (j)-(m)”, to specify a biological activity that is essentially and substantially similar to any biological activity of those polypeptides. 

31. However, claim 2 explicitly requires the antibody to inhibit osteoclast formation and/or osteoclastic bone resorption.  Thus, in part (n) of claim 2 the nucleotide sequence necessarily encodes a variant Siglec-15 polypeptide that contains an epitope that is relevant to the biological activity of Siglec-15 in osteoclast formation and/or osteoclastic bone resorption.  This construction of claim 2 is consistent with Dr Dunstan’s opinion that claim 2 defines “the same antibody as defined in claim 1, only in terms of its binding to proteins encoded by the polynucleotides specified in claim 2” (Dunstan#1 at [32]).    

    Claims 14 and 15

32. Claim 14 defines an antibody or fragment “having the same epitope specificity” as one of two specified monoclonal antibodies.  Claim 15 defines an antibody or fragment that “competes with” the same monoclonal antibodies.  The concepts of epitope specificity and competition between antibodies were well understood in the art before the priority date.  Antibodies with the same epitope specificity bind the same epitope (target site) on a protein/peptide of interest.  Competitive antibodies compete with each other for binding to a target protein, and bind either the same epitope or closely sited epitopes.  This construction is consistent with the way the experts use the terms (Mackay#2 at [38]; Dunstan#2 at [32]; Dunstan#1 at [39]; Mackay#1 at [20]), and the way the opposed application describes a competitive antibody (page 26, lines 18-24).

33. I accept Alethia’s submission that antibodies may indirectly compete for binding, which is consistent with Dr Dunstan’s evidence that an antibody bound to a first epitope may physically occlude the binding of a second antibody to a distinct epitope in close spacial proximity to the first (Dunstan#2 at [32]).  It follows that the competing antibody of claim 15 does not necessarily bind the same epitope as an antibody produced by one of the deposited hybridomas, and in this regard the scope of claim 14 is broader than, and not redundant on, claim 15.  This construction of claims 14 and 15 is consistent with Dr Dunstan’s evidence that the claims refer to antibodies “having similar binding properties to” the two monoclonal antibodies specified in claim 16. 

1. Claims 14 and 15 are ultimately dependent on claims 1 and 2, which imports the requirement that the antibodies inhibit osteoclast formation and/or osteoclastic bone resorption.

2. Regarding Alethia’s submission that the skilled addressee would understand the reference in claim 15 to a competing antibody to include commercial competition for sales - that is an absurd construction with no evidentiary basis. 

   Manner of Manufacture

3. It is a requirement of subsection 18(1) of the Patents Act 1990 (the Act) that the invention, so far as claimed in any claim, is a manner of manufacture.  The threshold requirement for a patentable invention is that it must not be apparent on the face of the specification that the claimed invention lacks the necessary quality of inventiveness for it to be a proper subject of letters patent under the Statute of Monopolies (NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15 at [9]; (1995) 183 CLR 655).

4. To establish that the subject matter of claims 1-15, 17-33 and 35 is obvious on the face of the specification, Alethia relied on the following paragraph on page 5 of the opposed specification:

   “Until recently, the physiological role of Siglec-15 was not revealed, however, it has been reported that the expression of Siglec-15 increases with the differentiation and maturation of osteoclasts, and the differentiation of osteoclasts is inhibited by decreasing the expression of Siglec-15 by RNA interference (WO2007/093042). However, the effect of an anti-Siglec-15 antibody on osteoclast differentiation has not been elucidated yet.”

5. Alethia submitted that the opposed application refers to WO 2007/093042 and explains that this earlier document discloses that inhibition of Siglec-15 inhibits the differentiation of osteoclasts.  However, the balance of Alethia’s submissions relevant to the claimed inhibitory antibodies relied on the disclosure of WO 2007/093042, rather than that of the opposed specification  On review of the opposed specification, I agree with Daiichi that the opposed claims relate to antibodies with particular functional properties, which the opposed application, on its face, does not admit were known. 

6. Alethia has not established that the claimed invention is not a manner of manufacture. 

   Novelty

7. Alethia submitted that at least claims 1-15, 17-33 and 35 lack novelty in light of its own patent document WO 2007/093042 A1 (Alethia Biotherapeutics Inc.) 23 August 2007 (WO’042).

   The Law

8. Subsection 18(1) of the Act requires that the invention, so far as claimed in any claim, is novel. Subsection 7(1) provides that an invention is taken to be novel unless it is not novel in the light of the prior art. A citation is part of the prior art base for the purposes of novelty if it was published before the priority date of the claim.

9. It is well established that the general test for anticipation or lack of novelty is the reverse infringement test.  The classic formulation of this test is that given by Aicken J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19 at [20]; (1977) 137 CLR 228 at 235:

   “The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement”

10. In AstraZeneca AB v Apotex Pty Ltd (AstraZeneca) [2014] FCAFC 99 at [293], the majority of the Full Court identified the following principles in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (General Tire) [1972] RPC 457 at 486 as the criteria for determining anticipation by a prior publication:

    “When the prior inventor’s publication and the patentee’s claim have respectively been construed by the Court in the light of all properly admissible evidence ... the question whether the patentee’s claim is new ... falls to be decided as a question of fact.  If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated.  The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor’s publications will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.

    If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness.  To anticipate the patentee’s claim the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented ... a signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.”

11. In AstraZeneca at [294], noting the “planting the flag” and “accuracy of a sniper” metaphors referred to in earlier decisions (ICI Chemicals & Polymers Ltd v The Lubrizol Corporation Inc [2000] FCA 1349 at [51], (2000) 106 FCR 214 at [51] and Apotex Pty Ltd v Sanofi-Aventis [2008] FCA 1194 at [91], (2008) 78 IPR 485 at [91]), the majority described them as underlining the importance of the specificity required in order for a prior art document to anticipate a claimed invention. Reinforcing the principles in General Tire, the majority in AstraZeneca stated at [302]:

    “Sufficiency of disclosure is a cardinal anterior requirement in the analysis of whether a prior art document anticipates a claimed invention.  It is only after the stage of assessing the sufficiency of disclosure – which involves a determination about whether a prior document has “planted the flag” as opposed to having provided merely “a signpost, however clear, upon the road” or, perhaps, something less – that the notion of reverse infringement comes into play as the final and resolving step of the required analysis.  It is not the first step of the required analysis; nor is it the only step.”

    Submissions

12. Alethia submitted that WO’042 discloses anti-Siglec-15 antibodies that inhibit osteoclast formation and/or osteoclastic bone resorption, and methods of making them, which involve raising antibodies in a host by immunizing the host with Siglec-15 or a fragment thereof and testing those antibodies for their ability to inhibit osteoclast formation.  Furthermore, that WO’042 provides the proof of principle, clear and unmistakable directions, and the motivation to make an anti-Siglec-15 antibody that inhibits osteoclast formation and/or osteoclastic bone resorption and to use it to treat bone remodelling disorders.  Consequently, Alethia argued that in carrying out the directions in WO’042 to make an inhibitory antibody to Siglec-15, the person skilled in the art would inevitably produce something within Daiichi’s claims. 

13. Responding, Daiichi summarised the disclosure as the identification of the Siglec-15 gene and its potential role in bone biology based on very preliminary mRNA inhibition studies.  Daiichi submitted that WO’042 does not disclose specific antibodies for the therapy of bone disorders, let alone specific antibodies to Siglec-15, and in the absence of the explicit disclosure WO’042 does not disclose the production of an antibody, nor does it describe the functional domains of the Siglec-15 gene that would be required for the production of an antibody.

14. For the reasons that follow, I am not satisfied that WO’042 anticipates the subject matter of Daiichi’s claims.

    The WO’042 disclosure

15. The priority date of the opposed application was not in dispute.  WO’042 was published before the priority date and forms part of the prior art base for novelty (and inventive step).

16. WO’042 is titled “Polynucleotide and polypeptide sequences involved in the process of bone remodelling”.  There was no dispute that the document discloses the identification of new therapeutic targets for the amelioration of symptoms of bone remodelling disorders using polynucleotide expression profiling of active osteoclasts, or that Siglec-15 (identified in WO’042 as AB0326) is among the targets identified.  Daiichi further acknowledged that WO’042 discloses that osteoclast differentiation is inhibited by decreasing Siglec-15 expression by RNA interference.  

17. To simplify matters, in the following reasons where WO’042 or the evidence refers to “AB0326” I have substituted “Siglec-15”.  

18. To establish the disclosure of inhibitory antibodies, Alethia drew my attention to a number of passages in WO’042.  On page 1, under the heading ‘Field of the invention’ WO’042 relevantly states:

    “In particular, this invention relates to polynucleotide expression profiles of active osteoclasts, the isolation and identification of polynucleotides, polypeptides, variants and derivatives involved in osteoclast activity, validation of the identified polynucleotides for their potential as therapeutic targets ….”

19. On page 10, reference is made to the use of an inhibitory compound to provide a therapeutic benefit:

    “The present invention also relates to a method of ameliorating bone remodelling disease or disorder symptoms, or for inhibiting or delaying bone disease or disorder, the method may comprise: contacting a compound capable of specifically inhibiting activity or expression of a polynucleotide sequence described herein or a polypeptide described herein, in osteoclasts so that symptoms of the bone remodeling disease or disorder may be ameliorated, or the disease or disorder may be prevented, delayed or lowered.”

