Regeneron Pharmaceuticals, Inc. v Kymab Limited
[2019] APO 36
•31 July 2019
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Regeneron Pharmaceuticals, Inc. v Kymab Limited [2019] APO 36
Patent Application: 2011266843
Title:Animal models and therapeutic molecules
Patent Applicant: Kymab Limited
Opponent: Regeneron Pharmaceuticals, Inc.
Delegate: Sophina Calanni
Decision Date: 31 July 2019
Hearing Date: 14 September 2018, in Melbourne
Catchwords: PATENTS - section 59 opposition to grant of a patent – grounds of novelty, inventive step, clarity and fair basis – whether the claims suffer from parameteritis – whether the prior disclosure is enabled – whether the citation is publicly available – whether two citations may be considered a single source of information – whether the claimed product is an inevitable consequence of an earlier disclosed method – opposition unsuccessful on all grounds
Representation: Counsel for the applicant: Mr Tom Cordiner
Patent attorney for the applicant: Amanda Stark and Gavin Adkins, Griffith Hack
Counsel for the opponent: Mr Ben Fitzpatrick
Patent attorney for the opponent: Dr Prue Cowin and Dr Ian Rourke, FB Rice
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2011266843
Title:Animal models and therapeutic molecules
Patent Applicant: Kymab Limited
Date of Decision: 31 July 2019
DECISION
The Opposition is unsuccessful.
Costs awarded against Regeneron Pharmaceuticals, according to Schedule 8 of the Regulations.
REASONS FOR DECISION
Background
1. Patent application 2011266843 (the application) was filed by Kymab Limited (Kymab) on 7 January 2011 under the provisions of the Patent Cooperation Treaty. The application claims priority from two priority documents, US 61/355,666 and PCT/GB2010/051122, with an earliest priority date of 17 June 2010.
2. The application was examined and advertised accepted on 30 April 2015. Regeneron Pharmaceuticals, Inc. (Regeneron) filed a notice of opposition under section 59 of the Patents Act 1990 (the Act) on 30 July 2015.
3. The statement of grounds and particulars (SG&P) was filed on 30 October 2015. Throughout the opposition process, the SG&P was amended several times, with the final SG&P filed 31 January 2018 and allowed on 15 February 2018.
4. Kymab proposed amendments to the specification, specifically the claims, under section 104 on 3 August 2016, 7 September 2016, 25 October 2016. These amendments were successfully opposed by Regeneron[1]. Kymab subsequently filed further amendments to the claims on 6 September 2017. These amendments were allowed unopposed on Jan 2018. This decision is in relation to the specification as amended.
Evidence
The parties relied upon evidence by several declarants as set out in the table below.
Evidence Declarant Date of Declaration Reference Exhibits In support Dr Ian J. Rourke 20 January 2016 Rourke IJR-1 to IJR-49 Dr Chris C. Goodnow 29 January 2016 Goodnow #1 CCG-1 to CCG-2 Dr Mark W. Sleeman 29 January 2016 Sleeman #1 MWS-1 to MWS-2 Dr Lynn E. Macdonald 26 January 2016 Macdonald #1 LEM-1 to LEM-4 In answer Dr Victor Tybulewicz 29 April 2016 Tybulewicz #1 VT-1 to VT-4 Dr Marcus van Dijk 30 April 2016 van Dijk #1 MVD-1 to MVD-5 In reply Dr Chris C. Goodnow 4 July 2016 Goodnow #2 CCG-3 to CCG-4 Dr Mark W. Sleeman 4 July 2016 Sleeman #2 Dr Lynn E. Macdonald 29 June 2016 Macdonald #2 LEM-5 Regulation 5.23 (Applicant) Dr Marcus van Dijk 8 June 2017 van Dijk #2 MVD-6 to MVD-9 Evidence in reply to further evidence Dr Chris C. Goodnow 29 August 2017 Goodnow #3 CCG-5 to CCG-12 Regulation 5.23
(Opponent)Dr Mark W. Sleeman 25 January 2018 Sleeman #3 MWS-3 to MWS-5 Evidence in reply to further evidence Dr Marcus van Dijk 28 March 2018 van Dijk #3 MVD-10 The opposition
Grounds of opposition
5. The grounds of opposition pressed by the opponent were novelty, inventive step, clarity and fair basis.
Onus
6. The request for examination in relation to the patent application was received on 11 April 2013. Consequently, the substantive amendments of 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.
7. The onus of proof in this opposition proceeding lies with the opponent, who must establish that it is clear or practically certain that the patent is invalid[2]
8. The standard of proof of evidence leading to a conclusion of lack of novelty or lack of inventive step as stated by Besanko J. in Aspirating IP Limited v Vision Systems Limited is proof to a level of practical certainty[3]:
“The primary facts are to be established on the balance of probabilities, but the ultimate facts – the facts leading directly to a conclusion of a lack of novelty or a conclusion of obviousness – must be proved to the level of practical certainty. In Austal Ships, Bennett J said (at 423 [12]):
‘I can accept that a lower standard may apply to proof of evidence such as whether a document has been published or, indeed, whether a prior art vessel was well-known. I do not accept that it properly applies to the factual question that itself is the test for obviousness or lack of inventive step. Where the factual question is itself the legal test, as set out in s 7(3) of the Act, it seems to me that it should be determined at the higher standard. That means that where there are two opposing expert views that are conclusive on obviousness, both presented bona fide by witnesses of accepted expertise, unless one set of views can be rejected on proper grounds, the legal burden to establish a ground of opposition is not discharged; the court cannot be practically certain that obviousness or lack of inventive step is established.’”
The specification
9. The application is titled “Animal models and therapeutic molecules”. The specification relates to non-human mammals and cells engineered to express exogenous DNA, in particular immunoglobulin (Ig) gene DNA, methods for the production of such animals, and the antibodies and antibody chains produced by the animals.[4]
10. The disclosure is broadly directed to methods for the construction of chimeric human heavy and light chain loci in a non-human mammal[5] to produce antibodies or antibody chains having a non-human mammal constant region and a human variable region.[6]
11. Before construing the specification, I note the comments of Middleton J in Eli Lilly and Company Limited v Apotex Pty Ltd[7]:
“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.”
The person skilled in the art
12. It is well established that many of the issues in an opposition are answered by reference to the person skilled in the art:
“He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious.”[8]
13. The hypothetical skilled person works in the field with which the invention is connected and is a non-inventive person or team likely to have a practical interest in the subject matter of the invention.[9]
14. At the hearing Kymab provided a number of submissions regarding the evidence provided by Professor Goodnow, Professor Sleeman and Dr Macdonald. In effect their submissions assert that Dr van Dijk and Professor Tybulewicz are more representative of a hypothetical skilled team and as a result, where there are opposing expert views their views should be preferred, and certainly not ignored.[10]
15. Kymab submitted that Professor Goodnow is an eminent scientist and caution must be taken in relying on his evidence to the extent that it relates to what would be known by and considered obvious to the skilled worker in the field.[11] Similarly, while Professor Sleeman and Dr Macdonald clearly have relevant experience in the field of the invention, they have each worked for Regeneron and their statements are influenced by knowledge gained by working at Regeneron that would not be available to the hypothetical skilled addressee.[12]
16. I am satisfied that the hypothetical team representing the skilled addressee would comprise persons with a significant experience in molecular biology, particularly the generation of transgenic animals. Given the focus on the development of molecular models for the generation of antibodies, the hypothetical team representing the skilled addressee would also have a clear understanding of B cell maturation and antibody genetics, including the processes associated with the generation of antibody repertoires.
17. I agree that each of the declarants in this opposition has experience and expertise relevant to establishing the knowledge relevant to the person skilled in the art. Where there is conflicting evidence, I will decide which evidence should be given greater weight bearing in mind the parties’ submissions, including the submissions above regarding knowledge and experience of the experts.
Background of the invention
18. The opposed application does not provide a detailed description of antibody (or immunoglobulin, Ig) structure. Nonetheless, to understand the invention described it is useful to set out some background information regarding antibody structure and the gene loci that encode the immunoglobulin domains of these proteins. I note that this information is taken from the Regeneron’s written submissions.
19. A mammalian antibody comprises a characteristic unit structure as illustrated below. It consists of two identical heavy chain (HC) polypeptides and two identical light chain (LC) polypeptides. Each of the polypeptide chains comprises a variable (V) region at its amino terminus, which contributes to the antigen binding site, and a constant (C) region.
20. The heavy- and light- chains of the antibody are synthesized from separate immunoglobulin genes. The heavy chain gene locus is comprised of a number of discrete coding segments in the germline DNA known as variable (V), diversity (D) and joining (J) gene segments and constant (C) gene segment. The light chain gene locus comprises V, J and C gene segments. As noted by the declarants for both Kymab and Regeneron, the location, structure and organisation of the human, mouse and rat Ig loci were all well known[13].
21. The Ig genes which encode the HC and LC of an antibody are not present in germline B cells in the form to be transcribed as a complete functional unit that encodes an antibody[14]. During B cell development, the immunoglobulin gene segments are rearranged and joined together in a stepwise manner as illustrated below. This is a combinatorial process in which any one of several gene segments from each of the V, D (HC only) and J are recombined to form a single gene. There are 56 V, 23 D and 6 J segments in the human genome.
22. If the rearrangement of Ig gene segments is productive, creating a rearranged, successfully spliced transcript, the mature B cell will produce a single heavy and light chain. This process of gene rearrangement combined with somatic hypermutation, ensures the animal can produce a large array, or repertoire, of antibodies[15].
23. The background to the invention described on page 1 of the opposed specification states that in order to get around problems with humanizing antibodies a number of companies set out to generate mice with human immune systems. The strategy used was to knockout the heavy and light chain loci in ES cells and complement these genetic lesions with transgenes designed to express the human heavy and light chain genes.[16] The specification identifies several limitations encountered when creating animal models in this manner, including limitations on the size of loci introduced, low efficiency and high complexity when producing homozygous transgenic strains and the production of antibodies with low affinity for the antigen.
The invention as described
24. The specification states that the invention described provides a process for the generation in non-human mammals of antibodies that comprise a human Ig variable region.[17] More particularly, the specification describes several aspects of the invention where at the genome level the non-human mammal comprises human HC and LC loci that comprise human HC Ig V, D and J regions or human LC V and J regions, upstream of a host-derived constant region.[18] These human variable regions are suitably inserted upstream of a non-human mammal constant regions, such that there is a suitable relative location of the two antibody portions to allow the variable and constant regions to form a chimaeric antibody in vivo in the mammal.[19]
25. The specification states that:[20]
“…the transgenic loci used for the prior art models were of human origin, thus even in those cases when the transgene were able to complement the mouse locus so that the mice produced B-cells producing fully human antibodies, individual antibody affinities rarely reached those which could be obtained from intact (non-transgenic) animals. The principal reason for this (in addition to repertoire and expression levels described above) is the fact that the control elements of the locus are human. Thus, the signalling components, for instance to activate hyper-mutation and selection of high affinity antibodies are compromised.
In contrast, in the present invention, host non-human mammal constant regions are maintained and it is preferred that at least one non-human mammal enhancer or other control sequence, such as a switch region, is maintained in functional arrangement with the non-human mammal constant region, such that the effect of the enhancer or other control sequence,…is exerted in whole or in part in the transgenic mammal.
This approach above is designed to allow the full diversity of the human locus to be sampled, to allow the same high expression levels that would be achieved by non-human mammal control sequences such as enhancers, and is such that signalling in the B-cell, for examples isotype switching using switch recombination sites, would still use non-human mammal sequences.
A mammal having such a genome would produce chimaeric antibodies with human variable and non-human constant regions, but these could be readily humanized, for example in a cloning step. Moreover the in vivo efficiency of these chimaeric antibodies could be assessed in these animals.”
26. The specification goes on to describe various aspects of the invention, identifying particular gene regions to be targeted for insertion, as well as specific sequences for insertion.[21] In a preferred aspect of the invention, the host non-human mammal constant region is the endogenous wild-type constant region located at the wild-type locus[22]. It is also contemplated that the non-human mammal native constant region may be inserted or duplicated at a different chromosomal locus[23].
