Sanofi v Amgen Inc

No judgment structure available for this case.

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE Sanofi v Amgen Inc. [2022] APO 67

Patent Applications:	2013203677, 2013203685, 2013203689, 2013203748, 2013203751
Title:	Antigen Binding Proteins to Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9)
Patent Applicant:	Amgen Inc.
Opponent:	Sanofi
Delegate:	Sophina Calanni
Decision Date:	26 September 2022
Hearing Date:	3-7 June 2019, in Melbourne
Catchwords:	PATENTS - section 59 opposition to grant of a patent – antibodies defined by binding properties – construction of claims – manner of manufacture – fair basis – clarity – definition of the invention – full description – best method of performing the invention – utility –
oppositions to all applications not successful
Representation:	Counsel for the applicant: Christian Dimitriadis SC and Christopher Burgess
Patent attorney for the applicant: Gary Cox and Dr Linda Kennaugh of Wrays
Counsel for the opponent: David Shavin KC
Patent attorney for the opponent: Lisa Taliadoros and Anthony Muratore of Jones Day

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Applications:	2013203677, 2013203685, 2013203689, 2013203748, 2013203751
Title:	Antigen Binding Proteins to Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9)
Patent Applicant:	Amgen Inc.
Date of Decision:	26 September 2022
DECISION

The oppositions are unsuccessful.
Subject to appeal, I direct the applications proceed to grant.

I award costs according to Schedule 8 against Sanofi.

REASONS FOR DECISION

1. Patent application numbers 2013203677 (677), 2013203685 (685), 2013203689 (689), 2013203748 (748) and 2013203751 (751) were filed on 11 April 2013 by Amgen Inc. (Amgen). All five applications claim divisional status from 2008288791 which was filed

under the provisions of the Patent Cooperation Treaty as PCT/US2008/074097, claiming
priority from several US provisional applications: 61/010,630 filed on 9 January 2008,
61/086,133 filed on 4 August 2008, 60/957,668 filed on 23 August 2007 and 61/008,965 filed
on 21 December 2007.

2. The five applications were examined and accepted by the Commissioner. Acceptance of the 677, 685, 689, 748 and 751 applications was advertised on 14 January 2016, 11 August 2016, 11 August 2016, 28 January 2016 and 22 September 2016 respectively. Notice of opposition to the applications, under s59 of the Act, was filed by Sanofi on 14 April 2016, 11 November 2016, 11 November 2016, 28 April 2016 and 22 December 2016 respectively.

3. Sanofi filed Statements of Grounds and Particulars within the required time in each opposition. Similarly, the evidence in support (EIS) of each opposition was filed within the required time.

4. Prior to filing evidence in answer (EIA), Amgen requested a direction that the evidence filed by them in any one of the oppositions be taken to be evidence in each of the other oppositions. Having considered the submissions made by each of the parties regarding the similarities in the specifications and the evidence, the Delegate ultimately decided that the oppositions should be joined. She directed that the EIS already filed for the oppositions be joined so as to represent the EIS for all oppositions and that the parties need only file one set of EIA and evidence in reply (EIR) in all the oppositions.

5. Amgen completed its EIA on 26 September 2017. Following the grant of an extension of time, EIR was completed by Sanofi on 28 February 2018.

6. On 4 May 2018, Amgen requested that the Commissioner consider information relevant to the hearing pursuant to Regulation 5.23. On 21 June 2018 the Delegate informed the parties that the information would be relied upon under regulation 5.23 and allowed Sanofi until 3 August 2018 to provide responding information. The responding evidence was filed on 3 August 2018.

7. On 29 August 2018, Sanofi requested that the Commissioner, pursuant to Regulation 5.16 amend their SGPs. The request was allowed on 5 October 2018.

8. On 11 December 2018 Amgen requested that the Commissioner, pursuant to Regulation 5.23 consider additional documents, namely further declarations in response to Sanofi’s Regulation 5.23 evidence. On 14 February 2019 the Delegate informed the parties that the information would be relied upon. Responding evidence was filed by Sanofi on 28 March 2019.

The Evidence

9. The table below sets out the evidence relied upon by the parties.

Evidence	Declarant	Date of	Reference	Exhibits
Declaration
*In support*
‘677	Stephen Michael	14 October 2016	Mahler 677
Mahler
Michael Parker	14 October 2016	Parker 677	MP-1 to MP-5
Stephanie Wan Jing	14 October 2016	Wang	SW-1 to SW-8
Wang
‘748	Stephen Michael	24 October 2016	Mahler 748
Mahler
Stephen James Rohl	28 October 2016	Rohl 748	SJR-1 to SJR-8
‘685	Stephen Michael	12 May 2017	Mahler 685	SM-1 to SM-9
Mahler
Stephen James Rohl	12 May 2017	Rohl 685	SJR-1 to SJR-8
‘689	Stephen Michael	12 May 2017	Mahler 689	SM-1 to SM-8
Mahler
Michael Parker	15 May 2017	Parker 689	MP-1 to MP-5
Stephen James Rohl	12 May 2017	Rohl 689	SJR-1 to SJR-8
‘751	Stephen Michael	22 June 2017	Mahler 751	SM-1 to SM-8
Mahler
Michael Parker	22 June 2017	Parker 751	MP-1 to MP-5
Stephen James Rohl	21 June 2017	Rohl 751	SJR-1 to SJR-8
*In Answer*
Peter Hudson	25 September	Hudson 1	PH-1 to PH-16
2017
Angel Francisco	21 September	Lopez 1	AFL-1 to AFL-
Lopez	2017	20
Gregory A Petsko	23 September	Petsko 1	GAP-1 to GAP-
2017	33
David Richmond	25 September	Sullivan	DS-1 to DS-9
Sullivan	2017
Chi Chien Oscar Pan	6 September	Pan
2017

Bindhu Ramesh 26 September Holavanahalli BRH-1 to BRH-

Holavanahalli 2017 5

In Reply

Stephen Michael 28 February Mahler 1 SM-R1 to SM-
Mahler 2018 R5
Michael Parker 28 February Parker 1 MP-R1 to MP-
2018 R20

First Reg 5.23

Peter Hudson 4 May 2018 Hudson 2 PH-1 to PH-46
Angel Francisco 4 May 2018 Lopez 2
Lopez

First Reg 5.23

In response

Michael Parker 3 August 2018 Parker 2 MP-R21 to MP-
R27

Second Reg

5.23

Peter Hudson 11 December Hudson 3 PH-47 to PH-51
2018
Gary Baxter Cox 11 December Cox GBC-1
2018

Second Reg
5.23 In

Response

Michael Parker 27 March 2019 Parker 3

Grounds of Opposition

10. The grounds of opposition set out in the Statement of Grounds and Particulars include manner of manufacture, fair basis, full description, definition, clarity, utility, novelty and inventive step. The ground of inventive step was not pressed at the hearing. Each party made submissions with respect to novelty at the hearing, however, on the final day of the hearing Mr Shavin indicated that Sanofi would not press this ground.

Onus of Proof

11. The requests for examination for all five applications were filed on 11 April 2013. As a result, the substantive amendments of the Patents Act 1990 (the Act) brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present patent applications. This includes the amendment to subsection 60(3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition has been made out. Instead, the onus of proof in this opposition lies with the opponent, who must establish that it is clear that a valid patent cannot be granted.

12. The requirement to show invalidity to the level of clear and practical certainty also has consequences for how the expert evidence is assessed. As Bennett J remarked in Austal Ships Pty Ltd v Stena Rederi Aktiebolag1 in the context of obviousness:

“…where there are two opposing expert views that are conclusive on obviousness, both presented as 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.”

13. While the above statement was made in the context of inventive step, it is also relevant to other grounds of invalidity including novelty, insufficiency and utility.

Background

14.

Before moving to a consideration of the specification and claimed inventions it is useful to set understanding of the role of PCSK9 in regulating blood cholesterol levels. This information is derived from the specification itself as well as a technical primer (the Primer) that provides a summary of antibodies, their structure, functionality and production that the parties helpfully provided. When the Primer is cross-referenced in this decision I refer to the paragraph numbers of the technical primer provided at Chapter 4 of the Applicant’s Submissions.

15. An antibody is a protein produced by the immune system in response to foreign substances. Each antibody binds to a particular target referred to as an antigen2.

16.	antibody consists of two identical heavy chain (HC) polypeptides and two identical light

A mammalian antibody comprises a characteristic unit structure as illustrated below. Each the polypeptide chains comprises a variable (V) region at its amino terminus, which contributes to the antigen binding site, and a constant (C) region.3

Figure 1: Antibody structure

17. The antibody variable regions have the same general structure, consisting of conserved framework regions (FR) and hypervariable regions known as the complementarity determining regions (CDRs).4 Both the heavy and light chains of the antibody contribute 3 CDR loops, which together effect binding of the target antigen.5

18. The region of the antigen recognised by the antibody is the antigenic determinant or epitope, as illustrated below in Figure 2.6

Figure 2: Antibody:antigen binding

19. An epitope may be linear or conformational. A linear epitope recognises a linear sequence of amino acids from the primary structure of antigen, whereas a conformational epitope is composed of amino acids from different parts of the polypeptide chain that have been brought together by protein folding.7 Epitopes may also be defined as structural or functional.

“Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction (e.g. hydrogen bonds, ionic interactions). Structural epitopes can be thought of as the patch of the target which is covered by the antibody.”8

20. For an antibody to bind an antigen, the antigen must have a three-dimensional shape that complements the three-dimensional shape of the region on the antibody. This is often referred to as shape complementarity. More specifically, binding occurs when the shape and contour of the two proteins results in the alignment of specific amino acids from the antigen and antibody, with the formation one or more individual non-covalent interactions between the amino acids of the two proteins resulting in binding.9 In antibody:antigen binding, amino acid residues within the CDRs form non-covalent interactions with residues on the surface of the antigen.10

21. The affinity of interaction between an antigen and antibody is a product of the non-covalent interactions between the antibody and its target antigen.11 As illustrated in Figure 3 below, the non-covalent interactions between the proteins may be salt (or ionic) bridges, hydrogen bonds and van der Waals interactions.

22. Typically, 15-20 residues are involved in the binding of any antibody to its antigen.12 While each individual interaction may be weak, together such interactions can result in strong binding.13

23. X-ray crystallography can be used to identify the three-dimensional arrangement of atoms in a molecule, or at the interface of two interacting proteins.14 Computational approaches can then be used to identify possible non-covalent interactions between the antigen and antibody.

Figure 3: Non-covalent interactions between complementary three-dimensional surfaces

The person skilled in the art

24. It is well established that many of the issues in an opposition are answered by reference to the person skilled in the art (PSA). The person skilled in the art:

“...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. ”15

25. The notional PSA is an artificial construct that is used as a tool of analysis which guides the court in determining, by reference to expert and other evidence, whether an invention as claimed does not involve an inventive step16. In general, the skilled person or addressee is the person who works in the art or science with which the invention is connected. He or she is a person, or team, likely to have a practical interest in the subject matter of the invention, and while the skilled person may be assumed to be well-versed in the relevant art, such a person must be taken to be non-inventive.17

26. The present opposition proceedings call upon a range of declarants who are representative of the person skilled in the art, at least in terms of their practical interest in the subject matter of the invention and understanding of the relevant art. It is clear that in the present case the

notional skilled person has knowledge of making and characterising antibodies, including a
strong understanding of structural and functional properties based on protein:protein
interactions between antibodies and antigens.

27. I note that the parties acknowledge that each of the independent experts have experience and expertise relevant to establishing the knowledge relevant to the person skilled in the art.

28. The opponent relies on declarations by Associate Professor Stephen Mahler and Professor Michael Parker as expert witnesses. Professor Mahler has more than 30 years’ experience in the field, including the discovery, research and development of monoclonal antibodies for therapeutic and diagnostic purposes.18 Professor Parker has more than 40 years’ experience in the field of structural biology including X-ray crystallography.19

29. The applicant relies on declarations by Professor Gregory Petsko, Professor Angel Lopez, Dr Peter Hudson and Associate Professor David Sullivan as expert witnesses. Professor Petsko has significant experience in the field of structural biochemistry, in particular protein structure

determination and design.20 Professor Lopez has over 35 years’ experience working in the
fields of antibodies and growth factors and over 20 year in the fields of structural and
molecular biology as it relates to receptor/ligand, antagonist/agonist and antigen/antibody
interactions.21 Dr Peter Hudson is experienced in the areas of X-ray crystallography, antibody
engineering, design, isolation and characterisation.22 Associate Professsor David Sullivan is a
clinician with experience in endocrinology, cardiology, gastroenterology and intensive care
units. His area of specialisation is lipid metabolism, including hypercholesterolemia,
cardiovascular disease, diabetes and obesity.23

The common specification

30. As Justice Middleton said in Eli Lilly and Company Limited v Apotex Pty Ltd:24

“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.”

31. All five applications are titled “Antigen binding proteins to proprotein convertase subtillsin kexin type 9 (PCSK9)”. Each specification relates to antigen binding proteins that bind to proprotein convertase subtilisin kexin type 9 (PCSK9) and methods of using and making the antigen binding proteins.25

32. The applications in the opposition share a common specification (CS) apart from the consistory clauses unique to each application and some other comparatively minor differences in text and figures. Throughout this decision the 677 application is used as the exemplar specification.

33. PCSK9 is a serine protease involved in regulating the levels of the low density lipoprotein receptor (LDLR) protein.26 The protein is expressed as a zymogen and is autocatalytically cleaved within the endoplasmic reticulum, causing the proprotein to mature to its active form

and then secreted from the cell into the plasma.27

34. Both in vitro and in vivo experiments have shown that increased PCSK9 levels lead to a decrease in LDLR protein levels. PCSK9 knockout mice (genetically modified mice where the gene is inactivated) have increased levels of LDLR in the liver, and various PCSK9 mutations that result in either increased or decreased levels of plasma LDL have been identified.28

35. The CS describes various embodiments of the invention, in particular, a series of antigen binding proteins that bind PCSK9. For example:

“an antigen binding protein as used herein means any protein that binds a specified antigen. In the instant application, the specified target antigen is the PCSK9 protein or fragment thereof. “Antigen binding protein” includes but is not limited to antibodies and binding parts thereof, such as immunologically functional fragments. Peptibodies are another example of antigen binding proteins.”29

36. The antigen binding proteins described in the specification include monoclonal antibodies that bind specific epitopes on human PCSK9 and block binding of PCSK9 to LDLR.30 While the examples provide a detailed characterisation of two specific antibodies, 31H4 and 21B12, the specification indicates that the invention relates to a broader range of antibodies that bind to PCSK9 to prevent PCSK9 from functioning in various ways.31

37. In some embodiments described the antigen binding proteins of the invention bind to PCSK9 and alter its functional properties. The antigen binding protein may block or reduce the ability of PCSK9 to interact with other substances. For example, the antigen binding proteins may block binding to PCSK9 in a manner that prevents or reduces interaction with LDLR.32

38.

LDLR for binding to LDL, which in turn decreases the amount of serum LDL thereby
reducing serum cholesterol in a subject. As such, a range of therapeutic uses are
contemplated, in particular the use of said antigen binding proteins in the treatment of
disorders that relate to, involve or can be influenced by varied cholesterol, LDL or LDLR
levels, in particular diseases manifested by an elevated total serum cholesterol, elevated LDL,
elevated triglycerides, elevated VLDL and/or low HDL.33 The antigen binding proteins of the

The capacity to alter interactions between PCSK9 and LDLR can increase availability of and affinity purification.34

39. The specification identifies a range of strategies for the preparation of antigen binding proteins. These include preparation by phage display or through immunisation of a transgenic mouse that incorporates an insertion of a substantial portion of the human antibody producing genome (XenoMouse). Recombinant techniques and expression in hybridoma cells may be used to produce a selected antigen binding protein.35

40. Variant antigen binding proteins may also be produced by random mutagenesis or targeted site-directed mutagenesis. In certain embodiments the antigen binding proteins of the invention include either conservative or non-conservative amino acid substitutions that may either increase or decrease the affinity of the antigen binding protein for PCSK9.36

41. Further aspects of the invention described include methods that use the described antibodies in the treatment or prevention of a condition associated with elevated serum cholesterol in a subject.37

42. The specification contains 43 examples. I note that there are two sets of examples labelled Example 8 and 9. Examples 1-3 describe the generation of anti-PCSK9 antibodies and hybridomas and the selection and screening of the antibodies produced to identify antibodies with favourable interactions with PCKS9. Examples 4-8(1) describe the production of specific antibodies (31H4, 21B12, 16F12) from both hybridomas and transfected cells. Examples 9(1)-18 and 25-41 describe the characterisation of these antibodies, including epitope binning, binding, structural and functional studies. Examples 19-24 provide examples of possible uses for PCSK-9 antibodies.

43. In terms of the claimed subject matter of the opposed applications those examples that assess the specific binding characteristics between PCSK9 and LDLR or the exemplified antibodies are pertinent to the present consideration. Examples 28-30 describe the solved crystal

structures of PCSK9 bound to the LDLR EGFa domain (Example 28), the 31H4 antibody
(Example 29), and a ternary complex between PCSK9 and the 31A4 and 21B12 antibodies
(Example 30). In the examples discussed below, all amino acid residues with at least one
atom less than or equal to 5A from the PCSK9 binding partner were designated as core
interaction interface amino acids. 5Å was chosen as the core region cut-off distance to allow
for atoms within a van der Waals radius plus a possible water-mediated hydrogen bond. All
amino acid residues with at least one atom between 5-8Å from the PCSK9 binding protein
were designated as boundary interaction interface amino acids.38

44. Example 28 presents the solved crystal structure of PCSK9 (amino acids 31-454 of SEQ ID NO:3) bound to the LDLR EGFa domain (amino acids 294-334) at 2.9Å resolution. Analysis of the crystal structure revealed that the EGFa domain binds to the catalytic domain of PCSK9. Specific core PCSK9 amino acid residues of the interaction interface are identified as S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380 and S381. Boundary PCSK9 amino acid residues of the interaction interface are identified as W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, 1368, G370, A371, S373, S376, and Q382. N157, H229 and G370 are identified as residues that are nearly or completely buried within PCSK9.