20. The “Background to the invention” on pages 1-5 of WO’042 describes, among other things, the role played by osteoblasts and osteoclasts in the dynamic process of bone remodelling in a local microenvironment and that any interference or imbalance in this process can produce skeletal disease, the most common and well known being osteoporosis (page 2). 

21. On pages 21-23, methods are provided for identifying endogenously differentially expressed nucleic acid sequences involved in osteoclast differentiation.  The sequences selected may be positive or negative regulators of osteoclast differentiation and may therefore represent attractive targets which may be inhibited or induced, respectively, to lower or prevent bone resorption (page 23).  On page 31, the invention provides isolated polypeptides involved in osteoclast differentiation in a mammal or mammalian cell or biologically active fragments or analogs of any of those polypeptides.  Described as the “lead gene” by Prof Mackay (Mackay#2 at [22]), WO’042 provides the polynucleotide sequences and encoded polypeptides for human and mouse Siglec-15.  SEQ ID NOs: 1 and 48 represent the nucleotide sequence encoding human Siglec-15 and the polypeptide, respectively (Table 1); the mouse Siglec-15 nucleic acid and encoded polypeptide are represented by SEQ ID NOs: 35 and 82 (Table 3).

22. On pages 33-34 of WO’042, the invention also relates to an antibody (e.g., isolated antibody), or antigen-binding fragment thereof, that may specifically bind to a protein or polypeptide described therein.  The antibody may be monoclonal, polyclonal, humanised, chimeric or an antibody generated using recombinant DNA technologies.  It may originate from a mouse, rat or any other mammal, or it may be a human antibody obtained, for example, from a transgenic non-human mammal capable of expressing human immunoglobulin genes.  Suitable antibodies include specified antigen binding fragments (Fab, F(ab')₂ and Fv fragments) or a single-chain antibody comprising an antigen-binding fragment.  On page 37, neutralising antibodies are especially preferred for therapeutic use. 

23. On page 35, the invention of WO’042 further relates to a method of producing antibodies to one of the polypeptides (or fragments or analogs), which methods are broadly described on pages 35-40.  Methods for humanisation are disclosed on pages 38-40.  Relevant to therapeutic antibodies, WO’042 notes the desirability of generating humanised monoclonal antibodies where they are to be administered to a patient for diagnostic or therapeutic purposes (page 38, lines 19-25).  Alternatively, WO’042 discloses that the antibodies may be useful for detecting the protein, variants and derivative polypeptides in specific tissues or body fluids (para bridging pages 40-41).  Immunoassays are broadly described between pages 41-42.

24. Other passages in WO’042 relied on by Alethia broadly refer to methods for identifying inhibitory compounds (inhibitors, antagonists) able to impair the function/activity or expression of the disclosed polypeptides and analogs thereof, and in particular a reduced ability of the polypeptide to inhibit or promote osteoclast differentiation (pages 42-45). 

25. Example I in WO’042, “RNA interference Studies”, broadly describes the principle behind the use of interfering RNA (RNAi) to produce a sequence-specific decrease in gene expression by targeting endogenously expressed mRNA for degradation (pages 81-82). 

26. On pages 82-83, Example J “Determination of knockdown effects on osteoclastogenesis ” describes the use of short hairpin RNA (shRNA - a form of RNAi) to attenuate (‘knockdown’) gene expression in human osteoclast precursor cells.  A commercial lentivirus shRNA delivery system was used to introduce, relevantly, Siglec-15-specific shRNA into human osteoclast precursor cells.  The cells were subsequently treated with receptor activator of nuclear factor kappa-B ligand (RANKL, a known inducer of osteoclast differentiation (Dunstan#1 at [11]; Martin#2 at [29])) to allow for differentiation of osteoclasts from the precursor cells.  Mature osteoclasts were formaldehyde-fixed, stained for tartrate-resistant acid phosphatase (TRAP) expression and visualised by light microscopy.  A significant decrease in the number of multinucleated osteoclasts was observed in the human precursor cells infected with Siglec-15 shRNA compared with controls, and the conclusion drawn that the results indicate that Siglec-15 gene expression is required for osteoclast differentiation. 

27. Example K, titled “Biological validation of the mouse orthologue for [Siglec-15] (SEQ ID. NO. 35) in osteoclastogenesis using the RAW 264.7 model”, provides “ a means of developing a drug screening assay for the discovery of therapeutic molecules capable of attenuating human osteoclasts differentiation and activity”, and in this regard, the mouse-derived RAW 264.7 (RAW) osteoclast precursor cell line is well known in the art as a murine model of osteoclastogenesis (i.e. osteoclast differentiation) (page 83). 

    In this example, RAW cells were stably transfected with shRNA under the control of a constitutive promoter to knockdown endogenous expression of the mouse Siglec-15 gene.  When treated with RANKL to induce differentiation to osteoclasts, the RAW cells with shRNA-attenuated Siglec-15 produced significantly less osteoclasts than controls, as revealed by TRAP staining.  Example K concludes as follows:

    “These results, coupled with that obtained in the human osteoclast precursor cells using the lentiviral shRNA delivery system (section J), demonstrate that in both human and mouse, [Siglec-15] gene product is clearly required for osteoclastogenesis.”

28. On pages 85-86, Example L provides “A functional complementation assay for SEQ. ID. NO. 1 [Siglec-15] in RAW 264.6 [sic] cells to screen for inhibitors of osteoclastogenesis”.  In this example, the cells of Example K with shRNA-attenuated mouse Siglec-15 expression, are ‘rescued’ by constitutive expression of human Siglec-15, thus restoring their ability to differentiate into osteoclasts in response to RANKL.  In effect, these ‘knockdown and rescued’ cells differ from the original RAW osteoclast precursor cells in that that they express human rather than mouse Siglec-15.  On pages 85-86, the conclusion is drawn that the mouse and human Siglec-15 are functionally conserved in osteoclast differentiation, and further that:

    “This particular type of cell-based assay can serve as the basis for screening compounds capable of binding to and inhibiting the function of human [Siglec-15].  A compound library could be applied to this ‘rescued’ cell line in order to identify molecules (small molecule drugs, peptides, or antibodies) capable of inhibiting [Siglec-15].  Any reduction in osteoclast differentiation measured by a reduction in the expression of TRAP would be indicative of a decrease in human [Siglec-15] activity.”

    Consideration

29. Dr Dunstan understands WO’042 to disclose a strategy for discovering genes and proteins whose expression is upregulated in osteoclasts.  He notes that the authors identified 35 genes that were specifically upregulated in differentiated osteoclasts, and Siglec-15 was selected for further validation as a causative factor of osteoclast differentiation. (Dunstan#1 at [23]). 

30. Professors Martin and Mackay understand WO’042 to describe standard methods of antibody production but not the preparation of an antibody, let alone an antibody that in fact reduces osteoclast formation and/or differentiation (Martin#2 at [17]; Mackay#2 at [16]).  To refute this, Dr Dunstan points to the following sentence on page 86 of WO’042 which he considers to describe antibodies that are capable of binding to an inhibiting Siglec-15 (Dunstan#2 at [21] and [28]):

    “A compound library could be applied to this ‘rescued’ cell line [of Example L] in order to identify molecules (small molecule drugs, peptides, or antibodies) capable of inhibiting [Siglec-15].” (Emphasis added)

31. However, the mere reference to an antibody library in that sentence does not identify with any specificity an antibody with the functionality required by the opposed claims.  Even if I am wrong, at best that sentence merely predicts that an antibody library could be applied to the cell line in Example L to identify antibodies with inhibitory activity.  It does not establish that an antibody library would necessarily include an inhibitory antibody within the scope of Daiichi’s claims. 

32. For completeness, Alethia submitted that following the standard procedures described on WO’042 achieving an inhibitory antibody would be inevitable.  However, Professors Martin and Mackay are in agreement that in there is no guarantee of success in achieving a therapeutic antibody (Martin#1 at [22], [24], Mackay#1 at [28]), a view not challenged by Dr Dunstan.  Alethia’s submission that it would not have imposed an undue experimental burden to make the inhibitory antibodies of the opposed claims on the basis of the information in WO’042 is best addressed under the ground of inventive step.

33. Alethia has not discharged the onus of establishing that the claims lack novelty.

    Inventive Step

34. Alethia submitted that claims 1-15, 17-33 and 35 lack an inventive step over WO’042. 

    The Law

35. It is a requirement of subsection 18(1) of the Act that the invention, so far as claimed in any claim, involves an inventive step. Under subsections 7(2) and 7(3), an invention is taken to involve an inventive step when compared with the prior art base unless it would have been obvious to a person skilled in the art. “Obvious” means “very plain” (Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21 at [51]-[52]; (2007) 72 IPR 447 at 461 [51]-[52]). The invention must be obvious in the light of the common general knowledge as it existed in the patent area before the priority date, either on its own or together with information in a document, or combination of documents, that the person skilled in the art could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant and, where necessary, combined.

1. The test for obviousness was provided by Justice Aicken in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12 at [45]; 148 CLR 262 at 286 as follows:

   “The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.”

