Sanofi v Amgen Inc. [2025] FCA 387 | Case summary

AMP Inc v Utilux Pty Ltd (1971) 45 ALJR 123

Sanofi v Amgen Inc. [2025] FCA 387 | Case summary | Zoe

[64]

The Applications were filed on 11 April 2013. The earliest asserted priority date for each of the relevant claims is 23 August 2007 ("the priority date").
Each of the Applications claims divisional status from Application No. 2008288791 ("the Parent Application") filed on 22 August 2008 under the provisions of the Patent Cooperation Treaty as PCT/US2008/074097. The Parent Application was first published on 26 February 2009.
Low density lipoprotein receptor ("LDLR") on the surface of the liver takes up low density lipoprotein ("LDL") which is then transported to lysosomes for degradation. The LDLR is then returned to the liver surface to take up more LDL. High levels of LDL cholesterol are associated with increased risk of cardiovascular and related diseases. Reduction in LDL cholesterol concentrations may therefore lead to improved health outcomes.
PCSK9 refers to proprotein convertase subtilisin kexin Type 9. PCSK9 is a protein involved in the degradation of LDLR. The Applications are concerned with isolated monoclonal antibodies ("isolated MAbs") that target PCSK9 (the antigen). The MAbs block or inhibit the activity of PCSK9 by binding to it, thereby increasing the level of LDLR available to clear LDL and reduce LDL cholesterol levels.
The binding of an antibody to its antigen occurs via non-covalent interactions between amino acid residues of the antibody and the antigen.
The Applications have a Common Specification ("CS"), which differs as between the Applications in the consistory-like clauses and some figures. Each of the independent claims of the Applications is to an isolated MAb. The term "isolated" means the MAb exists separate from the other components with which it would usually be found, and the term monoclonal describes uniform antibodies of the same specificity and comprising the same heavy and light chains, with some minor variations to their amino acid sequences to be expected. Most relevantly, MAbs will bind to the same epitope, a term which is defined immediately below.
The CS and the claims of some of the Applications refer to amino acid residues on PCSK9. The claims identify residues by reference to (inter alia) "SEQ ID NO: 1" and SEQ ID NO: 3", both being amino acid sequences of PCSK9 set out in Figures 1A and 1B to the CS, respectively. The term "epitope" refers to the specific region on the antigen to which the antibody binds. The amino acid sequences in Figures 1A and 1B are relevantly the same, except that Figure 1B includes the signal sequence, whereas Figure 1A does not. The specification teaches that "any amino acid position in SEQ ID NO: 1, will correspond to an amino acid position 30 amino acids further into the protein in SEQ ID NO: 3".
The parties have agreed upon a set of exemplary claims in each of the Applications ("the Exemplary Claims"). Those claims can be divided into the "Epitope Claims" and the "Residue Claims" of 677, 689 and 751, and the "Competition Claims" of 677, 685 and 748.
677 includes independent claims 1 and 5. Claim 1, an Epitope Claim, is for:
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.

[78]

(a) Failure to define the invention - The claims of each of the Applications fail to define the invention in that they pertain to any "isolated monoclonal antibody" having some claimed functional features only. The "blocking" function of an antibody, knowledge of the epitope or a residue or residues on an antigen to which an antibody binds, or reference to another antibody with which an antibody competes, does not define the structure of, or characterise the construction of, an antibody as claimed.

(b) Not a manner of manufacture - The claims of each of the Applications fail to define a manner of manufacture because they are for no more than a mere desideratum, namely, any MAb providing particular functional outcomes.

(c) Lack of fair basis - The claims travel well beyond any invention described in the specification and omit essential features of that invention and are therefore not fairly based.

(d) Lack of clarity - The Competition Claims lack clarity because it is not clear whether "competes" means any degree of competition or some particular numerical degree of competition and, in any event, there is no workable standard to determine the exact boundaries of the claims. Various alternative competitive binding assays described in the specification can produce different results.

(e) Failure to describe the invention fully - The claims of each of the Applications are properly characterised as claims to a multiplicity of inventions, each a different antibody with a unique amino acid sequence and binding to a different epitope on PCSK9. The Applications are therefore insufficient because the person skilled in the art ("PSA") would need to engage in the research project described in Examples 1 to 3 of the Applications in an attempt to produce one embodiment of each such invention.

(f) Lack of inventive step - The use of an antibody to inhibit PCSK9 had been postulated in well-known, peer-reviewed literature. LDLR residues in the PCSK9 and LDLR EGFa domain interface ("the PCSK9/EGFa interface") were known. It was "logical" that an antibody that blocks the binding of PCSK9 to LDLR (to any degree) would do so by binding to an epitope that included any one of the residues in the PCSK9/EGFa interface. It follows that the inventions do not involve any inventive step.

[83]

(i) the proper construction of a specification is a matter of law: Décor Corporation Pty Ltd v Dart Industries Inc [1988] FCA 399; (1988) 13 IPR 385 at 400 [(Décor Corporation Pty Ltd)];

(ii) a patent specification should be given a purposive, not a purely literal, construction: Flexible Steel Lacing Co v Beltreco Ltd (2000) 49 IPR 331; [2000] FCA 890 at [81] (Flexible Steel Lacing); and it is not to be read in the abstract but is to be construed in the light of the common general knowledge and the art before the priority date: [Kimberly]-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1; 177 ALR 460; 50 IPR 513; [2001] HCA 8 [(Kimberly-Clark v Arico)] at [24];

(iii) the words used in a specification are to be given the meaning which the normal person skilled in the art would attach to them, having regard to his or her own general knowledge and to what is disclosed in the body of the specification: Décor Corporation Pty Ltd at 391;

(iv) while the claims are to be construed in the context of the specification as a whole, it is not legitimate to narrow or expand the boundaries of monopoly as fixed by the words of a claim by adding to those words glosses drawn from other parts of the specification, although terms in the claim which are unclear may be defined by reference to the body of the specification: [Kimberly]-Clark v Arico at [15]; Welch Perrin & Co Pty Ltd v Worrel [1961] HCA 91; (1961) 106 CLR 588 at 610; Interlego AG v Toltoys Pty Ltd [1973] HCA 1; (1973) 130 CLR 461 at 478; the body of a specification cannot be used to change a clear claim for one subject matter into a claim for another and different subject matter: Electric & Musical Industries Ltd v Lissen Ltd [1938] 4 All ER 221 at 224-5; (1938) 56 RPC 23 at 39;

(v) experts can give evidence on the meaning which those skilled in the art would give to technical or scientific terms and phrases and on unusual or special meanings to be given by skilled addressees to words which might otherwise bear their ordinary meaning: Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd [1994] FCA 1529; (1994) 30 IPR 479 at 485-6 (Sartas No 1 Pty Ltd); the court is to place itself in the position of some person acquainted with the surrounding circumstances as to the state of the art and manufacture at the time ([Kimberly]-Clark v Arico at [24]); and

(vi) it is for the court, not for any witness however expert, to construe the specification; Sartas No 1 Pty Ltd at 485-6.

[92]

Professor Petsko is a Professor of Neurology at Harvard Medical School and Brigham Women's Hospital, Adjunct Professor of Biomedical Engineering at Cornell University and Emeritus Professor in Biochemistry and Chemistry at Brandeis University. He holds a Bachelor of Chemistry from Princeton University and a PhD in Molecular Biophysics from Oxford University. He is an elected member of the National Academy of Sciences (1995) and the American Academy of Arts and Sciences (2002). He has been recognised by the latter for his pioneering work in the field of X-ray crystallography. In 2023 he was awarded a National Medal of Science by the President of the USA.
Professor Petsko has expertise in various related fields including, most relevantly, structural biochemistry, and X-ray crystallography. He has authored or co-authored over 300 peer reviewed articles mostly detailing the relationship between protein structure and function. Much of his work has included the use of X-ray crystallography to solve the atomic structure of proteins either alone or in complex with other molecules. He is a co-author (with Professor Dagmar Ringe) of a textbook first published in 2003 concerning basic principles of protein structure and function entitled "Primers in Biology: Protein Structure and Function".
Sanofi submitted that Professor Petsko, while highly qualified, was often loquacious in his answers and "passionately committed to Amgen's case". Sanofi was also critical of Professor Petsko for not disclosing in his written evidence that he prepared or relied on an electron density map in respect of residue S153 on PCSK9.
Professor Petsko made clear in his oral evidence that his analysis of S153 relied only on the structural information that would be available to Professor M Parker and did not rely on the electron density map for S153. Professor Petsko's cross examination revealed he had seen the electron density map for S153 "a number of years ago" and that he could not "unsee" this information. When Professor Petsko was pressed on the topic of S153, he made clear he did not use the electron density map as part of his analysis, but instead used the B-Factors provided in Table 35.3 and the rotamer for S153 recorded in the coordinates in Table 35.3.
There are a few points I would make with regard to the suggestion that Professor Petsko was "loquacious" and "passionately committed to Amgen's case". First, much of Professor Petkso's oral evidence was directed to explaining the relevant science and the CS, often in answer to questions from the Court. In this regard, the impression I formed of Professor Petsko was not that he was loquacious, but that he is an excellent communicator with an impressive ability to explain the relevant science pellucidly. I reject Sanofi's submission that Professor Petsko's evidence was tendentious or affected by bias. I regard him as a very impressive witness whose evidence I found helpful.

[105]

The Antibody and Crystallography Experts agreed that the term "structural epitope" refers to the region of the target antigen covered by the antibody that binds it. They also agreed that the term "functional epitope" refers to the region of the target antigen that is directly involved in non-covalent interactions with the antibody that contribute to the affinity the two proteins have for each other.
The CS also distinguishes between linear and conformational epitopes. Amgen defines a conformational epitope as one "composed of discontinuous amino acid sequences that are brought together by protein folding in the antigen". Sanofi's definition, which varies only slightly, draws a distinction between conformational epitopes which "[conform] with the native three-dimensional structure of the antigen" and linear epitopes, composed of residues which are contiguous. I do not consider that there is a meaningful distinction between the two proposed definitions, but in any event, it is sufficient to refer to Amgen's definition.
The measure of the strength of binding between the antibody and antigen is referred to as affinity. The affinity of the binding between an antibody and its antigen is the sum of all the non-covalent interactions between the antibody and the antigen.
The specificity of an antibody is the ability of the antibody to distinguish between a particular molecular structure and all other structures. Specific binding occurs when an antibody binds preferentially to its antigen over other proteins. Non-specific binding occurs when an antibody binds to an epitope that is common across a range of proteins, including its antigen and unrelated proteins. Specificity is measured through assays that may examine, for example, whether an antibody binds to proteins other than the target protein.
Protein-protein (including antibody-antigen) binding occurs when the 3D shape and contours of one protein allow some of its amino acid residues to align with that of another protein, such that one or (typically) multiple individual non-covalent interactions between those residues can take place. The three major types of non-covalent interactions that may contribute to binding of an antibody to its antigen are:

[111]

Transgenic mice are mice that have been genetically modified, in this context to produce fully human antibodies. When a transgenic mouse is immunised (i.e. injected with) the antigen of interest, B cells are created, some of which produce antibodies that bind to the antigen. These B cells are "remembered" by the immune system and undergo random mutations, which may lead to antibodies having increased or reduced binding affinity.
After the spleens of the mice are removed, the B cells are isolated. Isolation of a single B cell from this sample and clonal expansion results in a colony of cells arising from that single "parent" cell. Antibodies produced from a unique parent cell (and its cloned colony) are termed "monoclonal antibodies" (i.e., MAbs).
B cells must be "immortalised" to survive outside the body. To do so, a B cell is fused with a myeloma cell to create a "hybridoma", which has the characteristics of both the B cell (in that it expresses and secretes a MAb) and the myeloma cell (in that it can grow and divide indefinitely ex vivo).
The hybridoma thus provides a cell "factory" that can be used in the large-scale production of MAbs. The hybridoma is cultured and MAbs are secreted to the outside of the cell, accumulating in the surrounding media. After an appropriate time in the cell culture, the media is harvested, and the antibody is purified from the media. The panel of antibodies produced by these hybridomas can then be screened to identify those with the desired attributes including, for example, their ability to bind to a target antigen.
The recovery of B cells from mice and their immortalisation, and the techniques for screening the binding of antibodies to a target antigen, as a general matter, were known procedures as at the priority date.
The Antibody Experts agreed that, once a mouse has been injected with the selected protein or part thereof which is the intended target antigen, the researcher has no control over how the mouse's immune system will react. As Professor Mahler said, once injection has occurred, "[t]he mouse immune system then takes over, and whatever antibodies are raised are raised...and you get what you get". I accept that evidence.

