Daiichi Sankyo Company Limited v Alethia Biotherapeutics Inc

[2015] APO 88

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Daiichi Sankyo Company Limited v Alethia Biotherapeutics Inc. [2015] APO 88

Patent Application:                   2007215334

Title:Polynucleotides and polypeptide sequences involved in the process of bone remodeling

Patent Applicant:  Alethia Biotherapeutics Inc.

Opponent:  Daiichi Sankyo Company, Limited

Delegate:  Dr B. Akhurst

Decision Date:  15 December 2015

Hearing Date:  31 July 2015 in Melbourne

Catchwords:  PATENTS - opposition to grant of a patent - full description - the process involved in performing the invention, although lengthy, is essentially routine - lack of full description not established - novelty - no clear and unmistakable directions to the invention as claimed - lack of novelty not established - inventive step – obviousness not established – opposition unsuccessful

Representation:  Patent applicant:  Clive Elliot QC instructed by Steve Gledhill of FB Rice.

Opponent:Ben Fitzpatrick of counsel, instructed by Mark Roberts and Rachel Stevenson of Davies Collison Cave.

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application:                   2007215334

Title:Polynucleotides and polypeptide sequences involved in the process of bone remodeling

Patent Applicant:  Alethia Biotherapeutics Inc.

Date of Decision:  15 December 2015

DECISION

The opposition is unsuccessful.  Subject to appeal of this decision, I direct the application proceed to grant.

I award costs according to Schedule 8 against Daiichi Sankyo Company, Limited.

REASONS FOR DECISION

Background

1. Alethia Biotherapeutics Inc. (Alethia) filed patent application 2007215334 on 13 February 2007, via the PCT, claiming priority from applications US 60/772,585 and US 60/816,858 filed on 13 February 2006 and 28 June 2006, respectively.  Alethia requested expedited examination, after which acceptance of the application was advertised on 21 November 2013. 

2. Daiichi Sankyo Company, Limited. (Daiichi) filed a notice of opposition on 21 February 2014 and a statement of grounds and particulars on 21 May 2014.  Evidence in support, answer and reply was completed on 21 August 2014, evidence in answer on 21 November 2014 and evidence in reply on 21 January 2015.  The matter was heard in Melbourne on 31 July 2015.

   The Evidence

3. Evidence in support consisted of declarations by:

   ·    Thomas John Martin (Martin#1) dated 21 August 2014 with Exhibits TJM-1 to TJM-9

   ·    Gethin Penar Thomas (Thomas) dated 20 August 2014 with Exhibits GPT-1 to GPT-17

   ·    William Gerrit Arends (Arends) dated 20 August 2014 with Exhibits WGA-1 to WGA-5

   ·    Suzanne Monica Hantos (Hantos) dated 18 August 2014 with Exhibits SMH-1 to SMH-6

4. Evidence in answer consisted of a declaration by:

   ·     Colin Dunstan (Dunstan) dated 20 November 2014 with Exhibits CD-1 to CD-8

5. Evidence in reply consisted of a declaration by:

   ·     Thomas John Martin dated 20 January 2015 (Martin#2)

   Grounds of opposition

6. The grounds of opposition pressed at the hearing were full description, or in the alternative novelty and inventive step, against Alethia’s claims featuring an antibody or or antigen binding fragment thereof that specifically binds to the Siglec-15 polypeptides or variants specified in the claims. 

   Onus of Proof

7. A request for examination in relation to the patent application was filed on 19 January 2012.  As a consequence, the substantive amendments of the Patents Act 1990 (the 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 proceeding lies with the opponent, who must establish that it is clear that a valid patent cannot be granted (F.Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [29], [67]; 50 IPR 305; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18], [22]; 79 IPR 426).

   The specification

8. 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.”

9. The opposed specification is titled “Polynucleotides and polypeptides involved in the process of bone remodeling”.  On page 1 it is stated:

   “This invention relates, in part, to newly identified genetic polynucleotides involved in the process of bone remodelling; variants and derivatives of the polynucleotides and corresponding polypeptides; uses of the polynucleotides, polypeptides, variants and derivatives; methods and compositions for the amelioration of symptoms caused by bone remodeling disorders, including but not limited to osteoporosis, … [there follows a list of additional bone disorders and other conditions that involve disordered bone remodeling].

   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 and use of the polynucleotides, polypeptides, variants and derivatives for the amelioration of disease states and research purposes, as well as in diagnosis of disease states or in the predisposition to develop same.”

10. The background to the invention is provided on pages 1-5 of the opposed specification.  In summary, bone is comprised of functionally distinct cell populations that support the structural, mechanical and biochemical integrity of bone and mineral homeostasis in the human body.  The principal cell types include osteoblasts that are responsible for bone formation, and osteoclasts that are responsible for bone resorption (bone breakdown and release of minerals).  These opposing functions contribute to the ongoing dynamic process of bone remodeling, which remains largely in equilibrium throughout the lifetime of an individual.  Any interference or imbalance in this process can produce skeletal disease, most commonly involving a net decrease in bone mass primarily caused by an increase in osteoclast number and/or activity.  The most common such disease is osteoporosis. 

11. On page 2, it is stated that bone remodeling is governed by a complex interplay of systemic and local factors.  However, since it takes place in discrete packets throughout the skeleton, locally produced hormones and enzymes may be more important than systemic hormones for the initiation of bone resorption and the normal remodeling process (page 2).  The specification discloses that many diseases linked to bone resorption are poorly understood and the treatment options suboptimal (pages 3-4).  Thus novel drugs developed on the basis of a better understanding of bone biology have the potential to change the face of treatment of bone disorders in the long term (pages 4-5).    

12. Dr Dunstan at [21] summarises the opposed specification as describing a strategy for discovering genes and proteins whose expression is upregulated during osteoclast differentiation.  He notes that the inventors used a model of osteoclast differentiation to generate subtracted libraries and identified 35 genes that are upregulated in differentiated osteoclasts in comparison to osteoclast precursors (at [21]).  The “AB0326” gene product in particular, which later became known as Siglec-15, was selected for validation as a causative factor of osteoclast differentiation (Dunstan at [20]-[21]).  For convenience, and consistent with the parties’ submissions and evidence, where the specification refers to AB0326, I have substituted Siglec-15. 

    The claims

13. 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 that 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.

14. The opposed claims are reproduced in Annex A to this decision.  Claim 1 defines an isolated antibody per se, or an antigen binding fragment thereof, having two properties.  The antibody or fragment must:  

    (i)specifically bind to a polypeptide consisting of SEQ ID NO: 48 (human Siglec-15) or SEQ ID NO: 82 (mouse Siglec-15); and

    (ii)impair an activity of the polypeptide in osteoclast precursor cells or in osteoclasts.  

15. Additional independent claims define an isolated antibody or antigen binding fragment thereof in terms of the method by which it is isolated (claim 5), methods of therapy (claim 16 and claim 28 in part), diagnostic methods (claim 32) and other investigative methods (claims 19, 38 and claim 28 in part).

16. Alethia advised at the hearing that “Swiss-style” claim 31 was incorrectly drafted as dependent on any one of claims 29-32.  However, insofar as claim 31 is presently dependent on claim 32, it encompasses the use of antibodies and antigen binding fragments thereof which specifically bind to the functionally active Siglec-15 polypeptides or variants specified in claim 32, in the manufacture of a medicament for modulating osteoclast differentiation or for treating bone diseases, bone remodelling, or bone resorption, which is subject matter opposed by Daiichi.

17. The ability of an antibody/fragment to specifically bind a target polypeptide and any functional activity the antibody may have once bound are distinct concepts, discussed further below.

    specific binding

18. A number of the opposed claims refer to an antibody or fragment thereof, which “specifically binds” to one or more specified polypeptides.  Strictly speaking “specific binding” is an absolute term meaning that the antibody/fragment binds to the specified protein, but does not bind any other protein (Martin#1 at [35], Martin#2 at [15]).  However, for practical purposes, the term is understood as a relative measure describing the property of an antibody binding to a given protein with significant selectivity when compared to other proteins (Dunstan at [49], Martin#2 at [15]).  Professor Martin summarises the situation as follows:

    “If no statistically significant competition for binding can be shown with any other tested agent, or if none of a number of alternative labelled ligands can bind, then that is specific binding.  Of course this can never exclude the possibility that something that has not been tested will bind.” (Martin#2 at [15])

19. Thus, claim 1 defines an antibody or fragment which binds the specified Siglec-15 polypeptides with significant selectivity in comparison to other proteins.  

    functional activity of the antibody or fragment

20. In the context of this opposition, the functional activity of an antibody or fragment relates to its ability to inhibit (antagonise or neutralise) or otherwise modulate the activity of the target polypeptide to which it is bound, as discussed below. 

    Claims 1, 4-5, 16, 19

21. Claim 1 requires that the antibody or fragment “impairs an activity of the polypeptide in osteoclast precursor cells or in osteoclasts”.  Construction of this phrase to mean that the antibody/fragment is capable of inhibiting the production of mature osteoclasts and/or inhibits the ability of mature osteoclasts to resorb bone, is consistent with Prof. Martin’s evidence (#1 at [36]) that there to are two measurable elements falling within this definition:

    (i)the impairment or reduction of the ability of osteoclast precursor cells to proceed through differentiation to mature osteoclasts; and

    (ii)the impairment or reduction of the ability of mature osteoclasts to resorb bone.

22. The requirement in claim 4 that the antibody or fragment “reduces differentiation of osteoclast precursor cells into osteoclasts” is consistent with the definition at (i) above (Martin#1 at [37]).  In claim 5, the phrase “which impairs osteoclastogenesis” has the same meaning (Martin#1 at [37]).

23. Claim 16 defines a method for treating bone remodeling, bone resorption or bone disease comprising administering to a subject in need, an antibody or antigen binding fragment thereof which specifically binds to a polypeptide consisting of SEQ ID NOs: 48 or 82 (human and mouse Siglec-15, respectively).  The requirement that the antibody or fragment ‘treat’ these conditions imposes the requirement for functionally active antibodies/fragments capable of modulating the activity of the specified Siglec-15 polypeptides, such that a condition encompassed by the terms bone remodeling, bone resorption or bone disease can be treated.