2. The High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd (AB Hässle) [2002] HCA 59 at [51]-[53]; 212 CLR 411 at [51]-[53] also approved the approach taken in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at 187 in which Graham J had posed the reformulated Cripp’s question, which can be summarised as follows:

   Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art and of the facts …, directly be led as a matter of course to try [the invention as claimed], in the expectation that it might well produce a useful alternative to or better drug than [existing compounds] (emphasis added)

3. Both approaches require that the person skilled in the art has a reasonable expectation of success, which is explicit in the expectation that an approach “might well” succeed and implicit in steps characterised as routine and to be tried as a matter of course (Generic Health Pty Ltd v Bayer Pharma Aktiengessellscaft [2014] FCAFC 73 at [71]). The reasonable expectation does not require a guarantee of success and includes some possibility that the steps taken will not achieve the intended result (AB Hässle at [74], [76]). A test for obviousness formulated in terms of “worthwhile to try” was rejected by the High Court in AB Hässle at [72].

   Submissions

4. Alethia submitted that its patent application WO’042 was identified by Daiichi on page 5 of the opposed specification and the applicant has simply proceeded to verify Alethia’s earlier work.  Alethia acknowledged the challenge in bringing a therapeutic antibody to market, but noted that Daiichi’s claims are not restricted to clinically approved therapeutic antibodies.  Alethia argued that the anti-Siglec-15 antibodies produced and claimed in the opposed specification are the same as in WO’042 - they are made in the usual manner and tested for inhibitory activity using standard osteoclast formation/osteoblastic bone resorption assays.  Alethia submitted that the relevant question is whether, in all the circumstances, there was a reasonable expectation that taking routine steps building upon the disclosure in Alethia’s patent application WO’042 would have resulted in the skilled addressee attempting to produce inhibitory anti-Siglec-15 antibodies in order to use them in a method of treating bone metabolism disorders.

5. Daiichi did not dispute that it was known how to prepare antibodies per se at the priority date.  However it argued that what was neither known nor disclosed in WO’042 was information that would directly lead the skilled addressee to produce therapeutic anti-Siglec-15 antibodies i.e. those that inhibit osteoclast formation and/or osteoclastic bone resorption.  Daiichi noted in particular, that it was not known or disclosed in WO’042 that Siglec-15 is a proper target for antibodies in terms of its cellular location, and there is no disclosure of the relevant epitope.  Daiichi also questioned whether the skilled addressee would embark on the project.  Daiichi submitted that it is not sufficient that the person skilled in the art would “sooner or later get there” for all downstream processes prophesised in a patent application.  It argued the mere reference to antibodies seems to find a way into all specifications and it can’t be a dead weight for development of downstream innovation. 

6. The usual approach to determining inventive step is the problem-solution approach.  Once the problem has been formulated and the common general knowledge and the prior art base has been determined, the question of whether the claimed solution is obvious must be addressed.

   The problem

7. On pages 3-4 of the opposed specification, it is stated that known drugs for treating bone metabolism diseases do not always exhibit a satisfactory therapeutic effect, and the development of an agent with a more potent therapeutic effect has been demanded.  Page 6 reveals that “the inventors studied … in order to find a substance having a therapeutic and/or preventive effect on abnormal bone metabolism”.  These statements are consistent with the expert evidence that before the priority date there was a large unmet medical need to treat bone metabolism-related diseases such as osteoporosis (Dunstan#1 at [14]) and that there was an interest in developing new drugs to inhibit or prevent bone resorption in order to treat diseases of bone metabolism (Dunstan#1 at [14]; Martin #1 at [11]).

8. On balance, I consider a reasonable formulation of the problem in this opposition to be the need to develop new compounds to inhibit or prevent abnormal bone metabolism and in particular bone resorption.  This problem is broadly consistent with the parties’ submissions. 

   The person skilled in the art

9. In general, the skilled person or addressee is the person who works in the art or science with which the invention is connected.  He or she is a person likely to have a practical interest in the subject matter of the invention.  While the skilled person may be assumed to be well-versed in the relevant art, such a person must be taken to be non-inventive. (Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [71]-[72], 49 IPR 225 at [71]-[72] referring to Catnic Components Ltd v Hill &Smith Ltd [1982] RPC 183 at 242 and General Tire [1972] RPC 457 at 485; Minnesota Mining & Manufacturing Co v Beiersdorf (Aust) Ltd (Minnesota Mining) [1980] HCA 9 at [115]; 144 CLR 253 at 293)

   The experts

10. Professor Martin has 50 years of experience in bone disease research, particularly in relation to the formation and differentiation of osteoclasts and osteoblasts.  While he has a particular interest in cancer-related bone disease, his research interests cover all aspects of bone biology and clinical bone disease.  (Martin#1 at [4]-[7], [22]; Exhibit TJM-1)  

11. Doctor Dunstan has been actively involved in research into bone metabolism since 1977.  Before the priority date, he directed research into the regulation of bone resorption and formation and was responsible for the development of a monoclonal antibody for the treatment of, among other things, osteoporosis.  Doctor Dunstan has also been instrumental in clinical trials to assess the efficacy of the antibody and other candidate therapeutic agents for the treatment of bone metabolism-related disorders.  (Dunstan#1 at [3]-[6]; Exhibit CD-1)

12. Professor Mackay is an immunologist and authority in the field of leukocyte migration and inflammatory diseases rather than bone biology, who since 1987 has gained extensive experience in the production of antibodies for research and therapeutic purposes (Mackay#1 at [4]-[16]; Exhibit CRM-1).

13. Professor Martin and Dr Dunstan each have substantial experience in the field of bone biology.  Professor Mackay and Dr Dunstan each have substantial experience in the production of antibodies, including for therapeutic use.  Professor Martin has a good understanding of the antibody production process and their potential as therapeutics.  I am satisfied that these experts are skilled in the art to which the application relates.

    The expert evidence

14. Daiichi submitted that Dr Dunstan was impermissibly led by being given a copy of the opposed application, along with copies of the prior art documents, before expressing his views on inventive step.  However, for the reasons that follow, I do not believe that this submission reflects the true circumstances.  

15. Dr Dunstan was approached by FB Rice in June 2012 to act as an independent expert in this opposition, at which time he was informed of the parties and that the opposed patent application “generally relates to the use of antibodies for treating bone disorders” (Dunstan#1 at [7]).  Dr Dunstan subsequently met with Alethia’s attorneys on 18 July 2012 and provided evidence regarding the general state of the art and available therapies for treating bone disease before the priority date (Dunstan#1 at [9]).  In particular, Dr Dunstan states:

    “At the time of that meeting I had not been provided with a copy of the patent application to which this opposition relates or even advised of any patent application number by FB Rice.  At the time of the meeting, I had specifically been requested not to undertake any independent investigation as to what the patent application in question might be.” (Dunstan#1 at [9])

16. Later, on 25 July 2012, Dr Dunstan was asked by Alethia’s attorneys to review and comment on the prior art, including WO’042 (Dunstan#1 at [22]).  It was only on 8 August 2012 that Dr Dunstan was provided with the opposed application for comment (Dunstan#1 at [29]). 

17. Given the context in which it was provided, I am not satisfied that Dr Dunstan’s evidence should be disregarded.  However, in according weight to his evidence, I must bear in mind that he was aware at the earliest stage that the opposed claims related to the use of antibodies in particular to treat bone disorders.  I am also mindful that Daiichi’s experts were aware of the broad subject matter of Daiichi’s claims and much of their evidence is provided in the context of therapeutic antibodies in particular rather than inhibitors more generally (Martin#2 at [4]; Mackay#2 at [3], see also para [19] above).  

    The common general knowledge in the art

18. A definition of common general knowledge was provided by Aitken J in Minnesota Mining [1980] HCA 9; 144 CLR 253 at 292 as:

    “… 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.”

19. The overall mechanisms regulating osteoclast formation/differentiation were well established before the priority date.  Generally, two major steps in this process were known to be:

    i)the formation of a pool of osteoclast precursor cells, requiring the activity of the cytokine macrophage colony stimulating factor (M-CSF); and

    ii)the differentiation of these precursor cells into osteoclasts, requiring the activity of RANKL. (Dunstan#1 at [11])

    In addition to these paracrine regulatory mechanisms, a number of autocrine loops were known to be involved in stimulating osteoclast formation/differentiation.  However, there was scope for further elucidation of the details of these mechanisms and for the identification and characterization of other, additional mechanisms which were considered likely to exist at the time. (Dunstan#1 at [11])

20. It was known before the priority date that abnormalities in osteoclast formation/differentiation contributed to the development of several diseases, such as osteoporosis associated with menopause or aging, and played a role in bone defects resulting from metastatic disease (Dunstan#1 at [12]).  Existing anti-resorptive agents included bisphosphonates and calcitonin (Dunstan#1 at [13]; Martin#1 at [10]).  Parathyroid hormone had been clinically established to increase bone formation (Dunstan#1 at [13]; Martin#1 at [10]).  It was also known that antibody-based therapies were in development for the treatment of bone metabolism-related disorders (Dunstan#1 at [13]; Martin#1 at [14]).  

21. There was no dispute between the parties that, in general, methods for the production of antibodies were well known and available in the art before the priority date (Dunstan#1 at [18]; Mackay#1 at [31]).

    Ascertained, understood and regarded as relevant

22. “Ascertained” means found or discovered (Commissioner of Patents v Emperor Sports Pty Ltd [2006] FCAFC 26 at [29]-[30], (2006) 67 IPR 488). A general test for relevance was provided in Beecham Groups Limited’s (Amoxycillin) Application [1980] RPC 261 at 282:

    “The test in my judgement is whether it can be expected that the skilled man will be likely to recognize the document in question as being particularly pertinent to, though it may not specifically solve the problem before him.”