45. Example 29 presents the solved crystal structure of PCSK9 bound to the Fab fragment (the region of an antibody that binds to antigens) of 31H4 at 2.3Å resolution. Analysis of the crystal structure shows that 31H4 binds to PCSK9 in the region of the catalytic site and contacts amino acid residues from both the prodomain and catalytic domain of the protein. Specific core amino acid residues are identified as W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383 and G384. The boundary residues are K69, D70, P71, S148, V149, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365, I368, I369, S372, S373, C378, F379, T385, S386, and Q387. V149, D186, G227, H229, P288, A290, G291, G316, G352, T353, G365, T385 and S386 are identified as residues that are nearly or completely buried within PCSK9.

46. Example 30 presents the solved crystal structure of PCSK9 (amino acid residues 31-449 of SEQ ID NO:3 bound to the Fab fragments of 31H4 and 21B12 determined at 2.8Å. The crystal structure shows that 31H4 and 21B12 have distinct binding sites on PCSK9 and that both antibodies can bind to PCSK9 simultaneously. The structure shows that the 21B12 antibody interacts with amino acid residues from the PCSK9 catalytic domain. Specific core amino acid residues are identified as S153, S188, I189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, and F379. The boundary residues are I154, T187, H193, E195, I196, M201, V202, C223, T228, S235, G236, A239, G244, M247, I369, S372, C375, and C378. I196, T228, S235 and G236 are identified as residues that are nearly or completely buried within PCSK9.

47. The specification states that analysis of each of the solved crystal structures can identify specific amino acid residues involved in interaction between PCSK9 and the partner proteins by taking into account the spatial requirements of PCSK9 and the partner proteins. This type of analysis can suggest ways to inhibit interaction between PCSK9 and LDLR.39

Construction of the claims

48. The principles applicable to construction of patent claims are well established. As discussed by Bennett J in H Lundbeck A/S v Alphpharm Pty Ltd40

“...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 are to be given the meaning which the person skilled in the art would attach to then, having regard to his or her own general knowledge and to what is disclosed in the body of the specification...
The claims are part 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...Those who attempt to elevate the "purposive construction" utilised by Lord Diplock in Catnic Components Limited v Hill & Smith limited...should understand the application of that approach to construction as explained by Lord Hoffman in Kirin-Amgen...
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.”

49. The claims under consideration in this opposition proceeding are summarised in the table below and are reproduced in Annex A to this decision.

Application Number of Independent claims
claims
677 42 Claims 1 and 5
685 30 Claim 1
689 30 Claim 1
748 30 Claim 1
751 42 Claims 1, 2, 10 and 13

50. The claims broadly relate to a class of monoclonal antibodies that have specific binding and functional activities, in particular an ability to bind to identified parts of PCSK9 (as set out in SEQ ID NO:1 and 3) and affect its interaction with LDLR.

51. For the purposes of claim construction, the independent claims of the patent applications can be divided three classes. My considerations in relation to the construction of the claims are focussed on these three claim classes, namely

A. the epitope claims;
677 application
“1: An isolated monoclonal antibody that binds an epitope on hPCSK9 comprising one or more of amino acid residues 207, 208, 162, 164, 167 or 123 of SEQ ID NO:1, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.”
751 application
“1: An isolated monoclonal antibody that recognizes an epitope on human PCSK9 comprising amino acid residues: S153, R194, D238, D374, T377, and F379 of SEQ ID NO: 3, wherein the monoclonal antibody reduces binding between PCSK9 and EGFa domain of LDLR.”
“10: An isolated monoclonal antibody that recognizes an epitope on human PCSK9 wherein the epitope comprises at least 10 of the following residues S153, I154, P155, R194, D238, A239, I369, S372, D374, C374, T377, C378, F379, V380, or S381 of SEQ ID NO:3 wherein the monoclonal antibody reduces binding between PCSK9 and an EGFa domain of LDLR.”

B. the residue claims;
677 application
“5: An isolated monoclonal antibody that binds to at least one of amino acid residues 207, 208, 162, 164, 167, or 123 of SEQ ID NO:1, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR”
689 application
“1: An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.”
751 application
“2: An isolated monoclonal antibody that binds to amino acids in human PCSK9 of SEQ ID NO:1, wherein the amino acids comprise S153, R194, D238, D374, T377 and F379 of SEQ ID NO: 3 and wherein the monoclonal antibody reduces binding between PCSK9 and an EGFa domain of LDLR.”
“13: An isolated monoclonal antibody that binds to amino acids in human PCSK9 wherein the amino acids comprise 10 or more of the following residues S153, I154, P155, R194, D238, A239, I369, S372, D374, C374, T377, C378, F379, V380, or S381 of SEQ ID NO:3 wherein the monoclonal antibody reduces binding between PCSK9 and an EGFa domain of LDLR.”

C. The competition claims
689 application
“1: An isolated monoclonal antibody that binds to human PCSK9 and reduces binding between human PCSK9 and an EGFa domain of LDLR, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises a heavy chain variable region of the amino acid sequence in SEQ ID NO: 67; and a light chain variable region of the amino acid sequence in SEQ ID NO: 12.”
748 application
“1: An isolated monoclonal antibody that binds to human PCSK9 and is neutralising in that an excess of said antibody reduces the quantity of human PCSK9 bound to LDLR in an in vitro competitive binding assay, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises: a heavy chain variable region of the amino acid sequence in SEQ ID NO:49, and a light chain variable region of the amino acid sequence in SEQ ID NO:23.”

52. I will consider the construction of each of these claim classes separately below. I note that each of the applications also contain a range of appended claims directed to an isolated nucleic acid or recombinant vector encoding the monoclonal antibody; host cells, hybridomas and methods that produce the antibody; pharmaceutical compositions that comprise the monoclonal antibody; and methods of treatment or prevention of a condition associated with an elevated serum cholesterol level in a subject by administering the antibody. However, at the hearing the central submissions were directed to the claims defining the different classes of monoclonal antibodies. Thus, I have taken the same approach in this decision.

53. Prior to considering each principal antibody claim class I note that each of the independent claims (of each of the applications) define an isolated monoclonal antibody, thus it is appropriate to consider the scope of this phrase first.

54. Sanofi submitted that the phrase monoclonal antibody means that the antibody is derived from a single B cell, which gives rise to its unique amino acid sequence.41

55. Amgen disputed Sanofi’s submission on the basis that it seeks to confine the phrase ‘monoclonal antibody’ to a single method of manufacture, that is production by B-cells. They noted that a monoclonal antibody may be produced by a range of different methods.42

56.	refers to antibodies which have identical amino acid sequences and bind to a single epitope on

Monoclonal antibodies were well understood in the art before the priority date. The term but different epitopes).43 While a monoclonal antibody is initially derived from a single B cell clone, it may also be produced using recombinant (genetic engineering) techniques.44

57. Thus, I agree with the interpretation provided by Amgen that the phrase does not limit the method of manufacture to production by B cells. Rather, the term relates to identical antibodies that recognise a single epitope.

58.	antibody” the parties are in agreement that in this context the word “isolated” specifies that

While the specification does not provide a definition for the term “isolated monoclonal identical amino acid sequences. I note that this meaning is also consistent with the definitions provided in the specification for isolated proteins and nucleic acids.45

59. As such, the antibodies encompassed by the claims of the opposed applications are antibodies that recognises a single epitope and said antibodies are separated from other proteins.

The Epitope claims

60. Broadly, the epitope claims define antibodies by reference to two key features, the epitope on PCSK9 to which the antibody binds and the ability of said antibody to block or reduce binding of PCSK9 to LDLR.

61. The residues specified in claim 1 of the 677 application represent a subset of the core residues said to be at the interaction interface when PCSK9 is bound by the antibody 21B12.46 I note in the claim the residues are identified with reference to SEQ ID NO:1, whereas in Example 30 of the applications the core amino acid residues are identified with reference to SEQ ID NO:3. SEQ ID NO:1 and SEQ ID NO:3 each represent human PCSK9; SEQ ID NO:1 is the mature form of PCSK9, whereas SEQ ID NO:3 also includes the 30 amino acid signal sequence. Thus, the core amino acid residues specified in the claim are equivalent to amino acid residues 237, 238, 192, 194, 153 of SEQ ID NO:3.

62. Amgen submitted that in the context of the epitope claim as represented by claim 1 of the 677 Application, the phrase “binds an epitope” the term refers to an interaction between an antibody and a region of its target protein i.e. the epitope.47 “Broadly speaking, the antibody interacts with a target (e.g PCSK9) by binding to (or interacting with) an epitope on that target, and within the epitope individual residues form noncovalent interactions with amino acids in the antibody.”48

63. Sanofi challenged the suggestion that the meaning of the term “bind” could be expanded to refer to anything other than non-covalent bonds between atoms of residues. They noted that Professors Petsko, Parker and Mahler all consider that:

In the context of the phrase “binds to an epitope on hPCSK9”, the term binds refers to non-covalent interactions between (atoms of) residues of the antibody and (atoms of) residues of PCSK9 in the “epitope” of the antibody.49

64. While the specification does not provide a definition for the term “binds”, this term and derivatives of the term, are used throughout the application. Below I have set out a selection of paragraphs where the term is used in the application.