24. Relevant to the opposed subject matter, claim 19 construed in light of dependent claim 24, encompasses a method for identifying an antibody or antigen binding fragment thereof able to inhibit osteoclast differentiation. 

    Claims 32 and 38

25. The antibodies or antigen binding fragments defined in claim 32 must specifically bind to a Siglec-15 polypeptide or variant or fragments thereof, which polypeptide is capable of modulating osteoclast differentiation.  However, consistent with their use in diagnosis, claim 32 does not require the antibodies or antigen binding fragments to have any modulatory activity with respect to the polypeptides, variants or fragments.  Similarly, claim 38 does not require the antibody or antigen binding fragment to have any functional activity.

    Full description

    The Law

26. Section 40(2)(a) requires that a complete specification must describe the invention fully, including the best method known to the applicant of performing the invention.  The “invention” in section 40 is “the embodiment which is described, and around which the claims are drawn” (Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (Kimberly-Clark) [2001] HCA 8 at [21], (2001) 207 CLR 1 at [21]).

1. In Kimberly-Clark at [25], the High Court provided the test for full description:

   “The question is, will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty?”

2. In assessing sufficiency, the complete specification is not to be read in the abstract; it is to be construed in the light of the common general knowledge and the art before the priority date; the court is to place itself “in the position of some person acquainted with the surrounding circumstances as to the state of art and manufacture at the time” (Kimberly-Clark at [24]).

3. A specification is not insufficient merely because some experiment of a routine character is necessary in the particular case (SNF (Australia) Pty Ltd v Ciba Specialty Chemicals Water Treatments Limited [2012] FCAFC 95 at [381]). Furthermore, whether the addressee works out the particulars of how to perform the invention in a given situation by a process of extrapolation or by “standard testing” is not to the point so long as the addressee is able to do so (PhotoCure ASA v Queen’s University at Kingston (Photocure) [2005] FCA 344 at [106], (2005) 216 ALR 41 at [106]).

   The expert evidence

4. It should be noted that of the experts, only Professor Martin and Dr Dunstan provide evidence directly regarding the opposed specification.  Dr Thomas’s evidence is more general in nature and relates to the technical knowledge in the field of bone biology before the priority date (Thomas at [1]-[3]). 

   Submissions

5. Daiichi submitted that the complete specification does not fully describe the invention of claims 1-19, 28, 31-32 and 36-38 because it does not sufficiently enable an antibody that is capable of inhibiting the activity of Siglec-15 in osteoclast precursor cells or osteoclasts.  Daiichi submitted that the opposed specification identifies the Siglec-15 nucleotide sequence as a potential target for a therapeutic agent, which is properly characterised is a starting point for a research programme.  It argued that the generation of an isolated antibody or antigen binding fragment thereof that impairs an activity of a polypeptide in its cellular environment, and has the potential to be of therapeutic use in humans, is a long, complex and uncertain process, involving many steps and with no guarantee of ultimate success.

6. Alethia responded that the law in Australia has never demanded a guarantee of success.  It argued that what is relevant for sufficiency is the nature and extent of any additional work involved and the time taken to reach and workable prototype of the invention.

   The disclosure of the opposed specification relevant to antibodies

7. Among others, the opposed specification discloses the polynucleotide and polypeptide sequences of human Siglec-15 in SEQ ID NOs: 1 and 48, respectively (Table 1).  The mouse Siglec-15 polynucleotide and polypeptide are represented by SEQ ID NOs: 35 and 82, respectively (Table 3).

8. Most relevant to the opposed subject matter, on pages 33-34 of the specification the invention is said to relate to an antibody or antigen-binding fragment thereof, that specifically binds to a protein/polypeptide described in the specification.  The antibody may be monoclonal, polyclonal, humanised or human, chimeric and/or generated using recombinant DNA technologies, and it may further comprise a detectable label (page 34).  It may originate from a mouse, rat or any other mammal, or from a transgenic non-human mammal capable of expressing human immunoglobulin genes (page 34).  Suitable antibodies may include antigen binding fragments, Fab, F(ab')₂ and Fv fragments, or a single-chain antibody comprising an antigen-binding fragment (page 34).  The antibodies may be mutated and selected based on increased affinity and/or specificity for a polypeptide described in the specification, and/or based on reduced immunogenicity in a desired host (page 34). 

9. On pages 34-35 of the opposed specification, the invention further relates to methods of producing specific antibodies to the polypeptides, which methods are broadly described between pages 35-40.  The method may involve immunisation of a mammal with the polypeptide, optionally producing a hybridoma, and isolating and selecting antibodies based on their binding specificity (pages 34-35).  Alternatively, antibodies may be produced by synthesising an antibody library on phage or ribosomes, isolating those that bind to the polypeptide and obtaining an antibody from the phage or ribosomes (pages 35-36).  The opposed specification 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).  Methods for humanisation are broadly summarised on pages 38-40.  On pages 40-41, the antibodies obtained by the methods described may be useful for investigative or diagnostic purposes. 

1. On page 37, it is stated that neutralising antibodies are especially preferred for therapeutic use.  Between pages 42-45, the opposed specification broadly discloses methods for identifying inhibitory compounds (inhibitors, antagonists) able to impair, relevantly, the function or activity of the disclosed polypeptides and analogs thereof, and in particular a reduced ability of the polypeptide to inhibit or promote osteoclast differentiation.  

2. Example I of the opposed specification, titled “RNA interference Studies”, describes the principles involved in the use of interfering RNA (RNAi, also known as antisense RNA) to produce a sequence-specific decrease in gene expression in a cell by targeting endogenously expressed mRNA for degradation (pages 81-82).  On pages 82-83, Example J titled “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.  When treated with RANKL in the presence of M-CSF, osteoclast precursor cells with shRNA-attenuated Siglec-15 showed a significant decrease in the number differentiating to multinucleated osteoclasts in comparison to controls (page 83).  Example K is titled “Biological validation of the mouse orthologue for [Siglec-15] (SEQ ID. NO. 35) in osteoclastogenesis using the RAW 264.7 model”.  On page 83, the mouse-derived RAW 264.7 (RAW) osteoclast precursor cell line is “well known in the art as a murine model of osteoclastogenesis”.  Example K discloses the preparation of RAW cells stably transfected with shRNA under the control of a constitutive promoter to knockdown endogenous expression of the mouse Siglec-15 gene.  When treated with M-CSF and RANKL to induce differentiation to osteoclasts, these Siglec-15-attenuated RAW cells produced significantly less osteoclasts than controls.  On page 84 the conclusion is drawn that the results in Examples J and K demonstrate that, in both human and mouse, the Siglec-15 gene product (i.e. the encoded protein) is clearly required for osteoclastogenesis.

3. Example L is titled “A functional complementation assay for SEQ. ID. NO. 1 ([Siglec-15]) in RAW 264.6 [sic] cells to screen for inhibitors of osteoclastogenesis” and discloses the cells of Example K (with shRNA-attenuated mouse Siglec-15 expression) being ‘rescued’ by constitutive expression of human Siglec-15, thereby restoring their ability to differentiate into osteoclasts.  On page 85, the conclusion is drawn that the mouse and human Siglec-15 gene sequences are functionally conserved in osteoclast differentiation.  Example L concludes with the statement that this type of cell-based assay can be used as a screening assay to identify compounds capable of binding to and inhibiting the function of human Siglec-15, and further that:

   “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 [tartrate-resistant acid phosphatase, an osteoclast-specific marker] would be indicative of a decrease in human [Siglec-15] activity.” (emphasis added)

4. The question is whether the disclosure of the complete specification is sufficient to enable the skilled addressee of the specification to produce the antibodies featured in the claims, without new inventions or additions or prolonged study of matters presenting initial difficulty.

   Validating the target

5. The evidence establishes that the first step in developing a new therapeutic antibody against a potential target molecule is to validate the target, in terms of its cellular location and its functional role (Martin#1 at [18], [21]; Thomas at [18]-[20]; Dunstan at [15]). 

6. Dr Dunstan understands the opposed specification to provide robust data and a convincing validation of Siglec-15 as a therapeutic target for treatment requiring the inhibition of osteoclasts (at [22]).  Professor Martin disagrees (#1 at [32]-[33]; #2 at [5]-[7]), but in any event he would conduct validation studies of his own prior to embarking on developing a therapeutic agent against a target (#1 at [18]).  Dr Thomas would validate a target identified from the literature (at [18]). 

7. In summary, one expert considers Siglec-15 a validated target, while two would conduct validation studies on a potential target identified from the literature.  The means for determining the cellular location of a target protein and its functional activity are discussed further below.

   Cellular location

8. Daiichi submitted that a conclusive disclosure of the cellular location of Siglec-15 is necessary to enable the skilled addressee to determine if a therapeutic antibody could be prepared to the protein.  Responding, Alethia submitted that the opposed specification clearly indicates that Siglec-15 is a cell surface protein and that the sequence information provided gives a clear demonstration that it is on the cell surface and could be used to predict extracellular regions.  Alethia also submitted at the hearing that the Siglec-15-expressing osteoclasts disclosed in the specification could be used to confirm that Siglec-15 was accessible for antibody binding

9. When setting out to make inhibitory antibodies, the cellular location of the target is an important consideration; soluble or cell surface proteins are more readily accessible for interaction with an antibody (Martin#1 at [21]-[22]; Thomas at [20]; Dunstan at [15]).  In Table 1, the opposed specification states the function of human Siglec-15 as “hypothetical protein LOC284266; membrane associated function unknown”.  In Table 3, the open reading frame of mouse Siglec-15 is stated to be “similar to neural cell adhesion molecule 2”.  While Alethia argued that these designations are suggestive, the opposed specification does not explicitly disclose Siglec-15 as a cell surface protein, with an extracellular domain available for antibody binding. 

10. Relevant to an implicit disclosure, in view of the reference to inhibitory antibodies in the opposed specification, Dr Dunstan at [29] considers it clear that the authors were convinced that Siglec-15 is a cell-surface protein.  In any event, Dr Dunstan states that the Siglec-15 polynucleotide and polypeptide sequences provided can be used to make reasonable predictions of any functional domains, structural domains and extracellular regions, facilitating its identification as a cell surface protein (at [17], [24]).  Professor Martin does not dispute these aspects of Dr Dunstan’s evidence, and Dr Thomas does not address them.