23. Before the priority date, if he were faced with the relevant problem and had conducted a search, Prof Martin does not believe he would have found WO’042 since he does not consider patents a fundamental source of information for the skilled researcher (Martin#2 at [6]).  Professor Martin does not comment on the databases he may have searched.  In the event that he had found WO’042, Prof Martin states that he would not have considered it relevant because it does not provide “sufficient validation of Siglec-15 as a potential target for the preparation of therapies for the treatment of bone metabolism disorders” (Martin#2 at [6], referring to [15]-[18]).  Nevertheless, it is clear from his evidence that Prof Martin understands WO’042 to relate in general to potential targets for the preparation of relevant therapies.  On this basis, it is reasonable to conclude that Prof Martin would have recognised the document as particularly pertinent to the problem identified above, although it may not specifically solve it.

24. Professor Mackay would have searched the patent literature (Mackay#2 at [13]).  Professor Mackay believes it likely he would have identified WO’042 on Google or a patent database since the title of WO’042 includes the term “bone remodelling” and he would have concluded that Siglec-15 might be interesting for bone biology (Mackay#2 at [14]).  I am satisfied Prof Mackay would have ascertained WO’042 and considered it relevant. 

25. Before the priority date, Dr Dunstan believes it likely that he would have identified WO’042 when searching the patent literature for new targets for the treatment of bone metabolism (Dunstan#2 at [14], [16]).  Daiichi submitted that Dr Dunstan’s opinion was tainted in relation to the documents he would have ascertained, since he was asked what types of documents he would have searched for and read when considering “whether to try to produce a new therapeutic antibody for the treatment of bone-metabolism-related disease” (emphasis added).  However, it is clear from his evidence that Dr Dunstan would conduct his search in terms of potential targets for therapy, rather than the therapeutic agent itself (Dunstan #1 at [16]; Dunstan#2 at [14]).  Therefore, I see no reason to discount Dr Dunstan’s evidence regarding whether a document would be ascertained.  Although Dr Dunstan does not comment directly on whether he would have considered WO’042 relevant, given his subsequent evidence it is reasonable to conclude he would have done so.    

26. WO’042 is in the English language and, if found, it would have been understood.  In seeking to solve a problem before the priority date, two of the three experts would have ascertained WO’042.  The evidence supports a conclusion that each of the three experts would have found the document relevant.  On this basis, I am satisfied that WO’042 could be reasonably expected to have been ascertained, understood and regarded as relevant.

    WO’042

27. The disclosure of WO’042 has been summarised above under the ground of novelty.  As noted above, there was no dispute that the document discloses the identification of new therapeutic targets for the amelioration of symptoms of bone remodelling disorders, or that Siglec-15 is among the targets identified.  

28. It is clear from the evidence that the steps involved in generating a therapeutic substance against a putative target protein is an iterative process, and that the outcome or results of experimentation at each point in the process will influence the decision as to whether or not to proceed (Dunstan#1 at [15]; Martin#1 at [24]-[29]; Mackay#1 at [20]-[28]).  The first requirement is to identify and validate a potential target for therapy (Dunstan#1 at [15], [19]; Martin#1 at [19], [23]; Mackay#1 at [20]-[23]; Mackay#2 at [11]).  If the target proved promising the next step would be to prepare modulatory agents against the target in order to treat the condition (Dunstan#1 at [15]; Martin#1 at [24]-[29]).

    Reasonable expectation of success

29. A reasonable expectation of success does not require a guarantee of success and includes some possibility that the steps taken will not achieve the intended result (AB Hässle at [74], [76]).

    Doctor Dunstan

30. Doctor Dunstan understands WO’042 to disclose Siglec-15 as a validated target for treating bone disorders (Dunstan#1 at [23]; Dunstan#2 at [11], [16]-[17], [19]).  In his second declaration at [11], Dr Dunstan states:

    “WO 2007/093042 … provides the first convincing validation of the role of Siglec-15 in osteoclastogenesis and therefore provides the first convincing indication that Siglec-15 is a legitimate, attractive target for antibody therapy in the treatment of bone metabolism-related diseases. …  In my view, this represents extremely convincing evidence of the role of Siglec-15 in osteoclastogenesis and demonstrates, for the first time, that bone metabolism-related diseases may be amenable to treatment with antibody therapy targeting Siglec-15.

31. I am mindful that Dr Dunstan knew the general field of Daiichi’s claims prior to giving evidence, and that this may have influenced his references to an antibody inhibitor in particular.  However, it is reasonable to conclude that in seeking to solve the problem and without the benefit of hindsight, on the basis of the information in WO’042, Dr Dunstan would directly be led as a matter of course to try inhibitory compounds against Siglec-15 in the expectation that it might well produce an alternative or better drug for the treatment of bone metabolism disorders. 

    Professors Martin and Mackay

32. Prior to being told the nature of the opposed claims and exposure to the prior art, Prof Martin confirmed that the purpose of an antisense experiment is to try and validate a target, and that inhibition by antisense is a proof of concept and a good indicator that it might be worth trying an antibody or a small organic compound (Martin#1 at [19]-[20]).  However, Prof Martin would always conduct validation studies of his own before embarking on developing a therapeutic agent against a target (Martin#1 at [19]; Martin#2 at [14]).  Relevant to his expectation of success if Siglec-15 were validated as a suitable target, albeit in the context of producing inhibitory antibodies in particular, Prof Martin states:

    “If the target is demonstrated to be functional, i.e. has something to do with osteoclast function, then it is likely that you will be able to develop an antibody that will block the function to at least to [sic] some extent.”

33. Professor Mackay understands WO’042 to disclose Siglec-15 as a potential target for treating bone disorders (Mackay#2 at [15]-[16], [23], [25]).  He views the data in WO’042 as preliminary, rather than providing concrete evidence regarding the role of Siglec-15 in bone biology.  He concludes that Siglec-15 “might be interesting for bone biology”; that it “could in some way be useful in bone”; and that it might be desirable to inhibit or over express Siglec-15 depending on the disease condition being targeted.  Furthermore, that “it might be an interesting target worth further investigation but that further validation was required to confirm its role” before he would consider developing a therapeutic compound.  On being asked the likelihood of success in developing in particular a “successful therapeutic antibody” against a known target, in his first declaration at [28], Mackay states:

    “If the antigen was a simple, reasonably large protein that was either secreted or on the surface of the cell then there would be a greater than 95% chance that an antibody could be made. … However, this is just to produce an antibody which binds to an epitope, there is no guarantee that the antibody would be therapeutically useful.”

1. Professor Mackay and Prof Martin’s evidence establishes that they would further validate Siglec‑15 as a potential target for the treatment of disorders of bone metabolism, before committing resources to the production of therapeutic agents.  Then, if the results proved promising both experts would have a reasonable expectation of being able to produce an inhibitory compound against Siglec-15 for the treatment of disorders associated with bone metabolism. 

2. Regardless of whether the person skilled in the art would further validate Siglec-15 as a potential therapeutic target or proceed directly to the production of antibodies, the question for obviousness purposes is whether the subsequent work would be a matter of routine. 

   Matters of routine

3. The experts outline the steps involved in first validating a potentially therapeutic target and then developing an inhibitory agent against that target.

   Validating the target

4. The experts agree that validation of the target is a primary concern in attempting to produce a therapeutic agent or antibody (Dunstan#1 at [19]; Martin#1 at [19]; Mackay#1 at [20]-[21]).  Accordingly, when initiating a new development programme for novel therapeutic agents the skilled addressee would, as a matter of routine, confirm:

   i)whether there was sufficient validation of the role of a target in the disease process (Dunstan#1 at [15]; Martin#1 at [19]; Mackay#1 at [20]); and

   ii)the nature of the target and its suitability for any given therapeutic strategy (Dunstan#1 at [15]; Martin#2 at [20]-[21]; Mackay#1 at [23]).

   The role of the target in the disease process

5. In order to develop an inhibitor against a target it is necessary to know the function of the target and what aspect of that function is to be inhibited (Dunstan#1 at [15]; Martin#1 at [19]; Mackay#1 at [20], [21]).  Genetic studies, in the form of a knock-out model revealing the physiological role of a potential target in generating a particular phenotype, would be powerful evidence of its suitability as a therapeutic target (Dunstan#1 at [15]).  One means is to use RNAi studies to interfere with the expression of a gene (Dunstan#1 at [23]; Martin#1 at [20]; Mackay#2 at [14]), as is disclosed in WO’042.  Additionally or alternatively, a gene-deficient (‘knockout’) mouse would reveal the physiological role of the target in generating a particular phenotype in vivo (Dunstan#1 at [15]; Martin#1 at [23]; Mackay#1 at [24]).  

6. Relevant to Daiichi’s submission that WO’042 does not identify the Siglec-15 epitope to be targeted by a therapeutic agent, Prof Mackay confirmed that it is not necessary to know the functional epitope of the target at the outset (Mackay#1 at [20], consistent with Mackay#2 at [24]).

   The nature of the target

7. Once a suitable target is identified, the strategy used to modify the activity of the target protein will depend on its cellular location (Martin#2 at [18]; Martin#2 at [23]; Mackay#1 at [23]) and its immunogenicity in other species (Mackay#1 at [27]-[28]). 