27. A range of possible insertions are contemplated in the different aspects of the invention described. These include the use of the entirety of human HC VDJ region, or LC VJ region, in its germline configuration with all of the V, D and J (HC) or V and J (LC) regions and intervening sequences[24], or the use of smaller portions of the human HC and LC VDJ or VJ regions[25]
28. The invention described also relates to vectors and methods used for the insertion or multiple DNA fragments into a DNA target. The method is especially applicable to the insertion of a large DNA fragment into a host chromosome which can be carried out in a stepwise fashion.[26]
29. The specification contains 6 examples, as summarised below.
30. Example 1 describes the overall strategy for producing the mouse model of the invention whereby ~960kb of the human heavy chain locus containing all the V, D and J-regions upstream of the mouse constant region and 473kb of the human kappa region are inserted upstream of the mouse constant region.
31. The specification states that insertion is achieved by gene targeting in ES cells using techniques well known in the art. In particular, insertion of the V-D-J region into each locus is achieved by insertion of human bacterial artificial chromosomes (BACs) into the locus. The relevant human BACs are an average 90kb in size.[27] In order to completely engineer the loci, it is necessary to perform a minimum of 10 targeting steps for IgH and 5 steps for IgK or IgL. Additional steps are also required to remove selection markers required for gene targeting.[28] Targeting of the genome of an ES cell to produce mice according to the invention is illustrated in Figures 1-18.
32. Example 2 provides an alternative method for the integration of transgenes into defined chromosomal loci via site specific recombination (SSR). The example describes insertion using a new SSR-based technique called sequential recombinase mediated cassette exchange (RMCE), which allows continuous insertion of the BAC inserts into the same locus.[29]
33. Example 3 represents the proof of concept approach illustrated in Figure 30 of the application where a landing pad is inserted into the mouse by homologous recombination. Sequential RMCE is used for iterative insertion of DNA into a landing pad at a defined genomic locus.
34. Example 4 uses the approach demonstrated in Example 3 to insert human sequences from the IGH locus. An engineered BAC was electroporated along with cre-expressing plasmid DNA into mouse ES cells containing the landing pad at the mouse IgH locus. The landing pad sequence being a nucleic acid region homologous to region of the target chromosome and comprising a nucleic acid site which permits recombinase-driven insertion of nucleic acids into the landing pad. Transfected cells were grown to select for appropriate insertion events. 7 clones were isolated.
35. Examples 5 and 6 characterise the mouse produced in example 4 These examples demonstrate that the inserted loci are functional in terms of gene rearrangement, junctional diversity and expression as analysed via real-time PCR and sequencing. Sequencing results indicate that the JH, DH and JK usages are similar to human results.
The claimed invention
36. The opposed application ends with 43 claims. Claims 1, 3, 14, 15 and 37 are independent claims. These claims broadly relate to transgenic animals that comprise a chimaeric immunoglobulin locus and the use of these animal models to produce a repertoire of antibodies. The claims are set out in full in the Annex to the decision.
Claim construction
37. The correct approach to the construction of the claims was summarised by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd[30]:
“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 claim which are unclear may be defined or clarified by reference to the body of the specification. The construction of a specification, including the claims, is ultimately a question of law for the decision maker.”
38. Where the construction of a claim was in dispute, I have addressed this below.
39. Claim 1 is the first independent claim. It reads:
A mouse whose genome comprises:
A plurality of human IgH V regions, one or more human D regions and one or more human J regions upstream of the mouse constant region;
one or more human Ig light chain kappa V regions or one or more human Ig light chain kappa J regions upstream of a mouse kappa constant region and optionally one or more human Ig light chain lambda V regions and one or more human Ig light chain lambda J regions upstream of a mouse lambda constant region;
wherein the mouse is able to produce a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a mouse constant region and a human variable region;
wherein the mouse genome comprises a chimaeric antibody chain locus, the locus encoding a chimeraric heavy chain; and
wherein the locus comprises a mouse constant region nucleotide sequence and a rearranged VDJ nucleotide sequence produced by in vivo rearrangement of a human V region, a human D region and a human J region;
the V region being a V1-3 segment; and
the mouse expressing more V1-3 JH4 or V1-3 JH6 antibodies than any of, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
40. Although this claim is quite complicated, it is at its core directed to a transgenic mouse expressing human Ig variable V, D and J genes and murine Ig constant region, where in B cells derived from the mouse there defined expression profiles in terms of specific V-J recombinations. The reasoning underpinning this construction is as follows.
A mouse whose genome comprises:
(a)A plurality of human IgH V regions, one or more human D regions and one or more human J regions upstream of the mouse constant region;
(b)one or more human Ig light chain kappa V regions or one or more human Ig light chain kappa J regions upstream of a mouse kappa constant region and optionally one or more human Ig light chain lambda V regions and one or more human Ig light chain lambda J regions upstream of a mouse lambda constant region;
41. These defined features encompass a mouse whose genome comprises:
·a plurality of human Ig heavy chain V regions;
·one or more human D regions; and
·one or more human J regions.
42. I understand “plurality” to mean more than one, therefore the mouse genome comprises more than one human Ig heavy chain V region.
43. The genome of the mouse also comprises one of the Ig LC kappa arrangements listed below:
·one or more human LC kappa V regions upstream of a mouse kappa constant region, or
·one or more human LC kappa J regions upstream of a mouse kappa constant region.
44. The mouse genome may optionally comprise one or more human LC lambda V regions and one or more human LC lambda J regions upstream of a mouse lambda constant region.
45. I note that in each of the gene arrangements described above, the human HC or LC V, D or J regions are upstream of the mouse constant region. I understand “upstream” to require that human gene region referred to is inserted at the 5’ end of the mouse constant region.
…wherein the mouse is able to produce a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a mouse constant region and human variable region;
46. As described above, an animal will produce a repertoire of antibodies following in vivo rearrangement of V, D and J gene sequences at the Ig gene loci. I consider that the limitation imposed by the above phrase demands that the mouse effectively carries out V, D, J gene rearrangement and produces a range of different B cells which each produce a different chimaeric antibody, or chimaeric HC or LC. The antibody, or HC and LC polypeptides, produced by the B cell will have a mouse Ig constant region and a human Ig variable region.
…wherein the mouse genome comprises a chimaeric antibody chain locus, the locus encoding a chimaeric heavy chain; and
wherein the locus comprises a mouse constant region nucleotide sequence and a rearranged VDJ nucleotide sequence produced by in vivo rearrangement of a human V region, a human D region and a human J region;
the V region being a V1-3 segment;47. At the hearing there was some contention regarding the term ‘genome’ in the context of this phrases above.
48. Regeneron asserted that the term genome typically relates to an organism’s full genomic DNA and as such it is unclear how the genome of the mouse described could include a rearranged VDJ nucleotide sequence produced by in vivo rearrangement[31]. As stated by Professor Sleeman[32]:
“…I find the use of the term “genome” scientifically incorrect in claim 1. More specifically, the term genome typically refers to the entire genetic material of an organism. However, the claim then refers to a “rearranged VDJ nucleotide sequence” which means some of the genome has been deleted…it is not clear if every cell of the mouse has a “rearranged VDJ nucleotide sequence” or just some. If I had to guess I assume it would be the latter option.”
49. Similarly, Professor Goodnow stated[33]:
“…it is not clear which part of “the genome” has the “rearranged VDJ nucleotide sequence”. Typically rearrangement only occurs in a fraction of cells. There is no evidence in the opposed application to suggest the animals comprise a rearranged VDJ sequence in their germline. It is assumed that the rearranged VDJ nucleotide sequence is referring only to a fraction of the cells (i.e., B cells) and not the genome in general (i.e., the germline).”
50. Kymab stated that generally the experts agreed that ‘genome’ in the specified context relates to the rearranged nucleotide sequence within the B cell. I also note that this is consistent with the use of the term in the specification where it is stated that “one skilled in the art could also sequence the genomes of B-cell clones derived from the chimeric animal and compare said sequence to wild-type sequence to ascertain the level of hypermutation, such hypermutation indicative of normal antibody maturation”.[34]
51. I consider that the evidence shows that the declarants for Regeneron understand that, in view of their general knowledge and the specification as a whole, the reference to the genome in the phrase above relates to the rearranged Ig gene locus within the B cell.
52. I therefore consider that, taken in view of the specification as a whole, the limitation imposed by the phrase above, requires that the mouse encompassed by the claim, at the B cell level, comprises a chimeric antibody chain locus where the nucleotide sequence encodes a chimaeric Ig heavy chain. The Ig heavy chain locus comprises a mouse heavy chain constant region and a rearranged human VDJ region that has been produced by in vivo rearrangement of the V, D and J Ig gene segments, and where the V-region must be a V1-3 Ig region.
53. I note that Regeneron submitted that, “the alleged invention is not directed to VH 1-3 antibodies at all. There is no requirement that the mice of the opposed application preferentially express VH1-3 antibodies.[35] At the hearing Kymab agreed with the suggestion that there was no requirement in the claims for a particular level, or more specifically, a higher frequency of VH1-3 usage in the rearranged human VDJ region of the HC locus. I agree that the above limitation requires the presence, at the B cell level, of B cell populations that use the VH1-3 segment following somatic rearrangement of the V, D and J gene segments however there is no requirement for higher frequency of VH1-3 usage. I also note that limitation does not infer the exclusion of other V segments in other B cell populations present in the mouse.
…the mouse expressing more V1-3 JH4 or V1-3 JH6 antibodies than any of, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies;
54. The parties disagreed on the appropriate construction of the phrase above.
55. Regeneron submitted that the combination of features referred to above requires that the mouse expresses antibodies having more V1-3 JH4 or V1-3 JH6 when compared to any one of V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5. That is the expression of either V1-3 JH4 or V1-3 JH6 antibodies needs to be higher than only one of the listed V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5.
56. Kymab submitted that the term ‘any’ has more than one acceptable definition. In one context it may refer to one or number of things as Regeneron have suggested, but another valid definition of the term obtained from the internet is ‘whichever of a specified class might be chosen’. It was their submission that, in the context of the specification as a whole, the latter is the appropriate definition to apply. That is, the claim encompasses a mouse where expression of V1-3 JH4 or V1-3 JH6 antibodies is higher than each of V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies. In support of this construction, Kymab pointed to Figures 35 and 39 (reproduced below) of the specification which each illustrate the distribution in JH usage in mice representative of the invention described. Turning to the figures, it can be seen that the experimental data demonstrates that looking at overall JH usage, the frequency of JH4 and JH6 usage is greater than each of JH1, JH2, JH3 or JH5. Similarly, with reference to JH usage in association with specific Ig V gene segments, specifically V1-3 as expressed in the present claim, the frequency JH4 and JH6 usage is again higher than each of JH1, JH2, JH3 and JH5. Kymab also noted that this observation accords with the interpretation offered by Professor Tybulewicz and Dr Van Dijk who state that claim 1 provides a mouse whose genome creates a preponderance of V1-3 spliced to JH4 or V1-3 spliced to JH6 in the rearranged gene loci[36].
Figure 35 Figure 39
57. I note that Professor Goodnow and Professor Sleeman’s understanding of the above phrase aligns with that of the Kymab declarants. That is, they each consider that the phrase relates to a “mouse having a rearranged V region which is a V 1-3 segment and that the mouse produces more V1-3 JH4 or V1-3 JH6 antibodies than other V1-3 antibodies”[37].
58. I agree with the interpretation applied by Kymab. I consider the phrase above relates to an evaluation of antibody VJ gene rearrangements within the mouse. The limitation imposed by the phrase demands an assessment of the frequency of JH usage within antibodies produced by the mouse, specifically those antibodies that utilise the V1-3 gene segment. The distinct VJ gene rearrangements are evaluated independently and to meet the limitation imposed the mouse must express more V1-3 JH4 or V1-3 JH6 antibodies than each of V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
59. The remaining independent claims relate to rat comprising the features described above and methods and uses of these mouse or rat animal models for the producing a repertoire of chimaeric antibodies or chimaeric heavy chains and chimaeric light chains or antibodies specific to a desired antigen. The comments at the hearing focused on claim 1 however it is apparent that due to the correlation between the independent claims the reasoning provided for claim 1 is also applicable for the remaining independent claims.