11. Furthermore, Alethia’s submission that the Siglec-15-expressing osteoclasts disclosed in the specification could be used to confirm that Siglec-15 was accessible for antibody binding, is not inconsistent with Dr Thomas’s evidence at [21] that, where inhibition was required, he would seek to develop an antibody against the target in order to validate it as suitable for therapeutic intervention. 

12. On balance, I am satisfied that if the skilled addressee was not convinced by the disclosure of the opposed specification that Siglec-15 was a cell surface protein or otherwise accessible for antibody binding, the skilled addressee could either predict this information from the sequence information provided or determine it experimentally based on the information provided in the opposed specification.

    Functional role of the target

13. In order to validate a potential target gene, Dr Thomas would have investigated its expression in rodent bone, undertaken cell differentiation analysis and may also have analysed the target in cell lines and primary bone cells (at [18], [31]).  This is broadly consistent with the approach in the opposed specification.  Dr Thomas confirms that there was a standard battery of tests that were known and routinely used before the priority date to monitor osteoclast and osteoblast activity in experimental models (at [19] referring to [15(x)]). 

14. Dr Dunstan understands the experimental results in the opposed specification to provide convincing evidence of Siglec-15’s role in osteoclast formation/differentiation (at [21]-[23]).  In contrast, Prof Martin considers the RNAi data deficient and an inadequate basis for a conclusion that Siglec-15 is required for osteoclast differentiation (#1 at [32]-[33]; #2 at [5]-[7]).  Despite Prof Martin’s reservations regarding the extent of the data in the opposed specification, the evidence nevertheless establishes that the effects on osteoclasts of under-expressing a gene could be investigated using antisense strategies (Thomas at [19], [31]; Martin#1 at [19], Martin#2 at [10]).  However, while inhibition by antisense is a good proof of concept that an inhibitor could have the desired effect (Thomas at [21]; Martin#1 at [19]), it does not guarantee that an inhibitory antibody would necessarily work for the same target (Thomas at [21]; and by inference Martin#1 at [19]).  In order to confirm the in vivo effect of a protein target, Prof Martin and Dr Thomas would, and Dr Dunstan could, further analyse its function by generating a knockout animal model (Martin#1 at [23]; Thomas at [16], [19]; Dunstan at [15]), which could take 12 months (Thomas at [19]).  Dr Thomas would then have proceeded to further analysis using viral transfection to overexpress the molecule in an animal, while analysing under-expression using antisense strategies (at [19]). 

15. Where it is determined that inhibition of an extracellular target is required, Dr Thomas (at [20]-[21]) would in the first instance seek to develop an antibody against the target, considering this a relatively easy option:

    “In the case of wishing to inhibit activity of the target molecule the most likely starting point is to develop an antibody against the target.  Even though a therapeutic molecule may ultimately end up being a small organic molecule rather than an antibody, the production of an antibody at least initially is likely to be far easier and less time consuming than a small organic molecule and is likely to represent a much more efficient means of demonstrating proof of principle that the target is suitable for therapeutic intervention.” (Thomas at [21])

    Summary of target requirements

16. The evidence establishes that, if it were deemed necessary, the steps involved in confirming the cellular location and role of a potential target protein in osteoclast function would have taken some 12 months or more (Thomas at [18]-[19], consistent with Martin#1 at [23]).  Although this is a relatively long period of time in the laboratory, the way the experts describe the process does not establish that the skilled addressee would be required to undertake new inventions or additions to produce a specific and functionally active antibody featured in Alethia’s claims.  However, the specification will nevertheless be insufficient if producing the antibodies featured in Alethia’s claims would require prolonged study of matters presenting initial difficulties. 

17. In considering whether prolonged study is required, the Courts have identified as a relevant consideration the nature of the work required in order to perform the invention.  As in the present case, in Pfizer Overseas Pharmaceuticals v Eli Lilly and Company (Pfizer) [2005] FCAFC 224, (2005) 225 ALR 416 it was argued at [342] that performing the invention as claimed would require a considerable investment of time and resources. Notwithstanding, the Full Court at [345]-[346] upheld the primary judge’s finding that where it was necessary to conduct a range of “essentially routine” tests in order to perform the claimed invention, the specification nevertheless gave a sufficient description for the purposes of s 40(2)(a). Relevant to the circumstances in this opposition, the primary judge, Heerey J, had observed that the term “routine” was not used as a synonym for “simple and easy”, and that while the tests involved were difficult, they were nevertheless essentially routine for persons holding the relevant qualifications and experience (Eli Lilly and Company v Pfizer Overseas Pharmaceuticals [2005] FCA 67 at [194]).

18. The evidence of Dr Dunstan and Dr Thomas, presented above, weighs in favour of a conclusion that although the process involved in validating a protein for antibody targeting was lengthy, it would nevertheless have been routine for the skilled addressee relevant to this opposition.  Professor Martin’s contrary view appears heavily influenced by his view that the experimental data provided in the specification is inadequate as a proof of concept (#2 at [9], referring to #1 at [31]-[33]).   It is not apparent from his evidence that Prof Martin has considered the common general knowledge possessed by the skilled addressee and their ability to carry out any further testing that may be deemed necessary.  Consequently, I accord Prof Martin’s evidence less weight on this point.

19. Daiichi has adduced no evidence that any person had attempted to validate Siglec-15 as suitable for antibody inhibition and failed, or that the process had posed more difficulties or required more time than would be encountered in validating any other protein target.  Thus, as it stands, the evidence weighs in favour of a conclusion that validating Siglec-15 as a target suitable for antibody inhibition would not require prolonged study of matters presenting initial difficulty. 

20. Daiichi has not established that the complete specification is insufficient to enable the skilled addressee to determine the cellular location and functional activity of Siglec-15.

    Generating an inhibitory antibody

21. Daiichi submitted that the subject matter of claims 1-18, 28, 31-32 and 36-38 is not fully described in the absence of any demonstration in the opposed specification that an antibody had been, or could be, produced that “specifically binds” to Siglec-15 and has the desired therapeutic effect.  

22. Responding, Alethia submitted that the opposed specification provides a detailed description of how specific antibodies can be made and provides methods for identifying which anti-Siglec-15 antibodies display the relevant inhibitory properties.  It referred in particular to: Example L for an example of a method to test for antibodies able to inhibit osteoclast formation; the RAW murine osteoclast precursor cell line and human osteoclast precursor cells on pages 61-62 as well known models of osteoclastogenesis; and additionally to a broad description of screening assays on pages 43-45 of the opposed specification. 

23. What must be determined is whether the disclosure of the opposed specification enables the skilled addressee to produce the Siglec-15-specific and functionally active antibodies within Alethia’s claims without new inventions or additions or prolonged study of matters presenting initial difficulty.

24. There was no dispute and the evidence confirms that before the priority date, the generation of antibodies that bind a polypeptide with no requirement for function was a routine process, whereas producing an antibody with inhibitory activity takes more time and there was no guarantee of success (Martin#1 at [23], [31]; Thomas at [21], [23]; Dunstan at [33]).  The first step towards developing an inhibitory antibody was to produce antibodies against the target (Dunstan at [17]; Martin#1 at [24]; Thomas at [23]), which would then be tested to identify those with the relevant inhibitory activity (Dunstan at [17]; Martin#1 at [25]; and by inference from Thomas at [23]).

25. In his first declaration at [24]-[30], Professor Martin outlines the work involved in identifying antibodies that demonstrate inhibitory activity in vitro and in vivo. 

    In vitro testing of antibodies for inhibitory activity

26. Describing the in vitro testing required to identify antibodies with the required inhibitory properties, Prof Martin states: 

    “… you … 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 conduct fluorescence labelling studies.  It is also important to show functional effects.  This requires growing the cells, and running osteoclast formation assays where you investigate whether any of the antibodies block osteoclast formation.” (Martin#1 at [25])

    “Whether or not an antibody inhibits formation of osteoclasts, another important step is to 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 of the culture dish, and put them onto bone slices and let them incubate with the antibody for 24 or 36 hours.  Then the amount of resorption of the bone surface by the osteoclasts is measured.  A good antibody will both block the formation of osteoclasts and will block osteoclast activity.” (Martin#1 at [26])

27. The evidence of Dr Dunstan and Dr Thomas supports a conclusion that the in vitro experimental work required to identify Siglec-15 antibodies with the ability to inhibit osteoclast formation or bone resorption would have been essentially routine for the skilled addressee.  Dr Thomas at [15(x)] confirms that a standard battery of assays was known and routinely used at the priority date to monitor osteoblast and osteoclast activity in experimental models and he exemplifies Chapters 88-90 of the textbook Bilezikian, Raitz and Rodan ‘Principles of Bone Biology’, Second Ed., Volume 2 (Academic Press 2002) - in evidence as Exhibit GPT-11 - which describe bone organ culture systems, primary bone cells and permanent bone-derived cell lines. 

28. Dr Dunstan states that “the standard, accepted model of osteoclast differentiation” used in the opposed application, in which osteoclast precursor cells are treated with RANKL and M-CSF, could be applied to identify functional antibodies, and that the performance of this “well-accepted and widely used assay was a matter of routine” (at [34]).  He adds that several routine assays were also widely known and available before the priority date to determine whether a particular antibody is able to inhibit a function of osteoclasts, Prof Martin’s bone slice assay being a good example, “which could have been performed as a matter of routine” (at [34]).

29. Professor Martin disagrees performing osteoclast differentiation and bone slice assays is routine, but he provides no reasons for this conclusion other than a broad statement of “the inadequacy of the experimental work reported in the opposed application” (#2 at [9]).  It is not apparent from his evidence that Prof Martin has had regard to the skills and abilities of the skilled addressee of the opposed specification in determining whether these assays would have been routine.  Professor Martin does not suggest that he would have had difficulties in performing these assays.  For these reasons, I accord Prof Martin’s evidence on this point less weight than that of Drs Dunstan and Thomas.

30. On balance, I find that testing Siglec-15 antibodies in vitro for inhibitory activity with respect to osteoclast formation and/or bone resorption would have been essentially routine for the skilled addressee.