   Immunogenicity

8. It is difficult to make antibodies to a protein that is totally conserved between species, since this would lead to a lack of immunogenicity (Mackay#1 at [27]).  In this regard, I accept Alethia’s submission that a simple comparison of the human and mouse Siglec-15 polypeptide sequences in WO’042 (SEQ ID NOs: 48 and 82) reveals they are not highly conserved, which is consistent with Prof Martin’s evidence (Martin #2 at [11]). 

   Cellular location

9. Secreted or cell surface proteins are the most appropriate targets for antibodies, ensuring access for antibody binding (Dunstan#1 at [15]; Martin#1 at [21]-[22]; Mackay#1 at [23]), whereas enzymes and other smaller targets are traditionally the types of targets that are more amenable to a small molecule chemistry approach (Mackay#1 at [23]).

10. WO’042 describes human Siglec-15 as “membrane-associated” (Table 1: SEQ ID Nos: 1 and 48) and mouse Siglec-15 as “similar to neural cell adhesion molecule 2” (Table 3 - SEQ ID Nos: 35 and 82).  However, WO’042 does not definitively identify the cellular location of Siglec-15. 

11. Relevant to determining the cellular location of a protein, Prof Mackay states that if a target demonstrated potential in a knockout mouse model, mouse monoclonal antibodies against the human target could be prepared for use in immunopathology or immunoassays to investigate target expression in human tissue or blood samples (Mackay#1 at [25]).  I infer from this that the application of such assays to identify the cellular location of target molecule would be a matter of routine.  Furthermore, consistent with Alethia’s submission, I consider that it would equally be a matter of routine to apply these ‘investigative’ antibodies to the knockdown and rescued cells prepared according to Example L of WO’042, to confirm in intact cells whether any part of human Siglec-15 is located extracellularly.  

    In silico predictions of structure and function

12. Dr Dunstan’s evidence establishes that, before the priority date, it would have been a matter of routine to predict the structure and function of a protein and its likely location using in silico means.  Doctor Dunstan explains:  

    “I was asked if I would have known in mid 2007 how to identify mature polypeptide sequences, signal sequences and extracellular domains in a given polypeptide sequence (or encoding polynucleotide sequences).  I would have been able to identify such characteristics of a given polypeptide at that time as a matter of routine.  I would have used (or would have directed a protein chemist on my team to use) publicly available software to identify any conserved domains within the polypeptide sequence that are indicative of functional features (e.g., transmembrane domains, signal sequences, etc.).  Transmembrane sequences could easily be predicted at the time, based on amino acid hydrophobicity.  In order to then predict which region of the protein is extracellular and which is intracellular, I would have looked for conserved ligand binding domains (e.g., the initial analysis of osteoprotegerin revealed that it had a conserved TNF binding site in what was therefore predicted to be an extracellular domain), and any other conserved domains in homologous family members which could be informative.  These methods would allow a reasonably sound prediction to be made of a protein’s structure, on which inferences could be made about the protein’s function.” (Dunstan#1 at [17]) 

    “… potentially epitopic regions of a protein could be predicted from protein sequence data (e.g., by identifying likely extracellular regions, or ligand-binding domains within such extracellular domains)” (Dunstan#1 at [18])

13. Relevant to WO’042, Dr Dunstan states:

    “[WO’042] also provides polynucleotide and polypeptide sequences which can be used to make reasonable predictions of any functional domains contained therein. Certainly, functional domains within these sequences, which share homology with other, known functional domains can be identified and transmembrane domains or signal sequences can be predicted with reasonable confidence.” (Dunstan#1 at [24])

14. It may take several months to express and verify the function of a protein target (Martin#1 at [23]).  However, in describing the processes involved in validating a potential target, the experts do not suggest that the work involved would have been other than a matter of routine.  On balance, although it may be a time-consuming process, I am satisfied that it would have been a matter of routine at the priority date for the person skilled in the art to further validate Siglec-15 to confirm its role in the disease process and its nature and suitability as a therapeutic target. 

    Inhibitory antibodies as opposed to any other inhibitor

15. Much of the expert evidence was provided on the basis of questions relating specifically to antibody-based therapies, which is not helpful to the determination of whether the person skilled in the art would seek to make inhibitory antibodies rather than other types of inhibitors to Siglec-15.  However, generally relevant to the choice of targeting strategy, Professor Mackay explains:

    “Most therapeutic antibodies are directed against large proteins, given that large targets, such the TNFs, are not suited to modulation with small molecules.  Enzymes and other smaller targets are traditionally the types of targets that are more amenable to a small molecule chemistry approach” (Mackay#1 at [23]). 

16. I infer from this that enzymes having a discrete catalytic site and small targets are more likely to be targeted using small molecule inhibitors, whereas larger and non-enzymatic proteins are suitable for antibody-based therapies.  There is no suggestion in WO’042 or the evidence that Siglec-15 is an enzyme or small target.  Accordingly, Dr Dunstan considers the document alone to provide a clear direction to produce an inhibitory antibody against Siglec-15 (Dunstan#1 at [25]).

17. Also relevant to the choice of targeting strategy, secreted or cell surface proteins are appropriate targets for antibodies (Dunstan#1 at [15]; Martin#1 at [21]-[22]; Mackay#1 at [23]).  There was no dispute that Siglec-15 is in fact a cell surface protein with an extracellular domain, and it is reasonable to conclude that this would have been confirmed by the validatory experiments.   

18. Lending further weight to a view that the skilled person would consider antibody-based therapies against Siglec-15, the evidence establishes that before the priority date, there was interest in developing therapies using alternative mechanisms of inhibiting bone resorption (Martin#1 at [11]) and antibody-based therapies were being pursued for this purpose (Dunstan#1 at [13]; Martin#1 at [11], [14]).  Doctor Dunstan states that antibody therapy was likely to overcome the known adverse side effects of bisphosphonate treatment due to the greater specificity of therapeutic antibodies (Dunstan#1 at [14]).

19. On balance, it is reasonable to conclude that, based on the information in WO’042 alone, or after further validation, the person skilled in the art would directly be led as a matter of course to try to prepare inhibitory antibodies against Siglec-15, in the expectation that it might well produce an alternative or better drug than existing therapies for bone metabolism disorders.

    Making antibodies and identifying inhibitory antibodies

20. There was no dispute, and the experts confirm, that in general the production of antibodies was a routine and well established process at the priority date (Dunstan#1 at [18]; Martin#2 at [14]; Mackay#1 at [17]- [18]; Mackay#2 at [24]).  Professor Mackay confirms that:

    “At around October 2007, while it took considerable time to get an antibody approved and into trials, the techniques of humanization, phage display and production of fully human antibodies were all available.” (Mackay#2 at [18]).

21. Professor Mackay nevertheless considers it “a vastly different concept to make a functional inhibitor to a target” (Mackay#1 at [31]).  As noted above, other than a brief summary of the claims Prof Mackay did not have access to the opposed application.  There are parts of his evidence in which his opinion regarding the difficulties in producing therapeutic antibodies may have been influenced by a view that the claimed monopoly relates to an antibody that must in fact be suitable for clinical use.  This view is apparent in his first declaration at [29]:

    “In summary, in following a research program to produce a therapeutic antibody against a known target, even now, there is no guarantee that you will get an antibody with the type of inhibition properties that you could take to clinical trials.” (Emphasis added)

22. The evidence establishes that inhibitory antibodies are made by the same means as any other antibody.  Once antibodies have been produced against a target, the inhibitory antibodies must be identified and isolated from the general antibody pool on the basis of the desired inhibitory (neutralising) activity (Mackay#1 at [22]; Dunstan#1 at [18]; Martin#1 at [25]). 

23. Setting up a screening assay in a new field to identify inhibitory antibodies is the only part of the antibody production process that Prof Mackay identifies as potentially laborious (Mackay#1 at [22]).  However, at Examples K and L WO’042 discloses cells for use in screening potential inhibitors of mouse and human Siglec-15, respectively.  Furthermore, WO’042 explicitly states on page 86, para 1 that antibodies can be applied to the ‘rescued’ cell line in Example L, to identify those capable of inhibiting human Siglec-15.  Thus, WO’042 explicitly provides the necessary screening assay. 

24. In his first declaration, Professor Martin summarises the steps involved in the production of a “clinically useful” therapeutic antibody as follows:

    “24.In developing an antibody therapeutic you need to raise a number of antibodies, including both monoclonals and polyclonals, which are useful for proof of concept experiments.  In my company we would want at least 6 or 8 promising polyclonals to be developed at any one time.  To show that you’ve got a good, clean and well characterised antibody can take at least 4-6 months even for a well renowned group.  To get a good monoclonal antibody would take at least 4-6 months of experimental work, but again, there is no guarantee of success.

    25.The antibodies need to be validated. It is not enough to simply “produce an antibody” you need to demonstrate that it is effective.  The antibody needs to be neutralising so you also need to develop an in vitro assay to show that your antibody neutralises either the formation of osteoclasts or the resorption function.  To determine the efficacy of the antibodies as therapeutics for bone disease, you would need to carry out in vitro osteoclast formation assays.  You might label the protein and show that using fluorescent labelling and appropriate microscopy, the labeled antibody specifically adheres to the target cells.  It is also important to show functional effects.  This requires growing the cells, and running osteoclast formation assays where you see whether any of your antibodies block osteoclast formation. 