[115]

Atoms within chemical molecules exist in a 3D conformation. X-ray crystallography (or simply, crystallography) enables determination of that 3D arrangement (x, y and z coordinates). From well before 2007/2008, crystallography has been universally accepted as the 'gold standard' technique for studying the precise manner of binding between two proteins.
The technique involves shining an X-ray beam onto a sample of the protein or protein complex. Some of the X-rays interact with electrons of the atoms in the sample, resulting in the production of new X-rays that are emitted in many directions ("diffracted").
However, when a beam of X-rays is directed at a single protein molecule, the scatter of the X‑ray beam will be too small to detect. Instead, a sample of the protein (or protein complex) in the form of a 3D crystal lattice consisting of a regular, repeating arrangement of the protein molecule (or protein complex) is required. A typical crystal has tens of thousands of identical, repeating "unit cells" which amplify the X-ray beam, creating a signal that has sufficient intensity to be detected. Obtaining crystals of a protein or protein complex relies on various factors (such as the stability of the protein complex) and is usually the most rate-limiting step of this process.
Using a protein (or protein complex) crystal, the 'diffraction pattern' of the scattered X-rays can be collected and then analysed mathematically to construct an initial 3D image of the electron clouds of the protein, referred to as an "electron density map". The electron density map is then compared to the amino acid sequence of the protein, and, based on knowledge of the chemical structure of each amino acid, the electron clouds observed can be assigned to particular amino acid residues. This process is called 'refinement' and involves considering all possibilities until the best consensus fit with the amino acid sequence is reached. It is done using a computer program. The overall percentage disagreement between the model's calculated diffraction pattern and the observed diffraction data is referred to as the "R factor".
The process of fitting amino acid residues in a protein to the electron density map makes it possible to identify 3D atomic coordinates for atoms in a protein (or protein complex), represented as x, y and z values.
Subject to the resolution of the crystallography experiment, the 3D coordinates of ligands, such as water, will be identified separately. Resolution can be thought of as the extent to which it is possible to identify atoms or groups of atoms. The higher the resolution, the greater the level of detail of the map and the greater the extent to which it is possible to distinguish one atom from another in the electron density map. Resolution is typically measured in angstroms ("Å"), which is 1×10-10 m (or 0.0000001 mm). Even at a high resolution, it may still be difficult to detect the position of certain side chains, if they are too mobile (or not well ordered enough).
Two relevant crystallography parameters are temperature (or 'B') factor, which is a measure of the spread of electron density, and occupancy, which is the fraction of an atom present within a particular site.
Computer programs can be used to generate depictions of the structure of a protein or a protein-protein complex from the atomic coordinates. These can be viewed in 3D on a computer. One such computer program, which was widely available as at 23 August 2007, is known as PyMOL.

[119]

ELISA is a technique designed to detect and quantify a protein of interest (e.g., an antigen or antibody). The technique was first designed in the early 1970s.
A sample of one protein is immobilised onto the surface of the well in a micro-plate, and then a sample containing another protein is added to the well. Detection of any binding between the two proteins is achieved in a number of different ways. The immobilisation of the first protein can also be achieved a number of different ways, in order to orient the antigen differently.
ELISA can be used to measure the binding of an antibody to an antigen or to detect competition between two or more antibodies binding the same antigen. For example, ELISA can be used to determine if an antibody blocks the binding of an antigen (e.g., PCSK9) to its target (e.g., LDLR).
There are different forms of ELISA, depending on the purpose of the assay to be undertaken. Direct ELISA involves the immobilisation of an antigen to the surface of a well, and the addition of an antibody which has been conjugated with a detection label. The antibody and antigen are incubated for a period of time to allow for binding, after which point, the well is washed to remove any unbound antibody. A substrate is added, which reacts with the detection label. If any antibody (now bound to the antigen) is present, the substrate reaction with the detection label results in a detectable colour. Typically, the detection methodology involves a colorimetric reaction that can be read by a spectrophotometer. The spectrophotometer detects the intensity of the colour, and the readout is measured in optical density ("OD") units. A higher OD indicates more antibodies are bound to the antigen in the well. Generally, an antibody that has a stronger affinity for the antigen will have a higher OD than an antibody with a weaker affinity.
Indirect Detection ELISA similarly involves the immobilisation of an antigen to a well, the addition of an antibody ("the primary antibody") and incubation to allow for binding. The well is then washed to remove the unbound primary antibody, and a "secondary antibody" is added and incubated for a period of time to allow the secondary antibody to bind to the primary antibody. The secondary antibody typically carries a label, which generates a colour, typically following a chemical reaction. The colour can be detected and measured, and the binding between the antigen and primary antibody can be calculated from the OD.
Sandwich ELISA is an alternative format of Indirect Detection ELISA. It can be used in competition assays, to detect whether an antibody can compete with the binding of another antibody to the same antigen. When used in this way, the surface of the well is coated with the "capture antibody", and the antigen is added to the well and captured. A "detection antibody", which carries a label that generates a colour, is then added. According to the Agreed Primer, the detection antibody can bind the antigen:

[132]

CS [0260]-[0262] describes by reference to various figures 32 different examples of antibodies and the amino acid sequences for the variable regions of their light and heavy chains. The MAbs referred to in Table 2 ("the Table 2 Antibodies"), at CS [0261], are a selection of those generated in XenoMouse mice which can produce fully human antibodies (Example 1). The mice were injected with PCSK9 eleven times. Selected mice were then sacrificed and their lymph nodes were used to create hybridomas to produce MAbs capable of binding to PCSK9 (Example 2).
Following the production of the hybridomas, a screening process was undertaken (Example 3). The first "primary screen" identified 3104 PCSK9 specific hybridomas of interest. This number was reduced to 2441 following a "confirmatory screen". Further screening identified 579 MAbs that bound to both mouse and human PCSK9. These MAbs were then screened for binding to a mutant variant of PCSK9 ("D374Y mutant"). This mutant was used because it has a higher binding affinity to LDLR. Over 96% of those antibodies identified as binding to wild-type PCSK9 (i.e., non-mutated) were found to bind to the D374Y mutant. A further assay then tested whether the MAbs could block the D374Y mutant from binding to LDLR, The D374Y screen identified a subset of 384 MAbs that blocked binding between D374Y and LDLR "well", and 100 which blocked the interaction "strongly".
This assay was repeated and 85 antibodies were found to block the interaction between the D374Y mutant and LDLR greater than 90%. A screen was also performed on those antibodies found to bind to wild-type PCSK9 but not the D374Y mutant, for their ability to block binding between wild-type PCSK9 and LDLR.
CS [0422] explains that based on the results of the assays described, "several hybridoma lines were identified as producing antibodies with desired interactions with PCSK9", and "[l]imiting dilution was used to isolate a manageable number of clones from each line" which were given line numbers (e.g., 21B12) and clone numbers (e.g., 21B12.1). The clones of each line generally behaved the same. The isolated clones were then expanded in hybridoma media, and the concentration and potency of the antibodies to PCSK9 in the supernatants of those cultures were tested. Those hybridomas with the highest titer of antibodies (i.e., highest detected amount) were identified. The selected hybridomas are listed in Table 2. Relevantly, CS [0260]-[0262] sets out:

[140]

In some embodiments, the ABP binds selectively to the form of PCSK9 that binds to LDLR (e.g., the autocatalyzed form of the molecule). In some embodiments, the antigen binding protein does not bind to the c-terminus of the cataylytic [sic] domain (e.g., the 5. 5-10, 10-15, 15-20, 20-25, 25-30, 30-40 most [sic] amino acids in the c-terminus). In some embodiments, the antigen binding protein does not bind to the n-terminus of the catalytic domain (e.g., the 5. 5-10, 10-15, 15-20, 20-25, 25-30, 30-40 most [sic] amino acids in the n-terminus). In some embodiments, the ABP binds to amino acids within amino acids 1-100 of the mature form of PCSK9. In some embodiments, the ABP binds to amino acids within (and/or amino acid sequences consisting of) amino acids 31-100, 100-200, 31-152, 153-692, 200-300, 300-400, 452-683, 400-500, 500-600, 31-692, 31-449, and/or 600-692. In some embodiments, the ABP binds to the catalytic domain. In some embodiments, the neutralizing and/or non-neutralizing ABP binds to the prodomain. In some embodiments, the ABP binds to both the catalytic and pro domains. In some embodiments, the ABP binds to the catalytic domain so as to obstruct an area on the catalytic domain that interacts with the pro domain. In some embodiments, the ABP binds to the catalytic domain at a location or surface that the pro-domain interacts with as outlined in Piper et al ... In some embodiments, the ABP binds to the catalytic domain and restricts the mobility of the prodomain. In some embodiments, the ABP binds to the catalytic domain without binding to the pro-domain. In some embodiments, the ABP binds to the catalytic domain, without binding to the pro-domain, while preventing the pro domain from reorienting to allow PCSK9 to bind to LDLR. In some embodiments, the ABP binds in the same epitope as those surrounding residues 149-152 of the pro-domain in Piper et al. In some embodiments, the ABPs bind to the groove (as outlined in Piper et al.) on the V domain. In some embodiments, the ABPs bind to the histidine-rich patch proximal to the groove on the V domain. In some embodiments, such antibodies (that bind to the V domain) are not neutralizing. In some embodiments, antibodies that bind to the V domain are neutralizing. In some embodiments, the neutralizing ABPs prevent the binding of PCSK9 to LDLR. In some embodiments, the neturalizing [sic] ABPs, while preventing the PCSK9 degradation of LDLR, do not prevent the binding of PCSK9 to LDLR (for example ABP3 1A4). In some embodiments, the ABP binds to or blocks at least one of the histidines depicted in Figure 4 of the Piper et al. paper. In some embodiments, the ABP blocks the catalytic triad in PCSK9.

[143]

[0280] Other antibodies that are provided are variants of the ABPs listed above formed by combination or subparts of the variable heavy and variable light chains shown in Table 2 and comprise variable light and/or variable heavy chains that each have at least 50%, 50-60, 60-70, 70-80%, 80-85%, 85-90%, 90-95%, 95-97%, 97-99%, or above 99% identity to the amino acid sequences of the sequences in Table 2 (either the entire sequence or a subpart of the sequence, e.g., one or more CDR). In some instances, such antibodies include at least one heavy chain and one light chain, whereas in other instances the variant forms contain two identical light chains and two identical heavy chains (or subparts thereof). In some embodiments, the sequence comparison in FIG. 2A-3D (and 13A-13J and other embodiments in 15A-15D) can be used in order to identify sections of the antibodies that can be modified by observing those variations that impact binding and those variations that do not appear to impact binding. For example, by comparing similar sequences, one can identify those sections (e.g., particular amino acids) that can be modified and how they can be modified while still retaining (or improving) the functionality of the ABP. In some embodiments, variants of ABPs include those consensus groups and sequences depicted in FIGs. 13A, 13C, 13F, 13G, 13H, 131 and/or 13J and variations are allowed in the positions identified as variable in the figures ...

