Over the past decade, therapeutic antibodies have become an important class of molecule in the immunotherapy space.
In Australia, the therapeutic goods regulator, the Therapeutic Goods Administration, has evaluated therapeutic antibodies for use in a host of diseases, including various cancers, asthma, psoriasis and, recently, as a treatment for COVID-19.1
In this article, we briefly consider selected patent claims protecting therapeutic antibodies that have been the subject of cases in Australia and the United States.
Keytruda litigation: claims to antibodies with a cross-competition function
In 2014, Merck Sharpe & Dohme Corp (MSD) commenced proceedings2 to invalidate certain claims of an Australian patent3 co-owned by Ono Pharmaceutical Co. and E.R. Squibb & Sons (Ono). MSD's proceedings were in anticipation of the commercialisation of 'Keytruda', now an important immunotherapy for the treatment of a number of cancers.
The invention described in the specification related to the use of anti-PD-1 antibodies and combination immunotherapy to treat cancer.4 The specification described a method of inhibiting the growth of tumour cells in vivo using these antibodies. The main claim in dispute5 was to monoclonal antibodies that cross-compete for binding to PD-1 with one of several reference antibodies, each defined by their amino acid sequence.
One issue in the proceeding was whether the words 'cross-competes for binding to PD-1', as used in the claim, were clear. MSD contended, amongst other things, that it was not clear whether the cross-competing monoclonal antibody was required to bind to the same epitope of PD-1 as one of the reference antibodies, or not. The proceedings were settled before the validity hearing and no judgment was therefore published addressing the above question.
Another interesting aspect of this case was MSD's application to rely on results of experiments showing certain prior art antibodies 'competed' for binding with the reference antibodies, as relevant to its lack of novelty case. The experiments were conducted overseas, including for the purposes of related proceedings in the United Kingdom, before the commencement of the Australian case. As a result, under the Federal Court Rules governing the use of experimental data as evidence6, it was necessary for the Court to consider whether leave should be granted to rely on the pre-litigation experiments.
Aspects of the debate between the parties included the extent to which experiments relating to reference antibodies not the subject of the Australian claims (i.e. extending beyond the facts sought to be proved in the Australian case) were relevant and which documents recording the conduct of the experiments (e.g. laboratory notebooks, raw data files, schedule of reagents, etc.) should be produced.
The patent in suit in the Keytruda case, having been examined under the Patents Act 1990 (Cth) prior to the commencement of the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth) (RTB Act) which came into force on 15 April 2013, would have been considered by reference to internal validity requirements now superseded in relation to patents examined after 2013. An important and interesting question is whether the validity of therapeutic antibody claims on grounds internal to the specification has been affected by the 2013 reforms. We refer to the Patents Act as it stood prior to, and post the 2013 amendments as the pre-RTB Act and post-RTB Act respectively.
The post-RTB Act seeks to align Australia's standards of patent validity, including relating to matters internal to the specification, with those of major international jurisdictions including the United Kingdom, Europe and the United States.7
The support requirement set out in section 40(3) of the post-RTB Act provides that claims must be 'clear and succinct and supported by the matter disclosed in the specification', and replaced the pre-RTB Act 'fair basis' requirement that claims be fairly based on the matter disclosed in the specification. To meet the fair basis requirement, claims had to be broadly directed to the same invention identified in the specification, read as a whole. The classic test was that of 'real and reasonably clear disclosure' confirmed by the High Court in Lockwood Security Products Pty Limited v Doric Products Pty Limited (2004) 217 CLR 274.
Initial guidance, provided in Merck Sharp & Dohme Corporation v Wyeth LLC (No 3)  FCA 1477 (MSD v Wyeth (No 3)) and adopted in subsequent decisions,8 suggests that the post-RTB Act support requirement requires a closer alignment between the claims and the specification than was required for fair basis.9
In particular, in MSD v Wyeth (No 3), Justice Burley adopted the summary provided by Justice Aldous in Schering Biotech, which has been often followed in the United Kingdom:
. to decide whether the claims are supported by the description it is necessary to ascertain what is the invention which is specified in the claims and then compare that with the invention which has been described in the specification. Thereafter the court's task is to decide whether the invention in the claims is supported by the description. I do not believe that the mere mention in the specification of features appearing in the claim will necessarily be a sufficient support. The word "support" means more than that and requires the description to be the base which can fairly entitle the patentee to a monopoly of the width claimed.10
To this test Justice Burley added the requirement that the technical contribution to the art must be ascertained. For example, for a product claim, the claimed product must be supported in the sense that the technical contribution to the art disclosed by the specification must justify the breadth of the monopoly claimed.11
The MSD v Wyeth (No 3) decision concerned competing streptococcus pneumoniae vaccines (not antibodies) and included a challenge to the validity of two divisional patents (in the same patent family) relating to multivalent immunogenic compositions comprising 13 distinct polysaccharide-protein conjugates, referred to in the decision as the 'composition patents'. As with most divisional patents, the composition patents' specifications were almost identical. The claims in suit for both of the composition patents included serotypes additional to those described in the specification.