    26.Whether or not an antibody inhibits formation of osteoclasts, another important step is to also see whether the antibody blocks the activity of osteoclasts once they are formed.  To do this you would generate osteoclasts, get them off the surface and put them onto bone slices and let them incubate with the antibody for 24 or 36 hours.  A good antibody will both block the formation of osteoclasts and will block osteoclast activity.

    27. Although an antibody may work in vitro, it may not work in vivo, in which case it may not be suitable for clinical development.  There are a number of further tests that can be carried out to see if an antibody is suitable for further development.

    28.To see whether the potential inhibitor functions to inhibit osteoclasts generated in response to stimulation by osteoblasts in vivo you would, for example, look to see whether the potential inhibitor of resorption will inhibit the bone loss accompanied by ovariectomy.  To do this you would ovariectomise a mouse and start treating the mouse with the inhibitor from that time and look to see whether the inhibitor has prevented the bone loss that would otherwise take place over the next month or six weeks.  I would then do a comparison against a known agent, the most obvious being oestrogen. 

    29. Once you have a resorption inhibitor that you think is powerful enough, … there are other assays you can use to test the efficacy of the inhibitor.  For example, if you inject cancer cells into the system of circulation in mice they grow in bone as several metastases.  If the inhibitor is a powerful inhibitor of bone resorption …, it will be able to inhibit this growth.

    30. All of this takes time and effort with no guarantee that you will be able to develop a therapeutic antibody that successfully treats a disease.  I consider that you would need to be very committed to developing an antibody therapeutic to carry out all the necessary validation steps.  To succeed it would be necessary not only to be well researched but also to have some luck that the target you have selected is suitable and that clinically useful antibodies can be produced.”

25. Prof Martin’s evidence establishes that once antibodies with the desired inhibitory activity are identified their activity must be confirmed in vivo and in vitro.  While Prof Martin’s evidence establishes that producing an inhibitory antibody against a target protein requires a significant commitment of time and effort, it does not suggest that the person skilled in the art would have to go beyond routine experimentation in order to produce the inhibitory antibodies within Daiichi’s claims on the basis of the WO’042 disclosure. 

26. I am satisfied that the evidence as a whole establishes that in seeking to develop new compounds to inhibit or prevent abnormal bone metabolism, the person skilled in the art would, as a matter of routine, first identify a potential target; conduct validatory experiments to confirm its role in bone metabolism and determine the appropriate targeting strategy; before proceeding to prepare inhibitors.  Furthermore, that in the case of inhibitory antibodies, antibodies generated against the validated target must be screened to identify those with inhibitory activity and this effect confirmed in vivo.  The evidence establishes that the manner and sequence in which these steps are carried out and the techniques used (where not explicitly disclosed by WO’042) are routine in the art. 

    Obviousness

27. In differentiating what is “obvious” or alternatively “worthwhile to try”, the majority in AB Hässle at [58] found that:

    “The tracing of a course of action which was complex and detailed, as well as laborious, with a good deal of trial and error, with dead ends and the retracing of steps is not the taking of routine steps to which the hypothetical formulator was taken as a matter of course.  In In re Farbenindustrie AG’s Patents [(1930) 47 RPC 289 at 322], Maugham J had said that while “mere verification is not invention”, what he likened to the citadel of invention:

    “may be captured either by a brilliant coup-de-main or by a slow and laborious approach by sap and mine according to the rules of the art; the reward is the same”.”

28. Similarly, in AB Hässle at [74], the High Court quoted Judge Rich In re O'Farrell 853 F 2d 894 at 903 (1988):

    “[F]or many inventions that seem quite obvious, there is no absolute predictability of success until the invention is reduced to practice.  There is always at least a possibility of unexpected results, that would then provide an objective basis for showing that the invention, although apparently obvious, was in law nonobvious.”

29. Daiichi submitted that, as in AB Hässle at [58], the citadel had not been captured by Alethia in WO’042. It argued that making inhibitory antibodies is a “complex, long and laborious process involving retracing of steps and dead ends etc.”, and that the uncertainty of success described by the High Court mirrors the practical reality in this case. However, the evidence adduced in this opposition does not support Daiichi’s view of the matter. Additionally, although Daiichi is in a unique position to do so, it adduced no evidence whatsoever regarding any difficulties, dead ends, or unexpected results it encountered in producing inhibitory antibodies to Siglec-15.

30. Daiichi submitted that its opposed specification contains extensive validation of the function and target, which is not present in WO’042.  Nevertheless, based on the evidence before me, I can only conclude that Daiichi has merely verified Alethia’s earlier work in WO’042 in order to produce the Siglec-15 antibodies it now claims. 

31. On this basis, I find that where they are not explicitly disclosed by WO’042, the steps required to proceed from that disclosure to the Siglec-15 inhibitory antibodies of claims 1-2 are of a routine nature, which the person skilled in the art would directly be led as a matter of course to try, in the expectation that it might well produce a useful alternative or better drug than the existing agents for the treatment of bone metabolism disorders.   

1. Regarding the dependent claims, Dr Dunstan’s evidence stands uncontested by Daiichi’s experts. 

2. Dependent claims 3-5 further define the antibody or fragment by way of its functional activity in inhibiting osteoclast fusion, TNFa-induced osteoclast formation, or osteoclastic bone resorption, respectively, which Dr Dunstan identifies as an inevitable consequence of inhibiting osteoclast differentiation (Dunstan#1 at [33]-[35]).  Dependent claims 6-10 further define the effective concentration of the antibody or fragment, which Dr Dunstan considers entirely expected of inhibitory antibodies (Dunstan#1 at [36]).  Regarding the methods defined by claims 11-12 for obtaining the antibodies or fragments of the earlier claims, Dr Dunstan considers the strategy of first producing the antibodies then screening for activity disclosed by WO’042 is routine in the art (Dunstan#1 at [37]).  Claim 13 requires the antibody or fragment to be monoclonal, which Dr Dunstan states is well known in the art (Dunstan#1 at [38]).  Claims 17‑22 further specify the antibodies as chimeric, humanised, human, IgG, or Fab, F(ab)2, Fab’, Fv or scFv fragments, all of which are identified by Dr Dunstan as routine modifications at the priority date (Dunstan#1 at [40]).  It is reasonable to conclude that the embodiments of claims 3-13 and 17-22 would be arrived at by routine steps.

3. The antibodies or fragments of claims 14 and 15 are required to have the same epitope specificity or to compete, respectively, with the antibodies produced by the specified hybridoma cell lines.  Doctor Dunstan acknowledges that Daiichi’s hybridoma antibodies were the most effective inhibitors of osteoclast formation (Dunstan#1 at [39]).  I infer from this that these monoclonal antibodies bind epitopes relevant to the biological activity of Siglec-15 in osteoclast formation.  I have found above that in the process of preparing an antibody inhibitor of Siglec-15, the person skilled in the art would screen anti-Siglec-15 antibodies to identify those with the required inhibitory activity.  The evidence establishes that antibodies binding to the same epitope can be expected to exhibit similar functional activity (Mackay#2 at [38]).  On this basis, it is reasonable to conclude that in screening for inhibitory antibodies in an antibody pool, the person skilled in the art would, as a matter of course, identify those that bind the same epitope as, or which would compete for binding with, the monoclonal antibodies produced by Daiichi’s deposited hybridomas. 

4. Claims 23-28 relate to pharmaceutical compositions comprising the antibodies or fragments of the earlier claims, optionally together with other agents and/or for treating specified conditions.  Most relevantly, Dr Dunstan’s evidence (Dunstan#1 at [41]-[44]) establishes that:

   ·    it was well known in the art how to prepare an antibody or fragment in the form of a composition suitable for human administration as required by claims 23-24;

   ·     that the additional agents in the pharmaceutical compositions of claim 25 were known to be used in the context of abnormal bone metabolism; and

   ·    the disorders listed in claims 26-28 were well known to result from some sort of abnormality in bone metabolism.

   It is reasonable to conclude that the embodiments defined by claims 23-28 would be arrived at by routine steps.

5. Furthermore, Dr Dunstan can see nothing new in claims 29-33, which he considers to simply repeat the subject matter of claims 24-28 (Dunstan#1 at [44]).  Claims 29 and 31-33 relate to methods of treating and/or preventing abnormal bone metabolism by administering at least one of the antibodies or fragments according claims 1-22, optionally with other agents and/or for treating specified conditions.  Claim 30, is a ‘Swiss’ claim to the use of the antibodies or fragments in the manufacture of a medicament for treating and/or preventing abnormal bone metabolism.  I am satisfied that it would be a matter of routine for the skilled person to apply the antibodies of the earlier claims in the methods and use defined by claims 29-33.

6. Claim 35 defines the subject matter of the earlier claims by reference to the Example and/or Figures.  I see no reason to distinguish this claim.

7. Insofar as claims 1-15, 17-33 and claim 35 encompasses inhibitory antibodies and associated pharmaceutical compositions and therapeutic/preventative methods, defined broadly in terms of the binding specificity with respect to the polypeptides or partial polypeptides of SEQ ID NOs: 2 or 4 or variants thereof; or encoded by the nucleotide sequences of SEQ ID NOs: 1, 3, 19 and 43 and variants thereof, I find the subject matter of these claims lacks an inventive step.