[0281] In certain embodiments, an antigen binding protein comprises a heavy chain comprising a variable region comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from at least one of the sequences of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60. In certain embodiments, an antigen binding protein comprises a heavy chain comprising a variable region comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from at least one of the sequences of [the previously mentioned SEQ IDs]. In certain embodiments, an antigen binding protein comprises a heavy chain comprising a variable region comprising an amino acid sequence at least 99% identical to an amino acid sequence selected from at least one of the sequences of [the previously mentioned SEQ IDs].

[0282] In some embodiments, the antigen binding protein comprises a sequence that is at least 90%, 90-95%, and/or 95-99% identical to one or more CDRs from the CDRs in at least one of sequences of [the previously mentioned SEQ IDs]. In some embodiments, 1, 2, 3, 4, 5, or 6 CDR (each being at least 90%, 90-95%, and/or 95-99% identical to the above sequences) is present.

[0283] In some embodiments, the antigen binding protein comprises a sequence that is at least 90%, 90-95%, and/or 95-99% identical to one or more FRs from the FRs in at least one of sequences of [the previously mentioned SEQ IDs]. In some embodiments, 1, 2, 3, or 4 FR (each being at least 90%, 90-95%, and/or 95-99% identical to the above sequences) is present.

[0284] In certain embodiments, an antigen binding protein comprises a light chain comprising a variable region comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from at least one of the sequences of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In certain embodiments, an antigen binding protein comprises a light chain comprising a variable region comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from at least one of the sequences of [the previously mentioned SEQ IDs]. In certain embodiments, an antigen binding protein comprises a light chain comprising a variable region comprising an amino acid sequence at least 99% identical to an amino acid sequence selected from at least one of the sequences of [the previously mentioned SEQ IDs].

[0285] In some embodiments, the antigen binding protein comprises a sequence that is at least 90%, 90-95%, and/or 95-99% identical to one or more CDRs from the CDRs in at least one of sequences of [the previously mentioned SEQ IDs]. In some embodiments, 1, 2, 3, 4, 5, or 6 CDR (each being at least 90%, 90-95%, and/or 95-99% identical to the above sequences) is present.

[0286] In some embodiments, the antigen binding protein comprises a sequence that is at least 90%, 90-95%, and/or 95-99% identical to one or more FRs from the FRs in at least one of sequences of [the previously mentioned SEQ IDs]. In some embodiments, 1, 2, 3, or 4 FR (each being at least 90%, 90-95%, and/or 95-99% identical to the above sequences) is present.

[0287] In light of the present disclosure, a skilled artisan will be able to determine suitable variants of the ABPs as set forth herein using well-known techniques. In certain embodiments, one skilled in the art can identify suitable areas of the molecule that may be changed without destroying activity by targeting regions not believed to be important for activity. In certain embodiments, one can identify residues and portions of the molecules that are conserved among similar polypeptides. In certain embodiments, even areas that can be important for biological activity or for structure can be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.

[0288] Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in a protein that correspond to amino acid residues which are important for activity or structure in similar proteins. One skilled in the art can opt for chemically similar amino acid substitutions for such predicted important amino acid residues.

[0289] One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar ABPs. In view of such information, one skilled in the art can predict the alignment of amino acid residues of an antibody with respect to its three dimensional structure. In certain embodiments, one skilled in the art can choose not to make radical changes to amino acid residues predicted to be on the surface of the protein, since such residues can be involved in important interactions with other molecules. Moreover, one skilled in the art can generate test variants containing a single amino acid substitution at each desired amino acid residue. The variants can then be screened using activity assays known to those skilled in the art. Such variants can be used to gather information about suitable variants. For example, if one discovered that a change to a particular amino acid residue resulted in destroyed, undesirably reduced, or unsuitable activity, variants with such a change can be avoided. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acids where further substitutions should be avoided either alone or in combination with other mutations.

[157]

The term "neutralizing antigen binding protein" or "neutralizing antibody" refers to an antigen binding protein or antibody, respectively, 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). In some embodiments, the term can also denote an antigen binding protein that prevents the protein to which it is bound from performing a biological function. In assessing the binding and/or specificity of an antigen binding protein, e.g., an antibody or immunologically functional fragment thereof, an antibody or fragment can substantially inhibit binding of a ligand to its binding partner when an excess of antibody reduces the quantity of binding partner bound to the ligand by at least about 1-20, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-85%, 85 90%, 90-95%, 95-97%, 97-98%, 98-99% or more (as measured in an in vitro competitive binding assay). In some embodiments, in the case of PCSK9 antigen binding proteins, such a neutralizing molecule can diminish the ability of PCSK9 to bind the LDLR. In some embodiments, the neutralizing ability is characterized and/or described via a competition assay. In some embodiments, the neutralizing ability is described in terms of an IC50 or EC50 value. In some embodiments, ABPs 27B2, 13H1, 13B5 and 3C4 are non-neutralizing ABPs, 3B6, 9C9 and 31A4 are weak neutralizers, and the remaining ABPs in Table 2 are strong neutralizers. In some embodiments, the antibodies or antigen binding proteins neutralize by binding to PCSK9 and preventing PCSK9 from binding to LDLR (or reducing the ability of PCSK9 to bind to LDLR). In some embodiments, the antibodies or ABPs neutralize by binding to PCSK9, and while still allowing PCSK9 to bind to LDLR, preventing or reducing the PCSK9 mediated degradation of LDLR. Thus, in some embodiments, a neutralizing ABP or antibody can still permit PCSK9/LDLR binding, but will prevent (or reduce) subsequent PCSK9 involved degradation of LDLR.

[159]

The CS includes as examples further work undertaken to characterise the binding profile of MAbs 16F12, 21B12 and 31H4. Various experiments were undertaken to measure the affinity of each of those MAbs to PCSK9. Measures of affinity using an affinity analysis (BIACore) are presented in Tables 7.1 and 7.2. A different affinity analysis (KinExA) was undertaken on MAbs 16F12 and 31H4 with results presented in Tables 8.1 and 8.2. MAbs 31H4 and 21B12 were also tested in Example 11 for efficacy in blocking D374Y mutant binding to LDLR.
A number of the examples in the CS (Examples 13-17) are concerned with the effect of MAb 31H4 and 16F12 on LDLR, serum cholesterol, and HDL using various experiment protocols in mice. Example 18 is concerned with "Epitope Mapping of Human Anti PCSK9 Antibodies". It describes methods that could be used to determine which residues in PCSK9 are involved in forming, or part of, the epitope of the ABPs described. The methods identified are SPOTs peptide array, combinatorial alanine scanning and "a combination of alanine scanning and/or arginine scanning, antibody FAB/PCSK9 co-crystallization, and limited proteolysis/LC-MS (liquid chromatography mass spec.)". This example does not contain any results of such experiments.
Examples 19-21 are concerned with the use of antibodies, including 31H4, 21B12 and 16F12, as monotherapy or in combination with a statin. Example 22 is concerned with the use of such antibodies as a diagnostic agent. Examples 23-24 are also concerned with the use of antibodies either as monotherapy or in combination with a statin.
Example 25 provides details of consensus sequences determined through analyses of CDRs corresponding to the heavy chain and light chain variable regions (VH and VL) of anti-PCSK9 antibodies. CS [0496] asserts the results in Figures 13A-13J "present a large amount of guidance as to the importance of particular amino acids ... and which amino acid positions can likely be altered ".
Example 26 provides results of testing the ability of antibodies to lower LDL in mice. The tests were conducted using antibodies 16F12, 21B12 and 31H4. Both 31H4 and 21B12 were said to show significant reductions in LDL cholesterol levels. Antibody 16F12 was less effective. The data is said to be consistent with binding data which shows near equivalent binding affinity between 31H4 and 21B12, and a lower affinity of 16F12 to human PCSK9.
Example 27 (read with Figures 16A and 16B) show that antibodies 31H4 and 21B12 bind to the ProCat domain of PCSK9. This was determined through combining either the ProCat or V domains of PCSK9 with 31H4 and 21B12 and analysing whether binding had occurred using Native PAGE for complex formation.
Example 28 presents the solved crystal structure of the PCSK9 ProCat domain bound to the LDLR EGFa domain. CS [0504] explains that this interaction "appears to occur across a surface of PCSK9 between residues D374 and S153" as depicted in Figure 17 reproduced below (identified according to their position in SEQ ID NO: 3).

[170]

Example 38 uses "Western Blot" analysis to demonstrate whether the epitopes for 13H1, 3C4 and 31A4 are linear or conformational. It was concluded that 13H1 bound to a linear epitope on the prodomain of PCSK9 whereas the other two antibodies appeared to bind to conformational epitopes. It is not apparent from the CS if any other MAbs were tested other than the three to which I have referred.
In Example 39, five MAbs representative of each "bin" were selected from Example 37 for further epitope analysis using arginine/glutamic acid scanning (a form of mutagnesis), as described above. In Example 39, comparisons are made between binding of the selected antibodies to the PCSK9 mutants (i.e. those with modified sidechains) and wild-type PCSK9. The mutated residues are identified in Table 39.1 and Fig 26. Both "EC50" and "Bmax" values are used in Example 39 to assess whether a particular residue is part of the structural epitope for the relevant MAb.
EC50 is a measurement of the concentration of the protein required to achieve 50% of the maximum binding signal over a range of concentrations tested. The lower the EC50 (i.e., the lower the antibody concentration required to achieve 50% of the maximum binding signal), the stronger the binding. An EC50 "hit" was recorded when the EC50 for binding to the wild-type PCSK9 was significantly lower than the EC50 for binding to the mutant PCSK9.
Bmax is a measurement of the maximum binding signal of the test antibody to PCSK9. The Bmax of the test antibody when bound to wild-type PCSK9 was compared to the Bmax of the test antibody when bound to the mutant form of PCSK9. A residue was registered as a Bmax "hit" when the Bmax of the test antibody bound to mutant PCSK9 was at least 70% lower than the Bmax of the test antibody bound to wild-type PCSK9. Alternatively, a hit was registered where the Bmax of the test antibody binding to the mutant PCSK9 was at least 50% lower than the Bmax of other antibodies to the same mutant, when all other antibodies had a Bmax of at least 40% to wild-type PCSK9.
Professor Petsko stated:

[202]

The word "construction" in the phrase "sufficient to characterize the construction of the article claimed" is used as a noun not a verb. The question is whether the claim sufficiently describes the properties of the claimed article such that the boundaries of the monopoly are clearly defined.
Mr Shavin KC, who appeared for Sanofi, submitted that each of the Exemplary Claims did not sufficiently define the structure of a MAb either by reference to its amino acid sequence or otherwise. He also submitted that the claims did not permit others to know whether a MAb that they proposed to make was either inside or outside the claims in advance of making it. Referring to Lord Russell of Killowen's well-known statement in Electric & Musical Industries Ltd v Lissen Ltd (1938) 56 RPC 23 ("EMI v Lissen") at 39, Mr Shavin submitted that his Lordship was there referring to the need for claims to define the monopoly claimed so that others may know in advance whether what they propose to do will trespass on the patentee's monopoly.
In support of the latter submission Mr Shavin KC also referred to the statement of Stephen J in Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59 ("Monsanto") at 60. The issue in that case was whether the claim language lacked clarity (rather than definition) due to the use of the adjective "substantial" in the phrase "any substantial effect as a cooling medium" which was said by the respondent in that case to make it impossible to determine the limits of the claim. Stephen J rejected that argument, holding (at 60) that "[t]here will ... be no difficulty in a third party ascertaining whether or not what he proposes to do falls within the ambit of the claim ...". Mr Shavin seized on his Honour's use of the words "what he proposes to do" in support of his argument that the claim must define the monopoly in terms which permit others to know whether a product will infringe in advance of it being made.
In its opening submissions Sanofi submitted that the claims do not define any invention:

[221]

The problem with the language of the claim which his Lordship went on to identify at 20-21 was that it extended to not only new, but also existing configurations of the relevant article, which anyone was free to make. The words of the claim were therefore insufficient to confine the article in question to those which were new.
Both the Master of the Rolls and Clauson LJ regarded claim 2 as a claim to an article which could be distinguished from the prior art only by the new use to which the claim contemplated it could be put. That the inventors had conceived a new use to which a known article might be put was not sufficient to make the known article patentable. The references to "screening grid" and "control grid", were understood to be words referring to the manner in which these components were arranged, but which did not sufficiently characterise the physical characteristics of the article claimed to render it patentable. Since those words did not define the article, but instead its use, and the article itself was not patentable, the claim was bad. But the claim might also have been disallowed for the simple reason that its language was unclear.
The decision in Mullard may be contrasted with the decision of the House of Lords in British Thomson-Houston Company Ld. v Corona Lamp Works Ld. (1922) 39 RPC 49. In that case, the Court of Appeal had upheld the trial judge's conclusion that a claim to an electric lamp consisting of (inter alia) a metal filament of large diameter or cross-section lacked definition. The claim was additionally limited by result "that the filament may be raised to a much higher temperature than is practicable in a vacuum lamp without prohibitive vaporisation or deterioration or excessive shortening of useful life". The complaint pressed was that there was insufficient definition to determine what constituted a large diameter because "the only way in which a lamp-marker can ascertain whether he is infringing [i.e., whether the largeness of the filament fell within the claim]... is by making experiments [to determine whether the result was obtained]": per Viscount Finlay at 77, quoting the Master of the Rolls (Lord Sterndale) upholding the reasoning of the trial judge. Viscount Finlay went on to say at 77:

[225]

Professors Petsko, Hudson and Lopez agreed that the CS identifies methods to determine whether an antibody had each of the features identified within, inter alia, the Exemplary Claims. Although Professors Mahler and M Parker did not agree with that proposition, their evidence does not persuade me that the PSA would not be able to determine whether a MAb falls within the claims without undue difficulty or invention.
First, as to the Epitope and Residue Claims, the Antibody and Crystallography Experts (aside from Professor Parker) agreed that arginine scanning, the method described in Example 39 of the CS, "can provide data that identifies residues in the structural epitope". Professors Lopez, Petsko and Hudson considered that the technique was useful when viewed in light of X-ray crystallography data. Professor Mahler qualified his answer with reference to the "limitations" of the technique and described instances where the results may correlate to other unintended structural changes or interactions, rather than showing which residues are part of the structural epitope. In oral evidence, he stated he did not agree with the conclusions reached in the CS about the results of Example 39. In the JER prepared by the Antibody and Crystallography Experts, he stated that "crystallography doesn't identify the functional or structural epitope".
Professor M Parker considered that, while the CS used arginine scanning mutagenesis to identify "residues that might interact", the results of that experiment poorly correlated with the predictions of interactions obtained from crystallographic analysis. However, in response to a question about arginine scanning, he explained the importance of combining arginine scanning with X-ray crystallography "to reach a convincing conclusion about residue interactions". Like Professor Mahler, he referred to evidence he had given that was critical of the use of arginine scanning as a "standalone approach" due to unintended results of residue substitution.
CS [0594] is consistent with the use of arginine scanning and crystallography together to identify the structural and functional epitopes. In this regard, the CS does not rely on a "standalone approach". Professor Hudson's responses to questions raised as part of the JER also indicate that the specification includes methods to account for false positives and negatives obtained through arginine scanning.
In relation to the Residue Claims specifically, Professor M Parker considered that X-ray crystallography could be used to predict non-covalent interactions, but that "complementary methods" are required to be convinced of such interactions (like mutagenesis) and the "robustness" of the data must also considered. Although the Crystallography Experts had differing views as to the parameters they would employ when conducting such an analysis, those differences do not suggest that the PSA would be unable to carry out experiments to determine whether an antibody fell within the Residue Claims without undue difficulty or invention.
Finally, as to the Competition Claims, Sanofi's complaint (which arises under the ground of lack of clarity) is not that the PSA would not have known how to conduct a competition assay, but instead that there are several different competition assays which it asserts may produce different results, coupled with a general lack of clarity as to the meaning of the word competes, leading to the absence of a "workable standard". Putting that complaint aside, the evidence does not indicate that the PSA would not know how to perform blocking and competition assays at the priority date in order to determine whether a particular antibody fell within the Competition Claims. The Antibody Experts all gave evidence indicating their familiarity with such techniques, including Professor Hudson who gave a detailed overview of the competition assays he was aware of in 2007.
The Exemplary Claims are not to any therapeutic agent that blocks or inhibits the activity of PCSK9. Implicit in the term "isolated monoclonal antibody" are specific physical characteristics common to all MAbs, including long strings of amino acid residues with distinct physical characteristics (e.g., heavy and light chains arranged in a 'Y'-shaped structure). Beyond this, the MAbs of the claims are defined by their function including, in the case of the Epitope Claims, their capacity to bind to a structural epitope which includes one or more identified amino acid residues or, in the case of the Residue Claims, to one or more identified residues (which are part of the functional epitope).
Leaving aside the lack of clarity from which the Competition Claims are said to suffer, it is not alleged by Sanofi that any of the other claims lack clarity. Nor did Sanofi contend in its closing submissions that the PSA would not be able to determine whether a MAb was within the scope of any of the Exemplary Claims. In any event, the evidence does not persuade me that any of the Exemplary Claims would for that reason be "clearly invalid" if the Applications were to proceed to grant.
I am not persuaded that it is necessary for the claims to define the MAbs by their amnio acid sequences or some fragment thereof. What is essential is that the PSA be able to determine whether a particular MAb is within or outside the claims. In this regard, it is important not to conflate the requirement that the claims define the invention with the requirement that the CS describe the invention fully (i.e. sufficiency) arising under s 40(2)(a) of the Act before amendment by the RTB Act. The functional limitations have not been shown to be insufficient to characterise the construction of the relevant MAbs so as to enable the PSA to determine whether any particular MAb falls within the scope of the claims. Sanofi's opposition based on lack of definition fails.

[226]

For an invention to be patentable, under s 18(1)(a) of the Act it must be a manner of manufacture within the meaning of s 6 of the Statute of Monopolies. The question that arises under s 18(1)(a) 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?: Aristocrat Technologies Australia Pty Ltd v Commissioner of Patents [2022] HCA 29; (2022) 274 CLR 115 at [21]. In addressing that question it is necessary to look to the "substance" of the claimed invention in order to determine whether it is to patentable subject matter: D'Arcy v Myriad Genetics Inc [2015] HCA 35; (2015) 258 CLR 334 ("Myriad") at [87]-[88] per French CJ, Kiefel, Bell and Keane JJ, and [145] per Gageler and Nettle JJ, citing Research Affiliates LLC v Commissioner of Patents [2014] FCAFC 150; (2014) 227 FCR 378 ("Research Affiliates") at [107].
Where the invention claimed falls within an established category of patentable subject matter, it will generally be a manner of manufacture if: (a) the invention claimed is for a product made, or a process producing an outcome, as a result of human action; and (b) the invention claimed has economic utility. However, broader considerations may become relevant where the subject-matter claimed is not within the established categories of what is patentable: Myriad at [28]. These considerations may include potential "chilling effects" on activities outside of those the subject of the exclusive rights of the patentee, the coherence of the law of patentability, and the patent laws of other countries.
Sanofi submitted that it is not possible to identify the structure of any putative "isolated monoclonal antibody" within the claims of the Applications. It submitted that the substance of the invention as claimed is not a MAb and is instead no more than an abstract idea or a "mere desideratum" of any antibody that has the desired functional outcome. By this I understood Sanofi to mean that each of the claims was, in substance, to no more than a desired result or outcome whereby the binding of PCSK9 to LDLR is blocked or inhibited.
This point was articulated by Sanofi in its written submissions as follows:

[258]

While the claim in that case was, in effect, to the "wished for result" of a substantially pure form of the compounds falling within the claimed formula, the invention was not to a mere desideratum. Nor did it matter that the claim encompassed formulations made using any method.
I do not accept that the Exemplary Claims are to abstract information or a mere idea or desideratum. The claimed MAbs are chemical compounds defined by their binding characteristics and their ability to block or inhibit interactions between LDLR and PCSK9. They are a product made through human action beginning with the immunisation of transgenic mice with PCSK9 so as to generate an immune response followed by the creation of hybridomas.
On the face of the specification, the substance of the claimed invention is MAbs that block PCSK9 binding to LDLR and: (a) have a structural epitope which includes one or more specific residues on PCSK9; (b) have a functional epitope which includes one or more of those specific residues; or (c) compete for binding to PCSK9with a reference antibody. They are physical molecules capable of binding to PCSK9 and blocking its interaction with LDLR.
Sanofi does not allege that the MAbs are not novel, and although Sanofi alleges that they do not involve an inventive step, it does not suggest that any such lack of inventiveness is apparent on the face of the specification: see Myriad at [130]-[131] per Gageler and Nettle JJ citing (inter alia) Commissioner of Patents v Microcell Ltd [1959] HCA 71; (1958) 102 CLR 232 and NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1995) 183 CLR 655 at 663-664; Merck & Co Inc v Arrow Pharmaceuticals Ltd [2006] FCAFC 91; (2006) 154 FCR 31 at [63] per Heerey, Kiefel and Dowsett JJ.
The MAbs of the Exemplary Claims are suitable for use in a variety of therapeutic treatments that are described in detail in the CS either as a monotherapy or in combination with other therapeutics: see CS [0358]-[0370]. Sanofi does not dispute that they have economic utility. Clearly, they are products that have been shown to be useful in the treatment of various cardiovascular and related diseases.
Although Research Affiliates, RPL Central and Encompass contain a discussion of relevant principes, they are decisions on their facts concerned with a particular class of subject matter which has been held to be unpatentable. I do not find those decisions of assistance in determining whether the Exemplary Claims are for a manner of manufacture. The invention that is claimed in this case is not at all comparable to a claim for an idea as to how to manage and display information utilising "suitably programmed software" or "generic computer technology".
As mentioned, Sanofi submitted that even if the Exemplary Claims may appear to encompass proper subject matter for the grant of letters patent, a closer analysis of the science demonstrates that the claims should be rejected under the principles considered in Myriad at [28] (i.e., the "chilling effect"). I do not accept that submission. The economic significance of the isolated nucleic acid claimed in Myriad resided in the genetic information (the nucleotide sequence) encoded on the BRCA1 and BRCA2 genes, and not in "chemical, structural or functional differences" between those nucleic acids and the isolated nucleic acids. That was, as the plurality in Myriad observed at [90], the focus of the claims. For that reason, the subject matter of the claims was at the boundaries of the concept of manner of manufacture.
In the present case, the Exemplary Claims are, in substance, to MAbs that block or inhibit the binding of PCSK9 to LDLR. The focus of the claims is on the effect that the MAbs of the claims have on the interaction of those molecules. That is not a focus on the genetic information conveyed by the MAbs. I do not consider the Exemplary Claims to be a new class of claim involving a significant new application or extension of the concept of manner of manufacture. It follows that there is no need to consider factors 3-6 set out by the plurality in [28] of Myriad, including whether allowing a claim will have a "chilling effect".
In any case, Sanofi's contention that the Exemplary Claims would, if allowed, have a chilling effect is by no means self-evident, and is not supported by the evidence. While it may be accepted that a company or person seeking to develop a MAb that blocks binding of PCSK9 to LDLR may not know whether any particular MAb is within the claims until after it has been produced and tested, that is not an uncommon circumstance in the case of claims limited by result. The plurality in Myriad, at [93], emphasised that the claims were to, essentially, the genetic information that the isolated nucleic acids the subject of the claims embodied and conveyed. That, coupled with the very large class of such compounds bearing that information, were factors which the plurality found raised the risk of a chilling effect.
The MAbs of the Exemplary Claims do not embody or convey information. While the claims convey information concerning the structural and functional epitopes to which those MAbs bind, this information is not embodied in or conveyed by the MAbs of the invention. Nor do the claims give rise to the problem identified in Myriad by Gordon J at [259]-[260]. This case therefore is not analogous to Myriad.
I accept, as Sanofi submitted, that pharmaceutical companies other than Amgen were engaged in research into various methods of inhibiting PCSK9. However, there is no evidence from which it can be inferred that any of those companies' research work was inhibited by the publication in 2009 of the Parent Application or any related patent application published any time thereafter. Nor is there any other evidence from which it may be inferred that the grant of a patent arising out of any of the Applications would have a chilling effect on activities involving the development or production of MAbs beyond the scope of the Exemplary Claims.
The Applications do not claim all the methods available for achieving the result of inhibiting PCSK9 activity to reduce LDL levels. The evidence shows that various companies filed patent applications after the publication of the Parent Application which were concerned with the inhibition of PCSK9 including by means involving anti-PCSK9 antibodies.
Finally, to the extent that any company or person runs the risk of making antibodies which fall within the scope of the Exemplary Claims in the course of research and development, the experimental purpose exemption found in s 119C of the Act provides them with very broad protection. Section 119C provides:

[322]

As to the omission of essential elements of the invention, Amgen said Sanofi's assertion that the Epitope and Residue Claims must correspond to those residues in the "sweet spot" does not reflect the language of the CS, which Amgen says discloses "useful antibodies [which] will bind to one or more of the core residues for 21B12 or 31H4, in addition to one [or] more core residues for EGFa".
Amgen said it does not need to rely on the PyMOL analysis performed by Professor Petsko, which it said was led in response to Sanofi's sufficiency attack that was largely abandoned. However, Amgen contended that the inputting of data of the kind contained in Table 35 of the CS (containing atomic coordinates) into PyMOL was routine at the priority date. It said that Sanofi's attack on Professor Petsko's analysis is misconceived, because Amgen does not need to prove that certain non-covalent bonds exist in order for the claims to be fairly based.
Amgen also submitted that Professor M Parker largely agreed with Professor Petsko's analysis of existing non-covalent interactions, and that no additional information outside of the CS is required to view, analyse and form conclusions about the residues on PCSK9 and their binding capabilities.
With respect to Sanofi's focus on S153, Amgen submitted again that it does not need to prove the existence of any particular non-covalent interaction (via arginine scanning mutagenesis or otherwise), but that, in any case, the evidence demonstrates that S153 is at least part of the structural epitope of 21B12. S153 is a core residue in the interaction interface with the EGFa domain of LDLR and was identified as an arginine scanning "hit" for antibody 12H11.
With respect to whether or not claims that specify residues in the structural and functional epitopes (i.e., the Epitope and Residue Claims) are fairly based on the designation of "core" and "boundary" residues in the CS, Amgen said that it did not need to prove that the core and boundary residues are involved in the structural or functional epitope of any antibody, as their disclosure alone provides a sufficient basis for the claims. However, Amgen submitted that based on the disclosures in the CS, this equivalency can be drawn.
Amgen submitted that the term "interaction interface" as used in the CS is a reference to the structural epitope, which includes the functional epitope. "Interaction interface", it says, includes both core and boundary residues, which are nominated in the claims. Amgen also says that the evidence does show that at least the core residues are "more likely than not to be involved in non-covalent interactions with the antibody". Although Professors M Parker and Mahler disagreed with this statement, Amgen said that "their evidence rose no higher than to speculate that there was a 'possibility' that there are core residues that don't interact". Amgen refers to CS [0542] which explains the basis for the selection of the 5 Å "cutoff". That paragraph states:

[326]

The key consistory clauses in relation to the Epitope and Residue Claims are set out at above. Those consistory clauses refer to antibodies that bind to particular epitopes comprising particular residues, or antibodies that bind directly to particular residues.
Starting with 677, the content of paragraph [007c] mirrors claims 1 and 5. Paragraph [007c] describes an isolated MAb that binds to an epitope of hPCSK9 comprising one or more of amino acid residues 207, 208, 162, 164, 167 or 123 of SEQ ID NO: 1, which blocks the binding of PCSK9 to LDLR. Claim 1 of 677 is to an isolated MAb that binds to an epitope which includes one or more of those residues (i.e., the residue is part of the structural epitope). Claim 5 is to an isolated MAb that binds to one or more of those residues (i.e., the residue is part of the functional epitope). Both claims 1 and 5 are limited by the secondary requirement that the MAb blocks the binding of PCSK9 to LDLR.
Paragraph [007c], in referring generally to an "epitope", encompasses both a structural and functional epitope to which the antibody binds. Any doubt about this is resolved by reference to CS [0571], which explains "[e]pitopes can 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...".
Paragraph [007b] of 689 similarly mirrors the content of claim 1 of 689. Paragraph [007b] describes an isolated MAb that, when bound to PCSK9, binds to at least one of the following residues of SEQ ID NO: 3: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381. Paragraph [007b] also requires that the MAb blocks binding of PCSK9 to LDLR. Those requirements are replicated in claim 1 of 689.
The same can be said of paragraphs [007b] and [007c] and claims 1 and 2 of 751. Paragraph [007b] of 751 describes an isolated MAb that recognises an epitope of human PCSK9 comprising the following amino acid residues: S153, R194, D238, D374, T377, and F379 of SEQ ID NO: 3, and reduces binding between PCSK9 and the EGFa domain of LDLR. Paragraph [007c] describes an isolated MAb that binds to those same amino acids and reduces binding between PCSK9 and the EGFa domain of LDLR. Claim 1 is a claim to an isolated MAb that recognises an epitope comprising those residues, which reduces binding between PCSK9 and the EGFa domain of LDLR. Claim 2 is to an isolated MAb which binds to those residues (i.e., the residues are in the functional epitope) and achieves the same function.
Claims 10 and 13 of 751 correspond to consistory clauses [007d] and [007e], which describe an isolated MAb that either recognises an epitope on human PCSK9 which comprises at least ten of the following residues of SEQ ID NO: 3: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381, or one which binds to at least ten or more of those residues, and which reduces binding between PCSK9 and the EGFa domain of LDLR. Claim 10 is to an isolated MAb that binds to an epitope comprising ten or more of those residues, while claim 13 is to an isolated MAb that binds to ten or more of those residues. Again, each antibody reduces binding between PCSK9 and the EGFa domain of LDLR. With respect to 751, it appears to be uncontroversial that "recognises an epitope" equates to "binds an epitope".
The various consistory clauses show that the invention the subject of each of the Applications is a class of antibodies which bind to structural or functional epitopes comprising one or more nominated residues, which either block or reduce binding between PCSK9 and LDLR (or more specifically, the EGFa domain of LDLR). The question is then whether the remainder of the CS describes the same invention as the consistory clauses.

[354]

I now turn to my consideration of Sanofi's first alternative argument with respect to the Epitope and Residue Claims. At the outset, I find that, the invention described in the CS is a class of antibodies which bind to particular structural or functional epitopes, identified by reference to certain residues on PCSK9.
After identifying certain residues on PCSK9 within 5 Å and 5-8 Å of the EGFa domain of LDLR (in the relevant interaction interface), the CS explains that the results "demonstrate where PCSK9 and EGFa interact", and that antibodies that interact with or block any of those residues "can be useful as antibodies that inhibit the interaction between PCSK9 and the EGFa domain of LDLR". Examples 29 and 30 identify residues in the interaction interface between PCSK9, 21B12 and 31H4. Those examples end with statements explaining that antibodies which interact with the identified residues or block the identified residues are anticipated to be useful in inhibiting the interaction of PCSK9 and the EGFa domain of LDLR. CS [0512] explains that "blocking" a residue in this context means blocking a residue "from other antigen binding proteins that bind to these residues".
In my view, the terms "interact" and "block", used in these examples, are wide enough to encompass situations where the identified residues fall within structural or functional epitopes of the relevant antibody. While it is clear that residues "interacting" must necessarily capture residues in the functional epitope (i.e., those involved in chemical interactions that contribute to affinity), residues interacted with or blocked by the antibody must also include residues in the structural epitope, which is "the patch of the target... covered by the antibody" (CS [0571]).
Accordingly, the Epitope and Residue Claims can be fairly based, even if the CS does not state that the residues within those claims are part of structural or functional epitopes for either of the reference antibodies, or for any other antibody. It is enough that the CS explains that antibodies which interact with, or block the residues identified in examples 28-30 will be useful in the inhibition of PCSK9 binding to LDLR. It is not necessary for the CS to provide scientific proof of the relationship between core and boundary residues and the functional and structural epitopes of any antibody.
A large part of Sanofi's first argument relied on the proposition that the claims cover many more antibodies than the true invention, which should be understood to be 21B12 and 31H4 (and perhaps 16F12). Sanofi has not pointed to any statement in the CS which shows that the invention disclosed is so limited. The CS describes a class of antibodies, in both the consistory clauses and elsewhere including in the discussion of Examples 28-32. In particular, CS [0524] states:

[361]