“[0002] The present invention relates to antigen binding proteins that bind to proprotein convertase subtilisin kexin type 9 (PCSK9) and methods of using and making antigen binding proteins.”
“[0037] In some aspects, the invention comprises a neutralising antibody that binds to PCSK9 and reduces a low density lipoprotein receptor (LDLR) lowering effect of PCSK9 on LDLR.”
“[0042] In some embodiments, an isolated antibody or antigen binding molecule that binds to PCSK9 at a location that overlaps with a location that LDLR binds to PCSK9 is provided.”
“[0044] In some embodiments, an antibody, antigen binding protein, or antigen binding molecule that binds to a surface of PCSK9 that overlaps with a surface that EGFa binds, Ab 21B12 binds, and/or 31H4 binds is provided. In some embodiments, an antibody, antigen binding protein, or antigen binding molecule that binds to PCSK9 in a manner that is similar to that depicted in the figures is provided.”
“[0160] Antigen binding proteins (such as antibodies and functional binding fragments thereof) that bind to PCSK9 are disclosed herein. In some embodiments, the antigen binding proteins bind to PCSK9 and prevent functioning in various ways. In some embodiments, the antigen binding proteins block or reduce the ability of PCSK9 to interact with other substances. For example, in some embodiments, the antigen binding protein binds to PCSK9 in a manner that prevents or reduces the likelihood that PCSK9 will bind to LDLR. In other embodiments, antigen binding proteins bind to PCSK9 but do not block PCSK9’s ability to interact with LDLR.”
“[0267] In some embodiments, the ABP binds to an epitope bound by one of the antibodies described in Table 2. In some embodiments, the antigen binding proteins bind to a specific conformational state of PCSK9 so as to prevent PCSK9 from interacting with LDLR.”
“[0511] As will be appreciated by one by one of skill in the art, FIG 18B depicts the interaction between the CDRs on the antigen binding protein and PCSK9. As such, the model allows one of skill in the art to identify the residue and/or CDRs that are especially important in the paratope, and which residues are less critical to the paratope. As can been seen in FIG. 18B, the heavy chain CDR1, CDR2 and CDR3 are most directly involved in the antigen binding protein’s binding to the epitope…”

65. I consider that in each of the above instances it is apparent that the term “binds” is used to broadly refer to the functional property of an interaction between the antigen binding protein and antigen, or particular regions of the antigen. As described by Professor Lopez:

“I, and I expect other persons of ordinary skill in the art would understand ‘binds’ to refer to the interaction of an antibody with a defined residue(s) or epitope in another molecule. In particular, in the context of the Amgen Application, it refers to the molecular interaction(s) between the antibody and the defined residue or epitope of the PCSK9 protein.
At the macromolecular level in the immunological field, this term refers to the complex formed between an antibody and an antigen (ligand) resultant from the complementarity of the three-dimensional shape of the antibody and an epitope to which it binds on the antigen. That complex is formed as a consequence of the individual residue to residue binding interactions between the two proteins.”50

66. Similarly, Professor Petsko states:

“I understand that word “binds” or “binding” as used in the claims means that the defined monoclonal antibody interacts with the defined epitope or amino acid residue as the claim demands. More particularly, a person of ordinary skill in the field understands, as I do, that an antibody “binds” an epitope or is “binding to” or “binding at” a specific amino acid residue of a target antigen when there are “interactions” between the residue or epitope of the antigen and certain amino acids in the binding regions of the monoclonal antibody. A person of ordinary skill in the field would recognize, as I do, these interactions as weak or non-covalent associations between amino acid residues on the antibody and the identified residue on the target antigen. Thus, a person of ordinary skill in the field understands, as I do, that “binds” to an epitope or residue means “interacts with” the epitope or residue.
When speaking to overall antibody:antigen (epitope) binding, the phrase “binds” to (sic) means that the two macromolecules form a complex with each other (e.g. due to spatial complementarity of the three-dimensional exteriors of both an antibody and the epitope to which it binds). Macromolecular binding occurs due to the additive effect of the individual reside-to-residue non-covalent binding interactions discussed in the paragraph above. Collectively, these interactions enable the antibody to bind its epitope on PCSK9.”51

67. It follows that in the context of Claim 1 of the ‘677 application the term “binds” refers more generally to an interaction between an antibody and a region of its target protein. In this instance the region of the target protein is an epitope comprising one or more of amino acid residues 207, 208, 162, 164, 167 or 123 of SEQ ID NO:1. The terms “comprising” and “comprises” are defined by a dictionary in the specification:

“Throughout the specification and claims, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.”

68. It is clear that when considering the claim, the term “comprise” should be understood as inclusive.

69. Thus, consistent with the definition provided at [0233] of the CS and the evidence provided by the experts, the epitope is not limited to residues that directly contribute to non-covalent interactions between the antibody and the antigen, but also includes residues on the surface of

the antigen that are covered by the antibody.52

70. Therefore, the phrase “binds an epitope of hPCSK9 comprising one or more of amino acid residues 207, 208, 162, 164, 167, or 123 of SEQ ID NO: 1” means that the claimed antibody interacts with a region on the surface of human PCSK9 that includes one or more of the nominated PCSK9 residues. The nominated PCSK9 residue(s) do not necessarily form non- covalent interaction(s) with the antibody and the epitope may include other unidentified residues.

Blocks/reduces binding of PCSK9 to LDLR

71. The construction of the phrase “blocks binding of PCSK9 to LDLR” represents a point of dispute between the parties in the construction of this claim.

72. Sanofi noted that the term “blocks” is not defined in claim 1 or otherwise in the Applications. Instead, the term “blocks” is used is used in a variety of ways throughout the specification. Referring to paragraphs [0160], [0229], [0246] and [0418] of the CS Sanofi suggest that the phrase is capable of encompassing either or both of the mechanism and extent to which the binding is “blocked”. Given that claim 1 does not specify any method by which ‘blocking’ is to be assessed, they submit that the claim encompasses antibodies that block binding of PCSK9 to LDLR by any degree as determined by any method.

73. In contrast, Amgen submitted that the person skilled in the art, on reading the CS would understand that the term “blocks” is used interchangeably in the CS with the terms “reduce(s), “inhibit” and “prevents(s)” to refer to in its most general sense interference of an interaction between PCSK9 and LDLR. They state that in the context of the phrase “blocks binding of PCSK9 to LDLR” the term “block” requires that the blocking agent has the ability to reduce or prevent PCSK9 binding to LDLR. This does not demand any mechanism or extent to understand what is meant by blocking.53

74. While a definition for the term ‘block’ is not provided in the application, I agree with Amgen that in its most general sense the term refers to interference of the interaction between PCSK9 and LDLR. I note that in each of the paragraphs referred to by Sanofi the term block is

clearly used as a distinction to the act of binding between PCSK9 and LDLR, for example:

“[160] …in some embodiments, the antigen binding protein binds to PCKS9 in a manner that prevents or reduces the likelihood that PCSK9 will bind to LDLR. In other embodiments the antigen binding proteins bind to PCSK9 but do not block PCSK9’s ability to interact with LDLR.”
“[246]…in some embodiments, the antigen binding proteins provided herein can interfere with, block, reduce or modulate the interaction between PCSK9 and LDLR…in some embodiments, the ABP prevents or reduces the adverse influence of PCSK9 on LDLR without blocking the LDLR binding site on PCSK9.”

75. Reading the specification as a whole it is clear that blocking represents the action of interfering with the interaction between PCSK9 and LDLR. Amgen have submitted that the language of the claim merely requires the event (blocking) to happen. This may be assessed relative to a control, with the control being PCSK9 binding to LDLR.54 Furthermore, as noted in Amgen’s submissions55 blocking of the PCSK9 and LDLR interaction does not require 100% elimination of the interaction, but merely a reduction in the interaction between PCSK9 and LDLR.56 I agree and accept the submissions of Amgen’s experts that the CS provides ample teaching of the assays that can be employed by the person skilled in the art to ascertain whether an antibody blocks the interaction of PCSK9 and LDLR.57

76. Thus Claim 1 of the 677 application encompasses monoclonal antibodies that interact with a region on the surface of human PCSK9 that includes one or more of residues 207, 208, 162, 164, 167, or 123 of SEQ ID NO: 1, and where that antibody interferes with the interaction

between PCSK9 and LDLR.

77. The remaining epitope claims (claims 1 and 10 of the 751 Application) define the claimed invention using slightly different terms to those used in the 677 application, though the claims broadly define antibodies with the same functional properties. That is, the antibodies encompassed by these claims bind to the LDLR binding site on PCSK9 and interfere with the interaction of PCSK9 and LDLR.

78. Specifically, the epitope claims of the 751 application refer to a monoclonal antibody that “recognizes an epitope on hPCKS9” and “reduces binding between PCSK9 and the EGFa domain of LDLR.”