    In vivo testing of antibodies for inhibitory activity

31. To test antibodies for in vivo functionality, Prof Martin and Dr Thomas each identify ovariectomised rodents as a suitable model (Martin#1 at [28]; Thomas at [21]-[22]).  The way they describe this approach supports a conclusion that these experiments would be essentially routine.  Professor Martin explains:

    “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 mice or rats and start treating the mice or rats with the inhibitor from that time. The aim is to establish 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.” (Martin#1 at [28])

1. Professor Martin confirms in his support evidence that the process of making inhibitory antibodies “takes time and effort with no guarantee that you will be able to develop a therapeutic antibody that successfully treats a disease” (#1 at [30]).  Furthermore, “to succeed it would be necessary not only to be well resourced but also to have some luck that the target you have selected is suitable and that clinically useful antibodies can be produced” (Martin#1 at [30]).  Responding to Prof Martin’s references to “clinically useful” and “therapeutic” antibodies, Dr Dunstan at [32] distinguishes the requirements for making an inhibitory antibody from the work required to get an antibody through regulatory approval and to market:

   “I understand from my experience that the final production of an approved (e.g., FDA-approved) clinically acceptable therapeutic antibody requires the investment of significant resources.  However, whilst there may be significant resources spent on the journey of antibody development from initial in vitro results through extensive toxicology studies, clinical trials, marketing efforts and regulatory approval processes, that is on an entirely different scale to the initial production of a functional (e.g., neutralizing) antibody, which, so long as the function of the protein is known, could have been performed as a matter of routine at 13 February 2006.”

2. In his reply evidence, Professor Martin disagrees with Dr Dunstan that the steps involved in producing a neutralising antibody would have been routine, and that “it would not have required a significant investment of time or money to do so” (Martin#2 at [8]).  On this point, Prof Martin continues:

   “While it may have been routine at the time to produce an antibody against a known protein, it was significantly more involved … to produce an antibody and demonstrate that it was neutralizing, in this case that impairs an activity of the specified polypeptide in osteoclast precursor cells or in osteoclasts, as specified in claim 1 of the application.”

3. In that passage, which is consistent with the balance of his evidence, Prof Martin confirms that having produced an antibody that binds a target protein, there was significantly more work required to identify those antibodies (if any), with the inhibitory activity specified in Alethia’s claims. The evidence of Drs Dunstan and Thomas is consistent with this conclusion. However, the evidence as a whole does not establish that the skilled addressee would be required to undertake other than essentially routine work in order to do so. Dr Dunstan at [32] states that providing the function of the target protein is known, production of a neutralising antibody would have been routine. Similarly, Dr Thomas states that production of an antibody targeted against a protein was a routine approach for inhibiting its activity (at [15(xi)], [21]).

4. For the reasons presented above, although it may be time consuming, I find that the in vitro and in vivo testing required to identify antibodies with the relevant inhibitory activity would be essentially routine for the skilled addressee.  Although an inhibitory antibody could not be guaranteed (Martin#1 at [23]; Thomas at [23]), I have no evidence before me that anyone had attempted, and failed, to produce an antibody to Siglec-15 with the binding specificity and inhibitory activity specified in Alethia’s claims.  It follows that Daiichi has not discharged the onus of establishing that the disclosure of the opposed specification is insufficient to enable the skilled addressee to produce an antibody, or fragment thereof, that specifically binds Siglec-15 and inhibits or modulates its activity as required by claims 1-18, 28, 31, 36-37, without new invention or addition or prolonged study of matters presenting initial difficulty.  

5. Properly construed, claims 32 and 38 do not require the Siglec-15 antibody or fragment thereof to have functional activity.  Since the experts are in agreement that the production of antibodies against a protein with no requirement for activity is routine in the art (Martin#1 at [23], [31]; Thomas at [21], [23]; Dunstan at [33]), I find the antibodies featured in these claims are fully described.

6. Independent claim 5 defines an antibody or fragment, which impairs osteoclastogenesis, isolated by way of a method involving testing the antibody or fragment to determine whether it reduces osteoclastogenesis.  Dr Dunstan states at [42] that it is clear to him, from the description of screening methods in the opposed specification (at page 42 lines 14-23 and Example J) and routine methods in the art, how the method of claim 5 should be performed.  Professor Martin’s contrary view is based on the absence in the opposed specification of an explicit disclosure of an inhibitory antibody that could be isolated by the claimed method (#1 at [40]; #2 at 16]).  There is no requirement that the specification provide examples if it is otherwise sufficient (PhotoCure [2005] FCA 344 at [105]). I have found above that the complete specification sufficiently enables the skilled addressee to produce antibodies to Siglec-15, which could be applied to the method of claim 5 to identify those with inhibitory activity. Consequently, I find the subject matter of claim 5 is fully described.

7. Dependent claim 10 defines an isolated antibody or fragment thereof according to any one of claims 1-8 which binds to a polypeptide consisting of SEQ ID NO: 48 (human Siglec-15) but does not bind to a polypeptide consisting of SEQ ID NO: 82 (mouse Siglec-15).  Daiichi submitted that without an explicit disclosure of such an antibody, or an assay to test this, the skilled person could not be sure that an antibody that specifically binds to the SEQ ID NO: 48 polypeptide would not bind the SEQ ID NO: 82 polypeptide.  To provide guidance, Alethia relied on page 40 lines 1-3 of the opposed specification, which broadly refers to antibodies characterised by high specificity for the polynucleotides of the invention, with little cross-reactivity to related antigens.  I have no evidence before me to establish that anyone had attempted, and failed, to produce an antibody within claim 10.  Furthermore, in the absence of evidence to the contrary, I am of the view that the skilled addressee could test the ability of any given antibody to bind each of the specified polypeptides in order to identify an antibody falling within claim 10, without the need for new invention or addition or prolonged study of matters presenting initial difficulty.  I find claim 10 is fully described. 

8. Dependent claim 11 defines an isolated antibody or fragment thereof of any preceding claim, which has sub-nanomolar affinity for the polypeptide.  Daiichi did not identify any expert evidence to support its submission that in the absence of a disclosure of such an antibody the skilled addressee would not be able to produce something within the scope of this claim.  As noted above, an example is not required if the specification is otherwise sufficient (PhotoCure [2005] FCA 344 at [105]). For this claim, Alethia relied on a statement on page 40, lines 3-6, that by screening antibody libraries having large repertoires of antibody fragments (2-10 x10¹⁰) a good diversity of high affinity monoclonal antibodies may be isolated, “with many expected to have subnanomolar affinities” for the peptides of the invention.  In the absence of evidence that the skilled addressee would be required to undertake new invention or addition or prolonged study of matters presenting initial difficulty in order to follow this direction to produce something within claim 11, or that any person had tried and failed to produce an antibody within claim 11, Daiichi has not established that the subject matter of this claim is not fully described. 

9. I have construed claim 16 as limited to the administration of Siglec-15 antibodies with a modulatory activity relevant to treating the specified conditions.  Therefore, Daiichi’s submissions based on an alternative construction are moot.  

10. Claim 19 defines a method for identifying a compound able to inhibit osteoclast differentiation comprising contacting a candidate compound with a specified Siglec-15 variant capable of inducing osteoclast differentiation, measuring activity or expression of the polypeptide and testing the ability of the compound to inhibit osteoclast differentiation or bone resorption, wherein a reduction in the activity or expression of the polypeptide and a reduction in at least one of osteoclast differentiation or bone resorption positively identifies a suitable inhibitory compound. 

11. Daiichi submitted that Example L of the opposed application does not involve the measurement of expression or activity of the protein of SEQ ID NO: 48 and without an inhibitory activity of sufficient amplitude, there would be little prospect of identifying Siglec-15 inhibitory activity having regard to the opposed specification.  In making this submission, Daiichi relied on Prof Martin’s evidence that in the absence of quantification or positive controls there is no measure of inhibition (Martin#1 at [41]-[42]).  Professor Martin does not directly address the question of whether the skilled addressee would be able to quantify, and where necessary optimise, the assay response to achieve sufficient amplitude.  Prima facie, quantification and optimisation of an assay response is generic in laboratory procedures, as is the use of appropriate controls.  In the absence of evidence to the contrary, or evidence that any person had tried and failed to identify a compound in accordance with claim 19, Daiichi has not established that the skilled addressee seeking to carry out the method of claim 19 would be required to undertake new invention or addition or prolonged study of matters presenting initial difficulty.  I find this claim is fully described.   

12. Daiichi submitted that claim 32 and dependent claims 31, 36 are insufficiently described because the specification does not demonstrate that it is possible to diagnose bone disease using the specified Siglec‑15 variant capable of modulating osteoclast differentiation or a specific antibody to such a polypeptide or fragments thereof.  Professor Martin’s evidence that the disclosure is insufficient because no such use has ever been made of any antibody against an osteoclast component (Martin#1 at 43]) does not establish that performing the invention as claimed would necessarily require new invention or addition or prolonged study of matters presenting initial difficulty on the part of the person skilled in the art.  Daiichi has not established that claim 32 or its dependent claims are not fully described.

13. Regarding claim 38, Daiichi submitted that the opposed specification does not demonstrate that differentiated osteoclasts could be detected (i) in the absence of a disclosure of the cellular location of Siglec-15, and (ii) given that macrophages and dendritic cells also express Siglec-15.  I have found above that the opposed specification is sufficient regarding the cellular location of Siglec-15.  Furthermore, the specification states on page 70 that Siglec-15 expression is markedly upregulated in osteoclasts compared to precursor cells.  On this basis, it is reasonable to conclude that the skilled addressee could detect differentiated osteoclasts in accordance with claim 38 in a mixed osteoclast/osteoclast precursor cell population in an osteoclast differentiation assay as described in the opposed specification.  Consequently, I am satisfied the disclosure enables the addressee of the specification to perform this embodiment of claim 38 without new inventions or additions or prolonged study of matters presenting initial difficulty.

14. In summary, Daiichi has not discharged the onus of establishing that the disclosure of the opposed specification does not enable the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty.  I find the subject matter of the opposed claims is fully described.

    Novelty

    The Law

15. 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.

16. 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”

17. In AstraZeneca AB v Apotex Pty Ltd (AstraZeneca) [2014] FCAFC 99 at [293], the majority of the Full Court identified the 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.”