The remainder of Sanofi's first argument is that the claims omit essential elements of the inventions. The crux of this argument is that certain residues, identified as part of the "sweet spot" or as core residues in certain interaction interfaces, do not appear in the claims.
There is no basis for this submission. A claim which lacks fair basis because it omits a particular element is one that, by that omission, becomes a claim to a fundamentally different invention. That is to say, an element of an invention will not be "essential" in this context unless, by failing to include that element, the invention becomes a quite different one. That was the case in AstraZeneca FFC, where the omission of a certain requirement from the claims would have had the effect that the invention claimed was fundamentally different from that described in the priority document (in the context of external fair basis). That is plainly not the case here.
Sanofi also submitted that, for a number of claims, the CS does not identify a specific antibody (i.e., by name or sequence, as has been done for the Table 2 Antibodies) that falls within the claim. In support of that submission, Sanofi relied on a concession by Professor Petsko that, in an analysis performed of the crystal structures of 21B12, 31H4, and the Later Crystallised Antibodies, he did not identify any antibody that had non-covalent interactions with more than nine amino acid residues, meaning he could not identify an antibody covered by claim 13 of 751. Sanofi's reliance on this concession is contrary to Sanofi's insistence that Amgen should not be allowed to rely on evidence about the Later Crystallised Antibodies. Nevertheless, as I have explained, the CS does not need to prove that any of the exemplified antibodies fall within the claims (i.e., form non-covalent interactions with the relevant residues or bind to epitopes containing the relevant residues) in order for the claims to be fairly based.
Sanofi's second alternative argument only arises if I accept that it is permissible to rely on the results of a PyMOL analysis. As set out above, this argument hinges on a criticism of Professor Petsko's analysis of whether a non-covalent interaction exists between 21B12 and S153.
Putting aside the question of whether or not it is permissible to rely on an analysis performed by Professor Petsko of the data contained in Table 35, Amgen is correct that it does not have to prove a non-covalent interaction between the residues in the claims and 21B12 or 31H4. That is not required in order to establish that the claims are fairly based, for the reasons given when addressing Sanofi's first argument. As such, Amgen does not need to rely on the PyMOL analysis.
Sanofi's third alternative argument was, in essence, that the Epitope and Residue claims are not fairly based because the CS does not actually disclose that the residues referred to in the Epitope and Residue Claims are part of the structural or functional epitopes for any antibodies. The crux of this argument is that the structural and functional epitopes for antibodies the subject of the invention are not actually identified in the CS. This argument can be rejected for the same reasons as Sanofi's first alternative argument. The disclosures in Examples 28-30, when read with the consistory clauses, provide a fair basis for the Epitope and Residue Claims.
Finally, Sanofi's fourth alternative argument seems to be a restatement of its claim definition argument. As I understand it, Sanofi's complaint here is that the CS does not sufficiently characterise, by reference to their amino acid sequences, all the antibodies that fall within the scope of the Epitope and Residue Claims. For the reasons set out above, this argument must fail. It is not necessary that the amino acid sequences for the entire class of antibodies be set out in order for the Epitope and Residue Claims to be fairly based.
The additional criticisms raised by Sanofi, including its criticism of aspects of Professor Petsko's evidence, address matters outside the CS and are irrelevant to fair basis. Amgen does not need to prove the correctness of Professor Petsko's analysis with respect to the crystal structures in order to establish fair basis.
In the result, I am not persuaded that any of the Epitope and Residue Claims would be clearly invalid for lack of fair basis.

[387]

Sanofi submitted that the priority date of the Epitope and Residue Claims could not be the date of filing of P1 (23 August 2007) because there is no description or disclosure in P1 of any epitopes or any residues to which any antibody binds. I do not accept that submission.
I accept that those parts of P1 to which I have referred do not identify specific epitopes or residues on PCSK9 to which antibodies disclosed in P1 bind. P1 does not describe the class of antibodies falling within the claims by reference to a set of residues to which the antibodies bind directly, or residues within the epitopes to which the antibodies bind. Instead, the language of P1 is much more general.
In its written submissions Sanofi characterised the further work recorded in P2 to P4 as no more than "routine experiments" directed to elucidating the properties of the antibodies previously made by the inventors. I accept that this further work was routine and non-inventive. Importantly, however, the Epitope and Residue Claims do not introduce any feature involving a new inventive step (beyond anything already disclosed in P1) or any other matter which represents a departure from the more general description of the invention in P1.
In my opinion, the CS follows "the same line of thought" disclosed in P1. Applying the test enunciated by Buckley LJ in Stauffer, I am not persuaded that P1 does not confer priority on the Epitope and Residue claims.
Although it is not necessary to do so, I will refer briefly to some submissions made by Sanofi in relation to P2 in case my conclusion in relation to the 23 August 2007 priority date is wrong.
Sanofi submitted that the "core" and "boundary" residues described in P2, and the atomic coordinates provided in P3, do not provide a real and reasonably clear disclosure of the residues within the epitopes for 21B12 and 31H4, or the residues to which those antibodies bind.
As I have set out above in the context of fair basis, the disclosure of core and boundary residues obtained through a crystallographic analysis of various interaction interfaces in Examples 28-30 is enough to fairly base the Epitope and Residue Claims. The core and boundary residues are described as being useful in the inhibition of PCSK9's interaction with LDLR. It follows that in the event that the disclosure in P1 is insufficient to confer priority from 23 August 2007, the disclosure of these residues in P2 is sufficient to confer priority on the Epitope and Residue Claims.
I note as well that the residues referred to in the claims of 677 identified by reference to SEQ ID NO: 1 (residues 207, 208, 162, 164, 167 and 123) are identified by reference to SEQ ID NO: 3 in P2 (although it is referred to as SEQ ID NO: 1 in that document) at [0025], which corresponds with CS [0040]. That paragraph describes embodiments of the invention in which the antibody binds to PCSK9 and is positioned 8 Å or less from at least one of the of the identified residues. Those same paragraphs also identify the other residues referred to in the Exemplary Epitope and Residue Claims.
As to P4, Sanofi also contended that the CS teaches that predictions based on X-ray crystallography need to be confirmed by other experimental approaches, such as arginine scanning. It referred to CS [0479] which states:

[392]

The notional skilled addressee, or the PSA, is a legal construct and a tool of analysis framed by reference to the available evidence. This will include the patent application and evidence of persons with knowledge and experience in the field of the invention. The skilled addressee brings to the reading of the relevant document the background knowledge and experience available to those working in that field. The legal construct may not be a single person but may be a team of persons "whose combined skills would normally be employed in that art in interpreting and carrying into effect instructions such as those which are contained in the document to be construed": General Tire at 485.
It is common ground that the PSA in this case will be a team. Amgen submitted that the PSA in this case was a team led by a senior biochemist/biologist and/or medicinal/organic chemist, which has expertise in discovering and developing drug therapies, and which would be able to call upon, inter alia, an antibody expert and a structural biologist with relevant crystallographic expertise. The team would have access to an expert on PCSK9, who would act as a consultant. Sanofi submitted that the PSA in this case is a notional team of skilled scientists with knowledge and experience in the field of antibodies, protein crystallography and PCSK9.
There is little difference between the parties' descriptions of the PSA except in so far as Amgen seeks to characterise various experts, including the PCSK9 expert, as sitting outside the core team. Thus, on Amgen's formulation, the PCSK9 expert is not a member of the team, but is instead a person with whom the team may consult.
Dr R Parker and Professor Horton were asked about the qualifications and experience of those with an interest in PCSK9 and its inhibition. Sanofi's submission as to the composition of the notional team broadly reflects the agreement reached between Dr R Parker and Professor Horton in the JER. Dr R Parker, who previously worked for BMS, provided some additional commentary which I found helpful:

[396]

[97] The common general knowledge is a general body of knowledge attributed to the hypothetical non-inventive skilled person or team. In Minnesota Mining and Manufacturing Company v Beiersdorf (Australia) Limited [1980] HCA 9; (1980) 144 CLR 253, Aickin J at 292 referred to common general knowledge as "... the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge". It is knowledge actually known and used by skilled persons in the relevant field generally or accepted by the bulk of those who are engaged in the particular art: Ranbaxy Laboratories Ltd v AstraZeneca AB [2013] FCA 368; (2013) 101 IPR 11, Middleton J at [215] ("Ranbaxy Laboratories") citing British Acoustic Films Ltd v Nettlefold Productions (1936) 53 RPC 221 at 250 ("British Acoustic Films"). Knowledge is not common general knowledge unless it is sufficiently widely known or used to become generally accepted and assimilated into the minds of people skilled in the relevant art and therefore part of the common general knowledge: see Gilead Sciences Pty Ltd v Idenix Pharmaceuticals LLC [2016] FCA 169; (2016) 117 IPR 252 at [210]- [214] ("Gilead") where Jagot J referred to some of the leading authorities including, Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411 at [31]. It will include publications to which the skilled addressee would refer as a matter of course: ICI Chemicals and Polymers Ltd v Lubrizol Corporation Inc [1999] FCA 345; (1999) 45 IPR 577 at [112] per Emmett J.

[98] However, information does not become common general knowledge merely because it might appear in a journal even if it is one read by persons in the art: Ranbaxy Laboratories at [217] per Middleton J citing (inter alia) Eli Lilly & Co Ltd v Apotex Pty Ltd [2013] FCA 214; (2013) 100 IPR 451 at [468]; Wake Forest University Health Sciences v Smith & Nephew Pty Ltd (No 2) [2011] FCA 1002; (2011) 92 IPR 496 at [96], General Tire at 482-3. In the latter case, the English Court of Appeal referred with approval to the following passage in the judgment of Luxmoore J in British Acoustic Films at 250:

[399]

Section 7(2), before its amendment by the RTB Act, refers to the common general knowledge "as it existed in the patent area". The limitation imposed by those words was removed by the RTB Act amendments. For the purposes of this case the limitation still applies.
Amgen submitted that Sanofi failed to establish what the common general knowledge was in Australia as at the priority date. In particular, it was submitted that there was no evidence from which it could be inferred that there was any common general knowledge in Australia relating to PCSK9 and its role as a potential therapeutic target. So, while Amgen accepted that the PSA would include the expertise of a PCSK9 expert, it also submitted that the common general knowledge as it existed in Australia at the priority date would include little if any information as to PCSK9 and its role as a potential therapeutic target.
There was little direct evidence as to the extent to which there were any researchers studying PCSK9 and its relationship to LDL in Australia at the priority date. The evidence touching on that question included affidavit and oral evidence from Dr R Parker and a scientific paper entitled "Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa" by Vivienne M Homer et al published in Atherosclerosis in 2008 ("Homer 2008") which was accepted for publication on 11 July 2007 and available online from 31 August 2007.
The lead author of Homer 2008, Vivienne Homer, is associated with Canterbury Health Laboratories in Christchurch, New Zealand, which is where I infer she conducted research work with four of her co-authors. Three other co-authors, Francesca Charlton, Fabien Mangilia and Phillip Barter, are associated with The Heart Research Institute, Camperdown, Sydney, NSW, which is where I infer they worked. Another author, David R Sullivan, is shown as associated with the Royal Prince Alfred Hospital in Sydney, NSW, where I infer he worked. Another author, Gilles Lambert, is shown as associated with both the Heart Research Institute in Sydney and the Université de Nantes Inserm in Nantes, France.
Homer 2008 includes the results of a study of patients with familial hypercholesterolemia ("FH") and the subsequent investigation of mutations in PCSK9 associated with FH. The study concludes, inter alia, "[b]ecause PCSK9 inhibition provides long-term protection against cardiovascular diseases ... the development of a pharmacological inhibitor of PCSK9 seems promising". The literature cited in Homer 2008 includes important papers by Lagace 2006 and Horton 2007 referred to in more detail later in these reasons. Publication details for each paper I refer to by the name of the lead author and publication year appear in the bibliography in Annexure A.
Dr R Parker's affidavit evidence was that, to the best of his recollection, none of his colleagues at BMS were from Australia, or left to work in Australia, and he was not aware of any Australian scientists or researchers with a knowledge or interest in PCSK9 prior to January 2008. However, he gave oral evidence in which he acknowledged having become aware of Homer 2008 at or about 31 August 2007. He also gave some oral evidence as to his expectations concerning common practice in the industry. As to that evidence, Dr R Parker was referred in his cross-examination to various publications including that of Lagace 2006 and other publications in "high-impact peer review journals". Dr R Parker gave the following evidence:

[401]

Amgen sought to answer this evidence by referring to Dr R Parker's affidavit evidence. It submitted that his oral evidence must have been speculation because he knew no Australian colleagues. I do not accept that submission. I consider it likely that there were researchers working on PCSK9 and exploring its relationship to FH in Australia before the priority date. I also infer that those researchers were, like Dr R Parker and others working in the field, staying abreast of developments by reading high-quality journals such as that in which Lagace 2006 appeared at the time of or shortly after their online publication. The evidence in my view supports the inference, and I find, that PCSK9 including its relationship to LDL cholesterol and the potential role of PCSK9 inhibitors in the reduction of LDL cholesterol levels, occupied a field of research that was essentially global in nature, and that what was known to, and accepted by, researchers in the United States, New Zealand, France and other countries, would have also been known and accepted by researchers working in the field in Australia.
Subject to there being a finding that the common general knowledge in the field was the same in Australia and overseas, Amgen accepted (for the purpose of this proceeding only) that, as at 23 August 2007, the common general knowledge included various matters set out in a document filed on 24 November 2023 ("the Amgen CGK Admissions"). I will refer to these admissions in more detail where necessary when considering the question of obviousness. Some of the Amgen CGK Admissions are cross-referenced to the publications from which they were drawn and include information drawn from various scientific papers relating to PCSK9, including Benjannet 2004, Rashid 2005, Maxwell 2005, Cohen 2006 and Lagace 2006.
Other matters admitted by Amgen to be common general knowledge in its submissions included:
- Genetic studies clearly established that the genetic loss of PCSK9 resulted in lower plasma LDL cholesterol levels and a reduction of cardiovascular events. It was clearly desirable to seek a PCSK9 inhibitor to reduce LDL levels (CGK1).
- The site at which PCSK9 functioned to lower LDL cholesterol and potentially the mechanism by which it worked would direct the approach used to identify and develop a PCSK9 inhibitor (CGK2).
- The literature reported studies investigating both an extracellular and intracellular pathway for PCSK9. Both pathways may have co-existed. The quantitative contributions of extracellular and intracellular pathways in the overall physiological action of PCSK9 were not known and were difficult to determine (CGK3).