Clarity
60. It is a requirement of subsection 40(3) of the Act that the claims be clear. This requirement is satisfied if a person could ascertain “whether or not what he proposes to do falls within the ambit of the claim”[38]. Sufficient clarity will be provided if the claim provides a “workable standard suitable to the intended use”[39]
61. Regeneron identified claims 1-7, 12, 18, 19, 24, 25, 27, 33-35 and 42 as lacking clarity[40]. In the consideration below, where an analogous issue is raised against several claims, I will only re-count the first claim at issue.
Claims 1, 3, 14, 15 and 39
62. Regeneron submitted that claim 1 and 3 are unclear as they relate to the term genome. I have considered these matters in the construction of claim 1 above at [47]-[53]. As noted in that consideration, Regeneron’s own experts demonstrate that the claims provide a workable standard suitable to the intended use, and therefore I am satisfied the scope of the claims would be clear to the skilled addressee.
Claims 2 and 4
63. Claim 2 reads as follows:
“A mouse cell obtained from the mouse of claim 1, wherein the cell is a B cell or hybridoma.”Regeneron construed the reference in claim 2 and 4 to a cell “obtained from” the mouse of rat, to indicate that the cell is directly obtained from the mouse or rat.
64. Kymab noted that the opponent had raised the same objection in amendment opposition. In that proceeding the Delegate was satisfied that the scope of claims 2 and 4 would be clear to the skilled addressee.
65. I agree with the approach taken by the Delegate in the amendment opposition. The skilled addressee would appreciate that hybridomas are an immortalised cell line formed by the fusion of a single antibody-producing cell to a tumour cell[41]. Thus, the common sense and logical construction of claims 2 and 4 is that the hybridoma cell is one obtained indirectly by fusing a B cell, or other antibody-producing cell, derived from the mouse with a tumour cell.
Claim 5
66. Claim 5 reads as follows:
“A mouse according to claim 1, a rat according to claim 3, or a cell according to claim 2 or claim 4 comprising a switch comprising SEQ ID NO 1.”67. Regeneron asserted that it is unclear how any molecule can comprise SEQ ID NO:1 as the sequence is merely a string of amino acids represented by letters on a page[42].
68. First, I note that the SEQ ID NO:1 is the nucleotide sequence for a rat switch not a string of amino acids as suggested by Regeneron. With regard to the switch sequence, the specification states[43]:
“The cell or mammal of the invention may therefore comprise a human or non-human mammal switch sequence and a human or non-human mammal enhancer region or regions. They may be upstream of a human or non-human mammal constant region. Preferably the control sequences are able to direct expression or otherwise control the production of antibodies comprising a constant region with which they are associated. One combination envisaged is a rat switch with mouse enhancer sequences and mouse constant regions in a mouse cell.”
69. I consider that the skilled addressee would understand that a ‘switch region’ refers to specific nucleotide sequence elements that control VDJ recombination. A switch comprising SEQ ID NO:1 demands that the switch sequence within the cell or mammal germline sequence comprises the rat switch nucleotide sequence represented by SEQ ID NO:1.
Claim 6
70. Claim 6 reads as follows:
“A mouse, rat or cell according to any one of claims 1 to 5, wherein the human VDJ regions are operably linked in the genome with a sequence from a rat mu constant region.”71. Regeneron asserted that there is no antecedent for the human VDJ regions referred to in claim 6.
72. Claim 1 and 3 to which claim 6 is appended each include the following phrase:
“wherein the locus comprises a mouse constant region nucleotide sequence and a rearranged VDJ nucleotide sequence produced by in vivo rearrangement of a human V region, a human D region and a human J region.”
I consider that the skilled addressee would understand the human VDJ regions to be the rearranged VDJ nucleotide sequence referred to above.
Claim 7
73. Claim 7 reads as follows:
“A mouse, rat or cell according to any one of claims 1 to 6, wherein the genome comprises endogenous VDJ regions which have not been deleted.”
74. Regeneron submitted that the phrase “the genome comprises endogenous VDJ region which have not been deleted” is unclear. In particular, they considered it is not apparent whether all, or just a part of the endogenous VDJ region is present and whether the region must be in its native location in the genome. Regeneron stated that the opposed application teaches retaining the entire endogenous VDJ region and achieving activation by inversion.
75. However, I consider that the specification supports a range of mechanisms for preventing the expression of native antibodies in the model animal or cell. Such methods include inactivation of all or part of the host non-human mammal Ig loci. This may be achieved by inversion of all or part of the non-human mammal VDJ region[44]. The person skilled in the art would understand that the disclosure provided supports methods where the entire endogenous VDJ region may be retained, or where molecular approaches are targeted to part of the VDJ gene locus. Claim 7 encompasses a mouse whose endogenous Ig VDJ regions are not deleted. I am therefore satisfied that the claim is clear.
Claim 12
76. Claim 12 reads:
“A cell according to any one of claim 2 and claims 4-9 which is immortalised.”77. Regeneron considered that claim 12 lacks clarity on the basis that it is not clear how you can have a non-immortalised hybridoma, or alternatively how a hybridoma which is immortalised can be immortalised again.
78. I note that the same issue was considered by the Delegate in her decision on the opposition to the amendments. The parties have not provided additional evidence for consideration and I agree with the reasoning provided in her decision. Accordingly, I consider the claim is clear.
Claim 18
Claims 18 reads as follows:
“Use according to claim 16 comprising providing
i.a nucleic acid encoding the antibody, or a part thereof, or
ii.sequence information which with a nucleic acid can be expressed encoding the antibody or a part thereof to be produced.”
79. Regeneron has asserted that in the absence of a definition in the application, it is not clear in what form the sequence information is to take and exactly what information is encompassed by the term. I am satisfied the skilled addressee would readily appreciate that a nucleic acid molecule can be provided in physical form in accordance with part (i) of claim 18, or alternatively via information that characterises its nucleic acid sequence. This constitutes “sequence information” in accordance with part (ii) of the claim and would enable the preparation of the nucleic acid molecule encoding the antibody or antibody part, thus allowing the antibody to be produced. I construe claim 18 accordingly.
Claim 19
80. Claim 19 reads as follows:
“Use according to claims 14 or 15, wherein the use further comprises obtaining a cell line derived from a cell of the mouse or rat respectively, the cell line comprising inserted rearranged human V, D, J, optionally encoding an antibody encoded by V1-2 JH4 or V1-3 JH6.”81. Regeneron argued that the use of the word “inserted” suggests that any additional rearranged sequences may be inserted.
82. Claim 19 is ultimately dependent on claims 14 or 15. Claims 14 and 15 relate to the use of a mouse or rat, respectively, having defined genomic characteristics and antibody expression profiles, for producing a repertoire of chimaeric antibodies or chimaeric heavy and light chains having a mouse or rat constant region and a human variable region. The additional limitation required by claim 19 is that the use further comprises obtaining a cell line derived from a cell of the mouse or rat. The cell line will comprise the human V, D, J sequences that were inserted into the animal and have undergone in vivo rearrangement. I do not consider that any additional rearranged sequences are inserted in the cell line.
Claim 24
83. Claim 24 reads:
“A method according to claim 23, further comprising replacing the mouse or rat constant region of an antibody or chimaeric antibody chain to produce a fully humanised antibody or antibody chain.”84. Regeneron stated that in the context of the invention, it is unclear how a non-chimaeric antibody (presumably covered by the phrase antibody) could be used to make a fully humanised antibody or antibody chain.
85. I consider that argument provided by the opponent applies a purely literal interpretation, rather than a purposive construction in view of the specification as a whole. The skilled addressee, reading the specification as a whole, would consider that the reference to an antibody in the claim relates to a chimaeric antibody. The claim is therefore clear.
Claim 25
86. Claim 25 reads:
“A method of claim 23 or 24 further comprising generating an antibody derivative of the antibody or antibody chain, wherein the derivative is specifically reactive with the antigen.”87. In relation to claim 25, Regeneron state that the specification does not provide any guidance as to what may or may not be considered an antibody derivative.
88. The specification states that:
“chimaeric antibodies or antibody chains generated in the present invention may be manipulated, suitably at the DNA level, to generate molecules with antibody-like properties or structure, such as a human variable region from a heavy or light chain absent a constant region, for example a domain antibody; or a human variable region with any constant region from either heavy or light chain from the same or different species; or a human variable region with a non-naturally occurring constant region; or human variable region together with any other fusion partner. The inventions relate to all such chimaeric antibody derivatives derived from chimaeric antibodies according to the present invention.”
89. I therefore consider that skilled addressee would understand that an antibody derivative refers to the modification of antibodies at the DNA level in accordance with the description above, resulting in the production of molecules with antibody-like properties or structures.
Claims 27 and 42
90. Claim 27 reads:
“A mouse, rat, cell us or method according to any one of claims 1 to 26 wherein the rearranged VDJ nucleotide sequence is produced by the in vivo rearrangement of human V1-3 and JH4 with D3-9, D3-10, D6-13 or D-19; or V1-3 and JH6 with D3-9, D3-10, D6-13 or D-19.”
91. Essentially the claim 27 defines a mouse, rat cell or method according to the preceding claims with specific D gene segment usage in the rearranged locus. Claim 42 covers similar subject matter and also specifies specific D gene segment usage.
92. Regeneron state that the claims are unclear because they refer to D-19, however such a D region segment does not exist.
93. The evidence establishes that the gene loci of the human Ig genes, including the regions of the human genome expressing the Ig heavy chain, Ig kappa light chain and Ig lambda light chain form part of the common general knowledge.[45] In view of their knowledge of the Ig gene structure Professors Sleeman and Goodnow read the claim as referring to D6-19. This is also consistent with the disclosure at page 29 of the specification[46]. It is therefore apparent that in the view of the specification as a whole the skilled addressee could readily resolve that the claim refers to D6-19, and therefore claims 27 and 42 are clear.
Claim 33
94. Claim 33 reads as follows:
A mouse according to claim 1 when made by a method comprising:
insertion of multiple DNA fragments into a mouse ES cell DNA target,
wherein the insertion is of a DNA fragment of >100kB into a host chromosome in a stepwise fashion,
and wherein during the stepwise insertion the 5’ end of the upstream 5’ DNA insert is increased in length,
wherein the method comprises insertion of a first DNA sequence into the target, the sequence having a DNA vector portion and a first sequence of interest (X1); insertion of a second DNA sequence into the vector portion of the first sequence, the second DNA sequence having a second sequence of interest (X2) and a second vector portion; and excising vector sequence DNA separating X1 and X2 to provide a contiguous X2X1 sequence within the target, wherein X1 and X2 are joined together directly without intervening sequences,
wherein X1 and X2 comprise human VDJ or VJ DNA,
the method further comprising modifying the mouse genome to prevent expression of fully host mouse specific antibodies in the mouse by inactivation of all or a part of the host mouse Ig loci, wherein said modifying is achieved by insertion of one or more site specific recombinase sites into the genome and then use of these sites in recombinase-mediated excision of all or part of the mouse Ig locus.95. Claim 33 defines the mouse of claim 1, when that mouse is made by a method which ultimately results in a DNA fragment of >100kB encoding a human VDJ or VJ sequence being inserted into a region of DNA in a chromosome in a mouse embryonic stem (ES) cell.
96. Regeneron stated that it is not clear whether each DNA fragment is to be >100kb or whether the total insert length is >100kb. I consider that read in context the total insert is >100kb. I note Professor Sleeman also applies this interpretation[47]. It is therefore apparent the phrase can be given meaning and is clear.
97. Regarding the method used to achieve the insertion of the sequences of interest into the target, Regeneron submitted that it was unclear whether in the method described the insertion steps referred to would result in the genome comprising multiple adjoining VDJ and/or VJ sequences.