18. In AstraZeneca at [294], noting the use of the “planting the flag” and “accuracy of a sniper” metaphors in earlier Australian 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.

    Mr Arends’ declaration

19. For novelty purposes, Daiichi relied on Mr Arends’ declaration in which he compares the subject matter of the opposed claims to the prior art disclosure.  However, I consider Mr Arends’ statements to be more in the nature of submissions rather than the evidence of a person with expertise in the relevant art.  There is nothing in evidence to suggest that Mr Arends has any practical experience in bone biology or in developing therapeutic antibodies.  To the contrary, Mr Arends is a qualified European patent attorney (Arends at [2]) who Daiichi acknowledged at the hearing has prosecuted its patent matters in Europe.  Daiichi’s submission that Mr Arends is “highly experienced in evaluating documents in relation to novelty” is consistent with his professional role.  Given Mr Arends’ lack of relevant experience, the nature of his evidence and to a lesser extent his relationship with Daiichi, I consider his evidence insofar as it relates to the application of the law to the facts in this opposition to be more in the nature of submissions, and I have treated them as such.

    Submissions

20. Daiichi opposed “at least” claims 1-11, 13, 16-24, 28, 31-32 and 36-38 for lack of novelty insofar as they relate to antibodies.  Daiichi submitted that if the prior art document discloses the polypeptide sequences of SEQ ID NO: 48 or SEQ ID NO: 82 and an instruction to make an antibody which specifically binds and impairs an activity of that polypeptide, then the resulting antibody will inherently, and by reason of its nature:

    i)    impair the activity in osteoclast precursor cells or in osteoclasts (opposed claim 1);

    ii)   inhibit osteoclast differentiation or the bone resorption activity of osteoclasts (opposed claim 2);

    iii)     impair osteoclastogenesis (opposed claim 3); or

    iv)     reduce differentiation of osteoclast precursor cells into osteoclasts (opposed claim 4).

21. To establish a lack of novelty, Daiichi relied on the following documents:

    WO 02/38602 A2 (Incyte Genomics, Inc.) 16 May 2002 (WO’602)

    WO 03/048305 A2 (Incyte Genomics, Inc.) 12 June 2003 (WO’305)

    EP 1580263 A1 (Research Association for Biotechnology) 28 September 2005 (EP’263)

22. The priority date of 13 February 2006 is not in dispute.  These three documents form part of the prior art base for novelty and inventive step.

    WO’602

23. Daiichi submitted that at least claims 1-9, 11, 13, 16-18, 21, 28, 31-32, 36 and 37, lack novelty in light of WO’602.  It argued that WO’602 teaches Siglec-15, a direction to make antagonistic antibodies, various screening assays, methods for producing the antibodies which are sufficient if this was routine and well known, such that the skilled addressee would arrive at antibodies within the claims.  Daiichi considered the specific binding and inhibitory activities specified in the claims would be an inherent property of the antibodies produced.

24. Responding, Alethia submitted that an essential feature of the antibody of the opposed claims, that it impairs an activity of the Siglec-15 polypeptide in osteoclast precursor cells or in osteoclasts, which is neither taught nor suggested in WO’602.  Alethia argued that WO’602 describes 63 hypothetical or putative secreted proteins identified from cDNA libraries, but does not identify any effect of inhibiting any of the proteins, and provides no specific link between SECP-33 and osteoclasts or the process of osteoclastogenesis.  Furthermore, that WO’602 merely discloses SECP expression as closely associated with the “generic laundry list” of various tissues, which do not include bone.

25. Relevant to Daiichi’s submission, in Novozymes A/S v Danisco A/S (Novozymes) [2013] FCAFC 6 at [187]; 99 IPR 417 at [187], Jessup J (with Greenwood and Yates JJ agreeing at [37] and [226], respectively) provided guidance on the application of the General Tire as it relates to inherency and inevitable outcome:

    “…, the General Tire approach, if taken at all, may be taken only with respect to the whole of any claim asserted to have been anticipated.  The “precise destination” at which the flag must have been planted is one which includes every integer of the claim.  The approach cannot, in my view, be taken for some integers only, leaving others to be dealt with by reference to the understanding of the skilled addressee.  In the present context, what this means is that, to the extent that [a party’s] case is based on General Tire, it is not sufficient that they be able to point to passages in the … patent from which it would appear to the skilled addressee that [a feature of a claim] was contemplated or intended by the earlier inventors.  It is necessary that they show that, if [the disclosure relied on] were worked as directed, it would inevitably, as a matter of hard fact, have involved [that feature].”

1. Opposed independent claims 1, 5, 16, 28, and claim 31 (as dependent on claim 32) each feature an antibody, or antigen-binding fragment thereof, that (i) specifically binds human or mouse Siglec-15 (as represented by SEQ ID NOs: 48 or 82, respectively) or specified variants and (ii) has an inhibitory or modulatory effect in the context of osteoclast differentiation and/or bone disease.  For these claims to lack novelty Daiichi must at least establish that in following directions in WO’602 the person skilled in the art would inevitably, as a matter of fact, produce an antibody or antibody fragment with these properties.    

2. In this regard, the evidence establishes that in order to develop an antibody capable of modulating the function of its target, specific antibodies to the target must be tested to identify those with the relevant modulatory activity (Dunstan at [17]; Martin#1 at [24]-[25]; and by inference from Thomas at [23]).  To demonstrate that an antibody has neutralising/inhibitory or other modulatory activity in the context of osteoclast function and/or bone disease, it is necessary to determine the effect of the antibodies on osteoclast differentiation and/or bone resorption (Martin#1 at [25]-[26]; Thomas at [32]; and by inference from Dunstan at [51]-[53]).  The question is whether WO’602 provides clear and unmistakable directions to carry out appropriate tests.  For the reasons that follow, I am not satisfied that it does.

3. Daiichi identified a number of passages in WO’602 that it relied on to establish lack of novelty, which are discussed below.  WO’602 is titled “Secreted proteins”.  On page 1, the technical field of the invention relates to: 

   “… nucleic acid and amino acid sequences of secreted proteins and to the use of these sequences in the diagnosis, treatment, and prevention of cell proliferative, autoimmune/inflammatory, cardiovascular, neurological, and developmental disorders, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of secreted proteins.”

4. The invention is stated to feature purified secreted polypeptides, identified collectively as “SECP” and individually as SECP-1 to SECP-63 (SEQ ID NOs: 1-63, respectively) (para bridging pages 8-9 of the WO’602 specification).  Most relevantly, SECP-33 (SEQ ID NO: 33) has 99.7% identity with SEQ ID NO: 48 in the opposed application (consistent with Arends at [15] and Martin#1 at [56]). 

5. Daiichi relied on pages 10-13 and 42 of WO’602 for a disclosure relevant to preparing antibodies to the SECP polypeptides with inhibitory (neutralising) or modulatory activity relevant to the opposed claims.  On page 10, the invention is said to provide an isolated antibody which specifically binds to polypeptides comprising a SECP amino acid sequence, specified naturally-occurring variants, and biologically active or immunogenic fragments of the SECP polypeptides. 

6. Most relevant to identifying the functional activity of antibodies, on pages 11-13, WO’602 broadly set out methods for screening a compound for effectiveness as an agonist or antagonist of the above SECP polypeptides, variants and fragments, the methods comprising:

   a)  exposing a sample comprising the SECP polypeptide, variant or fragment to a compound, and

   b) detecting agonist or antagonist activity in the sample. 

   On pages 15-16 the definitions of agonists and antagonists relevantly include antibodies. 

7. Between pages 12-13, a screening method to identify modulatory compounds comprises:

   a)  combining the SECP polypeptide or variant or biologically active or immunogenic fragments thereof with at least one test compound under conditions permissive for the activity of the polypeptide,

   b) assessing the activity of the polypeptide in the presence of the test compound, and

   c) comparing the activities of the polypeptide in the presence and absence of the test compound,

   wherein a change in the activity of the polypeptide in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide  

8. The above methods identify the modulatory (agonist, antagonist) activity of the test compound by its effect on the activity SECP polypeptide – this is explicitly stated in the second screening method and is implicit in the steps of the first.  Relevant to the activity of the SECP polypeptides, on pages 81-82, under the heading “Demonstration of SECP activity”, WO’602 exemplifies assays for determining: peroxidase activity; growth stimulating or inhibiting activity; TGF-b activity; modulation of neurotransmission in cultured cells; the amount of SECP in secretory, membrane bound organelles; protein kinase activity; and AMP binding activity.  On page 82, under the heading “Demonstration of immunoglobulin activity”, the amount of precipitable SECP-antigen complex is a measure of SECP activity, as is the expression of SECP on a non-leukocyte cell surface, or induction of cell aggregation induced by overexpression of SECP.  I have no evidence before me that establishes that an antibody to SECP-33 that inhibits or modulates any of these activities would necessarily, as a matter of fact, modulate the activity of Alethia’s Siglec-15 polypeptides in promoting osteoclast differentiation and/or bone resorption.   

9. On page 42, WO’602 discloses that the SECP polypeptides can be used to screen for compounds which specifically bind to and modulate the activity of SECP.  The method may involve producing cells which express SECP, and contacting these cells or SECP-containing cell membrane fractions with a test compound and analysing “binding, stimulation, or inhibition of activity of either SECP or the compound” (page 42, para 4).  The preferred cells in which to express SECP include those from “mammals, yeast, Drosophila or E Coli”.  Critically, there is no clear and unmistakable direction in this disclosure to express any SECP polypeptide in osteoclast precursor cells or osteoclasts in order to analyse the effect of a test compound on SECP activity  Supporting this conclusion, in the context of therapeutics, on page 44 WO’602 states that SECP expression is associated with the following tissues, none of which direct the skilled addressee to bone cells such as osteoclasts or osteoclast precursor cells: 

   “normal and tumorous lung, heart, brain, skin, colon epithelium, and cardiovascular tissues, as well as, neurological, urinary, reproductive, digestive, immunological, diseased, and tumorous tissues”.