[411]

Dr R Parker and Professor Horton agreed that the site at which PCSK9 functioned to lower cholesterol, and potentially the mechanism by which it worked, would direct the approaches used to identify and develop an inhibitor. As at the priority date, the site at which PCSK9 functioned to lower LDL cholesterol had not been conclusively determined.
Of the different approaches to PCSK9 inhibition available, there were some, which I have set out above, that were agnostic as to where PCSK9 functioned. Dr R Parker and Professor Horton disagreed as to the overall enthusiasm and feasibility of the various approaches at the priority date. Whether antibodies were feasible depended on the extent to which PCSK9 functioned extracellularly, something which had not been established at the priority date.
Professor Horton suggested that he placed little weight on the literature which suggested that PCSK9 functioned to reduce LDLR levels intracellularly for various reasons, including some relating to the design of the reported studies and the fact that in his opinion this hypothesis did not make biological sense. However, in my opinion this evidence is very likely the product of hindsight. His more contemporaneous statements on the topic appear in papers he co-authored. For example, in Horton 2007 he stated (at p 367) that "[t]he major cellular site at which PCSK9 acts has not been established". In a presentation Professor Horton gave on 21 December 2007 he (and his co-authors/co-presenters) stated that "[c]urrent evidence suggests that PCSK9 may work at two cellular sites". I find that it was common general knowledge at the priority date that the major cellular site at which PCSK9 degraded LDLR had not been established and that it was possible that it had both intracellular and extracellular activity. However, the extent of any extracellular activity had not been established. In this regard, I find that the state of the common general knowledge as at the priority date was as summarised by Lagace 2006 as follows:

[416]

[384] An invention is a patentable invention if the invention, when compared with the prior art base, involves an inventive step: see s 18(1)(b)(ii) of the Act. Section 7(2) of the Act uses the word "obvious" in the course of describing what must be established before an invention can be held not to involve an inventive step. Something may be "obvious" in light of the common general knowledge, or the common general knowledge coupled with relevant s 7(3) information.

[385] An invention may be obvious in light of the common general knowledge if the person skilled in the art faced with the same problem as the inventor would have taken, as a matter of routine, whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not. If the person skilled in the art would be directly led as a matter of course to take such steps in the expectation that doing so might well produce a useful or better alternative to the prior art then the invention will be obvious: Wellcome Foundation Limited v VR Laboratories (Aust.) Proprietary Limited (1981) 148 CLR 262 ("Wellcome") at 286 per Aickin J, [Aktiebolaget Hässle v Alphapharm Pty Limited [2002] HCA 59; (2002) 212 CLR 411 ("Alphapharm")] at [50]-[53]. In Alphapharm at [53] the plurality approved what is commonly referred to as the reformulated or modified Cripps question as providing an acceptable approach to obviousness.

[386] A claimed invention is not obvious merely because the person skilled in the art would consider that it was "worthwhile to try". However, there will be some cases in which the person skilled in the art will be directly led, as a matter of course, to try a number of different alternatives in the expectation that each may well produce a useful alternative. Merely because one pathway to an invention is shown to be obvious, does not mean that another such pathway might not also be obvious. Two or more pathways may be obvious, even though some of them might be more obvious than others.

[387] Further:

[422]

There are three points to make about Lagace 2006. First, the extracted passage states that the available data suggests PCSK9 can function both intracellularly and extracellularly but that it is not known which pathway predominates under normal conditions. The authors were of the view that additional studies were required to determine the relative contribution of extracellular PCSK9 to the regulation of LDLR levels. Secondly, the suggestion that antibodies might be developed to block or inhibit PCSK9's interaction with LDLR extracellularly is expressed to be dependent on PCSK9 functioning "as a secreted factor as suggested by the current data". Thirdly, the authors state that "if" that is the case then additional approaches (i.e., non-intracellular approaches) including the development of antibodies "can be explored".
While I accept that Lagace 2006 suggests that PCSK9 inhibiting antibodies might be developed, that suggestion is in my opinion highly qualified. The relevant discussion indicates that further research is required to confirm whether, and if so to what extent, PCSK9 functions extracellularly. I do not understand Lagace 2006 to be suggesting that antibodies are likely to be effective in blocking or inhibiting the PCSK9 and LDLR interaction. I consider the PSA reading Lagace 2006 would have understood that the potential for antibodies to be effective in that role was a matter of considerable uncertainty and dependent on the outcome of further research into the extracellular activity of PCSK9.
Zhang 2007 shows that PCSK9 bound to the EGFa domain of LDLR. That is to say, Zhang 2007 identified the site on LDLR to which PCSK9 bound (not the site on PCSK9 to which LDLR bound, or the site on PCSK9 to which an inhibitor could bind to prevent the LDLR/PCSK9 interaction). Even though Zhang 2007 determined that PCSK9 binds to the EGFa domain of LDLR, the binding site on PCSK9 was not defined. Zhang 2007 expressly recognised this at page 18602 where the authors state "the site of binding of PCSK9 to the extracellular domain of the LDLR has not been defined". Zhang 2007 also suggests that there may be substantially less binding affinity between PCSK9 and LDLR outside the cell compared to the acidic environment inside the cell, because binding between PCSK9 and LDLR at a pH of 5.2 (acidic) was 50-fold higher than at a pH of 7.0 (neutral). This observation is referred to by Amgen in its submissions as forming the basis for CGK5.
Sanofi also asserted that Kwon 2008 (a paper which published the residues of PCSK9 that bind to the EGFa domain of LDLR) formed part of the common general knowledge, or alternatively, could be relied upon under s 7(3). However, Kwon 2008 was published on 12 February 2008 (i.e., after the priority date) and is therefore not relevant to inventive step as CGK or s 7(3) information.
In its written submissions Sanofi emphasised Professor Horton's view that the literature had conclusively demonstrated the existence of an extracellular pathway for PCSK9 before the priority date of 23 August 2007. For reasons previously explained, I do not accept that this had been "conclusively" established as at that date. Professor Horton's response to the JER question that Sanofi relies upon in support of this submission as to his view does not use the word "conclusively" in his reference to several papers which had demonstrated the extracellular pathway. Earlier, in response to the same question, the JER records:

[425]

I have referred above to the acknowledgement in Horton 2007, a review article co-authored by Professor Horton and published in early 2007 that "[t]he major cellular site at which PCSK9 acts has not been established". Horton 2007 referred to data that suggested PCSK9 might promote degradation of LDLR as it migrates from the ER to the cell membrane. An alternative hypothesis, also referred to by the authors, was that PCSK9 might act on LDLR only after it is secreted. The text accompanying Figure 2 in Horton 2007 states that "[c]urrent evidence indicates that PCSK9 might work at two cellular sites". In their concluding remarks, the authors stated that "several important mechanistic and clinical questions remain" about PCSK9 and LDL in metabolism, and that "[f]urther studies will be required to identify the specific site(s) in the cell at which PCSK9 functions and to determine whether catalytic activity is required for LDLR degradation".
Dr R Parker gave evidence, which I accept, that as at the priority date, there was what he termed "an emerging hypothesis" that PCSK9 functioned extracellularly but which had not yet displaced the "prevailing notion that an intracellular mechanism of action of PCSK9 on LDLR functioned under usual physiological conditions". Similarly, Professor Seidah, who Dr R Parker described as a leading researcher in the field whose team first characterised PCSK9 (originally named NARC-1) in 2003, referred in a paper published in March 2007 (Seidah 2007) to "a yet unknown mechanism [by which] high levels of PCSK9 lead to a faster rate of degradation of cell surface LDLR, resulting in increased circulating LDL [cholesterol] ...".
Even if it was common general knowledge that PCSK9 had both an intracellular and extracellular pathway, Professor Horton explained in cross-examination that for an antibody to work against PCSK9, PCSK9 would need to have extracellular activity of at least 50%. While Professor Horton said that it was possible that lower levels of extracellular activity might have been effective, the 50% figure was based on "what we knew for a fact". This is consistent with the following statement appearing in Kwon 2008, a paper whose co-authors included Professor Horton and Dr Thomas Lagace:

[431]

While at BMS, Dr R Parker occupied a very senior research position in charge of a team he headed investigating PCSK9 inhibitors. In the JER, he identified the approach of suppressing PCSK9 gene expression at the mRNA level through the use of ASOs or siRNA as most promising. An important factor influencing this approach was the fact that it was agonistic as to PCSK9's mechanism of action in that it would suppress PCSK9 levels inside and outside the hepatocyte surface. Professor Horton's response to Dr R Parker's answer to this effect was that such approaches were not commonly taken, and the development and clinical use of these technologies was in its "infancy", although he agreed that they were completely agnostic as to where or how PCSK9 functioned.
There are several points to note about Dr R Parker's approach. First, it was consistent with the view that PCSK9's mechanism of action had yet to be established, and it sought to accommodate that unknown. Secondly, this approach was recognised and apparently favoured not only by Dr R Parker but by other researchers as well. Homer 2008 suggested that antisense inhibition (i.e. using ASOs) may provide a promising approach to PCSK9 inhibition. In addition to intracellular inhibition of PCSK9 catalytic activity, ASOs were also identified as an option in Horton 2009.
The reference to ASOs in Horton 2009 is significant, as it indicates that as at 2009, Professor Horton was aware of, and had contemplated, the use of ASOs in the inhibition of PCSK9. While Horton 2009 also refers to the possibility of using antibodies to inhibit PCSK9 activity, it does so subject to the express proviso that the success of the approach will depend on PCSK9 functioning primarily at the cell surface. Although Horton 2009 post-dates the priority date, it does not support the inference that as at the priority date, the PSA would have been likely to try antibodies far ahead of ASOs.
In its submissions, Sanofi characterised Dr R Parker as a contrarian whose approach was idiosyncratic and not representative of the PSA. Sanofi referred to evidence given by Dr R Parker as to his employer's approach to research. He said:

[445]