79. The term ‘recognizes’ is not defined in the application, however the experts agree that the term is used in immunology to refer to binding between the monoclonal antibody and an epitope.58 I therefore consider it appropriate to apply an equivalent meaning to that applied to Claim 1 of the 677 application, that is that the term recognize broadly refers to the functional property of an interaction between the antigen binding protein and antigen, or particular regions of the antigen.

80. Therefore, claim 1 of the 751 application encompasses monoclonal antibodies that interact with a region on the surface of human PCSK9 that includes the following residues, S153, R194, D238, D374, T377, and F379. The epitope must include each of the residues specified and may include others. I note that the residues identified in the claim are core residues from the interaction interface between PCSK9 and 21B12.

81. Similarly, the monoclonal antibodies encompassed by claim 10 of the 751 application must bind to a region on the surface of PCSK9 that includes at least 10 of the specified amino acid residues of human PCSK9. Like claim 1, the epitope may also include additional amino acids beyond those specified in the claim. The identified amino acid residues are core amino acid residues of the interaction interface with the LDLR EGFa domain.59

82. In each instance to fall within the scope of the claims the monoclonal antibody must also reduce the binding between PCSK9 and the EGFa domain of LDLR. Sanofi have submitted that the term ‘reduces’ is not clear. In particular, Professor Mahler has suggested that the term is vague. He states that:

“In my opinion, the term “reduce”, as used in the claim, is a vague term. In the field in which the antibodies described in the 748 Application are to be used, namely, to produce a biological outcome, the desired effect is the inhibition of binding to LDLR. In my opinion, inhibition is a meaningful term because it is measured by known methods.”60

83. The word “reduce” is defined in the Macquarie Dictionary as meaning “to bring down to a smaller extent, size, amount, number, etc.” Thus, in the context of the claim “reduces the binding between PCSK9 and the EGFa domain of LDLR” means that binding between

PCSK9 and the EGFa domain of LDLR is brought down or lowered. I note that none of the other experts raise a concern with construing this term, agreeing that this phrase means that the binding between PCSK9 and EGFa domain of LDLR, as measured by a binding assay, is

identifies that [0455] of the CS describes a method by which the extent of binding between

less than it would have been in the absence of the antibody.61 Indeed, even Professor Mahler methods.62 While Professor Mahler considers inhibition to be a more precise term to use, it does not mean that claim cannot be understood in a practical, common sense manner.

Residue claims

84. In the residue claims, the monoclonal antibodies of the invention are defined in terms of particular amino acid residues to which the antibody binds. The residues specified in the claims are specific core and boundary PCSK9 amino acid residues of the interaction interface

with the LDLR EGFa domain or the antibodies that bind to PCSK9 in that region, namely the
21B12 and 31A4 antibodies.63

85. In the context of these claims Amgen’s experts agree with the view previously presented by Sanofi that ‘binds to’ means that the claimed antibody forms a non-covalent interaction with at least one of the nominated residues of PCSK9.64 As explained by Professor Lopez:

“…in claim 5 in the 677 Application, the defined monoclonal antibody must interact with one or more of the amino acid residues 207, 207, 162, 164, 167 or 123 of SEQ ID NO:1. At least one of the identified residues must form part of a functional epitope bound by the claimed isolated monoclonal antibody.”

86. As defined in the CS a functional epitope includes those residues that directly contribute to the affinity of the interaction.65 Therefore, in the context of the residue claims the phrase “binds to” concerns direct interaction with the amino acid residue specified.

87. The phrases ‘blocking binding of PCSK9 to LDLR’ and ‘reduces binding of PCSK9 to LDLR’ are discussed in paragraphs [75] and [83] above; that analysis also applies to the residue claims.

88. Therefore, claim 5 of the 677 application encompasses any isolated monoclonal antibody that forms a non-covalent interaction with any one, or any combination of more than one, of the nominated PCSK9 residues, and interferes with the interaction of PCSK9 and LDLR.

89. Similarly, claim 1 of the 689 application defines an antibody that binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3. Like claim 5 of the 677 application, the claim encompasses any monoclonal antibody that forms a non-covalent interaction with any one, or any combination of more than one, of the nominated PCSK9 residues, and interferes with the interaction of PCSK9 and LDLR.

90. Claims 2 and 13 of the 689 application define a monoclonal antibody that “binds to amino acids in human PCSK9 wherein the amino acids comprise” six specified amino acid residues. Similar to the analysis provided in [85]-[86] this means that the antibody forms non-covalent interactions with the specified amino acid residues. The PCSK9 residues identified in the claims are those designated as core residues of the interaction interface with the EGFa domain of LDLR.66

91. Claim 2 encompasses those antibodies that form non-covalent interactions with the six nominated amino acid residues. Additional amino acid residues may also contribute to the non-covalent interactions involved in binding of the antibody to PCSK9. The phrase ‘reduces binding of PCSK9 to LDLR’ is discussed in paragraph [83] above (and is equally applicable here). Therefore, claim 2 encompasses those monoclonal antibodies that form non-covalent interactions with S153, R194, D238, D374, T377 and F379 of SEQ ID NO: 3 and result in a lower amount of binding between PCSK9 and the EGFa domain of LDLR.

92. Claim 13 encompasses those antibodies that form non-covalent interaction with at least 10 of the nominated amino acid residues – S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3. The specified amino acid residues are those residues on PCSK9 that are identified as core residues of the interaction interface with the LDLR EGFa domain.67 Similar to claim 2, additional amino acid residues from PCSK9 may also contribute to the non-covalent interactions involved in binding of the antibody to PCSK9. Furthermore, to meet the requirements of the claim binding between PCSK9 and EGFa must be lower than in the absence of the antibody.

The competition claims

685 Application

93. Claim 1 is as follows:

“An isolated monoclonal antibody that binds to human PCSK9 and reduces binding between human PCSK9 and an EGFa domain of LDLR, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises a heavy chain variable region of the amino acid sequence in SEQ ID NO: 67; and a light chain variable region of the amino acid sequence in SEQ ID NO: 12.”

94. The terms “monoclonal antibody”, “binds” and “reduces binding” have all been discussed above for the epitope/residue claims. In the context of claim 1 of the 685 application I consider that the term “binds” is used in the broad, general sense as discussed in [65]-[67]. The terms “isolated monoclonal antibody” and “reduces binding” are considered in [56]-[59] and [83] respectively; that analysis is equally applicable when construing the present claim.

95. The only feature not previously considered is the limitation that requires that “said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises a heavy chain variable region of the amino acid sequence in SEQ ID NO:67; and a light chain variable region of the amino acid sequence in SEQ ID NO:12.” SEQ ID NO: 67 and SEQ ID NO: 12 represent the heavy and light chain variable regions for the 31H4 monoclonal antibody.

96. The term “compete” is defined as follows:68

“…when used in the context of antigen binding proteins (e.g. neutralizing antigen binding proteins or neutralizing antibodies) that compete for the same epitope means competition between antigen binding proteins as determined by an assay in which the antigen binding protein (e.g., antibody or immunologically functional fragment thereof) being tested prevents or inhibits (e.g., reduces) specific binding of a reference antigen binding protein (e.g., a ligand, or a reference antibody) to a common antigen (e.g., PCSK9 or a fragment thereof).”

97. In the context of the present claim, the isolated monoclonal antibody:

a. binds to human PCSK9 and reduces binding between PCSK9 and the EGFa domain of LDLR; and
b. competes for binding to PCSK9 with an antibody that comprises the heavy and light chain variable regions of the 31H4 monoclonal antibody (31H4-variable region antibody). An antibody will be said to compete with a 31H4-variable region antibody if it reduces specific binding of the 31H4-variable region antibody to PCSK9.69

98. The person skilled in the art would understand that the phrase ‘competes for binding to PCSK9’ to refer to the ability of one antibody to contest the other when binding to PCSK9. The CS at [0231] clearly sets out a range of competitive binding assays that can be used to determine whether two antigen binding proteins compete with each other as required by the claim.

99. I accept Sanofi’s submission that competition between two antibodies can occur via direct and indirect means. Two antibodies may share the same or an overlapping epitope or may bind to different epitopes and interfere with each other’s binding due to steric hindrance.70 This is

also consistent with the CS.71 This means that a competing antibody of claim 1 does not
necessarily bind to the same epitope as a monoclonal antibody comprising the heavy and light
chain variable regions of 31H4.

748 Application

100. Claim 1 is as follows:
“1: An isolated monoclonal antibody that binds to human PCSK9 and is neutralising in that an excess of said antibody reduces the quantity of human PCSK9 bound to LDLR in an in vitro competitive binding assay, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises: a heavy chain variable region of the amino acid sequence in SEQ ID NO:49, and a light chain variable region of the amino acid sequence in SEQ ID NO:23.”

101. The terms “monoclonal antibody”, “binds” and “competes” have all been discussed with respect to the competition claims above. That analysis is equally applicable when construing the present claim.