98. In this regard I consider it is important to bear in mind the method defines a mouse according claim 1. The genome of the mouse of claim 1 comprises a chimaeric antibody chain locus that encodes a chimaeric heavy chain, with a mouse Ig constant region and human Ig variable region. There is no suggestion in claim 1 or elsewhere in the specification that there are multiple adjoining VDJ and/or VJ sequences, rather the figures and specification[48] describe the insertion of the entire VDJ and/or VJ regions, or parts thereof, in germline configuration. Thus, read in the context of the specification as a whole, the only logical construction is that the inserted sequence X2X1 encodes VDJ or VJ DNA. I note this is also consistent with the following explanation provided by Dr van Dijk: [49]
“I understand the claim in context means that X1 and X2 together comprise human VDJ or VJ DNA, consistent with the locus being built up in a stepwise manner and as described in the Figures. I do not consider that each X1 and X2 fragment contains VDJ segments, resulting in multiple separate VDJ VDJ insertions, for example: this is not the way I would read the claim in context.”
Claims 34 and 35
99. Claims 34 and 35 read as follows:
“34. The mouse of claim 33 in which the method comprises insertion of a further one or more DNA sequences, each DNA sequence having a further sequence of interest and a further vector portion, into the vector portion of the preceding DNA sequence, to build up a contiguous DNA fragment in the mouse ES cell DNA target and the inserted multiple DNA fragments form part of, or a complete human VDJ region.
35. A mouse according to claim 1 when made by a method comprising insertion of multiple DNA fragments into a mouse ES cell DNA target,
wherein the insertion is of a DNA fragment of >100kB into a host chromosome in a stepwise fashion,
and wherein during the stepwise insertion the 5’ end of the upstream (5’) DNA is insert is increased in length,
wherein the method comprises insertion of a first DNA sequence into the target, the sequence having a DNA vector portion and a first sequence of interest (X1); insertion of a second DNA sequence into the vector portion of the first sequence, the second DNA sequence having a second sequence of interest (X2) and a second vector portion; and excising any vector sequence DNA separating X1 and X2 to provide a contiguous X2X1 sequence within the target, wherein X1 and X2 are joined together directly without intervening sequences, wherein X1 and X2 comprising human VDJ,
the method further comprising modifying the mouse genome to prevent expression of the fully host mouse specific antibodies in the mouse by inactivation of all or part of the host mouse Ig loci, wherein said modifying is achieved by insertion of one or more site specific recombinase sites into the genome and then use of these sites in recombinase-mediated excision of all or part of the mouse Ig locus,
the method comprising insertion of a further one or more DNA sequences, each DNA sequences having a further sequence of interest and a further vector portion, into the vector portion of the preceding DNA sequence, to build up a contiguous DNA fragment in the mouse ES cell DNA target and the inserted multiple DNA fragments for part of, or a complete human VDJ region.”
100. Regeneron asserted that claims 34 and 35 are not clear for two reasons. First, they stated that with reference to the phrase “insertion of a further one or more DNA sequences, each DNA sequence having a further sequence of interest and a further DNA portion”, it is not clear which vector portion that additional DNA sequence is to be inserted into. Furthermore, as a consequence of the ambiguity regarding the insertion site for the further one or more DNA sequences it is not clear what is encompassed by the term “a contiguous DNA fragment”.
101. Claims 34 expands on the method of claim 33 to describe the insertion of additional DNA sequences to ultimately insert a >100kB DNA fragment encoding the human VDJ region (or part thereof) in the mouse ES cell DNA. It is therefore important to first consider the method defined in claim 33.
102. As discussed previously, claim 33 defines the mouse of claim 1, when that mouse is made by a method which ultimately results in a DNA fragment of >100kB encoding a human VDJ or VJ sequence being inserted into a region of DNA in a chromosome in a mouse. The insertion of the DNA fragment is achieved by the stepwise insertion of multiple (i.e. two or more) DNA fragments into the targeted region of the host chromosome, by means of DNA sequences comprising a vector sequence and human VDJ or VJ DNA (the V(D)J DNA being the first, second and any further sequences of interest). Once the second or any subsequent DNA sequence has been inserted, the vector portion separating the sequences of interest is excised, leaving contiguous sequences of interest. Claim 33 also requires that during the stepwise insertion the 5’ end of the upstream 5’ DNA insert is increased in length. That is, in building up the >100kB insertion each additional DNA fragment is inserted at the upstream end of the DNA already inserted, thus extending the length of the inserted DNA in the 5’ direction.
103. Claim 34 defines the insertion of a further one or more DNA sequences to form part of, or a complete human VDJ region. Having regard to the specification as a whole, and more particularly the method of claim 33 as required by the claim, I consider that any additional DNA fragments must be inserted at the upstream (5’) end of the DNA already inserted, in order extend the length of the inserted DNA in the 5’ direction. The ultimate requirement following the insertion of the two or more fragment is that the assembled fragment encodes the complete human VDJ (or VJ) region, or part thereof.
104. I consider that the DNA insertion strategy described above also extends to the method defined in claim 35. Accordingly, I do not consider there is any ambiguity, as suggested by Regeneron, as to the insertion site of the further one or more DNA sequences. That is, any additional DNA fragment for insertion is introduced upstream (5’) of the DNA already inserted. The inserted DNA fragment will therefore have the structure Xn…X3X2X1 (where n is the number of insertions performed) and will encode the complete human VDJ (or VJ) region, or a part thereof.
Summary of clarity
105. I find that claims 1-7, 12, 18, 19, 24, 25, 27, 33-35 and 42 are clear.
Novelty
106. Regeneron submitted that claims 1-4, 8, 12, 14-17, 19-25, 27, 30, 37 and 38-40 lack novelty in view of the following citations:
· WO 2002/066630 (Regeneron Pharmaceuticals, Inc.) 29 August 2002
· Macdonald et al. (2006) “VelociGene technology extended to humanization of several
megabases of complex gene loci” Poster as presented and in expanded format from 1st
International MUGEN Conferences on Animal Models for Human Immunological Disease, September 2006 (“the Macdonald poster”)· Stevens et al. “VelocImmune: Humanization of immunoglobulin loci using VelociGene technology” Poster as presented and in expanded format from 1st
International MUGEN Conferences on Animal Modesl for Human Immunological Disease, September 2006 (“the Stevens poster”)
107. Before dealing with the disclosure of the citation, I will first consider the first proposition put forward by Regeneron that the feature of V-J recombination frequencies is an inessential parameter and is representative of “parameteritis”.
Parametritis
108. Regeneron submitted that the feature describing the relative expression of V1-3 JH4 or V1-3 JH6 compared to V1-3 JH1, V1-3 JH2, V1-3JH3 or V1-3 JH5 should be regarded as a non-essential feature of the claim. They asserted that the inclusion of this parameter appears to be a case of parametritis as discussed by Laddie J in Raychem Corp’s Patents[50]
"This is the practice of seeking to repatent the prior art by limiting claims by reference to a series of parameters which were not mentioned in the prior art. Sometimes it includes reference to parameters measured on test equipment which did not exist at the time of the prior art. The attraction of this to a patentee is that it may be impossible to prove now that the prior art inevitably exhibited the parameters and therefore it is impossible for an opponent to prove anticipation. Even if that is what has happened here, it does not alter the task of the court. It must decide whether the opponent has proved anticipation or some other statutory ground of invalidity. Parametritismay make the court's task more difficult, but at the end of the day the test of invalidity must be the same, whatever the form of the claims."
109. At 46, Laddie J refers to the parameter (the S/D volume ration) that is used in the claims in that case as:
“essentially arbitrary and has little technical significance. The selection of a group of compositions by reference to such a parameter does not involve any inventive step. Although it may not be obvious, in the common use of that word, to limit a claim by reference to this particular meaningless and arbitrary parameter, that has nothing to do with patentability. Patents are not given for skill in inventing technically meaningless parameters.”[51]
110. In Australia there have been several cases where the issue has arisen, and they provide useful understanding. In Williams Advanced Materials Inc v Target Technology Co LLC (Williams)[52], Bennett J considered claims to an optical storage medium having a reflective layer including a silver – palladium alloy. Her Honour noted that the parameters were selected without a purpose:
“there is nothing in the specification that suggests that the proportions or the ranges of the metals in the alloys are in any way part of the invention, other than the mere reference to them. It is a case of ‘parameteritis’.”
Her Honour then found that certain of the claims were not novel.
111. In Austal Ships Pty Ltd v Stena Rederi Aktiebolag[53], Bennett J referred to the Williams case, and distinguished it because:
“there is reference in the patent specification and evidence which supports the fact that the parameters have been carefully chosen, are part of the invention and are related to a claimed advantage as part of the combination of the design”.
112. As stated in Euroceltique S.A. v Sandoz Pty Ltd,[54] the critical question is whether the parameters in a claim “have been chosen to achieve a technical effect, or they are an arbitrary convenience”. Put in the context of the present claims, the critical question is - has the expression profile incorporated in the claim been chosen to achieve a technical effect, or is it an arbitrary convenience?
113. Regeneron submitted that expression profile defined in the claim relates to arbitrarily chosen parameters. They submitted that the opposed application does not suggest that the inclusion of the integer (i.e. JH ratio) is an essential feature of the alleged invention or that it confers any technical effect. [55] Furthermore, both Professor Sleeman and Professor Goodnow consider that the claimed expression profile is an arbitrary selection of a feature from the data obtained from the mice exemplified in the application.[56]
114. Viewed in terms of the claim as a whole, Regeneron noted that an important point to consider is that the claim is directed to animal models that produce a repertoire of antibodies. The animal defined in the claims will produce a multitude of B-cells that express a range of rearranged of V, D and J segments depending on the gene segments inserted to form the chimaeric locus. In this context, the claim encompasses animals that may produce only a small percentage of antibodies that express the VH1-3 segment despite the alleged advantages of this feature.
115. In contrast, Kymab submitted that the claimed invention relates to animal model in which human-like V region usage with respect to JH combination is achieved. They submitted that the importance of this technical effect is taught in Example 5 which indicates that “JH, DH and JK usages (Figure 35 and Figure 36) are similar to those usages seen in humans (where VH regions are combined with JH4 or JH6 more than with any of, individually, JH1, JH2, JH3 or JH5).” They stated that it was not predictable at the priority date of the opposed application “that VH1-3 usage obtained with JH and DH and a mouse constant region would be similar in the animal model to those usages seen in humans.”
116. It is apparent that the expression profile defined in the claim is based on the experimental results presented in Example 5. In that example a range of experiments were conducted to assess the functionality. The data representative of the distribution of JH usage with VH segments tested is detailed in Figure 39.
Figure 39
117. In my opinion, the selection of the expression profile feature cannot be considered random or arbitrary as it clearly reflects the experimental results attained in the analysis performed. I accept Kymab’s submission that the feature is of technical significance because it demonstrates that following gene rearrangement a subpopulation of the B-cells within the repertoire of cells produced displays a human-like rearrangement in terms of VH 1-3 recombination with JH4 and JH6 genes which provides for an improved utility of the chimeric antibody repertoire.[57] Accordingly, the feature does not represent parameteritis and therefore for the claimed mouse to be anticipated the expression profile feature must be present in the prior disclosure or an inevitable consequence of the prior disclosure.
118. Subsection 7(1) of the Act states 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.
119. It is well established that the general test for lack of novelty is the reverse infringement test, as set out by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd][58]:
“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”.
120. This test is satisfied if the alleged anticipation discloses all the essential features of the invention as claimed[59]. The level of disclosure required is set out in General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd[60] (with references omitted):
“If carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated.
If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented. 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."
121. As summarised in Shell Internationale Research Maatschappij B.V. v ExxonMobil Research and Engineering Company[61] a prior publication which does not explicitly disclose all the integers of the claimed invention could still deprive the claimed invention of novelty if the missing integer is implicitly present such as where a missing integer is:
(a) inferable from information provided in the disclosure;
(b) an inherent property of an already existing product; or
(c) an inevitable or inexorable result of following the directions provided in the prior art.
122. For a feature to be ‘inferable’ from a citation, the skilled worker would need to be able to directly derive it from information in the disclosure or be able to understand the feature is present even if it is not explicitly mentioned.
123. If the skilled person cannot infer a feature from the disclosure, then the onus is on the opponent to show that it was nonetheless an ‘inherent property’ of the disclosed product or method. In such cases, the test for anticipation is necessarily a high one and an opponent must prove that:
(a) the prior art product necessarily had the claimed properties; or
(b) performing the prior art method would inevitably produce the same result.
124. As Lord Hoffman noted in SmithKline Beecham[62]:
“But the infringement must be not merely a possible or even likely consequence of performing the invention disclosed by the prior disclosure. It must be necessarily entailed. If there is more than one possible consequence, one cannot say that performing the disclosed invention will infringe. The flag has not been planted on the patented invention, although a person performing the invention disclosed by the prior art may carry it there by accident or (if he is aware of the patented invention) by design”.
WO 2002/066630
125. WO 2002/066630 (WO ‘630) was published on 29 August 2002. The document was published before the priority date of the claim and is therefore part of the prior art base.
126. WO ‘630 describes a method that enables the use of targeting vectors containing large regions of homology so as to modify endogenous genes or chromosomal loci in eukaryotic cells via homologous recombination. The large DNA targeting vectors used, referred to as LTVECs, are derived from fragments of cloned genomic DNA larger than those typically used by other approaches intended to perform homologous targeting in eukaryotic cells[63].
127. In describing the prior art methods WO ‘630 states that (references excluded):[64]
“The problem of engineering precise modifications into very large genomic fragments, such as those cloned in BAC libraries, has largely been solved through the use of homologous recombination in bacteria, allowing for the construction of vectors containing large regions of homology to eukaryotic endogenous genes or chromosomal loci. However, once made, these vectors have not been generally useful for modifying endogenous genes or chromosomal loci via homologous recombination because of the difficulty in detecting rare correct targeting events when homology arms are larger that 10-20 kb. Consequently, vectors generated using bacterial homologous recombination from BAC genomic fragments must still be extensively trimmed prior to use as targeting vectors. Therefore, there is still a need for a rapid and convenient methodology that makes possible the use of targeting vectors containing large regions of homology so as to modify endogenous genes or chromosomal loci in eukaryotic cells.
128. Broadly described, the citation discloses a method for creating and screening eukaryotic cells which contain modified endogenous genes or chromosomal loci. The method includes three key steps:[65]
1. The use of bacterial homologous recombination to precisely engineer a desired genetic modification within a large cloned genomic fragment, thereby creating a large targeting vector for use in eukaryotic cells (LTVECs);
2. Introducing the LTVEC into eukaryotic cells to modify the endogenous chromosomal locus of interest in the cells; and
3. The cells in which the targeted allele has been modified as desired are identified by an assay for modification of allele (MOA) of the parental allele that does not require sequence information outside of the targeting sequence, such as, for example, quantitative PCR.
129. A number of preferred embodiments are contemplated, including one in which the LTVEC is capable of accommodating large DNA fragments greater than 20kb, and in particular large DNA fragments greater than 100kb.[66] Another preferred embodiment is a genetically modified endogenous gene or chromosomal locus that is produced by the method of the invention.[67]
130. Example 3[68] of the citation contemplates the use of the methods described in accordance with the preferred embodiments discussed above to create a mouse that produces hybrid antibodies containing human variable regions and mouse constant regions. This is accomplished by direct, in situ replacement of the mouse variable region genes with their human counterparts.[69]
131. WO ‘630 states the following:
“Large insert (BAC) clones spanning the entire VDJ region of the human heavy chain locus are isolated (Figure 4A). …In this example, large insert (BAC) clones are isolated from the ends of the mouse VDJ region as a source of homology arms which are used to direct integration via homologous recombination of the human VDJ sequences in a two-step process.
In the first step, LTVEC1 (Figure 4D) is constructed by bacterial homologous recombination in E. coli. LTVECl contains, in order: a large mouse homology arm derived from the region upstream from the mouse DJ region but whose absolute endpoints are not important; a cassette encoding a selectable marker functional in ES cells (PGK-neomycin in this example); a loxP site; a large human insert spanning from several V gene segments through the entire DJ region; and a mouse homology arm containing the region immediately adjacent to, but not including, the mouse J segments. The 5' end of the downstream arm and the placement of the loxP sites define the 3' end of the region to be replaced in the locus. Mouse ES cells will be transformed by standard techiniques, for example, electroporation, with linearized LTVECl. Because direct introduction of LTVECl results in a modification of the endogenous variable gene locus, neomycin resistant colonies can be screened for correct targeting using a MOA assay. These targeted ES cells can give rise to mice that produce antibodies with hybrid heavy chains. However, it will be preferable to proceed with subsequent steps that will eliminate the remainder of the mouse variable segments.
In the second step, LTVEC2 (Figure 4C) is constructed by bacterial homologous recombination in E. coli. LTVEC2 contains, in order: a large mouse homology arm containing the region adjacent to the most distal mouse V gene segment, but not containing any mouse V gene segments; a large insert containing a large number of distal human V gene segments; a mutant loxP site called lox511 [Hoess, R.H., Wierzbicki,A. and AbremskLK. Nucleic Acids Res. 14:2287-2300 (1986)] in the orientation opposite to that of the wild type loxP sites in LTVEC2 and LTVECl (this site will not recombine with wild type loxP sites but will readily recombine with other lox511 sites); a wild type loxP site; a second selectable marker (PGK-hygromycinR in this example); and a mouse homology arm derived from the V region, but whose absolute endpoints are not important. The 3' end of the upstream homology arm and the placement of the loxP sites define the 5' end of the region to be replaced in the locus. Mouse ES cells that were correctly targeted with LTVEC1 will then be transformed by standard techniques with linearized LTVEC2, and hygromycin resistant colonies will be screened for correct targeting using a MOA assay for modifications in the endogenous variable gene locus. Correctly targeted ES cells resulting from this transformation will hereafter be referred to as "double targeted ES cells".
Subsequent transient expression of CRE recombinase in the double targeted ES cells will result in deletion of the remainder of the mouse V region.
Alternatively, the double targeted ES cells can be injected into host blastocysts for the production of chimeric mice. Breeding of the resultant chimeric mice with mice expressing CRE recombinase early in development will result in deletion of the remainder of the mouse V region in the progeny F1. This later alternative increases the likelihood that the hybrid heavy chain locus will be passed through the germline because it involves culturing the ES cells for fewer generations.”
132. A second proposed approach is also disclosed in the document. This approach is similar to that outlined above however the LTVECs contain only mouse sequence to introduce lox sites at the proximal and distal ends of the mouse variable region locus, followed by replacement of the mouse sequence with the whole or part of the orthologous human locus. RMCE is used to introduce the human sequence.
133. WO ‘630 the indicates that the final step is creating the mouse with a chimeric Ig locus will be performing the equivalent variable region substitutions on the lambda and kappa light chain loci and breeding all three hybrid loci to homozygosity together in the same mouse.[70]
134. A key point on which the experts disagreed was whether the disclosure of WO ‘630 provides sufficiently detailed information for a person skilled in the art to make the mice and antibodies disclosed.
135. It is well established that the level of disclosure required of a prior art document must “be such that a person of ordinary knowledge of the subject would at one perceive, understand and be able to practically apply the discovery without the necessity of making further experiments an gaining further information before the invention can be made useful”.[71]
136. The extent to which further experimentation may be permissible in cases where there is less than a literal disclosure was interpreted by Lord Reid in Van der Lely v Bamfords as follows:[72]
“Lord Westbury must have meant experiments with a view to discovery something not disclosed. He cannot have meant to refer to the ordinary methods of trial and error which involve no inventive step and are generally necessary in applying any discovery to product a practical result.”
137. The Full Bench in Apotex v Sanofi[73] provided a summary of some relevant principles as follows (without references):
· Where the prior publication discloses exactly what is claimed, there is anticipation.
· There is anticipation if the skilled addressee would add missing information to what is disclosed in the prior art as a matter of course and without the application of inventive ingenuity or undue experimentation. A disclosure is sufficient if it enables the skilled addressee, in the ordinary course and without invention, to add what is missing in the prior publication to obtain the claimed invention.
· If the prior art discloses the very subject matter of the invention, the person skilled in the art is assumed to be willing to make trial and error experiments to get it to work. If the disclosure is of an invention which, if performed, would infringe the patent, there is anticipation.
· The question is whether the disclosure is sufficient to enable the skilled addressee to perceive, understand and, where appropriate, apply the prior disclosure necessarily, but within the ordinary limits of trial and error, to obtain the invention.
138. In the present circumstances I must consider whether the information provided for the methods for achieving the targeted insertion of the human Ig variable locus (or elements thereof) is sufficiently specific to enable the skilled addressee to perceive, understand and apply the prior disclosure within the ordinary limits of trial and error, to obtain the invention.
139. Regeneron asserted that given the disclosure provided in WO ‘630 the skilled address has sufficient information to put the alleged invention in practice. As stated by Professor Goodnow[74]:
“In my opinion, there is sufficiently detailed information for a person with knowledge of the technical aspects of the field to make the transgenic mic and human antibodies. The reason for this is, as noted above, WO 2002/066630 contains a detailed description of steps that can be used to produce a transgenic mouse which produces chimeric antibodies which consist of human variable domain and mouse constant domain. These steps include the use of bacterial homologous recombination to create large targeting vectors, introduction of the targeting vector into eukaryotic cells for modification of endogenous chromosomal loci and analysis of eukaryotic cells to detect modified alleles (see e.g. page 4 lines 21-30). Whilst I accept that the production would take some time, nevertheless, in light of the detailed disclosure the skilled person would be able to produce the transgenic mouse taught.”
140. In contrast, Kymab’s experts considered that WO ‘630 could have inspired someone to start thinking about a research project to produce the mice with chimeric Ig loci conceptualised in the application, however the document does not provide sufficient information to put the alleged invention into practice.[75]
141. Referring to the disclosure provided by Example 3, Professor Tybulewicz states:[76]
“The method illustrated in Figure 4 and described in Example 3 suggests that in step 1 you need to use homologous recombination with LTVEC1 to insert 200 to 300kb of DNA containing at least one VH gene and all the DH and JH genes from the human heavy chain locus flanked by mouse homology arms of indefinite length. BAC-based vectors have a limit of about 350kb so if the insert was 200kb in length, the arms could not in total be more than 150kb between them. The homologous recombination step with LTVEC1 is said to also delete all the mouse variable locus DH and JH genes, which implies a deletion of at least 99.5kb. To perform what is described requires homologous recombination using a BAC-based vector to insert at least 200kb and delete around 100kb. There is no evidence in IJR8 that this was ever done and to my knowledge there is no evidence in the literature that targeting by homologous recombination to insert 200kb and simultaneously delete 100kb has ever been done, even to this very day, the issue being the large sizes of both the insertion and the deletion.”
142. The concerns raised by Kymab’s experts appear to relate to two issues, the level of detail provided about the targeting vectors and the size of the insertion and deletion proposed in Example 3.
143. The evidence shows that the mouse and rat genome Ig loci were known before the priority date of the application.[77] Thus in the absence of any evidence to the contrary, I am satisfied that, as stated by Professor Goodnow[78], the skilled addressee, would be capable of identifying the appropriate regions of the gene loci to incorporate into the targeting vector described.
144. The second consideration is whether the large insertions and deletions required to produce LTVEC1 could be achieved as described in WO ‘630. One difficulty here is that WO ‘630 describes a method that is said to enable the use of targeting vectors containing large regions of homology to modify endogenous genes or chromosomal loci[79], however the method has not been reduced to practice with inserts of the sizes envisaged. In the examples that have been reduced to practice only relatively small inserts (<10kb) were introduced into the targeted locus.[80] An insertion of this size is equivalent in size to the insertions attainable by the prior art methods available at the time.[81] As such, I do not consider that these examples on their own support the notion that larger targeted genetic insertions as described for the Ig locus were achievable at that time.
145. In their submissions, Regeneron noted that Kymab’s experts argue that WO ‘630 only describes homologous recombination to produce the insertion of 200kb and deletion 100kb envisaged in Example 3, where in fact WO ‘630 discloses several methods for making the specified genetic insertion. In particular, referring to Professor Goodnow’s declaration[82] they noted that WO ‘630 also describes the generation of a LTVEC comprising a mouse homology arm derived from the region upstream from the mouse DJ region, a cassette encoding a selectable marker, a lox P site, a large human insert spanning several V gene segments through the entire DJ and a mouse homology arm containing the region immediately adjacent to, but not including, the mouse J segments.[83] However I note that the method referred to by Professor Goodnow specifically refers to the construction of a LTVEC by homologous recombination[84] and the size of the insertion referred to is 144kb and therefore presents the same questions with regard to whether an insertion of this size could be made at that time.
146. Furthermore, with regard to the second approach described in the citation, none of the experts for either party has specifically considered whether the disclosure provided for RMCE is an enabling disclosure. However, I note that WO ‘630 clearly states that the method is similar to the method discussed above with the exception that site-specific recombinase sequences are introduced on the mouse LTVEC and Cre recombinase is used to specifically target in the human loci by cassette exchange. Further, while the evidence provided by the parties does not expressly address this method, I note that indirect evidence adduced by Dr van Dijk references the VelocImmune History Document[85] that had previously been filed and considered by the UK High Court in their decision in Regeneron Pharmaceuticals Inc v Kymab Limited & Novo Nordisk A/S.[86] This document provides a number of details about the development of the VelocImmune mouse and clearly states that “no-one had demonstrated efficient RMCE using inserts of the sizes required”.[87] Given that the method described requires the insertion of a large gene segment I consider that, on balance, it is reasonable to consider that this method would face the similar challenges with regard to size of the insertion required as discussed above with regard to homologous recombination.
147. In their submissions Regeneron referred to the decision of the UK Court of Appeal[88] , indicating that the decision reversed the finding of the UK High Court concluding that it would have been obvious to the skilled team and technically feasible at the priority date, to produce a transgenic mouse that would produce hybrid antibodies containing human variable regions and mouse constant regions using a mini-gene approach.[89] I note that this decision hinged on evidence provided by the experts regarding the possible approaches the skilled addressee would consider within the ordinary limits of trial and error to obtain the invention. Regeneron have not adduced any such information in the present opposition, and therefore I must afford this submission little weight in my consideration of the matter at hand.
183. Furthermore, in response to the allegation that the 1284HO 1242 HO mice used in the experiments described in her first declaration are not the same as those described in the Macdonald and Stevens posters, Dr Macdonald has clearly stated:
“The 1284HO 1242HO mice (aka 80 VH 40 VH mice) described in Macdonald et al (2014) are the same mice used in the experiments described in my first Declaration and those described in IJR-9 to IJR-11 and IJR-46 to IJR-49. Although not shown in the figures of IJR-9 to IJR-11 and IJR-46 to IJR-49, the most distal mouse VH gene segment was present in the 3h VH mice and all generations of 'VelocImmune' mice. The fact is, mice having the genotype used in the experiments in my first Declaration were first bred in 2006, and the actual mice used for the experiments in my first Declaration were born in 2010.”[124]
184. While Dr Macdonald has indicated the mice used in her experiments are genetically the same as VelocImmune III mice, she has also acknowledged that there is an inconsistency between the information provided in the poster and how the VelocImmune mice were in fact made. Thus, the evidence of experiments said to have been conducted using the VelocImmune III (1284HO 1242HO) mice to determine the antibody expression profile does not necessarily correspond to what would occur in a mouse produced according to the Macdonald and Stevens posters. Specifically, as the posters do not indicate that the VH1-86 gene segment was retained, I must consider whether a mouse that does not contain this mouse VH segment will inevitably produce a mouse that expresses more V1-3 JH4 or V1-3 JH6 antibodies than each of V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
185. The parties disagree about the relative importance of the VH1-86 gene segment. Kymab asserts that the retention of the mouse gene segment was deliberate since it was assumed to contain control elements important in locus expression and/or rearrangement, whereas Regeneron maintains that the omission that this gene segment would have no consequence.[125] The evidence presented in support of these statements is limited to a paper[126] by Dr Macdonald published in 2014, well after the priority date of the application. The paper states the following:
“This most distal variable gene segment which is a pseudogene in C57BL/6 mice, but potentially active, albeit with a poor RSS sequence, in the targeted 129 allele, was retained due to reports at the time (21) that elements at the distal end of the heavy chain locus might contain elements controlling locus expression and/or rearrangement. Although the elements 20–30 kb from the last VHJ558.55 have since been shown to be dispensable for IgH locus recombination (30), maintenance of mouse sequences at the most distal end of the locus may have buffered against the loss of other functional elements yet to be described.”
186. Given the paper was published almost 4 years after the priority date of the opposed application, I am not satisfied that this evidence can be used to establish what was known about the importance, or otherwise, of the VH1-86 gene segment.
187. In terms of the observed human antibody repertoire, the evidence[127] establishes that there is a recombinational bias, with variable gene usage biased towards particular gene sequences. However, the basis of the biased usage is not clear. A range of factors are considered to be involved including a range of genetic elements such as recombination sequence signals, enhancers, cis-acting elements that influence chromatin accessibility,[128] as well as a selection bias toward particular B cell populations.
188. Regeneron argued that it was known by the priority date that JH4 and JH6 are the most frequently used JH regions in the normal human antibody repertoire.[129] In particular, they referred to an article by Gallo et al (Gallo)[130] in support of their view that the person skilled in the art would expect a preference for human JH4 and JH6 in transgenic mice, and that the placement of the human heavy chain VDJ region in a mouse genome upstream of the heavy chain constant region will result in a chimaeric antibody repertoire with V1-3 JH4 and V1-3 JH6 usage as defined in the claims of the opposed application.[131]
189. Gallo describes the analysis of the frequency of human V and J usage in genetically modified mice (XenoMouse) expressing the majority of human V, D and J gene segments. With regard to Ig VH and JH usage, their analysis demonstrates that VH and JH gene segment use closely parallels that reported for human repertoires in every respect, with VH3 and VH4 the most frequently used VH gene segments and JH4 and JH6 the most frequently used JH gene segments.[132]
190. However, I question the inference by Regeneron that the analysis provided in Gallo supports their assertion that the placement of the human heavy chain VDJ region in a mouse genome upstream of the heavy chain constant region will result in a chimaeric antibody repertoire with V1-3 JH4 and V1-3 JH6 usage as defined in the claims of the opposed application. The analysis performed is at the level of VH or JH usage alone; there is no analysis of particular VH-JH combinations. I do not consider it reasonable to assume that the analysis of JH usage at the level of the whole antibody repertoire necessarily mean particular VH-JH combinations will demonstrate the same profile of JH usage. Even Professor Goodnow, having regard to Gallo, would only go as far as to state that there would most likely be a preference for JH4 and JH6.[133]
191. Taking into consideration
(a) the differences genetic elements in the VelocImmune mouse versus a mouse produced according to the information provided in the Macdonald and Stevens posters;
(b) limitations in the understanding of the specific elements that affect recombinatorial bias; and
(c) the lack of evidence about specific VH-JH combinations in the antibody repertoire;
it is my opinion that Regeneron has not established that a mouse produced according to the information provided in the Macdonald and Stevens poster would inevitably contain the claimed expression profile. As a consequence, I am not satisfied to the level of practical certainty required that the Macdonald and Stevens posters deprive the claims of their novelty.
Summary of Novelty
192. It has not been shown that the claims lack novelty.
Inventive Step
193. It is a requirement of subsection 18(1) of the Act that the invention, so far as claimed in any claim, involves an inventive step. Subsection 7(2) states that an invention is taken to involve an inventive step unless it would have been obvious to a person skilled in the art in the light of the common general knowledge, considered alone or together with the prior art (subsection 7(3)).
194. The test for whether an invention is obvious is to ask whether it would have been a matter of routine to proceed to the claimed invention. In Wellcome Foundation Ltd v V.R. Laboratories (Aust.) Pty LtdAickin J stated:[134]
“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.”
195. In Aktiebolaget Hassle v Alphapharm Pty Ltd the High Court also endorsed the reformulated Cripps question:[135]
“Would the notional research group at the relevant date, in all circumstances, which include the knowledge of all the relevant prior art and 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 solution to the problem.”
196. Regeneron submitted that to the extent that WO ‘630 does not anticipate all of the claims its combination with the common general knowledge deprives the claims of inventiveness.
197. The inventive step argument presented by Regeneron relies on the disclosure of WO ‘630, which I have determined does not represent an enabling disclosure. In my consideration above I decided that WO ‘630 does not provide sufficient information to put the alleged invention into practice and noted that the experts had not provided any information about the possible approaches the skilled addressee would consider within the ordinary limits of trial and error to obtain the invention. I consider that if the notional research group does not have sufficient information to perform the methods described, it necessarily follows that they would not be led as a matter for course to use these methods, nor expect that such methods would produce a solution to the problem being addressed. Accordingly, the inventive step case presented by Regeneron must fail.
Fair Basis
198. Regeneron identified claims 1-4, 14, 15, 28, 29, 31, 32, 39 and 41 as lacking fair basis.
199. In considering fair basis, the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd approved the words of Gummow J in Rehm Pty Ltd v Websters Security System (International) Pty Ltd[136]
“the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification.”
Claims 1 to 14, 15, 39 and 41
200. Regeneron submitted that the application provides no guidance how to produce a mouse or rat where only one of V1-3 JH4 or V1-3 JH6 antibodies are present at higher levels, than, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5.
201. Kymab suggested that basis for the contested feature can be found in several parts of the specification including pages 29-30, as well as relevant consistory clauses describing the first to sixth aspects of the invention. Similarly, claim 39 is in the same terms as claim 1 with the additional feature of that the mouse is a hybrid of C57BL/6, M129 such as 129/SV or BALB/c, which finds basis in the specification at page 21, paragraph 8.
202. The consideration of fair basis is not “a superficial test based solely on the presence or absence of words”,[137] rather I must consider what the specification discloses as the invention. In the present circumstances I find that the specification as a whole broadly describes methods for producing mice with chimaeric antibody chain loci comprised of a mouse constant region and human variable region. The skilled addressee would appreciate that mice created according to the principles described in the specification would produce different populations of B cells and that a range of antibody profiles could be expressed by the mouse. While the present specification exemplifies mice that exhibit particular antibody profiles, I am satisfied that a variety of mice would be broadly consistent with the body of the specification. Kymab has referred to specific consistory clauses and disclosures in the specification that provide a real and reasonably clear disclosure of mice with the features defined in claims 1 to 14, 15, 39 and 41. I agree. Claims 1 to 14, 15, 39 and 41 do not travel beyond the disclosure of the specification as a whole and are therefore fairly based.
Claims 28. 29, 31 and 32
203. Regeneron also contended that claims 28, 29, 31 and 32 directed to pharmaceuticals or kits comprising the antibody or antibody heavy or light chains of the invention lack fair basis as specific methods for producing a pharmaceutical or kit are not described.
204. Kymab pointed to the ninth and tenth aspects of the invention which specify a pharmaceutical composition or kit comprising an antibody produced by a method where a mouse or rat according to the invention is immunized and the antibody recovered. They also noted that Professors Sleeman and Goodnow[138] express the opinion that the claims define standard features and procedures, and as such do not travel beyond what is disclosed in the body of the specification.
205. I agree that claims 28, 29, 31 and 32 are consistent with what is disclosed in the specification as a whole and are therefore fairly based.
Conclusion
206. I find that the opposition was unsuccessful on all grounds.
Costs
207. Both parties submitted that costs should follow the event. I see no reason to depart from the principle that costs should follow the event. I therefore award costs in accordance with Schedule 8 against Regeneron.
Sophina Calanni
Delegate of the Commissioner of PatentsAnnex I Claims
1. A mouse whose genome comprises:
(a) a plurality of human lgH V regions, one or more human D regions and one or more human J regions upstream of a mouse constant region;
(b) one or more human lg light chain kappa V regions and one or more human lg light chain kappa J regions upstream of a mouse kappa constant region and optionally one or more human lg light chain lambda V regions and one or more human lg light chain lambda J regions upstream of a mouse lambda constant region;
wherein the mouse is able to produce a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a mouse constant region and a human variable region;
wherein the mouse genome comprises a chimaeric antibody chain locus, the locus encoding a chimaeric heavy chain; and
wherein the locus comprises a mouse constant region nucleotide sequence and a rearranged VDJ nucleotide sequence produced by in vivo rearrangement of a human V region, a human D region and a human J region;
the V region being a V1-3 segment; and
the mouse expressing more V1-3 JH4 or V1-3 JH6 antibodies than any of, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
2.A mouse cell obtained from the mouse of claim 1, wherein the cell is a B cell or hybridoma.
3.A rat whose genome comprises:
(a) a plurality of human lgH V regions, one or more human D regions and one or more human J regions upstream of a rat constant region;
(b) one or more human lg light chain kappa V regions and one or more human lg light chain kappa J regions upstream of a rat kappa constant region and optionally one or more human lg light chain lambda V regions and one or more human lg light chain lambda J regions upstream of a rat lambda constant region;
wherein the rat is able to produce a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a rat constant region and a human variable region;
wherein the rat genome comprises a chimaeric antibody chain locus, the locus encoding a chimaeric heavy chain; and
wherein the locus comprises a rat constant region nucleotide sequence and a rearranged VDJ nucleotide sequence produced by the in vivo rearrangement of a human V region, a human D region and a human J region, the V region being a V1-3 segment; and
the rat expressing more V1-3 JH4 or V1-3 JH6 antibodies than any of, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
4.A rat cell obtained from the rat of claim 3, wherein the cell is a B cell or hybridoma.
5. A mouse according to claim 1, a rat according to claim 3, or a cell according to claim 2 or claim 4 comprising a switch comprising SEQ lD NO 1.
6. A mouse, rat or cell according to any one of claims 1 to 5, wherein the human VDJ regions are operably linked in the genome with a sequence from a rat mu constant region.
7. A mouse, rat or cell according to any one of claims 1 to 6, wherein the genome comprises endogenous VDJ regions which have not been deleted.
8. A mouse, rat or cell according to any one of claims 1 to 7, wherein the genome does not comprise constant region DNA from another non-human organism.
9. A mouse cell, or a mouse comprising said mouse cell, according to any one of claims 1, 2 and 5-8 wherein the mouse cell is a hybrid of C57BL/6, a hybrid of M129 such as 129/SV, or a hybrid of BALB/c.
10. A rat or mouse according to any one of claims 1, 3 and 5-8 whose genome comprises an antibody chain locus comprising a germline human kappa V1-8 and germline human kappa J1 sequence, and wherein an antibody is obtainable by in vivo recombination in said rat or mouse of the V1-8 and J1 sequences and wherein the antibody has a variable region sequence which is different from that which is encoded by germ line human kappa V1-8 and germline human kappa J1 sequences.
11. A rat or mouse according to any one of claims 1, 3 and 5-8 whose genome comprises an antibody chain locus comprising a germline human kappa V1-6 and germline human kappa J1 sequence, and wherein an antibody is obtainable by in vivo recombination in said rat or mouse of the V1-6 and J1 sequences and wherein the antibody has a variable region sequence which is different from that which is encoded by germ line human kappa V1-6 and germline human kappa J1 sequences.
12.A cell according to any one of claim 2 and claims 4-9 which is immortalised.
13.A cell according to claim 12 which is immortalised by fusion to a tumour cell to provide an antibody producing cell, or made by direct cellular immortalization.
14. Use of a mouse for producing a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a mouse constant region and a human variable region, the mouse genome comprising:
(a) a plurality of human lgH V regions, one or more human D regions and one or more human J regions upstream of a mouse constant region;
(b) one or more human lg light chain kappa V regions and one or more human lg light chain kappa J regions upstream of a mouse kappa constant region and optionally one or more human lg light chain lambda V regions and one or more human lg light chain lambda J regions upstream of a mouse lambda constant region;
wherein the mouse is able to produce a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a mouse constant region and a human variable region;
wherein the mouse genome comprises a chimaeric antibody chain locus, the locus encoding a chimaeric heavy chain; and
wherein the locus comprises a mouse constant region nucleotide sequence and a rearranged VDJ nucleotide sequence produced by the in vivo rearrangement of a human V region, a human D region and a human J region, the V region being a V1-3 segment; and
the mouse expressing more V1-3 JH4 or V1-3 JH6 antibodies than any of, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
15. Use of a rat for producing a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a rat constant region and a human variable region, the rat genome comprising:
(a) a plurality of human lgH V regions, one or more human D regions and one or more human J regions upstream of a rat constant region;
(b) one or more human lg light chain kappa V regions and one or more human lg light chain kappa J regions upstream of a rat kappa constant region and optionally one or more human lg light chain lambda V regions and one or more human lg light chain lambda J regions upstream of a rat lambda constant region;
wherein the rat is able to produce a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a rat constant region and a human variable region;
wherein the rat genome comprises a chimaeric antibody chain locus, the locus encoding a chimaeric heavy chain; and
wherein the locus comprises a rat constant region nucleotide sequence and a rearranged VDJ nucleotide sequence produced by the in vivo rearrangement of a human V region, a human D region and a human J region, the V region being a V1-3 segment; and
the rat expressing more V1-3 JH4 or V1-3 JH6 antibodies than any of, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
16. Use according to claims 14 or 15, the use comprising immunizing the mouse or rat respectively with a desired antigen and recovering antibody specific to the antigen.
17. Use according to claim 16, wherein the antibody or cells expressing the antibody are recovered, and then replacing the mouse or rat constant region respectively with a human constant region to produce a fully humanised antibody.
18.Use according to claim 16 comprising providing
(i) a nucleic acid encoding the antibody, or a part thereof, or
(ii) sequence information from which a nucleic acid can be expressed encoding the antibody or a part thereof to be produced.
19. Use according to claims 14 or 15, wherein the use further comprises obtaining a cell line derived from a cell of the mouse or rat respectively, the cell line comprising inserted rearranged human V, D, J, optionally encoding an antibody encoded by V1-3 JH4 or V1-3 JH6.
20. Use according to claims 14 or 15, wherein the use further comprises growing a cell line from a cell of the mouse or rat respectively, the cell line comprising rearranged human V, D, J, optionally encoding an antibody encoded by V1-3 JH4 or V1-3 JH6.
21.Use according to claims 19 or 20 wherein the cell line is an immortalised cell line.
22. Use according to claim 21 wherein the cell line is immortalised by fusion to a tumour cell to provide an antibody producing cell line, or is made by direct cellular immortalisation.
23. A method for producing an antibody or antibody heavy chain or antibody light chain specific to a desired antigen, the method comprising immunizing a mouse according to any one of claims 1 or 5 to 8 or a rat according to any one of claims 3 or 5 to 8 with the desired antigen and recovering the antibody or antibody chain or recovering a cell producing the antibody or antibody chain.
24. A method according to claim 23, further comprising replacing the mouse or rat constant region of an antibody or chimaeric antibody chain to produce a fully humanised antibody or antibody chain.
25. A method according to claim 23 or claim 24 further comprising generating an antibody derivative of the antibody or antibody chain, wherein the derivative is specifically reactive with the antigen.
26.A method for making an antibody, or part thereof, the method comprising providing
(i) a nucleic acid encoding an antibody, or a part thereof, the antibody being obtained according to the method of any one of claim 23-24; or
(ii) sequence information from which a nucleic acid can be expressed to allow an antibody or a part thereof to be produced, the antibody being obtained according to the method of any one of claim 23-24.
27. A mouse, rat, cell, use or method according to any one of claims 1 to 26 wherein the rearranged VDJ nucleotide sequence is produced by the in vivo rearrangement of human V1-3 and JH4 with D3-9, D3-10, D6-13 or D-19; or V1-3 and JH6 with D3-9, D3-10, D6-13 or D-19.
28. A method according to any one of claims 23 to 25 further comprising combining the antibody, antibody chain or antibody derivative with a pharmaceutically acceptable carrier or other excipient to produce a pharmaceutical composition.
29. A method according to any one of claims 23 to 25 further comprising making a kit comprising the antibody, antibody chain or derivative.
30. An antibody, antibody chain or antibody derivative, or a recovered cell producing the antibody or antibody chain, produced by a method according to any one of claims 23 to 25.
31. A pharmaceutical composition comprising an antibody, antibody chain or antibody derivative produced by a method according to any one of claims 23 to 25 and a pharmaceutically acceptable carrier or other excipient.
32. A kit comprising an antibody, antibody chain or antibody derivative produced by a method according to any one of claims 23 to 25 or a pharmaceutical composition according to claim 31.
33.A mouse according to claim 1 when made by a method comprising insertion of multiple DNA fragments into a mouse ES cell DNA target,
wherein the insertion is of a DNA fragment of >100kB into a host chromosome in a stepwise
fashion,
and wherein during the stepwise insertion the 5' end of the upstream (5') DNA insert is
increased in length,
wherein the method comprises insertion of a first DNA sequence into the target, the sequence having a DNA vector portion and a first sequence of interest (X1 ); insertion of a second DNA sequence into the vector portion of the first sequence, the second DNA sequence having a second sequence of interest (X2) and a second vector portion; and excising vector sequence DNA separating X1 and X2 to provide a contiguous X2X1 sequence within the target, wherein X1 and X2 are joined together directly without intervening sequences,
wherein X1 and X2 comprise human VDJ or VJ DNA,
the method further comprising modifying the mouse genome to prevent expression of the fully host mouse specific antibodies in the mouse by inactivation of all or a part of the host mouse lg loci, wherein said modifying is achieved by insertion of one or more site specific recombinase sites into the genome and then use of these sites in recombinase-mediated excision of all or a part of the mouse lg locus.
34. The mouse of claim 33 in which the method comprises insertion of a further one or more DNA sequences, each DNA sequence having a further sequence of interest and a further vector portion, into the vector portion of the preceding DNA sequence, to build up a contiguous DNA fragment in the mouse ES cell DNA target and the inserted multiple DNA fragments form part of, or a complete human VDJ region.
35.A mouse according to claim 1 when made by a method comprising insertion of multiple DNA fragments into a mouse ES cell DNA target,
wherein the insertion is of a DNA fragment of >100kB into a host chromosome in a stepwise fashion,
and wherein during the stepwise insertion the 5' end of the upstream (5') DNA insert is increased in length,
wherein the method comprises insertion of a first DNA sequence into the target, the sequence having a DNA vector portion and a first sequence of interest (X1); insertion of a second DNA sequence into the vector portion of the first sequence, the second DNA sequence having a second sequence of interest (X2) and a second vector portion; and excising any vector sequence DNA separating X1 and X2 to provide a contiguous X2X1 sequence within the target, wherein X1 and X2 are joined together directly without intervening sequences,
wherein X1 and X2 comprise human VDJ,
the method further comprising modifying the mouse genome to prevent expression of the fully host mouse specific antibodies in the mouse by inactivation of all or a part of the host mouse lg loci, wherein said modifying is achieved by insertion of one or more site specific recombinase sites into the genome and then use of these sites in recombinase-mediated excision of all or a part of the mouse lg locus
the method comprising insertion of a further one or more DNA sequences, each DNA sequence having a further sequence of interest and a further vector portion, into the vector portion of the preceding DNA sequence, to build up a contiguous DNA fragment in the mouse ES cell DNA target and the inserted multiple DNA fragments form part of, or a complete human VDJ region.
36. A mouse according to claim 1 when made by a method comprising inserting into a mouse ES cell genome a plurality of human IgH V regions, one or more human D regions and one or more human J regions upstream of the host mouse heavy chain constant region; wherein
(a) the insertion of the human heavy chain DNA is made between the mouse constant region and the last, 3', mouse J region;
(b) the insertion is such that the mouse is able to produce a repertoire of chimaeric antibodies or heavy chains having a mouse constant region and a human variable region; and
the method comprises modifying the mouse genome to prevent expression of the fully host mouse specific antibodies in the mouse by inactivation of all or a part of the host mouse mammal lg loci, wherein said modifying is achieved by insertion of one or more site specific recombinase sites into the genome and then use of these sites in recombinase-mediated excision or inversion of all or a part of the mouse lg locus.
37. A mouse according to claim 1 when made by a method comprising inserting into a mouse ES cell genome a plurality of human lgH V regions, one or more human D regions and one or more human J regions upstream of the host mouse heavy chain constant region; wherein
(a) the insertion of the human heavy chain DNA is made between the mouse constant region and the last, 3', mouse J region;
(b) the insertion is such that the mouse is able to produce a repertoire of chimaeric antibodies or heavy chains having a mouse constant region and a human variable region; and
(c) wherein the insertion process commences at a site where an initiation cassette has been inserted into the genome, providing a unique targeting region; wherein the insertion of a first DNA fragment into the initiation cassette is followed by insertion of a second DNA fragment into a portion of the first DNA fragment;
(d) and wherein during the stepwise insertion the 5' end of the upstream (5') DNA insert is increased in length.
38. A mouse or mouse cell or rat or rat cell according to any of claims 1-13 or 33-37, or use according to any one of claims 14- 22, wherein the mouse or rat genome comprises the following human regions:
Vh 2-5, 4-4, 1-3, 1-2, 6-1;
Dh 1-1, 2-2, 3-3, 4-4, 5-5, 6-6, 1-7, 2-8, 3-9, 3-10, 4-11, 5-12, 6-13, 1-14, 2-15, 3-15, 4-17, 5-18, 6-19,
1-20, 2-21, 3-22, 4-23, 5-24, 6-25, 1-26, 7-27;
Jh 1, 2, 3, 4, 5, 6;
Vk 1-9, 1-8, 1-6, 1-5; and
Jk 1, 2, 3, 4, 5
39.A mouse whose genome comprises:
(a) a plurality of human lgH V regions, one or more human D regions and one or more human J regions upstream of a mouse constant region;
(b) one or more human lg light chain kappa V regions and one or more human lg light chain kappa J regions upstream of a mouse kappa constant region and optionally one or more human lg light chain lambda V regions and one or more human lg light chain lambda J regions upstream of a mouse lambda constant region;
wherein the mouse is able to produce a repertoire of chimaeric antibodies, or chimaeric heavy chains and chimaeric light chains, having a mouse constant region and a human variable region;
wherein the mouse genome comprises a chimaeric antibody chain locus, the locus encoding a chimaeric heavy chain; and
wherein the locus comprises a mouse constant region nucleotide sequence and a rearranged VDJ nucleotide sequence produced by in vivo rearrangement of a human V region, a human D region and a human J region;
the V region being a V1-3 segment; and
the mouse expressing more V1-3 JH4 or V1-3 JH6 antibodies than any of, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
wherein the mouse is a hybrid of C57BL/6, a hybrid of M129 such as 129/SV, or a hybrid of BALB/c.
40.A mouse cell when obtained from the mouse according to claim 39.
41. A mouse according to claim 1 or claim 33-37 or claim 39, a cell according to claim 2 or claim 4, a rat according to claim 3 or use according to claim 14 or claim 15, in which the mouse or rat or cell expresses more V1-3 JH6 antibodies than any of, individually, V1-3 JH1, V1-3 JH2, V1-3 JH3 or V1-3 JH5 antibodies.
42. A mouse, rat, cell or use according to claim 41 wherein the rearranged VDJ nucleotide sequence is produced by the in vivo rearrangement of human V1-3 and JH6 with D3-9, D3-10, D6-13 or D-19.
43. A mouse according to claim 1 or claim 33-37 or claim 39, a cell according to claim 2 or claim 4, a rat according to claim 3, use according to claim 14 or claim 15, a method according to claim 23 or claim 26, an antibody, antibody chain or antibody derivative, or a recovered cell producing the antibody or antibody chain, according to claim 30, a pharmaceutical composition according to claim 31, or a kit according to claim 32, substantially as hereinbefore described, with reference to the examples and figures.
[1]Regeneron Pharmaceuticals v Kymab Limited [2017] APO 37.
[2] Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [67]; [2000] FCA 283; 50 IPR 305, Commissioner of Patents v Sherman [2008] FCAFC 182 at [18]; [2008] FCAFC 182; 79 IPR 426.
[3][2010] FCA 1061 at [35]; [2010] FCA 1061; 88 IPR 52.
[4]Specification p 1, paragraph 1.
[5]Specification p 5, last paragraph 8.
[6]Specification p 7, paragraph 6.
[7][2013] FCA 214;100 IPR 451 at [139].
[8]Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70].
[9]Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70]-[72].
[10]Kymab’s Written Submissions at [5.5].
[11]Kymab’s Written Submissions at [5.10] - [5.12].
[12]Kymab’s Written Submissions at [5.16]- [5.17].
[13]Consistent with Goodnow #1[20], Sleeman #1 [24].
[14]Regeneron’s written submissions [13], consistent with Goodnow #1 [21], Sleeman #1 [26]-[27], Tybulewicz #1 [3.6].
[15]Consistent with Goodnow #1 [21], Sleeman #1 [26].
[16]Specification page 1, paragraph 2.
[17]Specification page 1, penultimate paragraph.
[18]Specification pages 2-3c.
[19]Specification page 8, paragraph 6.
[20]Specification page 8, final paragraph- page 9 paragraph 4.
[21] Specification page 9, paragraph 6-page 20. paragraph 3.
[22] Specification page 8, paragraph 2.
[23] Specification page 8, paragraph 4.
[24] Specification page 9, paragraph 5.
[25] Specification page 6, paragraphs 5-7.
[26] Specification page 23, paragraph 3.
[27] Specification page 35, paragraphs 3-5.
[28] Specification page 36, paragraph 5.
[29] Specification pages 42-45.
[30] [2009] FCAFC 70, 81 IPR 228 at [118]–[120].
[31] Regeneron’s written submissions at [232].
[32] Sleeman #1[88].
[33] Goodnow #1 [78].
[34] Specification, page 38, paragraph 1.
[35] Regeneron’s written submissions [87].
[36] Consistent with Tybulewicz #1 [4.3] and van Dijk #1 [5.5].
[37] Sleeman #1 [90], consistent with Goodnow #1 [76].
[38] Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59at 60.
[39] Minnensota Mining & Manufacturing Cov Beiersdorf (Australia) Ltd [1980] HCA 9; (1980) 144 CLR 253 at 274.
[40] Regeneron’s written submissions [231]-[246].
[41] See for example Henderson’s Dictionary of Biology, 13th Edition, 2005.
[42] Regeneron’s written submissions [234].
[43] Specification p17, paragraph 5.
[44] Specification, p 22, final paragraph - p 23, paragraph 2.
[45] Goodnow #1 [21], Sleeman #1 [24], van Dijk #1 3.2
[46] Specification, page 29, final paragraph
[47] Sleeman #3 [49]
[48]Specification, Figures 10-13; page 9, paragraphs 5, 7; page 11, last paragraph.
[49] van Dijk #3, paragraph 3.18.
[50] [1997] EWHC 372, [1998] RPC 31 at 37.
[51] [1997] EWHC 372, [1998] RPC 31 at 46-47.
[52] [2004] FCA 1405 [2004] FCA 1405; 63 IPR 645 at 654.
[53]
[54] [2009] APO 21 at [112].
[55] Regeneron’s Written Submissions at [90].
[56] Goodnow #1 [29]-[30] and Sleeman #1 [93].
[57] Kymab’s written submissions 1.11, 6.20.
[58] [1977] HCA 19 at [20]; [1977] HCA 19; 137 CLR 228 at 235.
[59] Nicaro Holdings Pty Ltd v Martin Engineering Co [1990] FCA 40; (1990) 91 ALR 513 at 517.
[60] General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd, [1972] RPC 457 at 485-486.
[61] [2014] APO 31.
[62] [2006] RPC 10 at [23].
[63] WO ‘630, page 1 lines 11-15.
[64] WO ‘630, page 3 lines21- page 4 line 4.
[65] WO ‘630, page 4 lines 21-30.
[66] WO ‘630, page 6 lines 4-.6
[67] WO ‘630 page 6 lines 22-23.
[68] WO ‘630 pages 41- 52.
[69] WO ‘630 page 43 lines 15-17.
[70] WO ‘630 page 52 lines 6-9.
[71] Hill v Evans [1862] EngR 365; (1862) 6 LT 90.
[72] Van der Lely NV v Bamfords Ltd [1963] RPC 61.
[73] Apotex Pty Ltd v Sanofi-Aventis [2009] FCAFC 134 at [104].
[74] Goodnow #1 paragraph 47, consistent with Sleeman #1.
[75] van Dijk #1 4.5, Tybulewicz #1 5.3.
[76] Tybulewicz #1 paragraph 5.4.
[77] IJR 32-35, consistent with Goodnow #1 [20], Sleeman #1 [24].
[78] Goodnow #2 [17].
[79] WO ‘630 page 4 lines 6-8.
[80] WO ‘630 Examples 1 and 2.
[81] WO ‘630 page 2 line 14–page 3 line 2.
[82] Goodnow #2 [19]-[21].
[83] Regeneron’s submissions at [158].
[84] WO ‘630 page 46 lines 21-27.
[85] MVD-13.
[86] [2016] EWHC 87 (PAT).
[87] MVD-13, see in particular pages 2 and 3.
[88] Regeneron Pharmaceuticals Inc v Kymab Limited, Novo Nordisk A/S [2016] EWHC 87 (Pat)
[89] Regeneron’s written submissions [161].
[90] See IJR-9, IJR-11, IJR-48 and IJR-49, Macdonald #1 paragraph 14 and 17.
[91] Smith Kline and French Laboratories Application [1968] RPC 415 and Nicaro Holdings v Martin Engineering Co, [1990] FCA 40;91 ALR 513 (at 531).
[92] Rourke [48].
[93] Rourke [48].
[94] Kymab’s written submissions at 11.6.
[95] (2005) 67 IPR 68 at [54].
[96] IJR-9 and IJR-11.
[97] Macdonald #1 at [15].
[98] Macdonald #2 at [16].
[99] Tybulewicz [5.34].
[100] Tybulewicz [5.31]-[5.35].
[101] Tybulewicz [5.30].
[102] Tybulewicz [5.33].
[103] Macdonald #1 [15], Macdonald #2 [16].
[104] Sleeman #2 [21].
[105] Goodnow #2 [29], consistent with Sleeman #2 [21].
[106] Goodnow #2 [29].
[107] Kymab’s written submissions 11.14.
[108] Tybulewicz [5.39].
[109] van Dijk [4.31].
[110] Goodnow #2 [11] and [12], consistent with Sleeman #2 [19].
[111] See [169]
[112] See [137]
[113] IJR 32-34.
[114] Nicaro Holdings Pty Ltd v Martin Engineering Co [1990] FCA 40 at [21].
[115] (1927) 44 RPC 367 at 402.
[116] Macdonald poster, Figure 7.
[117] Macdonald poster, Figure 9.
[118] Macdonald poster, Abstract.
[119] Sleeman #1 [138].
[120] Macdonald #1 [13], [17].
[121] LEM-4, Figures 1-3.
[122] van Dijk #1 [4.34].
[123] van Dijk #1 [4.35].
[124] Macdonald [14].
[125] Goodnow #2 [12], Sleeman #2 [24].
[126] Macdonald et al (2014,) Proceedings of the National Academy of Sciences, 111(14):5147-5152 (MVD-4, VT-2).
[127] IJR-22 to 29; Goodnow #1 [ ], Sleeman #1 [ ]
[128] See for example IJR 24, page 538, right hand column; IJR-25, page 3724, left column.
[129] Goodnow #1 [62], [79]-[80].
[130] IJR-24 – Gallo, M. L. et al (2000) European Journal of Immunology, 30: 534-540.
[131] Regeneron’s written submissions [80].
[132] IJR-24, Tables 1-3.
[133] Goodnow #1 [63].
[134] [1981] HCA 12; 148 CLR 262 at 286.
[135] [2002] HCA 59; (2002) 212 CLR 411 at [53].
[136] Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58 at 69.
[137] Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2011] FCAFC 132.
[138] Goodnow #1 [94], Sleeman #1 [110].
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