   Clarity

8. Subsection 40(3) of the Act requires that that claim or claims of a specification are clear. A claim is lacking in clarity if a third party could not ascertain whether an act would fall within the scope of the claim (Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59 at 60). However, a claim does not lack clarity because it uses inexact language or is difficult to construe, as long as it provides a “workable standard” suitable to the intended use (Minnesota Mining [1980] HCA 9 at [46], (1980) 144 CLR 253 at 274).

9. Alethia opposed claims 1, 2, 14 and 15 for lack of clarity.  I have addressed Alethia’s submissions under this ground in construing the claims and I have been able to give them a meaning. 

10. Alethia has not established that any claim is not clear.

    Fair basis

11. Subsection 40(3) requires that the claim or claims in a patent specification be fairly based on the matter described in the specification. As the test for fair basis, the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (Lockwood) [2004] HCA 58 at [69]; [2004] HCA 58; (2004) 217 CLR 274 at 300 [69] approved the words of Gummow J in Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 at 95:

    “... the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification.”

12. Alethia’s submissions that claims 1-2, 14-15 are not fairly based substantially reiterate those used to justify a lack of clarity in the claims. 

    Claims 1 and 2

13. For claims 1 and 2, Alethia’s submissions are moot, that the opposed application does not provide a suitable explanation of how a relevant antibody can be made where it binds to a protein with no structural resemblance to Siglec-15, since I have found above that the claims do not encompass this subject matter.  Alethia has forwarded no submissions to the effect that the specification does not provide a real and reasonably clear disclosure of the invention of claims 1 and 2, properly construed. 

    Claim 14

14. Alethia submitted that claim 14 lacks fair basis because it encompasses any antibody which inhibits osteoclast formation and/or osteoclastic bone resorption and which happens to bind to the same epitope to which the antibodies produced by hybridomas #32A1 or #41B1 bind, since the body of the specification does not identify the relevant epitopes. 

15. A consistory clause for claim 14 appears on page 11, lines 16-19 of the opposed specification.  Furthermore, a means for identifying antibodies with the same epitope specificity is provided on page 25 last para to page 26, line 18 of the opposed specification:

    “The term “epitope” as used herein refers to a partial peptide of Siglec-15 to which a specific anti-Siglec-15 antibody binds.  The above-mentioned epitope which is a partial peptide of Siglec-15 can be determined by methods well known to those skilled in the art such as an immunoassay.  Alternatively, for example, the following method can be employed.  Various partial structures of Siglec-15 are produced. In the production of the partial structures, a known oligopeptide synthesis technique can be used.  For example, a series of polypeptides having appropriately reduced lengths obtained by sequentially shortening Siglec-15 from the C terminus or N terminus are produced using a genetic recombination technique known to those skilled in the art.  Thereafter, the reactivity of an antibody against these polypeptides is examined and a recognition site is roughly determined.  Then, peptides having shorter lengths are synthesized and the reactivity with these peptides is examined, whereby the epitope can be determined. 

    If a second anti-Siglec-15 antibody binds to a partial peptide to which a first anti-Siglec-15 antibody binds, it can be determined that the first antibody and the second antibody share the same epitope.”

16. The opposed specification does not explicitly disclose the epitopes bound by the antibodies produced by hybridomas #32A1 and #41B1.  However, in the above disclosure, the opposed specification provides a method of determining the Siglec-15 epitope to which the #32A1 and #41B1 monoclonal antibodies bind and instructs the reader that the Siglec-15 partial peptides defining these epitopes can then be used to identify other antibodies binding the same epitope.  Professor Mackay states that antibodies binding the same epitope can be expected to have the same functional activity, although the degree of activity may vary (Mackay#2 at [49]).  Doctor Dunstan does not dispute this aspect of Prof Mackay’s evidence. 

17. I am satisfied that in the above disclosure, the opposed specification provides a real and reasonably clear disclosure of the antibodies encompassed by claim 14. 

    Claim 15

18. Alethia submitted that claim 15 lacks fair basis because the opposed specification provides no description of any antibodies which have been made or isolated by virtue of their competition with the antibodies produced by hybridomas #32A1 or #41B1.

19. A consistory clause for claim 15 appears on page 11, lines 20-22.  At page 26, line 18 to page 27, line 3), the opposed specification states:

    “… by confirming that the second anti-Siglec-15 antibody competes with the first anti-Siglec-15 antibody for the binding to Siglec-15 (that is,  the second antibody inhibits the binding between Siglec-15 and the first antibody), it can be determined that the first antibody and the second antibody share the same epitope even if the specific epitope sequence has not been determined.  Further, when the first antibody and the second antibody bind to the same epitope and also the first antibody has a special effect such as an antigen-neutralizing activity, the second antibody can be expected to have the same activity.”

20. Commenting on that paragraph, Prof Mackay states that it would only be under exceptional circumstances where an antibody that competitively binds to the same or an overlapping epitope (even if the epitope sequence was not determined) would not exhibit similar functional characteristics, although the degree of functional activity may vary (Mackay#2 at [49]).  Doctor Dunstan adds that the second antibody may bind a distinct epitope, and still physically occlude the epitope of the first (Dunstan#2 at [32]). 

21. At least in the consistory clause and the paragraph reproduced above, the opposed specification contains a real and reasonably clear disclosure of a method for identifying competitive antibodies within the scope of claim 15.  It is not necessary that they are disclosed as having, in fact, been made.   

    Useful

22. Subsection 18(1) of the Act requires that the invention, so far as claimed in any claim, is useful. The requirements for utility in a claimed invention under section 18(1)(c) were provided by the Full Court of the Federal Court as follows:

    “If the claimed invention does what it is intended by the patentee to do and the end result obtained is itself useful, the invention is useful within the meaning of s 18(1)(c) … As to the first aspect, the invention as claimed must attain the result promised by the patentee”  (Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC [2008] FCAFC 82 at [141]; 77 IPR 449)

    “A claim is bad if it covers means that will not produce the desired result, even if a skilled person would know which means to avoid.  That is to say, everything that is within the scope of a claim must be useful, otherwise the claim will fail for inutility.” (H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at [81], [217]; 81 IPR 228)

23. In summary, Alethia’s submissions under this ground are that claim 1 is not useful because antibodies binding to a polypeptide sequence defined in terms of para (i) of the claim encompasses antibodies and fragments that bind to a protein having “no sequence similarity to any known functional protein” which would not have the required therapeutic effect. 

24. I have construed claim 1 above to define inhibitory antibodies that necessarily bind epitope(s) that are relevant to the biological activity of the Siglec-15 polypeptides and variants in osteoclast formation and/or osteoclastic bone resorption and inhibit this activity.  Consequently, this ground of opposition fails. 

    Conclusion

25. The opposition is successful.  Claims 1-15, 17-33 and 35 lack an inventive step.  

26. It is possible to overcome this deficiency by amendment of the claims.  I therefore allow Daiichi 2 months from the date of this decision to propose such amendments.

    Costs

27. It is usual in proceedings before the Commissioner that costs follow the event.  I see no reason to depart from the normal award of costs.  I award costs according to Schedule 8 against Daiichi Sankyo Company, Limited.

    Barbara Akhurst
    Delegate of the Commissioner of Patents

    Annex A: The opposed claims

    1. An antibody which specifically recognizes one or more polypeptides comprising an amino acid sequence described in any one of the following (a) to (i) and inhibits osteoclast formation and/or osteoclastic bone resorption, or a functional fragment of the antibody:

    (a)   an amino acid sequence represented by SEQ ID NO: 2 in the Sequence Listing;

    (b)   an amino acid sequence consisting of amino acid residues 21 to 328 of the amino acid sequence represented by SEQ ID NO: 2 in the Sequence Listing;

    (c)   an amino acid sequence consisting of amino acid residues 1 to 260 of the amino acid sequence represented by SEQ ID NO: 2 in the Sequence Listing;

    (d)   an amino acid sequence consisting of amino acid residues 21 to 260 of the amino acid sequence represented by SEQ ID NO: 2 in the Sequence Listing;

    (e)   an amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing;

    (f)    an amino acid sequence consisting of amino acid residues 21 to 341 of the amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing;

    (g)   an amino acid sequence consisting of amino acid residues 1 to 258 of the amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing;

    (h)   an amino acid sequence consisting of amino acid residues 21 to 258 of the amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing; and

    (i)    an amino acid sequence including substitution, deletion or addition of one or several amino acid residues in the amino acid sequence described in (a) to (h).

    2.    An antibody which specifically recognizes one or more polypeptides comprising an amino acid sequence encoded by a nucleotide sequence described in any one of the following (j) to (n) and inhibits osteoclast formation and/or osteoclastic bone resorption, or a functional fragment of the antibody:

    (j)    a nucleotide sequence represented by SEQ ID NO: 1;

    (k)   a nucleotide sequence represented by SEQ ID NO: 3;

    (1)   a nucleotide sequence represented by SEQ ID NO: 19;

    (m) a nucleotide sequence represented by SEQ ID NO: 43; and

    (n)   a nucleotide sequence of a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to the nucleotide sequence described in ( j ) to (m) under stringent conditions wherein the polynucleotide encodes a polypeptide having a biological activity comparable to that of a polypeptide encoded by a nucleotide sequence described in (j) to (m).

    3. The antibody or a functional fragment of the antibody according to claim 1 or 2 which inhibits the process of cell fusion of osteoclasts.