10. For novelty purposes, Daiichi also identified the following “key” passage on page 46 of WO’602, disclosing antibody antagonists to the SECP proteins:

    “In a further embodiment, an antagonist of SECP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of SECP.  Examples of such disorders include, but are not limited to, those cell proliferative, autoimmune/inflammatory, cardiovascular, neurological, and developmental disorders described above. In one aspect, an antibody which specifically binds SECP may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissues which express SECP.” (Emphases added)

11. The reference in that passage to the “disorders described above”, refers back to a paragraph on pages 44-45 of WO’062, which commences:

    “Therefore, in one embodiment, SECP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SECP.  Examples of such disorders include, but are not limited to, … [there follows a list of specified cell proliferative disorders, autoimmune/inflammatory disorders explicitly including osteoporosis, and cardiovascular, neurological and developmental disorders]” (Emphasis added)

12. Acknowledging that the listed disorders are numerous (they extend over 1.5 pages), Daiichi nevertheless relied on the inclusion of osteoporosis.  It submitted that if the passages on page 44 (identifying osteoporosis) and on page 46 (referring to the use of an antagonist of SECP) are read together, there is a clear and unmistakable disclosure of an antibody which specifically binds SECP, which may be used directly as an antagonist and which may be administered to a subject to treat or prevent a disorder such as osteoporosis.  Daiichi submitted that the antibody to SECP‑33 would inherently have the functional properties required by the opposed claims. 

13. The expert evidence does not support Daiichi’s view of the matter.  Dr Dunstan understands WO’602 to provide a very basic analysis of several proteins, but no information regarding the physiological function of SECP-33 or any other SECP protein (Dunstan at [51]-[52]).  Dr Thomas does not comment on WO’602.  Professor Martin confirms the concordance between the SECP‑33 polypeptide in WO’602 and SEQ ID NO: 48 of the opposed application and confirms that an antibody that binds SECP-33 would also bind the SEQ ID NO: 48 polypeptide (Martin#1 at [56]).  However, when addressing the function and potential uses of the SECP polypeptides (Martin#1 at [55]-[56]), Prof Martin does not distinguish SECP-33 from the other SECP polypeptides nor does he associate any individual SECP polypeptide with osteoclast function or bone disease.

14. Daiichi also considered claims 11 and 32 in WO’602 a relevant disclosure.  Claim 11 defines an antibody which specifically binds a polypeptide selected from the group consisting of polypeptides comprising SEQ ID NOs: 1-63 and naturally occurring amino acid sequences having at least 90% identity to SEQ ID NOs: 1-63.  Claim 32 defines a composition comprising the antibody of claim 11 and an acceptable excipient, which Daiichi relied on to disclose a relevant functional activity in the antibody.  However, I have no evidence before me that establishes that a SECP-33 antibody encompassed by claim 11 (construed in the light of claim 32) would necessarily have the functional properties required by the opposed claims. 

15. At best, in SECP-33, WO’602 discloses a polypeptide with 99.7% identity to human Siglec-15, in the context of numerous cell proliferative, autoimmune/inflammatory, cardiovascular, neurological and developmental disorders.  WO’602 teaches that agonists, and conversely antagonists, of the same SECP polypeptide can be used to treat the same disorders.  WO’602 broadly describes methods of making antibodies to the SECP polypeptide and identifying inhibitory and modulatory properties of those antibodies in a cellular environment. 

16. Nevertheless, for the reasons provided above I am not satisfied that the document provides clear and unmistakable directions to investigate the functional properties of SECP-33-specific antibodies in a manner that would necessarily identify, and thereby facilitate isolation of, those that inhibit the function of Siglec-15 specifically in osteoclasts or osteoclast precursor cells.  It follows that Daiichi has not established that WO’602 discloses antibodies with the specific-binding and inhibitory activities specified in the opposed claims, or their use in the context of osteoclast function and bone disease, with sufficient specificity to anticipate the antibody per se of opposed claim 1 and dependent claims, or the antibodies featured in opposed claims 5, 16, 28 and 31 and dependent claims.

17. Claims 19 and 21 define a method for identifying a compound able to inhibit osteoclast differentiation.  Claims 32 and 38 relate to the use of antibodies to specified Siglec-15 polypeptides or variants in the diagnosis of bone disease or to detect differentiated osteoclasts.  Daiichi has adduced no evidence to the effect that WO’602 discloses the combination of features in any of these claims or dependent claims and on review of the document I am satisfied that it does not do so.

18. Daiichi has not established that the opposed claims lack novelty in light of WO’602. 

    WO’305

19. Daiichi opposed at least claims 1-11, 13, 16-18, 21-22, 28, 32, 36-37 in light of WO’305.

20. WO’305 is titled “Receptors and membrane-associated proteins”, which are collectively abbreviated in the document to “REMAP”.  Mr Arends identifies the relevant disclosure in WO’305 as follows:

    “19. … [WO’305] relates to a receptor and membrane-associated protein referred to as 7505722CEP’263 which is referred to as SEQ. ID NO. 8 within [WO’305].  The protein is also referred to as “REMAP-8” in [WO’305] (see page 26, lines 21 to page 27, line 13 of [WO’305]) and corresponds to the polypeptide of SEQ ID NO. 48 of [the opposed application].  It is stated in page 70, lines 26 to 30 of [WO’305] that:

    “In a further embodiment, an antagonist of REMAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of REMAP.  Examples of such disorders include, but are not limited to, those cell proliferative, autoimmune/inflammatory ..... disorders described above.  In one aspect, an antibody which specifically binds REMAP may be used directly as an antagonist. ...” (emphasis added).

    20. The list of “autoimmune/inflammatory disorders described above” is provided in page 67, line 29 to page 68, line 6 which states:

    “an autoimmune/inflammatory disorder such as .... osteoporosis …”.

21. The extent of the WO’305 disclosure is similar to that of WO’602, discussed above.  WO’305 teaches 47 REMAP polynucleotides and polypeptides (Dunstan at [59]), of which the REMAP-8 polypeptide (SEQ ID NO: 8) corresponds to SEQ ID NO. 48 (human Siglec-15) in the opposed specification (Dunstan at [24]; Arends at [19]).  Listed disorders associated with increased expression or activity of REMAP to which antagonists may be applied extend across three pages in WO’305, and include osteoporosis.  On page 67, WO’305 discloses these same diseases as examples of disorders associated with decreased expression or activity of REMAP, which may be treated with a REMAP protein (i.e. an agonist).  Claim 11 of WO’305 encompasses an isolated antibody or fragment thereof, which specifically binds a polypeptide comprising any one of the 47 REMAP polypeptides and naturally-occurring variants with no requirement for functional activity. 

22. On page 65-66 of WO’305 in order to identify compounds that specifically bind to and modulate the activity of REMAP, cells expressing REMAP (preferred cells are from mammals, yeast, Drosophila, or E. coli) are contacted with a test compound and binding, stimulation, or inhibition of activity of either REMAP or the compound is analysed.  On pages 121-123, under the heading “Demonstration of REMAP activity” a number of assays are disclosed predominantly by monitoring REMAP-mediated cellular processes, none of which are clearly applicable to osteoclast differentiation or bone resorption.    

23. Dr Dunstan at [58] does not consider WO’305 to contain any disclosure of the subject matter of the opposed claims.  In particular, he concludes that there is nothing in WO’305 to suggest that Siglec-15 plays a role in osteoclastogenesis and there is no suggestion in WO’305 at all that the inhibition of Siglec-15 using a neutralising antibody may be an effective therapy for treating bone metabolism-related diseases (at [59]).  Professor Martin and Dr Thomas do not mention WO’305 in their evidence. 

24. Given the nature of the WO’305 disclosure and the lack of supporting expert evidence, I am not satisfied that WO’305 discloses inhibitory or modulatory antibodies to Siglec-15 or variants, or their use in the context of osteoclast function and bone disease, with sufficient specificity that it can be considered to provide clear and unmistakable directions to the subject matter of opposed claims 1, 5, 16, 28, 31-32 and 38 and all dependent claims.  Regarding claims 21-22, there is no expert evidence to the effect that WO’305 discloses the subject matter of these claims, and on review of the document I am satisfied that it does not do so.

25. I find the opposed claims novel in light of WO’305.

    EP’263

26. EP’263 is titled “Full-length cDNA clones”.  On page 2, the field of the invention is said to relate to “polynucleotides encoding novel polypeptides, polypeptides encoded by the polynucleotides, and new uses of these”.  It discloses the isolation of 2443 full-length cDNA sequences and predictions for the encoded proteins (Martin#1 at [47]). 

27. At para [0027], Table 1 lists the cDNA clones and discloses (by reference to SEQ ID NOs in a sequence listing), the full-length nucleotide sequences, the predicted coding DNA sequences (CDS) and the translated polypeptides (Martin#1 at [47]).  The position of the coding sequence within each polynucleotide was predicted using conventional means - the start position corresponding to an ATG start codon, and the final position to a stop codon where present (para [0027], consistent with Martin#1 at [47]).  Most relevant to the opposed claims, in Table 1 on page 19, clone D3OST20024170 is listed, represented by nucleotide sequence SEQ ID NO: 703, with the information that nucleotides 1373-1714 of this sequence encode the polypeptide of SEQ ID NO: 3146 (consistent with Dr Dunstan at [47]-[48]).  At paras [0263]-[0264], D3OST20024170 is identified as one of 56 genes involved in osteoporosis based on altered expression of RANKL an in vitro osteoclast differentiation assay (Dr Dunstan at [46]; Martin#1 at [52]-[53]). 

28. Daiichi acknowledged that EP’263 did not disclose the Siglec-15 protein sequence as such, which accords with Dr Dunstan’s evidence that the protein encoded by SEQ ID NO: 703 is entirely different to Siglec-15 (at [48], [50]).  Instead, Daiichi submitted that in SEQ ID NO: 703, EP’263 discloses a nucleic acid sequence with at least one area of significant homology to the nucleotide sequence SEQ ID NO: 1 in the opposed application which encodes human Siglec-15.  Specifically, nucleotides 2-223 and 223-840 of SEQ ID NO: 703 in EP’263 correspond to nucleotides 162-383 and 519-1136, respectively, of SEQ ID NO: 1 in the opposed specification (Dunstan at [47]; Arends at [6]; consistent with Martin#1 at [51]).  Daiichi’s reference to “at least one area” of homology acknowledges that given the position of nucleotide 223 in each homologous SEQ ID NO: 703 region, they are in different reading frames. 