According to Dr R Parker, advantages of this technology were that the discovery process was faster and less costly than antibody technology, and resulted in biologics smaller in molecular size than antibodies with potentially faster tissue penetration. As I understand it, the smaller size was attractive primarily because it allowed for a higher concentration of therapeutic to be administered in a lower dose, which alleviated some of the perceived issues with antibodies based on Dr R Parker's understanding at the time of the extracellular environment.
Research into the development of these biologics as PCSK9 inhibitors began at BMS in mid-2008. Dr R Parker described it as a complementary program that provided an alternative to other research approaches including the development of PCSK9 inhibiting ASOs, which BMS had been pursuing since early 2007. Dr R Parker provided the following evidence about the diversity of approaches to finding a PCSK9 inhibitor at BMS
1. The diversity of approaches that we attempted at BMS to finding a PCSK9 inhibitor therapeutic reflects, in my opinion, the fact that the pathway to identifying a PCSK9 inhibitor was not clear or straightforward. There were many uncertainties that I had to confront in relation to the mode of action of PCSK9 within the body and it was not evident at [the priority date] which drug (inhibitor) modality would succeed.
2. The range of options pursued by BMS did not include an antibody approach. This was not simply a reflection of the types of therapeutic candidates that BMS had focused on traditionally. BMS had antibody expertise, and in any event, the collaborations and acquisitions described above make it clear that my team under my supervision was prepared to pursue all therapeutic options that appeared viable, based on what was known about PCSK9 at the time. I and my BMS Research Team considered the possibility of using specialized antibody technology but concluded that an antibody was not a promising option to pursue.
That evidence is consistent with Dr R Parker's oral evidence and is in my view persuasive. In particular, I accept that he and his research team at BMS did not consider antibody technology as a promising option to pursue in the search for an effective PCSK9 inhibitor.
Sanofi's antibody expert, Professor Mahler, agreed that "before you read the common specification, you would not know ... if it was possible to make antibodies that inhibit the binding interaction of PCSK9 and LDLR". Similarly, Professor Hudson's evidence, with which Professor Lopez agreed, suggested that the chances of finding an antibody that inhibited PCSK9 (or which competed with 21B12 or 31H4) were "pretty low". Professor Hudson said:

[452]

The term "compete" 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). Numerous types of competitive binding assays can be used to determine if one antigen binding protein competes with another, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahli et al., 1983, Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J. Immunol. 137:3614-3619) solid phase direct labeled [sic] assay, solid phase direct labeled [sic] sandwich assay (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using I-125 label (see, e.g., Morel et al., 1988, Molec. Immunol. 25:7-15); solid phase direct biotin-avidin EIA (see, e.g., Cheung, et al., 1990, Virology 176:546-552); and direct labeled [sic] RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82). Typically, such an assay involves the use of purified antigen bound to a solid surface or cells bearing either of these, an unlabelled test antigen binding protein and a labeled [sic] reference antigen binding protein. Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test antigen binding protein. Usually the test antigen binding protein is present in excess. Antigen binding proteins identified by competition assay (competing antigen binding proteins) include antigen binding proteins binding to the same epitope as the reference antigen binding proteins and antigen binding proteins binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antigen binding protein for steric hindrance to occur. Additional details regarding methods for determining competitive binding are provided in the examples herein. Usually, when a competing antigen binding protein is present in excess, it will inhibit (e.g., reduce) specific binding of a reference antigen binding protein to a common antigen by at least 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75% or 75% or more. In some instances, binding is inhibited by at least 80-85%, 85-90%, 90-95%, 95-97%, or 97% or more.

[458]

CS [0231] identifies various types of assays that may be used to determine whether the test ABP competes with a reference ABP, but it does not require that they compete to any particular degree. The range of percentages provided in the paragraph is not exhaustive, and is prefaced with the word "usually". The claims require that the MAb competes with a reference antibody so as to prevent or inhibit the latter binding to PCSK9. Some MAbs will compete strongly, while others will compete less strongly. Either way, on what I regard as the proper construction of the Competition Claims, if there is any competition between the relevant MAb and the reference antibody, this requirement of the claim will be met.
My construction of the Competition Claims broadly accords with Professor Hudson's and Professor Lopez's evidence of their understanding of the term. Although Professor Hudson did, at one point, suggest that for antibodies to be competing within the meaning of the specification there had to be "significant competition", his response indicates that he was focussed on CS [0231] and was qualified by his clarification, "[a]nd I think you're asking me is 45 per cent significant. Yes. If that was the question." His responses to other questions during cross-examination support the view that he understood competition to be a binary concept, in particular his statement that "competition is competition" and "[i]t's a sliding scale from 100 per cent down to zero". His evidence, and Professor Lopez's evidence, indicates that competition which was less than "complete" would still be understood to fall within the Competition Claims. Contrary to Sanofi's submission, I do not accept that the Competition Claims lack clarity because they fail to impose a numerical threshold for the purpose of determining whether there is competition.
CS [0231] does not mandate the use of any particular type of competitive binding assay but merely describes a number of different types that can be used. It follows that there is nothing in the CS which would preclude the skilled addressee from ascertaining whether a MAb competes with a reference antibody for binding to PCSK9 using a different type of competition assay to those referred to in CS [0231].
Professor Hudson stated that it was not unusual to get different results from different competitive binding assays. In this regard, Professor Hudson said:

[462]

PROF MAHLER: So what it means is that - what it means is that when you - when you go through immunisation protocol and raise antibodies, you don't have any control over what you get. You can't - it's not as though you have a preconceived idea that, "I'm going to make antibodies that compete and therefore I'm going to do this" ... You don't know what you're going to get and so you're going to immunise with PCSK9, you're going to generate a panel of antibodies, and then you will test them, and then you will know whether they compete or not.

But you can't have a preconceived idea about - about what you want and translate that into some protocol that gives you something that - that the animal does...You have no control over which antibodies are going to be raised. Everything happens downstream with the testing of what you have got so - so what I meant by that is that you - you - you can't have a preconceived idea that the application is going to assist me to make antibodies that compete, because it - it doesn't. That - that's the way I read the question.

HIS HONOUR: Well, it assists you to determine whether or not they compete at the very end of your program.

PROF MAHLER: It's after you - it's after you let the animal do the work. You - you screen the antibodies, you end up with a panel, then you can say whether they compete. But the fact that you want - you want antibodies that compete - well, there's nothing you can do. The application doesn't assist or give you any - it can't. It - it's not possible. It can't.

HIS HONOUR: Well - - -

PROF MAHLER: It can't tell you how to make antibodies that compete.

HIS HONOUR: What about the assistance it gives at that very last step ... though?

PROF MAHLER: Which last step is that, sorry?

HIS HONOUR: Determining whether or not they do compete.

PROF MAHLER: Of course, because you have got - right at the end you have got the antibodies that they compete with so then you can test them. But that's totally independent of do these antibodies assist me in generating antibodies that compete. They - they don't.

[478]

In any event, Sanofi's submission on this point appears to relate to both 748 and 685. It submitted that the amount of "excess" antibody affects the results of a competitive binding assay, and too little excess (and, I infer, the absence of an excess) can result in a false negative. The concept of an "excess" is referred to in CS [0231], which explains that when conducting a competitive binding assay, "[u]sually the test antigen binding protein is present in excess".
Professor Mahler gave evidence concerning the term "excess" and suggested, at least at some points in his evidence, that it was unclear to him what amount of excess needed to be used. However, I ultimately understood him to accept that he could determine how much antibody would be required to give "an excess of said antibody", something which his evidence does not suggest would be beyond the capacity of the PSA. Professor Mahler agreed that, if necessary, the amount of antibody to be used in the competition assay could be determined by carrying out a separate assay for that purpose.
Professor Hudson said that "excess means excess" and that an assay could be used to identify a relevant excess. Professor Lopez said that "when we talk about excess antibody ... [we are] trying to make sure we have got enough antibody ... to be able to detect an inhibitory effect". Both Professors Hudson and Lopez agreed that the results of a competitive binding assay would be the same regardless of whether a small or large excess was used, because in each case the excess would by definition be more than the amount required. It was not put to either of Professors Hudson Lopez that it would be beyond the skill of the PSA to determine an appropriate concentration of antibody to provide an excess in a competition assay.
Professor Mahler is the co-inventor of a patent published in 2014 entitled "Anti-CD83 antibodies and use thereof". Claim 15 of that patent is for a CD83 binding protein which (inter alia) competitively inhibits binding of a reference antibody or which binds to the same epitope in CD83 as that antibody. The specification includes a statement that "[a]ssays for determining a CD83 binding protein that competitively inhibits binding of an antibody will be apparent to the skilled artisan". Professor Mahler accepted that the specification did not include any description of any competitive binding assay. In particular, he agreed that there was no description in the specification of the level of excess antibody required to perform the competition assay. That evidence strongly suggests to me that Professor Mahler would accept that ascertaining how much antibody to use when conducting a competition assay is something that the PSA could do using standard and well-known techniques.
I am not persuaded that the Competition Claims do not provide a workable standard due to a failure to identify a particular competition assay. In particular, I am not satisfied that the use of different assays, to determine whether two antibodies compete for binding to the same antigen, would be likely to produce materially different results. I am also satisfied that the skilled addressee could determine how much antibody to use in a competition assay to ensure that there was an excess of the relevant antibody. In the result, I am not persuaded that any of the Competition Claims lack clarity.

[487]

In Meat & Livestock v Cargill, Beach J at [906] also observed that the claim under consideration in Tramanco at [207] "was in form and in substance a claim to a method of producing alternative results or outcomes". His Honour distinguished the claims in the case before him on that basis, finding that the claims were sufficiently enabled because the PSA could readily perform an embodiment of the invention within the scope of each claim.
The claims in the present case do not claim distinct alternative outcomes. The outcome postulated in claims 1 and 5 of 677 and claim 1 of 689 is one in which "the monoclonal antibody blocks binding of PCSK9 to LDLR". Claim 23 of 677 necessarily describes that same outcome, as it is dependent on earlier claims, but through an antibody which also competes for binding to PCSK9 with 21B12. In the case of claims 1, 2, 10 and 13 of 751, the outcome is that "the monoclonal antibody reduces binding between PCSK9 and an EGFa domain of LDLR". It follows that Tramanco is distinguishable.
Nor am I persuaded that each of the claims is for a number of different inventions. When considering the issue of fair basis I concluded that the each of the specifications for 677, 689 and 751, which include various consistory clauses and mutual examples, describe a class of antibodies which bind either directly to certain nominated residues, or to epitopes containing certain nominated residues. That conclusion was based not merely on matters of form, but also the substance of the relevant disclosures. That characterisation of the invention is at odds with Sanofi's argument (which I reject) that each of the claims of 677, 689 and 751 include many different inventions.
In the result, I am not persuaded that any of the claims of 677, 689 or 751 would be clearly invalid for non-compliance with s 40(2)(a) of the Act.
Although Sanofi's submissions on this point focussed on the Epitope and Residue Claims, it also submitted that the Competition Claims in 685 and 748 had a "similar vice" and were also properly understood to be claims to a multiplicity of inventions. This submission can be rejected for the same reasons given in relation to the Epitope and Residue Claims. The Competition Claims are to a class of antibodies defined by competition and to one singular outcome (i.e., reduction of binding between PCSK9 and the EGFa domain of LDLR in the case of 685, and neutralisation of PCSK9 as observed in a competitive binding assay in the case of 751).

[491]

Annexure A

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Sanofi v Amgen Inc.

At a glance

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Judgment (491 paragraphs)

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Legislation Cited (2)

Cases Cited (51)