Interestingly, the pre-RTB Act applied to one of the composition patents, and the post-RTB Act applied to the other. The Court found the requirements of the fair basis ground were met under the pre-RTB Act, but the support ground requirements under the post-RTB Act were not met. In particular, the Court found the specification identified and provided the 'practical means' to add six serotypes to an existing vaccine (Prevnar 7) but it was not possible to extrapolate the data to other, unidentified, serotypes.12
Less judicial commentary is available on the post-RTB Act 'disclosure' requirement.13 However, in order for an invention to be disclosed in a manner which is 'clear enough and complete enough' for it to be performed by a person skilled in the relevant art (PSA), it appears to be accepted that the PSA must be able to perform the full scope of the claims without undue experimentation, that is the full scope must be 'enabled'.14 This represents a significant shift from the pre-RTB Act sufficiency test, which was satisfied if the PSA could follow the specification and produce one thing within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty.15
Repatha litigation: functional antibody claims in the US
In the United States, the test for determining whether a functional therapeutic antibody claim is enabled appears to be in a state of flux. The high profile decision of the US Court of Appeals for the Federal Circuit in the Sanofi v Amgen proceedings16 found that antibodies defined by their dual-function of binding to a combination of sites (residues) on the protein, in a range from one residue to all of them, and blocking the protein/receptor interaction,1718
In concluding that undue experimentation would be required to practice the full scope of this and the other claims in suit, the Court of Appeals noted that broad functional claim limitations 'raise special problems because one may not know whether a species is within the scope of a generic claim until one has made it and one can ascertain whether it possesses the claimed function', and therefore these claims raise the bar for enablement. The Court of Appeals noted the following factors are relevant to determining whether such claims are enabled:
- the number and functional diversity of embodiments that fall within the scope of the claims;
- the predictability of the field of science and the need for testing; and
- the effort required for a PSA to discover undisclosed claimed embodiments-e.g., through trial and error and screening or by discovering the antibodies de novo according to a randomisation-and-screening 'roadmap'.
Amgen has sought judicial review of this decision by the Supreme Court. Should the Supreme Court decide to hear the case, a question that will be answered is whether the statutory test for enablement requires that a specification enable those skilled in the art 'to reach the full scope of claimed embodiments' without undue experimentation-i.e., to cumulatively identify and make all or nearly all embodiments of the invention without substantial 'time and effort'.
The Australian Repatha Patent Office decision
The first Australian 'Repatha' related decision, Sanofi v Amgen Inc.  APO 67, permitting Amgen's patent applications19 to proceed to grant despite opposition, was recently published by the Australian Patent Office.
The claims in suit were grouped into the following three classes:
- Epitope claims20, which define monoclonal antibodies by reference to two key features, the epitope on PCSK9 (proprotein convertase subtilisin kexin type 9) to which an antibody binds and the ability of said antibody to block or reduce binding of PCSK9 to LDLR (low density lipoprotein receptor).
- Residue claims21, which define monoclonal antibodies in terms of particular amino acid residues to which an antibody binds.
- Competition claims22, which define monoclonal antibodies that compete for binding to PCSK9 with an antibody with defined heavy and light chain variable regions.
The case was decided under the pre-RTB Act, and the Patent Office was satisfied that general disclosures in the specification and the experimental results provided a basis for the claims in the specification and sufficiently described the invention (i.e. pre-RTB Act sections 40(3) and 40(2)(a) were satisfied).
Specifically in relation to the epitope and residue claims, the Patent Office considered that proof that the antibodies encompassed by the claims 'bind'23 to one or more of the identified residues was not necessary and it was reasonable to extrapolate and infer that the amino acid residues within the region identified by the experiments were involved in non-covalent interactions that effect binding between PCSK9 and the antibody.24 The Patent Office also noted the specification describes the means for generating and identifying such antibodies.
In relation to the competition claims, the Delegate was satisfied that general references in the specification to competition assays, which included competition by steric hindrance, provided a real and reasonably clear disclosure of the claimed invention.