29. Critically, EP’263 does not disclose nucleotides 2-223 or 223-840 of SEQ ID NO: 703 as polypeptide coding sequences.  There is no overlap between nucleotides 1373-1714 of SEQ ID NO: 703 that EP’263 identifies as the coding DNA sequence, and nucleotides 2-223 or 223-840 relied on by Daiichi (Dr Dunstan at [50]).  In effect therefore, Daiichi’s case for lack of novelty is that if the person skilled in the art ignores the explicit teaching of EP’263 that nucleotides 1373-1714 of SEQ ID NO: 703 encode the SEQ ID NO: 3146 polypeptide, and they interrogate SEQ ID NO: 703 to identify polypeptide sequences “encoded” by what EP’263 discloses as non-coding nucleotides, and then they express and make antibodies to those polypeptides, then the antibodies would fall within the scope of the antibodies in Alethia’s claims.  Notwithstanding that only nucleotides 2-223 or 223-840 of SEQ ID NO: 703 could potentially encode a polypeptide relevant to Alethia’s claims, this rather tortuous path lies against a conclusion that EP’263 provides clear and unmistakable directions to the subject matter of the opposed claims. 

30. However, even if I am wrong, to make good its case for lack of novelty, Daiichi would at least need to establish that a region of homology in any alternative polypeptide would result in an epitope sufficiently similar to a Siglec-15 epitope, such that a specific anti-Siglec-15 antibody would be produced.  Although Mr Arends states at [8] that “epitopes would be shared between the polypeptides encoded by SEQ ID NO. 703 and the polypeptide of SEQ. ID NO. 48 [i.e. human Siglec-15 of the opposed application]”, I am not satisfied that this determines the matter since the nature and accessibility of an epitope in a larger polypeptide sequence is influenced by more than just the primary protein structure.  However, I do not need to decide this point. 

1. On the assumption that there are shared epitopes, I accept at face value Mr Arends’ conclusion that “at least some of antibodies [sic] which bind to a polypeptide encoded by SEQ. ID NO. 703 of EP’263 would also bind to the polypeptide of SEQ. ID NO. 48 [i.e. human Siglec-15] of AU’334” (emphasis added).  Based on a comparison of the nucleotide sequences apparently without regard to the predicted coding sequence, Prof Martin concludes at [51] that polynucleotides SEQ ID NO: 1 of the opposed application and SEQ ID NO: 703 are closely related and that there is “a good chance that an antibody that binds to a protein encoded by SEQ ID NO: 703 from EP’263 would also bind to … the protein of SEQ ID NO: 48” (emphasis added).  This evidence that “at least some” of the antibodies raised against a SEQ ID NO: 703-encoded polypeptide would bind to the SEQ ID NO: 48 human Siglec-15 polypeptide, or there being “a good chance” that such an antibody would do so, falls short of establishing that antibodies to Mr Arends’ alternative polypeptides would have even the binding specificity for Siglec-15 required by the opposed claims.  

2. Daiichi has not established that EP’263 anticipates the subject matter of any opposed claim.

   Novelty Summary

3. Daiichi has not discharged the onus of establishing that the claimed invention lacks novelty.

   Inventive Step

4. Daichi opposed claims of the patent, at least insofar as they relates to antibodies, in light of EP’263.

   The Law

5. Subsection 18(1) of the Act requires 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.

6. 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, and confirmed by the High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd (AB Hässle) [2002] HCA 59 at [50]; 212 CLR 411 at [50] 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.”

7. The High Court in AB Hässle [2002] HCA 59 at [53]; 212 CLR 411 at [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)

8. 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]).

9. 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 have been determined, the question of whether the claimed solution is obvious must be addressed.

   The problem

10. The experts identify a need in the art to develop new therapeutics for the treatment of bone-metabolism-related disorders (Thomas at [15(viii)]; Dr Dunstan at [14]; Martin#1 at [12]), which is broadly consistent with the disclosure of the opposed specification.  It is reasonable to formulate the problem accordingly.

    The person skilled in the art

11. 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, or team, 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 referring to Catnic Components Ltd v Hill &Smith Ltd [1982] RPC 183 at 242 and General Tire [1972] RPC 457 at 485; Minnesota Mining [1980] HCA 9 at [115]; 144 CLR 253 at 293).

12. There was no dispute that the person skilled in the art in this case has significant research experience in the area of developing of new therapies for bone remodeling and associated bone disorders and knowledge of and/or experience in the production of inhibitory antibodies. 

13. There was no dispute that Professor Martin, Dr Thomas and Dr Dunstan each have relevant experience.  Professor Martin has 50 years of experience in bone disease research, particularly in relation to the formation and differentiation of osteoclasts and osteoblasts, and his research interests cover all aspects of bone biology and clinical bone disease. (Martin#1 at [4]-[9]; Exhibit TJM-1)  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 at [3]-[6]; Exhibit CD-1)  Dr Thomas has been actively involved in bone research since 1989 in both academia and the biotechnology industry.  Before the priority date, Dr Thomas’s work included investigation of the effects of various agents on osteoblast and bone biology, and drug development including screening for and validating potential target genes for improving bone growth. (Thomas at [3]-[8]; Exhibit GPT-3)

14. Alethia submitted that Mr Arends and Ms Hantos were not skilled in the relevant art, and I did not understand Daiichi to suggest otherwise.  However for completeness, I have found above that Mr Arends does not have relevant practical experience in the field to which the application relates.  For the same reasons, neither does Ms Hantos, who has also worked in the intellectual property profession since graduating with Batchelor and Masters degrees in chemistry and library and information science (Hantos at [1.1]-[2.7]). 

    The common general knowledge in the art

15. A definition of common general knowledge was provided by Aitken J in Minnesota Mining and Manufacturing Company and Another v Beiersdorf (Australia) Limited [1980] HCA 9; 144 CLR 253 at 292:

    “The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade.  It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.”

16. Dr Thomas at [15] sets out some important aspects of bone biology that were well understood by persons working in the field of bone biology before the priority date, which relevantly include the following:

    ·    The major bone cell types are osteoblasts that produce bone tissue and osteoclasts that resorb bone tissue.  Most diseases of bone result from an imbalance of the competing activities of osteoblasts and osteoclasts in the process of bone remodelling, which is the continual process of removal of bone tissue and its replacement with new bone tissue.

    ·    Osteoporosis in particular is an important disease associated with an imbalance of bone remodelling, where there is an over activity of the osteoclasts resulting in a progressive loss of bone tissue with the result that bone mass and density is reduced and the bones become brittle and subject to fracture.

    ·    In view of the problems with existing treatments, there was a clear and well recognised need in early 2006 to develop new therapeutic agents that could shut down osteoclast activity without also reducing bone growth.

    ·    There was a standard battery of assays that were known and routinely used by early 2006 to monitor osteoblast and osteoclast activity in experimental models.

    ·    A routine approach for the inhibition of the activity of a protein or polypeptide before February 2006 was to produce an antibody targeted against the polypeptide or protein.  Small organic compound inhibitors could also be developed.

    The prior art base

17. EP’263 forms part of the prior art base for the purposes of inventive step.

    Ascertained, understood and regarded as relevant

18. “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.”

19. EP’263 is in English and it is reasonable to conclude that if found, it would have been understood.

20. Daiichi submitted that EP’263 would have been ascertained because the patent family to which EP’263 belongs was identified in the shortlist created by a patent searcher.  Alethia accepted that the person skilled in the art would have some industry involvement and be aware of the commercial issues relating to a new therapeutic product, which accords with the evidence of Dr Thomas and Dr Dunstan that before the priority date they had access to and read the patent literature during the course of their work (Thomas at [12], [17]; Dunstan at [16]).  However, Alethia took issue with the breath of Ms Hantos’ search and the number of documents found, and additionally, the fact that on reviewing the result of Ms Hantos’s search (the search transcript), Dr Dunstan failed to find EP’263. 

21. Ms Hantos’s search transcript is in evidence as exhibit SMH-5.  It identifies 1203 patent families, of which family number 245 includes EP’263 among 20 family members.  Ms Hantos’ evidence has some limitations insofar as her search transcript is relied on to establish that EP’263 would have been ascertained, because she conducted her search on the basis of instructions from patent attorney Mark Roberts (Hantos at [3.1] and exhibit SMH-2).  There is nothing in evidence to suggest that the search strategy adopted by Ms Hantos, which relies heavily on patent classification marks, reflects a strategy that would have been used by the person skilled in the art in this opposition.  While Dr Thomas confirms at [25] that the patent searcher’s search strategy was “a valid and appropriate approach of the type that could have been conducted before February 2006” (emphasis added), he does not comment on how he would have approached the task. 

22. In any event, I do not need to decide this point.   

    Is the invention obvious?

23. The EP’263 disclosure has been summarised above.  Daiichi submitted that EP’263 is directed to osteoporosis genes and to therapeutic antibodies directed to proteins derived from those genes.  Daiichi’s submissions continue:

    “As noted above in relation to novelty, [EP’263] discloses a nucleotide and protein sequence with significant regions of high homology with Siglec-15. [EP’263] teaches that the disease associated with SEQ ID NO. 703 is osteoporosis. Accordingly, the skilled person, following the directions of [EP’263] would be motivated to produce antibodies to the sequence which impaired its activity.  Given the high degree of homology, there is a very high likelihood that, utilising the screening methodologies detailed [160]-[166] of [EP’263], the skilled person would produce antibodies falling within the scope of the claims.”

24. There was no dispute that EP’263 does not disclose the nucleotide or polypeptide sequences of Siglec-15.  However, as indicated above, in SEQ ID NO: 703, EP’263 discloses a polynucleotide sharing two regions of homology with the polynucleotide sequence encoding human Siglec-15 (SEQ ID NO: 1) in the opposed application, albeit that both lie outside nucleotides 1373-1714 of SEQ ID NO: 703 that EP’263 explicitly identifies as the polypeptide-encoding region (Table 1) (Dunstan at [50]).

25. I have no evidence before me that establishes that in all the circumstances and without the benefit of hindsight, the person skilled in the art would directly be led as a matter of course to express and raise antibodies to a polypeptide “encoded by” nucleotides 2-223 and/or nucleotides 223-840 of SEQ ID NO: 703, still less inhibitory antibodies relevant to Siglec-15, with a reasonable expectation that this would provide a useful agent in the context of abnormal bone remodeling and associated disorders.