102. The term ‘neutralizing antibody’ is defined in [0229] of the CS
“ “neutralizing antibody” refers to an…antibody… that binds to a ligand and prevents or reduces the biological effect of that ligand. This can be done, for example, by directly blocking a binding site on the ligand or by binding to the ligand and altering the ligand’s ability to bind through indirect means (such as structural or energetic alterations in the ligand).”
103. As set out in the claim, the isolated monoclonal antibody has the following features:

a. it binds to human PCSK9;
b. an excess of the antibody must reduce the quantity of PCSK9 bound to LDLR in an in vitro competitive binding assay; and
c. the monoclonal antibody competes for binding to PCSK9 with an antibody that comprises heavy chain variable region of the amino acid sequence in SEQ ID NO:49, and a light chain variable region of the amino acid sequence in SEQ ID NO:23.

104. Similar to the analysis above for the 685 application, a neutralising antibody encompassed by the claim may be determined using a range of competitive binding assays that allow the skilled addressee to determine whether an excess of the antibody results in a reduction of the quantity of PCSK9 bound to LDLR. Further, the monoclonal antibody must compete for binding to PCSK9 with an antibody that comprises the heavy chain variable region of the 21B12 antibody. Again, competition between the two antibodies may be via direct or indirect means.

Clarity

105. Subsection 40(3) of the Act requires that that claim or claims of a specification are clear.

A claim is lacking in clarity if a third party could not ascertain whether an act would fall within the scope of the claim.72 However, a claim does not lack clarity because it uses inexact language or is difficult to construe, as long as it provides a “workable standard” suitable to the intended use.

106. Sanofi have opposed the claims of the applications for lack of clarity. The issues raised in their submissions essentially relate to the use of inexact language in the claims, for instance terms such as binds, blocks, reduces, neutralizing and competes. However, in my analysis of the construction of the claims above I have been able to give these terms and the claims meaning.

107. Sanofi have also suggested that the claims are not limited by a requirement to measure particular functional characteristics such a blocking, binding, neutralization or competition using a specifically defined assay. Furthermore, their experts are concerned by a lack of a level or threshold measurement for these functional characteristics.73

108. Amgen submit that in terms of each of these features the claim language merely requires a that determining the presence or absence of a feature is merely a task for the PSA of comparing a test reaction against a negative control and determining whether there is an effect above background, and that such experiments are routine basic scientific experimentation.

feature to be present or absent depending on the claim element that is assessed. They submit identifying the invention.

109. Amgen’s evidence also establishes that the PSA would have no difficulty in determining

whether a particular step or requirement in the claims, such as binding, blocking, neutralizing or competition arises with the methods described in the CS representing standard procedures in the art at the priority date.74

110. In my analysis of the construction of the claims above I have been able to give the claims

a meaning. Furthermore, I am satisfied on the evidence that the claims provide a workable standard. The evidence shows that a person would be able to establish whether an antibody falls within the scope of the claims using techniques that were routine in the art as of the

priority date and are also set out in the common specification. As such, Sanofi has not

established that any claim is not clear.

Manner of manufacture

111. Section 18(1) of the Act relevantly reads:
Subject to subsection (2), an invention is a patentable invention for the purposes of a standard patent if the invention, so far as claimed in any claim:

(a) is a manner of manufacture within the meaning of section 6 of the Statute of
Monopolies;

112. The concept of manner of manufacture has developed over time and is not readily reduced to a simple formula. The classic definition of manner of manufacture is set out in National Research Development Corporation v Commissioner of Patents:75

“The inquiry which the definition demands is an inquiry into the scope of the permissible
subject matter of letters patent and grants of privilege protected by the section. It is an
inquiry not into the meaning of a word so much as into the breadth of the concept which
the law has developed by its consideration of the text and purpose of the Statute of
Monopolies. ... The right question is: “Is this a proper subject of letters patent according to
the principles which have been developed for the application of s 6 of the Statute of
Monopolies?” ”76

113.

The High Court then went on to set out a test in terms relevant to the facts of that case: of Monopolies has supplied, must be one that offers some advantage which is material, in the sense that the process belongs to a useful art as distinct from a fine art ... that its value to the country is in the field of economic endeavour.”77

and

“The effect produced by the appellant's method exhibits the two essential qualities upon which 'product' and 'vendible' seem designed to insist. It is a 'product' because it consists in an artificially created state of affairs, discernible by observing over a period the growth
of weeds and crops respectively on sown land on which the method has been put into practice. And the significance of the product is economic; for it provides a remarkable advantage, indeed to the lay mind a sensational advantage, for one of the most elemental
activities by which man has served his material needs, the cultivation of the soil for the
production of its fruits.”78

114. The High Court has consistently made it clear that NRDC, and all other cases, were not laying down a precise formulation that can be applied unthinkingly:

“Nothing said in the Court's reasons for decision in that case can be taken as an exact verbal formula which alone captures the breadth of the ideas to which effect must be given.”79
“This Court in NRDC did not prescribe a well-defined pathway for the development of the
concept of 'manner of manufacture' in its application to unimagined technologies with
unimagined characteristics and implications. Rather, it authorised a case-by-case
methodology.”80

115. That case-by-case approach must have regard to the substance of the claimed invention, not simply the form of the claim.81 As Gageler and Nettle JJ summarised in the Myriad case:

“Whatever words have been used, the matter must be looked at as one of substance and
effect must be given to the true nature of the claim.”82

116. It is settled law that certain categories of inventions are not patentable. For the purposes of this matter it is relevant to note that mere discoveries are not considered to be patentable subject matter. However, “the practical application of a naturally occurring phenomenon to a particular use” is patentable,83 as is an invention that “builds on, uses, practically applies and reduces to practice a discovered substance found in nature.”84

The subject matter of the claims?

117. The subject matter of the claims is monoclonal antibodies defined by their binding characteristics.

What is the contribution to the claimed art?

118. Based on my reading of the specification I consider that the invention is based on the discovery of the binding site or interaction interface between PCSK9 and LDLR. Antigen binding proteins that bind to this site inhibit the interaction of LDLR and PCSK9. I consider that the invention is properly seen as a compound (monoclonal antibody) that has the requisite binding to interfere with the interaction between PCSK9 and LDLR and either bind to defined epitopes or residues, or compete for binding to PCSK9 with a reference antibody that comprises the heavy and light chain variable regions of the 21B12 and 31A4 antibodies exemplified in the applications.

Is the substance of the invention patentable?

119. It is well established that a compound which is the product of human action and has a practical application is a manner of manufacture.85 The present application claims monoclonal antibodies. These are biological compounds with particular binding characteristics for an antigen that have applications as therapeutics. Therefore, the substance of the invention is patentable. I consider that the antibodies claimed can be distinguished from the Myriad case and may be properly considered to represent a compound as they do not embody or convey genetic information and themselves confer the ability to inhibit the interaction of LDLR and PCSK9.

Other considerations

120. Sanofi has raised several issues that do not neatly fit the above analysis. I will consider

them now. As will become apparent, these issues are essentially different ways of raising the same issue – the claims are not set out in terms of the chemical structure of the antibody, and consequently it is asserted that the scope of the claims is uncertain.

121. First, Sanofi has floated the question of whether the claims represent a class of claims on innovation.86 Sanofi considered that the Myriad decision created this as an additional criterion in assessing manner of manufacture.87 Even assuming that this is a correct understanding of the Myriad decision, there is no evidence before me of a chilling effect on innovation if the present invention is treated as a manner of manufacture. Further, it is not correct that the claims lack well-defined boundaries – I have found that there is no lack of clarity. The fact that the subject matter of the claims is defined in functional terms rather than structural terms does not mean that the claim is any less clear. The determination of the boundaries of the claim would require some testing, but that is work that is standard in the art.

which by their very nature lack well-defined boundaries or have a negative or chilling effect employed to discern the binding properties of the claimed antibodies.

122. Second, Sanofi questioned whether the present claims are effectively protecting the binding site, and the binding site is naturally occurring information.88 At this point it is relevant to note MLA v Cargill at [453]:

“…the claims of the 253 Application are directed to methods and other embodiments
involving the practical application of the identification of SNPs from a nucleic acid
sample of the bovine subject and their association with a trait of interest. So, the claims
are directed to artificial subject matter being the result of human action, rather than
something that exists in nature per se.”

123. In the present case, the substance of the invention does not lie in the binding site, but in the application of the binding site information to produce an antibody with a particular functional properties..

124. Third, Sanofi noted that the claims define the antibodies by their function rather than their in an antibody, and as a consequence the claims are directed to any antibody that has the desirable features – a situation that can be seen as a mere desideratum (a wished for result – as explained in Eli Lilly v Pfizer Overseas89). But the present claims are not directed simply to an antibody that binds PCSK9, they are limited by the residues to which they bind (in the epitope/residue claims) or the nature of a competitive binding test (in the competition claims).

structure. This leads to an argument that the functional features are merely desirable features cancer”.

125. Fourth, Sanofi said that the epitope/residue claims are so wide that they have no real meaning90, and consequently cannot be considered to be a product. The argument runs that as they are not a product they are a mere desideratum or mere discovery. I have already stated that I do not consider the claims are lacking in clarity. Instead the claims are directed to a subset or class of monoclonal antibodies that bind a particular epitope or amino acid residue(s) and block the binding of LDLR to PCSK9.