The Patent Office also dismissed Sanofi's concerns that the skilled addressee would need to undertake a research project25 to produce something within the claims and considered that, based on the disclosures provided, the addressee would be able to produce an antibody that binds either to an epitope comprising the stated amino acid residues, or to the residues themselves.26 This finding was based in part on Sanofi's failure to prove that the characterised antibodies 27 will not bind the core residues, or that the exemplified antibodies do not fall within the scope of the claims.28 Sanofi also failed to establish that the work required to produce one antibody embodying each claim using the information provided in the specification involved anything more than what is routine in the art, even if such work may be complex, time consuming and expensive.
Sanofi has appealed this decision to the Federal Court of Australia.
Australian courts have not yet considered how the post-RTB Act applies to functional antibody claims. When they do, it will be interesting to see if they follow a similar approach to the US Court of Appeals for the Federal Circuit.
It will also be interesting to see if the US Supreme Court will hear Amgen's appeal and, if so, the insights provided.
1 GlaxoSmithKline's SOTROVIMAB.
2 Merck Sharp & Dohme Corp v Ono Pharmaceutical Co Ltd  FCA 1015.
3 AU 2011203119 titled Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics.
4 Tasuku Honjo and James Allison were awarded the 2018 Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation.
5 Claim 3: A monoclonal antibody, or an antigen-binding portion thereof, which cross-competes for binding to PD-1 with a reference antibody or reference antigen-binding portion thereof comprising:
a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 1 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID No: 8;
b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 2 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 9;
c) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 3 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID No: 10; or
d) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 6 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 13.
6 Federal Court Rules 2011 (Cth) r 34.50.
7 Explanatory Memorandum to the RTB Act states the amendment to s 40 "is intended to align the Australian requirement with overseas jurisdictions' requirements (such as the UK). Overseas case law and administrative decisions in respect of the 'support' requirement will be available to Australian courts and administrative decision-makers to assist in interpreting the new provision."
8 See, for example, Cytec Industries Inc. v Nalco Company  FCA 970, Rakman International Pty Ltd v Trafalgar Group Pty Ltd  FCA 464 and Jusand Nominees Pty Ltd v Rattlejack Innovations Pty Ltd  FCA 540.
9 MSD v Wyeth (No 3) at - citing the adoption of the summary provided by Aldous J in Schering Biotech Corp's Application  RPC 249 at 252-256 as cited by Dr S D Barker in CSR Building Products Ltd v United States Gypsum Company  APO 72.
10 MSD v Wyeth (No 3) at -.
11 Ibid at .
12 Ibid at .
13 Section 40(2)(a) of the post-RTB Act provides that a complete specification must disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by the person skilled in the relevant art.
14 See, for example, Cytec Industries Inc. v Nalco Company  FCA 970 at - and Re Evolva SA  APO 57.
15 See, for example, Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1 at .
16 Amgen Inc. v. Sanofi, Aventisub LLC (No 2020-1074) (Fed. Cir. Jun 21, 2021) and Amgen Inc v Sanofi 987 F. 3d 1080 (Fed. Cir. 2021).
17 An example of one of the dual-functional claims that was considered is: An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks bind-ing of PCSK9 to LDLR
18 Patent Laws 35 U.S.C. 112(a): The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention (emphasis added).
19 Australian patent application numbers 2013203677, 2013203685, 2013203689, 2013203748, 2013203751.
20 AU Sanofi v Amgen Decision at  and .
21 AU Sanofi v Amgen Decision at  and .
22 AU Sanofi v Amgen Decision at  and .
23 The Delegate considered the term binds refers to the broader functional property of an interaction between the antigen binding protein and antigen, or particular regions of the antigen.
24 The Delegate was satisfied that the residues of PCSK9 that the specification demonstrates are within the region covered by the antibody, namely the interaction interface, represented the epitope.
25 Sanofi submitted that a PSA seeking to produce something within the scope of the claim invention would be required to make a biosimilar of the antibodies disclosed in the application using transgenic techniques, or alternatively would need to obtain antibodies by means of hyperimmunization of transgenic mice and then carry out the experiments discussed in the applications to characterise and test the antibodies.
26 The claims will be found sufficient if the person skilled in the art could follow the specification and produce "something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty" Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1 at ,
27 Being 21B12 and 31H4.
28 The Delegate referred to Austal Ships Pty Ltd v Stena Rederi Aktiebolag (2005) 66 IPR 420 per Bennett J at  stating that the onus will not be met where two bona fide experts of accepted expertise reach opposing views.
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