26. Dr Dunstan confirms that with no overlap between nucleotides 1373-1714 of SEQ ID NO: 703 and the nucleotide sequence of SEQ ID NO: 1 of the opposed application, the protein disclosed by EP’263 is completely different to Siglec-15 (at [48], [50]).  Dr Dunstan does not suggest that he would look to what EP’263 implicitly discloses as non-coding regions of the polynucleotides to identify potential polypeptide targets for antibody production. 

27. Prof Martin’s evidence does not establish that in seeking to solve the problem, and without the benefit of hindsight, he would directly be led to try antibodies to polypeptides encoded by nucleotides 2-223 or nucleotides 223-840 of SEQ ID NO: 703, with a reasonable expectation that this would provide a useful agent in the context of abnormal bone remodeling and associated disorders.

28. On being asked to identify possible targets in EP’263 for diseases associated with aberrant bone remodelling, Dr Thomas identifies among others the “D3OST” category of cDNA clones which include SEQ ID NO: 703 (at [29]-[30]).  As the next step, Dr Thomas would have identified motifs with specificity and enrichment in bone, and would have pursued validation of suitable targets and determined whether they involved in a phenotype of interest (at [31]-[32]).  If a validated target was suitable for modulation by antibodies, Dr Thomas would have adopted this approach (at [32]).  However, Dr Thomas’s evidence does not establish that in following this strategy, he would directly be led as a matter of course to generate antibodies that specifically bind Siglec-15 (by way of a polypeptide encoded by nucleotides 2-223 or 223-840 of SEQ ID NO: 703) with a reasonable expectation that this would provide a useful agent in the context of abnormal bone remodeling and associated disorders.

29. Daiichi has not discharged the onus of establishing that the claimed invention lacks an inventive step.

    CONCLUSION

30. The opposition is unsuccessful.

    COSTS

31. It is usual in proceedings before the Commissioner that costs follow the event and the parties’ submissions were consistent with this approach.  Daiichi has been unsuccessful in its opposition, and I can see no reason to depart from the usual award to costs.  I award costs according to Schedule 8 against Daiichi Sankyo Company Limited.

    Dr Barbara Akhurst
    Delegate of the Commissioner of Patents

    Annex A: The opposed claims

    1. An isolated antibody or antigen binding fragment thereof, which specifically binds to a polypeptide consisting of SEQ ID NO: 48 or SEQ ID NO: 82 and which impairs an activity of the polypeptide in osteoclast precursor cells or in osteoclasts.

    2.The isolated antibody or antigen binding fragment thereof of claim 1, which inhibits osteoclast differentiation or bone resorption activity of osteoclasts.

    3. The isolated antibody or antigen binding fragment thereof of claim 1, wherein the activity is osteoclastogenesis.

    4. The isolated antibody or antigen binding fragment thereof of claim 1 or claim 2, which reduces differentiation of osteoclast precursor cells into osteoclasts.

    5. An isolated antibody or antigen binding fragment thereof, which impairs osteoclastogenesis, the antibody or antigen binding fragment thereof being isolated by the method of:

    a.    providing a candidate antibody or antigen binding fragment thereof able to bind to a polypeptide consisting of SEQ ID NO: 48 or SEQ ID NO: 82 to an osteoclast precursor cell;

    b.    testing osteoclastogenesis, whereby reduced osteoclastogenesis positively identifies an antibody or antigen binding fragment thereof which impairs osteoclastogenesis;

    c.    isolating the antibody and;

    d.    optionally producing antigen binding fragments of the isolated antibody.

    6. The isolated antibody or antigen binding fragment thereof of claim 5, which inhibits osteoclast differentiation or bone resorption activity of osteoclasts.

    7. The isolated antibody or antigen binding fragment thereof of any preceding claim, wherein the antibody is a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody or an antigen binding fragment thereof.

    8. The isolated antibody or antigen binding fragment thereof of any preceding claim, wherein the antigen binding fragment is a FV, a Fab, a Fab' or a (Fab')₂.

    9. The isolated antibody or antigen binding fragment thereof of any preceding claim, which is capable of binding to a polypeptide consisting of SEQ ID NO: 48 and to a polypeptide consisting of SEQ ID NO: 82.

    10. The isolated antibody or antigen binding fragment thereof of any one of claims 1 to 8, which binds to a polypeptide consisting of SEQ ID NO: 48 and does not bind to a polypeptide consisting of SEQ ID NO: 82.

    11. The isolated antibody or antigen binding fragment thereof of any preceding claim, which has sub-nanomolar affinity for the polypeptide.

    12. The isolated antibody or antigen binding fragment thereof of any preceding claim, which is linked to a toxin, an enzyme or a cytokine.

    13. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of any preceding claim and a pharmaceutically acceptable carrier.

    14. The pharmaceutical composition of claim 13, further comprising a drug or hormone.

    15. The pharmaceutical composition of claim 14, wherein the drug is an antiresorptive drug or a drug which increases bone mineral density.

    16. A method for treating bone remodeling, bone resorption or bone disease comprising administering an antibody or antigen binding fragment thereof which specifically binds to a polypeptide consisting of SEQ ID NO: 48 or SEQ ID NO: 82 to a subject in need.

    17. The method of claim 16, wherein the antibody or antigen binding fragment thereof is as defined in any one of claims 1 to 12 or is administered in a composition as defined in any one of claims 13-15.

    18. The method of claim 16 or claim 17, wherein the subject in need suffers from a condition selected from the group consisting of bone loss, osteoporosis, osteopenia, osteomalacia, hyperparathyroidism, hyperthyroidism, hypogonadism, thyrotoxicosis, systemic mastocytosis, adult hypophosphatasia, hyperadrenocorticism, osteogenesis imperfecta, Paget's disease, Cushing's disease/syndrome, Turner syndrome, Gaucher disease, Ehlers-Danlos syndrome, Marfan's syndrome, Menkes' syndrome, Fanconi's syndrome, multiple myeloma, hypercalcemia, hypocalcemia, arthritides, periodontal disease, rickets, fibrogenesis imperfecta ossium, osteosclerotic disorders such as pycnodysostosis and damage caused by macrophage-mediated inflammatory processes.

    19. A method for identifying a compound able to inhibit osteoclast differentiation, the method comprising:

    a.    contacting a candidate compound with a polypeptide having 80% identity with SEQ ID NO: 48 or SEQ ID NO: 82 or a cell expressing the polypeptide, wherein said polypeptide is capable of inducing osteoclast differentiation;

    b.    measuring activity or expression of the polypeptide;

    c.    testing the ability of the candidate compound to inhibit osteoclast differentiation or bone resorption,

    wherein a reduction in the activity or expression of the polypeptide and a reduction in at least one of osteoclast differentiation or bone resorption positively identifies a suitable inhibitory compound.

    20. The method of claim 19, wherein the polypeptide has a sequence at least 90% identical to SEQ ID NO: 48 or to SEQ ID NO: 82, at least 95% identical to SEQ ID NO: 48 or to SEQ ID NO: 82 or identical to SEQ ID NO: 48 or to SEQ ID NO: 82.

    21. The method of claim 19 or claim 20, wherein the step of measuring the activity or expression of the polypeptide comprises determining osteoclast differentiation.

    22. The method of any one of claims 19 to 21, wherein the method further comprises a step of inducing osteoclast differentiation.

    23. The method of any one of claims 19 to 22, wherein said candidate compound is capable of binding to the polypeptide.

    24. The method of any one of claims 19 to 23, wherein said candidate compound is an antibody or an antigen binding fragment thereof or an siRNA or a shRNA.

    …

    28. A compound capable of interfering with the activity or expression of a polypeptide consisting of SEQ ID NO: 48 or SEQ ID NO: 82 or a polypeptide encoded by SEQ ID NO: 1 or SEQ ID NO: 35 when used in modulating osteoclast differentiation or for treating bone disease, bone remodeling or bone resorption, wherein said compound is selected from the group consisting of isolated antibodies and antigen binding fragments thereof binding specifically to the polypeptide or to a fragment thereof and siRNAs or shRNAs specifically inhibiting activity or expression of a polypeptide encoded by SEQ ID NO: 1 or by SEQ ID NO: 35.

    …

    31. Use of an isolated polypeptide, isolated polynucleotide or compounds as defined in any one of claims 29 to 32, in the manufacture of a medicament for modulating osteoclast differentiation or for treating bone disease, bone remodeling, or bone resorption.

    32. Use of at least one polypeptide or antibody or antigen binding fragment thereof which specifically binds to the polypeptide in the diagnosis of bone disease, the polypeptide being selected from the group consisting of polypeptides having 80% identity with SEQ ID NO: 48 or SEQ ID NO: 82 which are capable of modulating osteoclast differentiation and fragments thereof.

    …

    36. The isolated polypeptide according to claim 25, the isolated polynucleotide according to claim 26 or 27, the compound according to claim 28, the pharmaceutical composition of claim 29 or 30, the use according to claim 31, 32 or 33, or the method of claim 34 or 35, wherein the bone disease is selected from the group consisting of bone loss, osteoporosis, osteopenia, osteomalacia, hyperparathyroidism, hyperthyroidism, hypogonadism, thyrotoxicosis, systemic mastocytosis, adult hypophosphatasia, hyperadrenocorticism, osteogenesis imperfecta, Paget's disease, Cushing's disease/syndrome, Turner syndrome, Gaucher disease, Ehlers-Danlos syndrome, Marfan's syndrome, Menkes' syndrome, Fanconi's syndrome, multiple myeloma, hypercalcemia, hypocalcemia, arthritides, periodontal disease, rickets, fibrogenesis imperfecta ossium, osteosclerotic disorders such as pycnodysostosis and damage caused by macrophage-mediated inflammatory processes.

    37. The isolated antibody or antigen binding fragment thereof of any one of claims 1 to 12, or the pharmaceutical composition of any one of claims 13 to 15, when used for treating bone remodeling, bone disease or bone resorption in a mammal.

    38. Use of an isolated antibody or antigen binding fragment thereof which specifically binds to a polypeptide consisting of SEQ ID NO: 48 or SEQ ID NO: 82 in the detection of differentiated osteoclasts.