    4. The antibody or a functional fragment of the antibody according to any one of claims 1 to 3 which inhibits osteoclast formation induced by TFN-a [sic].

    5.The antibody or a functional fragment of the antibody according to any one of claims 1 to 4 which inhibits osteoclastic bone resorption.

    6. The antibody or functional fragment of the antibody according to any one of claims 1 to 4 which inhibits in vitro osteoclast formation at a concentration of 30 μg/ml or less.

    7.The antibody or a functional fragment of the antibody according to claim 5 which inhibits in vitro osteoclast formation or in vitro osteoclastic bone resorption at a concentration of 3 μg/ml or less.

    8. The antibody or a functional fragment of the antibody according to claim 7 which inhibits in vitro osteoclast formation at a concentration of 1 μg/ml or less.

    9. The antibody or a functional fragment of the antibody according to claim 8 which inhibits in vitro osteoclast formation at a concentration of from 63 ng/ml to 1 μg/ml.

    10.The antibody or a functional fragment of the antibody according to claim 7 which inhibits in vitro osteoclastic bone resorption at a concentration of from 0. 3 μg/ml to 3 μg/ml.

    11. The antibody or a functional fragment of the antibody according to any one of claims 1 to 10 which is obtained by a method comprising the following steps 1) and 2):

    1) a step of producing an antibody which specifically recognizes one or more polypeptides comprising an amino acid sequence described in any one of the following (a) to (i) :

    (a) an amino acid sequence represented by SEQ ID NO: 2 in the Sequence Listing:

    (b) an amino acid sequence consisting of amino acid residues 21 to 328 of the amino acid sequence represented by SEQ ID NO: 2 in the Sequence Listing;

    (c) an amino acid sequence consisting of amino acid residues 1 to 260 of the amino acid sequence represented by SEQ ID NO: 2 in the Sequence Listing;

    (d) an amino acid sequence consisting of amino acid residues 21 to 260 of the amino acid sequence represented by SEQ ID NO: 2 in the Sequence Listing;

    (e) an amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing;

    (f) an amino acid sequence consisting of amino acid residues 21 to 341 of the amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing;

    (g) an amino acid sequence consisting of amino acid residues 1 to 258 of the amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing;

    (h) an amino acid sequence consisting of amino acid residues 21 to 258 of the amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing; and

    (i) an amino acid sequence including substitution, deletion or addition of one or several amino acid residues in the amino acid sequence described in (a) to (h); and

    2) a step of screening an antibody which exhibits an inhibitory activity against osteoclast formation and/or an inhibitory citivity [sic] against bone resorption.

    12. The antibody or a functional fragment of the antibody according to any one of claims 1 to 10 which is obtained by a method comprising the following steps 1) and 2):

    1) a step of producing an antibody which specifically recognizes one or more polypeptides comprising an amino acid sequence encoded by a nucleotide sequence described in any one of the following ( j ) to (n)

    (j) a nucleotide sequence represented by SEQ ID NO: 1;

    (k) a nucleotide sequence represented by SEQ ID NO: 3;

    (1) a nucleotide sequence represented by SEQ ID NO: 19;

    (m) a nucleotide sequence represented by SEQ ID NO: 43; and

    (n) a nucleotide sequence of a polynucleotide which hybridizes to a polynucleotide comprising a nucleotide sequence complementary to the nucleotide sequence described in (j) to (m) under stringent conditions; and

    2) a step of screening an antibody which exhibits an inhibitory activity against osteoclast formation and/or an inhibitory activity against bone resorption.

    13.The antibody or a functional fragment of the antibody according to any one of claims 1 to 12, wherein the antibody is a monoclonal antibody.

    14.The antibody or a functional fragment of the antibody according to claim 13, wherein the antibody or functional fragment thereof has the same epitope specificity as an antibody produced by hybridoma #32A1 (FERM BP-10999), or hybridoma #41B1 (FERMBP-11000).

    15.The antibody or a functional fragment of the antibody according to claim 13, wherein the antibody or functional fragment thereof competes with an antibody produced by hybridoma #32A1 (FERM BP-10999), or hybridoma #41B1 (FERMBP-11000).

    16.The antibody or a functional fragment of the antibody according to claim 14, wherein the antibody or functional fragment thereof is an antibody produced by hybridoma #32Al (FERM BP-10999), or hybridoma #41Bl (FERMBP-11000).

    17. The antibody or a functional fragment of the antibody according to any one of claims 1 to 16, wherein the antibody or functional fragment thereof is a chimeric antibody.

    18.The antibody or a functional fragment of the antibody according to any one of claims 1 to 17, wherein the antibody or functional fragment thereof is humanized.

    19.The antibody or a functional fragment of the antibody according to any one of claims 1 to 15, wherein the antibody or functional fragment of the antibody is a human antibody.

    20.The antibody or a functional fragment of the antibody according to any one of claims 1 to 19, wherein the antibody or functional fragment thereof is an IgG antibody.

    21.The functional fragment of the antibody according to any one of claims 1 to 20 which is selected from the group consisting of Fab, F(ab')2, Fab' and Fv.

    22.The antibody according to any one of claims 1 to 15, wherein the antibody is an scFv.

    23.A pharmaceutical composition which comprises at least one of the antibodies or functional antibodies according to claims 1 to 22.

    24.The pharmaceutical composition according to claim 23, which is a therapeutic and/or preventive agent for abnormal bone metabolism.

    25.A pharmaceutical composition for treating and/or preventing abnormal bone metabolism which comprises at least one of the antibodies or functional fragments of the antibodies according to claims 1 to 22 and at least one member selected from the group consisting of bisphosphonates, active vitamin D3 , calcitonin and derivatives thereof, hormone preparations such as estradiol, SERMs (selective estrogen receptor modulators), ipriflavone, vitamin K2 (menatetrenone) , calcium preparations, PTH (parathyroid hormone) preparations, nonsteroidal anti-inflammatory agents, soluble TNF receptor preparations, anti-TNF-cx antibodies or functional fragments of the antibodies, anti-PTHrP (parathyroid hormone-related protein) antibodies or functional fragments of the antibodies, IL-1 receptor antagonists, anti-IL-6 receptor antibodies or functional fragments of the antibodies, anti-RANKL antibodies or functional fragments of the antibodies and OCIF (osteoclastogenesis inhibitory factor).

    26.The pharmaceutical composition according to claim 24 or 25, wherein the abnormal bone metabolism is selected from the group consisting of osteoporosis, bone destruction accompanying rheumatoid arthritis, cancerous hypercalcemia, bone destruction accompanying multiple myeloma or cancer metastasis to bone, giant cell tumor, tooth loss due to periodontitis, osteolysis around a prosthetic joint, bone destruction in chronic osteomyelitis, Paget's disease of bone, renal osteodystrophy and osteogenesis imperfecta.

    27.The pharmaceutical composition according to claim 26, wherein the abnormal bone metabolism is osteoporosis, bone destruction accompanying rheumatoid arthritis or bone destruction accompanying cancer metastasis to bone.

    28.The pharmaceutical composition according to claim 27, wherein the osteoporosis is postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis due to the use of a therapeutic agent such as a steroid or an immunosuppressant, or osteoporosis accompanying rheumatoid arthritis.

    29.A method of treating and/or preventing abnormal bone metabolism wherein the method comprises administering at least one of the antibodies or functional fragments of the antibodies according to claims 1 to 22.

    30.Use of at least one of the antibodies or functional fragments of the antibodies according to claims 1 to 22 for the manufacture of a medicament for treating and/or preventing abnormal bone metabolism.

    31.A method of treating and/or preventing abnormal bone metabolism wherein the method comprises simultaneously or successively administering at least one of the antibodies or functional fragments of the antibodies according to claims 1 to 22 and at least one member selected from the group consisting of bisphosphonates, active vitamin D3, calcitonin and derivatives thereof, hormone preparations such as estradiol, SERMs (selective estrogen receptor modulators), ipriflavone, vitamin K2 (menatetrenone), calcium preparations, PTH (parathyroid hormone) preparations, nonsteroidal anti-inflammatory agents, soluble TNF receptor preparations, anti-TNF‑a antibodies or functional fragments of the antibodies, anti-PTHrP (parathyroid hormone-related protein) antibodies or functional fragments of the antibodies, IL-1 receptor antagonists, anti-IL-6 receptor antibodies or functional fragments of the antibodies, anti-RANKL antibodies or functional fragments of the antibodies and OCIF (osteoclastogenesis inhibitory factor).

    32. The treatment and/or prevention method according to claim 29 or 31 or the use according to claim 30, wherein the abnormal bone metabolism is osteoporosis, bone destruction accompanying rheumatoid arthritis or bone destruction accompanying cancer metastasis to bone.

    33.The treatment and/or prevention method or use according to claim 32, wherein the osteoporosis is postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis due to the use of a therapeutic agent such as a steroid or an immunosuppressant, or osteoporosis accompanying rheumatoid arthritis.

    34.The hybridoma #32Al (FERM BP-10999) or the hybridoma #41Bl (FERM BP-11000)

    35.An antibody according to any one of claims 1 to 20 or 22, or a functional fragment of an antibody according to any one of claims 3 to 21, or a pharmaceutical composition according to any one of claims 23 to 28, or a method according to any one of claims 29 or 31 to 33, or use according to claim 30 or a hybridoma according to claim 34 substantially as hereinbefore described with reference to the Examples and/or Figures.