126. Fifth, Sanofi says that the claims are directed to an idea because they do not define the amino acid sequence of the antibodies.91 I am not aware of any authority for the proposition that underpins this assertion. The claims are clearly directed to a biological compound defined in terms of its functional features and the specification describes in great detail several such compounds. As noted by Amgen, “it is also noteworthy that none of the antibody claims that were held to be a manner of manufacture in Alethia Biotherapeutics were defined by the amino acid sequence of the antibody”.92

127. As such, I do not consider that any of the additional submissions presented by Sanofi motivate me to reconsider any of the analysis provided at [117]-[119]. Thus, the claimed subject matter is a manner of manufacture.

Fair basis

128. Sanofi asserts that the claims of the each of the applications opposed does not comply with s 40(3) of the Act in that the claims are not fairly based on the matter described in the specification.

129. In considering fair basis, the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (Lockwood) approved the words of Gummow J in Rehm Pty Ltd v Websters Security System (International) Pty Ltd93:

“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.”
130. Further, the High Court in Kimberly-Clark Australia Pty Ltd v Arico Trading

International Pty Ltd (Kimberly-Clark)94 and Lockwood95 approved the principle provided by
Barwick CJ in Olin Corporation v Super Cartridge Co Pty Ltd96:

“The question whether the claim is fairly based is not to be resolved, in my opinion, by considering whether a monopoly in the product would be an undue reward for the disclosure. Rather, the question is a narrow one, namely whether the claim to the product… as expressed, travels beyond the matter disclosed in the specification.”
131. In Lockwood the High Court also confirmed that the existence in the body of the

specification of a consistory statement that reiterates the claimed invention is not sufficient to
provide fair basis97:

“…the correct position is that a claim based on what has been cast in the form a consistory clause is not fairly based if other parts of the matter in the specification show that the invention is narrower than that consistory clause. The inquiry is into what the body of the specification read as a whole discloses as the invention. An assertion by the inventor in a consistory clause of that of which the invention consists does not compel the conclusion by the court that the claims are fairly based nor is the assertion determinative of the identity of the invention. The consistory clause is to be considered by the court with the rest of the specification.”

132. Sanofi submitted that in the present Applications, the real and reasonably clear disclosure the indeterminate number of antigen binding proteins that are contemplated in the CS.98

is not found by looking to the numerous consistory clauses set out in the applications, nor in proteins that, by virtue of the unique 3D structure, have the ability to interact with PCKS9 with such affinity that the antibody “blocks” the interaction of PCSK9 and LDLR with the biological effect of inhibiting the effect of PCSK9 in reducing the levels of LDLRs. This is significant because LDLRs beneficially reduce the level of plasma LDL cholesterol levels.”99 They go on to submit that:

“The only two antibodies disclosed in the Applications as having been made and tested and shown to block the binding of PCSK9 to LDLR, and thereby lower plasma LDL levels are 21B12 and 31H4.
It is these two antibodies which constitute the “invention” in substance disclosed in the specifications of the Applications. The “invention” does not extend to other Table 2 antibodies (that are not shown to be “blocking” or to have any effect on plasma LDL levels, or additional antibodies “visualized” or theorised about, including by way of amino acid substitutions not employed in the Applications.”100

133. According to Amgen, support in the specification for the claims need not be limited to the examples but can and should be gleaned from the textual disclosure of the specification as a whole. It is apparent that the invention described in the applications extends well beyond the 31H4 and 21B12 antibodies. For example, the specification describes the invention as follows:

“[0009] In some aspects, the invention comprises an isolated antigen-binding protein that specifically binds to an epitope that is bound by any of the antigen- binding proteins disclosed herein.”
“[0015] In some aspects, the invention comprises an isolated antigen binding protein that competes for binding to PCSK9 with an antigen binding protein disclosed herein.”
“[0039] In some aspects, the invention comprises a neutralizing antibody that binds to PCSK9, wherein the antibody binds to PCSK9 and reduces the likelihood that PCSK9 binds to LDLR.”
“[0044] In some embodiments, an antibody, antigen binding protein, or antigen binding molecule that binds to a surface of PCSK9 that overlaps with a surface that EGFa binds, Ab 21B12 binds, and/or 31H4 binds is provided.”
“[0334] …epitopes that are bound by the presently disclosed antibodies are particularly useful. In some embodiments, antigen binding proteins that bind to any of the epitopes that are bound by the antibodies described herein are useful. In some embodiments, the epitopes bound by any of the antibodies listed in Table 2 and FIGs. 2 and 3 are especially useful. In some embodiments, the epitope is on the catalytic domain PCSK9.”

134. In each of the paragraphs above the specification consistently indicates that the invention extends to antigen binding proteins that bind to the same region or compete with those that are specifically disclosed in the application.

135. In addition, in describing the X-ray crystallography experiments (Examples 28-36) and the determined three-dimensional structure of the exemplified antibodies when bound to PCSK9 the specification again indicates that the invention extends to antibodies that bind to the EGFa domain of LDLR or antibodies that bind at or near the identified binding sites for 21B12 and 31A4.

“[0507] As will be appreciated by one of skill in the art, the results from this examples demonstrate where PCSK9 and EGFa interact. Thus, antibodies that interact with or block any of these residues can be useful as antibodies that inhibit the interaction between PCSK9 and the EGFa domain of LDLR (and/or LDLR generally). In some embodiments, antibodies that, when bound to PCSK9, interact with or block any of the above residues or are within 15-8, 8, 8-5 or 5 angstroms of the above residues are contemplated to provide useful inhibition of PCSK9 binding to LDLR.
“[0512] As will be appreciated by one of skill in the art, the results from Example 29 demonstrate where antibodies to PCSK9 can interact on PCSK9 and still block PCSK9 from interacting with EGFa (and thus LDLR). Thus, antigen binding proteins that interact with any of these PCSK9 residues, or that block any of these residues (e.g., from other antigen binding proteins that bind to these residues), can be useful as antibodies that inhibit the interaction of PCSK9 and EGFa (and LDLR accordingly). Thus, in some embodiments, antigen binding proteins that interact with any of the above residues or interact with residues that are within 5 A of the above residues are contemplated to provide useful inhibition PCSK9 binding to LDL. Similarly, antigen binding proteins that block any of the above residues (which can be determined, for example, via a competition assay) can also be useful for inhibition of the PCSK9/LDLR interaction.”
“[0517] As will be appreciated by one of skill in the art, the results from Example 30 demonstrate where antigen binding proteins to PCSK9 can interact on PCSK9 and still block PCSK9 from interacting with EGFa (and thus LDLR). Thus, antigen binding proteins that interact with any of these PCSK9 residues or that block any of these residues can be useful as antibodies that inhibit the interaction of PCSK9 and EGFa (and LDLR accordingly). Thus, in some embodiments, antibodies that interact with any of the above residues or interact with residues that are within 5 Å of the above residues are contemplated to provide useful inhibition PCSK9 binding to LDLR. Similarly, antigen binding proteins that block any of the above residues (which can be determined, for example, via a competition assay) can also be useful for inhibition of PCSK9/LDLR interaction.”
“[0524]: As will be appreciated by one of skill in the art, Examples 28-32, and their accompanying figures, provide a detailed description of how and where EGFa interacts with PCSK9 and how two representative neutralizing antigen binding proteins, 21B12 and 31H4 interact with PCSK9 and produce their neutralizing effect. As such, one of skill in the art will readily be able to identify antigen binding molecules than can similarly reduce the binding between EGFa (including LDLR) and PCSK9 by identifying other antigen binding molecules that bind at or near at least one of the same locations on PCSK9. While the relevant locations (or epitopes) on PCSK9 are identified in the figures and the present description, it can also be advantageous to describe these sites as being within a set distance from residues that have been identified as close to the EGFa binding site.”
“[0526]: In some embodiments, the antigen binding molecule binds to a surface on PCSK9 that is bound by at least one of EGFa, 21B12, or 31H4. In some embodiments, the antigen binding molecule binds to PCSK9 at a location that overlaps with the interaction locations between PCSK9 and EGFa, Ab 31H4, and/or Ab 21B12 (as described in the above examples and figures).”
“[0529]: As will be appreciated by one of skill in the art, any molecule that blocks or binds to the above noted PCSK9 residues (or within the recited distances), or that inhibits one or more of the interactions noted in the above examples and figures, can be used to inhibit the interaction of EGFa (or LDLR generally) and PCSK9.”

136. In essence, Sanofi’s submission with respect to fair basis is that the Applications have only disclosed two antibodies that have been made, tested and shown to interfere with the binding of PCSK9 to LDLR, and thereby lower plasma LDL levels. They assert that it is these two antibodies, 21B12 and 31A4, for which the specification provides a real and

reasonably clear disclosure.101

137. In [133]-[135] I have drawn attention to parts of the CS that Amgen have identified as

providing a real and reasonably clear disclosure of their invention. I agree that these parts of the specification indicate that the invention described extends beyond the specific antibodies isolated and characterised in the Applications, to include related antigen binding proteins that:

a) bind to the same or an overlapping region of PCSK9 as the EGFa domain of LDLR;
b) bind to the same region or an overlapping region of PCSK9 as bound by 21B12 and 31A4;
c) bind to PCSK9 and compete with an antigen binding protein that comprises the heavy and light chain variable regions of the 21B12 and 31A4 antibodies; or
d) bind to any of the identified residues or interact with residues that are within 5 Å of those residues.

39. A method when used in the treatment or prevention of a condition associated with an elevated serum cholesterol level in a subject, said method comprising the step of: administering to a patient in need thereof an isolated monoclonal antibody that binds an epitope on hPCSK9 comprising one or more of residues 207,208, 162, 164, 167or 123 of SEQ ID N0:1, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

40.	elevated serum cholesterol level in a subject, said method comprising the step of:

A method when used in the treatment or prevention of a condition associated with an one or more of amino acid residues 207,208, 162, 164, 167or 123 of SEQ ID NO:1, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

41.	or 40, wherein the condition is selected from the group comprising:

The use according to claim 36 or 37 or the method according to any one of claims 38, 39 coronary heart disease, atherosclerotic diseases, diabetes, stroke, Alzheimers disease, hyperlipidemia, dyslipidemia, familial hypertriglyceridemia, familial hypercholesterolemia, heterozygous hypercholesterolemia, hypothyroidism, chronic renal failure, Cushing' s syndrome, primary biliary cirrhosis, glycogen storage diseases, hepatoma, cholestasis, acromegaly, insulinoma, isolated growth hormone deficiency, alcohol-induce hypertriglyceridemia.

42. The isolated monoclonal antibody according to any one of claims 1-23, or a method according to any one of claims 38-40, substantially as herein before described with reference to the Examples.

Claims of the 685 application

1. An isolated monoclonal antibody that binds to human PCSK9 and reduces binding between human PCSK9 and an EGFa domain of LDLR, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises a heavy chain variable region of the

amino acid sequence in SEQ ID NO: 67; and a light chain variable region of the amino acid
sequence in SEQ ID NO: 12.

2. The isolated monoclonal antibody according to claim 1, wherein said monoclonal antibody is a human or a humanized monoclonal antibody.

3. The isolated monoclonal antibody according to claim 1, wherein said monoclonal antibody is an IgG.

4. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises an intact immunoglobulin, a fragment of an intact immunoglobulin.

5. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a heavy chain that comprises the amino acid sequence of SEQ ID NO: 154.

6. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a heavy chain that comprises the amino acid sequence of SEQ ID NO: 155.

7. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a human kappa light chain.

8. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a human lambda light chain.

9. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a light chain that comprises the amino acid sequence of SEQ ID NO: 156.

10. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a light chain that comprises the amino acid sequence of SEQ ID NO: 157.

11. An isolated nucleic acid encoding the monoclonal antibody according to any one of claims 1- 10.

12. A recombinant expression vector comprising the nucleic acid molecule according to claim 11.
13. A host cell comprising the vector according to claim 12.
14. A hybridoma which produces the antibody according to claim 11.

15. A method of making the isolated monoclonal antibody according to any one of claims 1-10, comprising the step of preparing said antigen binding protein from a host cell that secretes the antibody.

16. A method of producing an isolated monoclonal antibody, the method comprising the steps of introducing the expression vector according to claim 12 into an isolated host cell, growing the cell under conditions permitting production of the monoclonal antibody, and recovering the

antibody so produced.

17. A monoclonal antibody produced by the expression of recombinant DNA in the host cell according to claim 13 or the hybridoma according to claim 14.

18. The method according to claim 16 or the isolated monoclonal antibody according to claim 17, wherein the host cell is selected from the group consisting of Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells, and human epithelial kidney 293 cells.

19. A pharmaceutical composition comprising at least one monoclonal antibody according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

20. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is for use prior to, concurrent with, or subsequent to, the use of at least one other therapeutic agent.

21. The pharmaceutical composition according to claim 20, wherein the at least one other therapeutic agent is selected from the group comprising: a statin, nictotimic acid, fibric acid, bile acid sequestrants, cholesterol absorption inhibitors, combinations of nicotinic acid and statin, combinations of a statin with an absorption inhibitor, lipid modifying agents, PPAR gamma agonists, PPAR alpha/gamma agonists, squalene synthase inhibitors, CETP inhibitors, anti-hypertensives, anti-diabetic agents, insulin, ApoB modulators, MTP inhibitors, and arteriosclerosis obliterans treatments.

22. A kit when used in the treatment of cholesterol related disorders comprising the composition according to any one of claims 19 to 21.

23. Use of the monoclonal antibody according to any one of claims 1 to 10 in the manufacture of a medicament when used for treating or preventing a condition associated with an elevated serum cholesterol level in a subject.

24. Use of the monoclonal antibody according to any one of claims 1 to 10 in the treatment or prevention of a condition associated with an elevated serum cholesterol level in a subject.

25. A method when used in the treatment or prevention of a condition associated with an elevated serum cholesterol level in a subject, said method comprising the step of administering to a patient in need thereof a therapeutically effective amount of an isolated monoclonal antibody according to any one of claims 1 to 10 or a pharmaceutical composition according to any one of claims 19 to 21.

26. The use according to claim 23 or 24, wherein the condition is selected from the group comprising: hypercholesterolemia, heart disease, cardiovascular diseases, metabolic syndrome, coronary heart disease, atherosclerotic diseases, diabetes, stroke, Alzheimers disease, hyperlipidemia, dyslipidemia, familial hypertriglyceridemia, familial hypercholesterolemia, heterozygous hypercholesterolemia, hypothyroidism, chronic renal failure, Cushing'ssyndrome, pnmary biliary cirrhosis, glycogen storage diseases, hepatoma, cholestasis, acromegaly, insulinoma, isolated growth hormone deficiency, alcohol-induce hypertriglyceridemia.

27. The use according to 24 or 25, wherein the condition is hypercholesterolemia, hyperlipidemia, dyslipidemia, familial hypertriglyceridemia, familial hypercholesterolemia, or heterozygous hypercholesterolemia.

28. The use according to 24 or 25, wherein the condition is heart disease, cardiovascular diseases, coronary heart disease, or atherosclerotic diseases.

29. The use according to claim 24 or 25, wherein the condition is metabolic syndrome or diabetes.

30. The isolated monoclonal antibody according to any one of claims 1, or a method according to claims 15 or 16, substantially as herein before described with reference to the Examples.

Claims of the 689 application

1. An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, 1154, Pl55, Rl94, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO: 3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

2. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least S153.

3. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least 1154.

4. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least Pl55.

5. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least T377.

6. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least R194.

7. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least D238.

8. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least A239.

9. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least 1369.

10. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least S372.

11. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least D374.

12. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least C375.

13. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least C378.

14. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least F379.

15. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least V380.

16. The isolated monoclonal antibody of claim 1, wherein the monoclonal antibody binds to at least S381.

17. A pharmaceutical composition comprising an isolated monoclonal antibody, wherein, when bound to PCSK9, the isolated monoclonal antibody binds to at least one of the following residues: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO: 3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

18. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody blocks the binding of PCSK9 to LDLR by at least 80%.

19. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody binds to at least two of the following residues: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381 of PCSK9 listed in SEQ ID NO: 3.

20. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody binds to at least four of the following residues: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381 of PCSK9 listed in SEQ ID NO: 3.

21. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody is a human antibody.

22. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody is a humanised antibody.

23. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody binds to at least two of the following residues: Sl53, 1154, Pl55, Rl94, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381 of PCSK9 listed in SEQ ID NO: 3 and blocks the binding of PCSK9 to LDLR by at least 80%.

24. The isolated monoclonal antibody of claim 23, wherein the isolated monoclonal antibody is a human antibody.

25. The isolated monoclonal antibody of claim 23, wherein the isolated monoclonal antibody is a humanised antibody.

26. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody binds to at least four of the following residues: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381 of PCSK9 listed in SEQ ID NO: 3 and blocks the binding of PCSK9 to LDLR by at least 80%.

27. The isolated monoclonal antibody of claim 26, wherein the isolated monoclonal antibody is a human antibody.

28. The isolated monoclonal antibody of claim 26, wherein the isolated monoclonal antibody is a humanised antibody.

29. A pharmaceutical composition comprising an isolated monoclonal antibody, wherein the isolated monoclonal antibody binds to at least two of the following residues: Sl53, 1154, Pl55, Rl94, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381 of PCSK9 listed in SEQ ID NO: 3, and blocks the binding of PCSK9 to LDLR by at least 80%.

30. The isolated monoclonal antibody according to claim 1 substantially as described herein.

Claims of the 748 application

1. An isolated monoclonal antibody that binds to human PCSK9 and is neutralizing in that an excess of said antibody reduces the quantity of human PCSK9 bound to LDLR in an in vitro competitive binding assay, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises: a heavy chain variable region of the amino acid sequence in SEQ ID NO: 49; and a light chain variable region of the amino acid sequence in SEQ ID NO: