Seqirus Inc. v ModernaTX, Inc. [2025] APO 15

I allow the applicant two (2) months from the date of this decision to file amendments to overcome the deficiencies identified in this decision.

1. Patent application 2015249553 (the opposed application) in the name of ModernaTX, Inc. (the applicant) was advertised as accepted on 4 March 2021. Epiphany Law opposed the grant of a patent under section 59 of the Patents Act 1990 (Cth) (the Patents Act). The notice of opposition was subsequently amended to identify the opponent as Seqirus Inc. (the opponent**)**.

1. The Statement of Grounds and Particulars (SGP) identified nine grounds of opposition: entitlement, manner of manufacture, novelty, inventive step, utility, clear enough and complete enough disclosure, best method of performance, support and clarity. At the hearing, only five grounds were pressed: novelty, inventive step, clear enough and complete enough disclosure, support and utility.

1. The parties relied upon evidence by several declarants. Evidence in Support (EIS) consists of declarations by Leaf Huang (L Huang-1) and Declan McKeveney (McKeveney). Evidence in Answer (EIA) consists of declarations by Eric Huang (E Huang), Christian Cobaugh (Cobaugh) and Liangfang Zhang (Zhang). Evidence in Reply (EIR) consists of a declaration by Leaf Huang (L Huang-2).

1. At the hearing I asked whether the opponent could point to any evidence which showed that a mRNA vaccine within the scope of claim 1 of the opposed application did not 'work'. In response to my question, the opponent brought the post-filing document Hassett K. J. et al., Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines, Mol. Ther. Nucleic Acids. 2019, Vol. 15, pages 1-11 (Hassett) to my attention. As this document was not in evidence, I directed the opponent to submit a request under Regulation 5.23 (Reg 5.23) for me to consider this document. In my decision of 3 June 2024, I invoked Reg 5.23 and decided to consult Hassett for the purposes of deciding this opposition.

1. The parties provided further evidence on Hassett. A declaration by Leaf Huang for the opponent (L Huang-3) and a declaration by Liangfang Zhang for the applicant (Zhang-2).

1. The opposed application claims priority from two priority documents, US 61/983,250 filed on 23 April 2014 and US 62/088,994 filed on 8 December 2014, the contents of which are incorporated into the present specification by reference. The specification as accepted comprises description pages from 1 to 903, claims from pages 904 to 910, and drawings pages 1/86 to 86/86 . There are 67 claims, including one independent claim (claim 1). The claims in full appear in the ANNEX at the end of this decision.

1. Before commencing to construe the specification, I note what Middleton J said in Eli Lilly and Company Limited v Apotex Pty Ltd:[1]

"It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date."

1. The application is titled "Nucleic Acid Vaccines".

"relates to compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation and/or use of vaccines, specifically nucleic acid vaccines (NAVs)."[2]

1. The broadest statement of the invention can be found in the "Summary of the Invention" which states:

"The NAVs or NAV compositions of the invention may be designed to comprise one or more nucleic acid molecules, e.g., polynucleotides, which encode one or more wild type or engineered proteins, peptides or polypeptides (e.g., antigens). In some embodiments the nucleic acid molecule, e.g., polynucleotide, is an mRNA."[3]

1. The specification further elaborates on the NAV carrier formulation that reflects claim 1:

"Some aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, formulated in a carrier having a molar ratio of about 20-60% cationic lipid: 5-25% non-cationic lipid: 22-55% sterol; and 0.5-15% PEG-modified lipid."[4]

1. The specification further describes that the NAVs can comprise mRNA encoding an antigen.[5] The specification states that while attempts have been made to produce functional RNA vaccines, including mRNA vaccines and self-replicating RNA vaccines, the therapeutic efficacy of these RNA vaccines have not yet been fully established.[6]

1. The specification then discusses the surprising findings of the invention:

"Quite surprisingly, the inventors have discovered a class of formulations for delivering mRNA vaccines in vivo that results in significantly enhanced, and in many respects synergistic, immune responses including enhanced antigen generation and functional antibody production with neutralization capability. These results are achieved even when significantly lower doses of the mRNA are administered in comparison with mRNA doses used in other classes of lipid based formulations. The formulations of the invention have demonstrated significant unexpected in vivo immune responses sufficient to establish the efficacy of functional mRNA vaccines as prophylactic and therapeutic agents.

The invention involves, in some aspects, the surprising finding that lipid nanoparticle (LNP) formulations significantly enhance the effectiveness of mRNA vaccines, including chemically modified and unmodified mRNA vaccines. The efficacy of mRNA vaccines formulated in LNP was examined in vivo using several distinct viral antigens and in a variety of different animal models. The results presented herein demonstrate the unexpected superior efficacy of the mRNA vaccines formulated in LNP over other mRNA vaccines formulated in other lipid based carriers as well as over protein antigens."[7]

"The LNP used in the studies described herein has been used previously to deliver siRNA various [sic] in animal models as well as in humans. In view of the observations made in association with the siRNA delivery of LNP formulations, the fact that LNP is useful in vaccines is quite surprising. It has been observed that therapeutic delivery of siRNA formulated in LNP causes an undesirable inflammatory response associated with a transient IgM response, typically leading to a reduction in antigen production and a compromised immune response. In contrast to the findings observed with siRNA, the LNP-mRNA formulations of the invention are demonstrated herein to generate enhanced IgG levels, sufficient for prophylactic and therapeutic methods rather than transient IgM responses."[8]

1. The specification further details NAVs which includes a statement that they can be used both as therapeutic or prophylactic agents.[9] The specification goes on to discuss (i) NAVs, (ii) infectious agents and antigens, (iii) design, synthesis and quantification of NAV polynucleotides, (iv) modifications and (v) pharmaceutical vaccine compositions.

1. Examples 1-10 relate to the manufacturing, capping, tailing and quantification of polynucleotides.

1. Example 11 refers to the formulation of modified mRNA using lipidoids, Example 12 relates to methods of screening for protein expression and Example 13 relates to cyclization and cocatemerization of polynucleotides.[10]

1. Example 14 details a list of infectious agent antigens or variants (Tables 28-30).

1. Example 15 shows an influenza mouse study for the H1N1 haemaglutinin (HA) antigen using an mRNA LNP vaccine with LNP formulated as follows (mol%): DLin-KC2-DMA (50%), DSPC (10%), Cholesterol (38.5%) and PEG-DOMG (1.5%).[11] The data showed that there was 100% rescue from lethal influenza challenge with rapid onset of protective antibody titers after 1 week and high antibody titers, i.e., 50 fold over unmodified mRNA and 20 fold over the protein vaccine. Furthermore, it was shown that for ribonucleic acid vaccines of the invention a much lower effective mRNA dose is required, i.e., ten fold less than unmodified mRNA (Figure 10).[12] All vaccinated mice displayed 100% survival against a lethal dose of INFV, compared to the naïve group which was not vaccinated.[13]

1. Example 16 shows a methicillin-resistant Staphylococcus aureus (MRSA) mouse study using a mRNA LNP vaccine with different LNP formulated as follows (mol%): (1) DLin-KC2-DMA (50%), DSPC (10%), Cholesterol (38.5%) and PEG-DOMG (1.5%), or (2) DLin-MC3-DMA (50%), DSPC (10%), Cholesterol (38.5%) and PEG-DOMG (1.5%).[14] Efficacy was not shown with either the tested RNA vaccine construct or the controls (inactivated bacteria and protein control) in either challenge model, suggesting that the model was not adequate for testing the constructs.[15]

1. Example 17 shows a Dengue mouse study where antibody signal was detected for a mRNA LNP vaccine in three out of 42 test groups (Table 38).[16] Example 18 discusses a tuberculosis study,[17] Example 19 discusses a human enterovirus study,[18] Example 20 discusses a MERS-Cov study[19] and Example 21 discusses a H10N8 study.[20] It is noted that none of Examples 18-21 describe the use of a LNP.

1. Example 22 describes an influenza mouse study for the H1N1 HA antigen using mRNA vaccines with LNP formulated with both KC2 and MC3 LNPs.[21] Example 22 shows HAI titres in mice were highest at doses of 10µg mRNA/mouse (400 µg mRNA/kg) with both the KC2 and MC3 formulations administered ID or IM (Table 39).[22]

1. Example 23 describes an influenza mouse study which evaluated the efficacy of an mRNA vaccine encoding influenza A/PR/8 (H1N1) in female BALB/c mice following lethal challenge with influenza A/PR/8 virus. BALB/c mice were vaccinated with mRNA encapsulated in LNP and mice vaccinated with mRNA all displayed 100% survival, while mice that were unvaccinated displayed between 0 and 40% survival (Table 40).[23]

1. Example 24 describes the evaluation of H1 and H7-specific T cell responses in an influenza vaccine. The results demonstrated that T cell responses were antigen specific.[24]

1. Example 25 shows an influenza mouse study for the H1, H10 and H7 HA antigen using mRNA LNP vaccines with LNP formulated with both KC2 and MC3 LNPs.[25]

1. Example 26 shows an influenza mouse study for the H7 and H10 HA antigens using an mRNA LNP vaccine with LNP formulated as follows (mol%): DLin-MC3-DMA (50%), DSPC (10%), Cholesterol (38.5%) and PEGDOMG (1.5%).[26]

1. Example 27 describes an influenza study in monkeys for the H10 HA antigen.[27] Cynomoglus monkeys were vaccinated with various doses of NAV encoding H10 HA/LNP formulations.[28] Serum samples were taken from the monkeys weekly and evaluated for inhibition of hemagglutinin (Table 45, Figure 19).[29]

1. Example 29 shows an influenza study in ferrets for the H7N9 HA antigen using an mRNA LNP vaccine with LNP formulated with MC3.[30] In this study, ferrets were vaccinated with the H7N9 mRNA NAV vaccine before an influenza (H7N9) challenge via the intranasal route.[31] The lung homogenate data show that a single vaccination at any concentration resulted in a reduction in viral titres, with a time to onset of immunity before 7 days post vaccination (Table 46).[32] A statistically significant increase in antibody titres was observed relative to the pre-vaccination blood sample.[33] Furthermore, this example showed that, surprisingly to the inventors, the vaccine constructs of the invention reduced viral titres in the lungs when exposed to virus just 7 days following vaccination.[34]

1. The person skilled in the art (PSA) was considered in Root Quality Pty Ltd v Root Control Technologies Pty Ltd:[35]

"He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious."

1. However, the PSA is not a real person, but an artificial construct that is used as a tool of analysis which is used to make the determination:

"The notional person is not an avatar for expert witnesses whose testimony is accepted by the court. It is a pale shadow of a real person - a tool of analysis which guides the court in determining, by reference to expert and other evidence, whether an invention as claimed does not involve an inventive step."[36]

1. The opponent submits that the PSA is a team, comprising a person who has experience with lipid particle formation and the use of this in delivering therapeutic agents, such as a Ph.D., qualified lipid formulation scientist and/or membrane biophysicist and/or biochemist.[37] With regard to the PSA, Prof. Leaf Huang asserts that:

"providing a formulation for delivery of mRNA as a vaccine would require a team including a person with knowledge of how to prepare the appropriate mRNA, such as modified mRNA encoding for the appropriate antigenic peptide; a lipid formulation chemist, who might have a PhD and background in organic chemistry or, like myself, membrane biophysics; and an immunologist for testing and advising on vaccine activity and any final formulation details specific to a vaccine." [38]

1. The applicant submits that the PSA has been characterised similarly by all four expert witnesses, as involving a team that comprises (at least) a lipid formulation scientist, an mRNA scientist and an immunologist.[39]

1. The parties appear to be in substantial agreement about the characterisation of the hypothetical PSA. In agreement with the parties, I am satisfied that the hypothetical team representing the PSA would have skills in lipid formulation, mRNA therapeutics and immunology.

1. The opponent submits that Prof. Leaf Huang is an independent expert who has qualifications and experience that enable him to provide expert evidence from the perspective of a PSA.[40] Prof. Leaf Huang has a Ph.D. in Biophysics, highly relevant to lipid particle and membrane formulation and endosomal release, and has significant expertise in the field of delivery of therapeutics using lipid particle vectors.[41] He is also a pioneer in the field of liposomal non-viral vectors and has worked extensively on the development of various lipid particle approaches to nucleic acid delivery.[42]

1. The applicant submits that the opponent's single witness, Prof. Leaf Huang, is at odds with the consensus that the team comprises at least a lipid formulation scientist, an mRNA scientist and an immunologist.[43] The applicant submits that each of their expert witnesses has relevant expertise with a particular focus, but which also flows into other relevant areas.[44] For example, Prof. Liangfang Zhang has expertise in lipid nanoparticle formulation which also flows into areas of nucleic acids and immunology, Dr. Christian Cobaugh has expertise in mRNA which also flows into areas of immunology and lipid formulation, and Dr. Eric Huang has expertise in immunology which also flows into areas of mRNA and lipid formulation.[45]

1. Despite the applicant's assertion that the hypothetical PSA is a team and the opponent only provides a single witness, I consider that Prof. Leaf Huang's evidence could represent the views of a hypothetical team as he has experience that crosses across the skills of lipid formulation, mRNA therapeutics and immunology.

1. The opponent further provides that Prof. Leaf Huang was not provided with a copy of the opposed application prior to forming his views on the common general knowledge, which the opponent argues the same can not be said of the applicant's experts who were either provided with a copy of the opposed application before providing comments, or in the case of the inventor Dr Eric Huang, were already otherwise familiar with the purported invention.[46] For these reasons, the opponent submits that the evidence of Prof. Leaf Huang, particularly in the technical area of lipid particle development for the delivery of nucleic acid therapeutics, should be afforded greater weight.[47] The applicant responds submitting that Prof. Zhang and Dr. Cobaugh both later attested to the non-obviousness of the invention disclosed in the opposed application, so there is no issue of using any benefit of hindsight to engage in an impermissible ex post facto "cherry picking" exercise.[48] Furthermore, the applicant argues that neither Prof. Zhang nor Dr. Cobaugh had any knowledge of the art cited, or the allegations raised in the SGP or the assertions put forward in the EIS, until after their opinions on the CGK had been established.[49]

1. While the opponent submits that the applicant's experts are either employees or have, or have had, working collaborations with the applicant,[50] I do not consider that this relationship necessarily compromises their evidence as both Dr. Cobaugh and Prof. Zhang have explicitly stated that they do not have any interest, financial or otherwise, in the applicant, and that they have provided impartial assessments.[51] I am satisfied that each of the declarants have backgrounds that enable them to give evidence as to what the skilled person would have known or done, and I will weigh the evidence of the declarants in the usual manner.

1. The correct approach to the construction of claims was discussed by Bennet J in H Lundbeck A/S v Alphapharm Pty Ltd:[52]

"the words in a claim should be read through the eyes of the skilled addressee in the context in which they appear ... while the claims define the monopoly claimed in the words of the patentee's choosing, the specification should be read as a whole ... it is not permissible to read into a claim an additional integer or limitation to vary or qualify the claim by reference to the body of the specification ... terms in the claim which are unclear may be defined or clarified by reference to the body of the specification."

1. Claim 1 is the only independent claim. It reads:

one or more mRNA polynucleotides having an open reading frame encoding an antigenic polypeptide, formulated in a cationic lipid nanoparticle having a molar ratio of about 20-60% cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol; and about 0.5-15% PEG-modified lipid."

1. In the definitions section of the specification, a vaccine is defined as "a biological preparation that improves immunity in the context of a particular disease, disorder or condition."[53] Under the heading of "Activation of the immune response" the word "vaccine" is defined as referring to "a composition , for example, a substance or preparation that stimulates, induces, causes or improves immunity in an organism, e.g., an animal organism, for example, a mammalian organism (e.g., a human.).[54] These two definitions share the feature of improving immunity in an organism.

1. In the view of Prof. Leaf Huang, the vaccine of the opposed application:

"must provide functional and protective immunity in a subject following its administration, or improve existing immunity, and not just induce a potentially low level or transient immune response as might be achieved by any administered mRNA composition following protein expression."[55]

"I consider that claim 1 requires that the vaccine formulation is a 'true' vaccine in that it must produce a protective immune response generating immunological memory in a subject and not just some small, non-protective or very transient immune response."[56]

"I do not believe it is or was ever regarded in the field that something to be regarded as a "vaccine", there must be immunological memory generated. This is overly narrow and at odds with what is accepted in the field. Certainly a vaccine must elicit an immune response, but that does not need to extend to long-term immunological memory."[57]

1. Prof. Huang in the EIR disagrees with Cobaugh stating:

"Any formulation which is suggested to provide protection against an antigen but which does not result in immunological memory ... could not properly be termed a vaccine. A vaccine absolutely requires immunological memory and, indeed, is largely the point of vaccinating a population against pathogens such as the influenza virus in advance of the 'flu season'."[58]

1. I construe the word "vaccine" in line with the dictionary definitions provided in the opposed application as "a composition that improves immunity". I am not persuaded by anything in the evidence to part from this broader definition. Therefore a vaccine does not necessarily have to result in immunological memory.

"any polynucleotide which encodes at least one peptide or polypeptide of interest and which is capable of being translated to produce the encoded peptide polypeptide of interest in vitro, in vivo, in situ or ex vivo."[59]

1. The specification expressly states that "[t]he polynucleotides of the NAVs of the invention are not [emphasis added] self-replicating RNA."[60]

1. When asked whether he considered self-amplifying RNA (saRNA) to be a form of mRNA, Prof. Leaf Huang stated:

"the answer is clearly yes. Self-amplifying RNA is often referred to as self-amplifying (or self-replicating) messenger RNA (SAM RNA). It encodes for protein production, in addition to the replication component and I would have considered it to be a form of messenger RNA just as conventional or non-amplifying messenger RNA is a form of mRNA."[61]

1. However, somewhat contradictory, Prof. Huang in his EIR states:

"It is clear that saRNA and conventional mRNA are not the same thing [emphasis added] and they clearly go through a different process in the cell to ultimately have the protein of interest expressed."[62]

1. Prof. Zhang defines mRNA as "RNA that in vivo is transcribed from DNA and then translated into a protein / polypeptide. mRNA can also be made in vitro, and in this context is sometimes called "IVT mRNA"."[63] Zhang also explains the differences between mRNA and self-amplifying RNA:

"mRNA is also quite different to self-amplifying RNA, functionally, structurally and in terms of size. Self-amplifying RNA is derived from a virus and includes a first open reading frame ("ORF") encoding four virus-derived non-structural proteins, a 26S promoter, and a second ORF encoding a GOI. It encodes its own replication machinery called a replicase or replicon, and accordingly is much larger than mRNA, possessing around 10,000 nucleotides. The GOI encoded by self-amplifying is not itself translated, but rather is transcribed using the replicase or replicon to form subgenomic RNA."[64]

1. Prof. Zhang in response to Prof. Leaf Huang also states:

"I am aware that the literature contains examples of self-amplifying RNA described in different ways, and that some literature refers to self-amplifying RNA as "self-amplifying mRNA" or "SA-mRNA"." For the reasons demonstrated above, this is strictly speaking incorrect, and inconsistent with the literature otherwise correctly referring to "self-amplifying RNA" or "saRNA" without reference to "m" or "messenger"."[65]

1. Similarly Dr. Cobaugh, who has specific expertise in mRNA states: "saRNA, which like siRNA, was considered different to mRNA."[66] Cobaugh also states:

"I do not consider self-amplifying RNA vaccines to be a form of mRNA vaccines because the open reading frame encoding the antigen in self-amplifying RNA is not translated. Rather, this open reading frame is transcribed into short genomic RNA transcripts that are then translated into the antigenic polypeptide. This is functionally different to mRNA, where the encoded antigen is translated directly from the mRNA vaccine."[67]

1. Despite saRNA ultimately having the protein of interest expressed as per the comments of Prof. Leaf Huang, the protein is not translated from the saRNA but rather transcribed using the replicase or replicon to form subgenomic RNA (as discussed by Prof. Zhang). As both Prof. Leaf Huang, Prof. Zhang and Dr. Cobaugh (who has specific expertise in this area) all agree that mRNA and saRNA are different and due to the fact that the opposed application expressly states the same, I construe mRNA as defined in the specification as different to saRNA.

1. The specification fails to define the term "antigenic polypeptide". None of Prof. Leaf Huang, Dr. Cobaugh or Dr. Eric Huang provide a definition of an "antigenic polypeptide".

1. While Prof. Zhang does not provide an explicit definition of "antigenic polypeptides", he does discuss how they are to be used to be successful:

"Antigenic polypeptides perform a very different role to non-antigenic polypeptides. For example, in order to be successful [emphasis added], antigenic polypeptides must be formulated in such a way that a functional immune response is elicited."[68]

1. As neither the specification nor the evidence provides an explicit definition of "antigenic polypeptide", I'll consider the plain meaning of the phrase. Henderson's Dictionary of Biology defines "antigenicity" as "the property possessed by a substance that can bind specifically to the antigen receptors on B or T lymphocytes, and thus, in principle, is able to stimulate a specific immune response."[69]

1. While Prof. Zhang does state that for an antigenic polypeptide to be successful it must be formulated to elicit a functional immune response, I consider the functionality or protective success of the immune response is not necessarily required for a polypeptide to be considered "antigenic". Using the plain meaning of "antigenic polypeptide", all that is required is that the polypeptide is capable of producing a specific immune response.

1. Therefore I construe the word "antigenic polypeptide" to mean a polypeptide that is capable of stimulating an antigen specific immune response.

1. The specification fails to explicitly define the term "cationic lipid".

1. The specification provides numerous examples of cationic lipids. For example, cationic lipids include 2,2-dilinoleyl-4-dimethylaminoethyl-[l,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319).[70] In one embodiment, the cationic lipid may be a low molecular weight cationic lipid such as those described in US Patent Application No. 20130090372.[71] The cationic lipid may be selected from any lipid known in the art such as, but not limited to, DLin-MC3-DMA, DLin-DMA, Cl2-200 and DLin-KC2-DMA.[72] In another aspect, the lipid may be a cationic lipid such as, but not limited to, DLin-DMA, DLin-D-DMA, DLin-MC3-DMA, DLin-KC2-DMA, DODMA and amino alcohol lipids. The amino alcohol cationic lipid may be the lipids described in and/or made by the methods described in US Patent Publication US20130150625, incorporated in the opposed application by reference in its entirety.[73]

1. The specification further lists another four compounds (Compounds 1-4) as non-limiting examples of cationic lipids.[74] In another embodiment, the cationic lipid may be selected from, but not limited to, formula A described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638 and WO2013116126 or US Patent Publication No. US20130178541 and US20130225836; the contents of each of which is incorporated into the opposed application by reference in their entirety.[75] The specification goes on to list numerous non limiting examples of cationic lipids that could be used in the invention.[76]

1. It is clear from the references in the specification that the term "cationic lipid" is considered in the specification to include a large number of lipids including those selected from numerous non-exhaustive lists.

1. Prof. Leaf Huang defines a "cationic lipid" as "any lipid which can present an overall positive charge."[77] None of Dr. Cobaugh, Dr. Eric Huang or Prof. Zhang define a "cationic lipid" in their evidence. As the specification does not provide a definition for cationic lipid, nor do any of the applicant's experts, I will adopt Prof. Leaf Huang's definition, particularly as Prof. Huang is an expert on lipid formulation. Therefore I construe a "cationic lipid" as a lipid which can present an overall positive charge.

1. The specification fails to explicitly define the term "non-cationic lipid". In some embodiments, the cationic lipid is a neutral lipid[78] or DSPC.[79] Prof. Leaf Huang defines a "non-cationic lipid" as any lipid which does not present a positive charge including anionic lipids and neutral lipids.[80] For the same reasons as above, I will adopt Prof. Huang's definition.

1. The specification fails to explicitly define the term "sterol". In some embodiments the sterol is a cholesterol.[81]

"I understand that the claims of a patent can be broader than the Examples but it seems to me that the formulations of the Examples only use cholesterol as a sterol and this was really the only sterol that was generally used or proposed for commercial LNP formulations immediately prior to 23 April 2014. I'm not sure what other sterols the inventors of the Opposed Application were envisaging but cholesterol was in almost universal use at that time in these kinds of LNP formulations and I don't see how you could know if another sterol would play the same important role as cholesterol does."

1. The Chemical Entities of Biological Interest Database defines "sterol" as "any 3-hydroxy steroid whose skeleton is closely related to cholestane-3-ol (addition of carbons may be added in the side chain)".[82] In light of this technical definition and Huang's comments above, where he envisioned that the current application (and the words of the specification implied this) intended to claim broader than a sterol being only "cholesterol", I construe sterol any 3-hydroxy steroid whose skeleton is closely related to cholestane-3-ol.

1. The specification fails to explicitly define the term "PEG-modified lipid". The specification provides that PEG-modified lipids include, but are not limited to, PEG-distearoyl glycerol (PEG-DMG) (also referred herein as PEG-C14 or C14-PEG), PEG-cDMA (further discussed in Reyes et al. J. Controlled Release, 107, 276-287 (2005) the contents of which are incorporated in the opposed application by reference in its entirety).[83]

1. Prof. Leaf Huang defines a PEG-modified lipid as any lipid which has been synthetically modified to present a PEG moiety.[84]

1. I construe this term in the same manner as Prof. Huang.

1. It is well established that the general test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aickin J:

"The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement."[85]

1. This test is satisfied if the alleged anticipation discloses all the essential features of the invention claimed.[86]

1. To meet this requirement, the prior art must contain "clear and unmistakable directions to do what the patentee claims to have invented... A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee. If ... the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way that would not do so, the patentee's claim will not be anticipated."[87]

1. A prior disclosure will only invalidate a claim if, after having read it, the skilled addressee would, rather than could, have produced all the essential features of the claim. As stated in Canadian General Electric Co., Ltd v Fada Radio Ltd:[88]

"Where the question is solely one of prior publication, it is not enough to prove that an apparatus described in an earlier specification could have been used to produce this or that result. It must also be shown that the specifications contain clear and unmistakable directions to use it."

1. In AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99 (AstraZeneca), the full Federal Court held:

"Sufficiency of disclosure is a cardinal anterior requirement in the analysis of whether a prior art document anticipates a claimed invention. It is only after the stage of assessing the sufficiency of disclosure which involves a determination about whether a prior document has 'planted the flag' as opposed to having provided merely 'a signpost, however clear, upon the road' or, perhaps, something less that the notion of reverse infringement comes into play as the final and resolving step of the required analysis. It is not the first step of the required analysis; nor is it the only step."

1. In relation to the specificity required in order for a prior art document to anticipate the claimed invention, the full court in AstraZeneca also quoted with approval the following quote from Gyles J in Apotex Pty Ltd and Another v Sanofi-Aventis and Another [2008] FCA 1194; (2008) 78 IPR 485 at [91]:

"anticipation is deadly but requires the accuracy of a sniper, not the firing of a 12 gauge shotgun".

1. Schedule 1 of the Patents Act defines "prior art base" as:

(b) in relation to deciding whether an invention is or is not novel:

(i) information of a kind mentioned in paragraph (a); and

(ii) information contained in a published specification filed in respect of a complete application where:

(A) if the information is, or were to be, the subject of a claim of the specification, the claim has, or would have, a priority date earlier than that of the claim under consideration; and

(B) the specification was published on or after the priority date of the claim under consideration; and

(C) the information was contained in the specification on its filing date.

1. The information referred to in (b)(ii) is often referred to as "whole of contents" novelty.

1. In E I Du Pont de Nemours and Co v ICI Chemicals and Polymers Ltd [2005] FCA 892 (Du Pont), Emmett J discussed the conceptual basis for the part of the definition of "prior art base" in Schedule 1 of the Patents Act that speaks of information in a published patent specification having an earlier priority date than the claim under consideration, if that information were to be the subject of a claim: see paragraph (b)(ii)(A) of the definition at paragraph [77] above.

"In order to satisfy the pre-requisite of paragraph (b)(ii)(A) of the definition of prior art for the purposes of novelty, it is necessary first to identify information contained in the Daikin Patent. Secondly, it is necessary to demonstrate that that information either is the subject of a claim of the Daikin Patent or could be the subject of a claim of the Daikin Patent. The latter alternative is the consequence of the requirement that, if the information were to be the subject of a claim, that claim would have a priority date earlier than that of the Claims of the Binary Application and the Ternary Application.

There are at least two possible interpretations of paragraph (b)(ii)(A). They are as follows:

• having identified a relevant piece of information, consideration is then given to whether that information was present in a document that would take priority over the claims under consideration; or

• having identified a relevant piece of information, consideration is then given to whether that information is the subject of an actual claim. If the information is the subject of an actual claim, consideration is then given to whether the claim would take priority over the claims under consideration. If the information is not the subject of an actual claim, consideration is then given to whether the information could be the subject of a claim. If the information could be the subject of such a notional claim, consideration is then given as to whether that notional claim would take priority over the claims under consideration.

One aspect of the second construction is whether any such notional claim needs to be capable of being characterised as a valid claim. That is to say, the question is whether such a notional claim would satisfy the requirements of s 40 in relation to the complete specification of the patent said to contain the relevant information."

1. Emmet J considered that the second construction should be preferred and concluded that:

"it is necessary to determine first whether there is any information contained in the Daikin Patent that:

• anticipated the inventions of the Binary Application and the Ternary Application; and
• is the subject of a claim of the Daikin Patent or could be the subject of a valid notional claim of the Daikin Patent."[89]

1. WO 2013/151736 A2 (designated D1) was published on 10 October 2013. Consequently it is part of the prior art base.

1. D1 is titled "In Vivo Production of Proteins". D1 discloses compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and mmRNA molecules (Abstract). D1 discloses "vaccines" as one of several broad target categories that the mmRNA of the invention may be designed to encode polypeptides of interest.[90] D1 defines a "vaccine" as a biological preparation that improves immunity to a particular disease or infectious agent.[91] D1 further disclosed that an immune response may be elicited by delivering a lipid nanoparticle.[92]

1. D1 discloses a range of delivery options. D1 discloses that the polynucleotide, primary construct, and mmRNA of the invention can be formulated using one or more liposomes, lipoplexes, or lipid nanoparticles.[93] In one embodiment, the polynucleotides, primary constructs or mmRNA may be formulated in a lipid nanoparticle such as those described in International Publication No. WO2012170930.[94] D1 further discloses that the LNP formulation may contain PEG-DMG 2000 (l,2-dimyristoyl-sn-glycero-3-phophoethanolamine-N-[methoxy(polyethylene glycol)-2000), DLin-DMA, DSPC and cholesterol in a molar ratio of 2:40:10:48 (see e.g., Geall et al., Nonviral delivery of self-amplifying RNA vaccines, PNAS 2012; PMID: 22908294; incorporated in the opposed application by reference in its entirety).[95]

1. D1 discloses the LNP formulation comprising the four lipid components claimed in the opposed application: cationic lipid, neutral lipid (e.g. DSPC), sterol (e.g. cholesterol), and a PEG-lipid (e.g. PEG-c-DOMG, PEG-DSG, PEG-DPG).[96] The cationic lipid may be selected from any lipid known in the art such as, but not limited to, DLin-MC3-DMA, DLin-DMA, C12-200 and DLinKC2-DMA.[97]

1. Examples 11-14 describe synthesis of a number of lipids, including members of the DLin series, and formulation into nanoparticles.[98] In the section "Formulation of Modified RNA Nanoparticles", D1 discloses formulations of mmRNA and describes that these examples used various cationic lipids:DSPC:Cholesterol:PEG-c-DOMG at molar ratios of 50:10:38.5:1.5.[99] Example 14 discloses the use of these formulations with a number of different cationic lipids formulated with mRNA encoding mCherry.[100] Example 23 discloses the delivery of modified mRNA LNP formulations (G-CSF and EPO) to non human primates to measure protein expression.[101]

1. I consider that D1 provides clear and unmistakeable directions to make compositions comprising mRNA nucleotides, formulated in a cationic lipid nanoparticle comprising a cationic lipid, non-cationic lipid, sterol and a PEG-modified lipid, with molar ratios that fall within the scope of claim 1 of the opposed application. However, I do not consider D1 discloses that the mRNA has an open reading frame encoding an "antigenic polypeptide".

"D1 focuses on encoding a non-antigenic polypeptide (e.g. for protein replacement therapy, or to provide anti-microbial or anti-viral proteins). No mRNA vaccine encoding an antigenic [emphasis added] polypeptide is taught in D1."[102]

"D1 focuses on polypeptide production, whereas the opposed application focuses on mRNA vaccines involving eliciting an immune response ... I cannot see any actual data in D1 demonstrating mRNA encoding an antigen and being used as a vaccine."[103]

1. Therefore, I consider that D1 only discloses, with clear and unmistakeable directions, formulations comprising mRNA encoding for non-antigenic polypeptides for therapeutic purposes. While D1 discloses generally that vaccines may be used to improve immunity, I consider that there is not the requisite degree of specificity in the disclosure of that immune response being antigen specific. Therefore, I consider claim 1 is novel in view of D1. As claims 2-67 are dependent on claim 1, it follows that these claims are also considered novel in view of D1.

1. US 61/618,868 (designated D1A) was one of a large number of priority documents for WO 2013/151736 A2. D1A was dated 2 April 2012 and was incorporated by reference in its entirety to D1.

1. D1A discloses the polypeptides of interest or "targets" or "vaccines" of the invention listed in Table 6 - Vaccine Targets.[104] Table 6 proceeds to list 327 different vaccine targets. With regard to Table 6 in D1A, the applicant submits that Table 6 is simply a list of medicines that were in development at the relevant time, including a wide range of non-immunology targets, such as cardiovascular, gastrointestinal, musculoskeletal and central nervous system targets, and none of these targets involve the use of an mRNA polynucleotide encoding an antigenic peptide, but instead involve the use of a therapeutic, non-antigenic polypeptide.[105]

1. In addition, D1A discloses mmRNA encoding one or more vaccines.[106] D1A discusses the use of mmRNA to reduce, evade or avoid the innate immune response of a cell.[107] D1A defines a "vaccine" as a biological preparation that improves immunity to a particular disease or infectious agent.[108] The applicant submits that the term "vaccine" in D1A is not specific to an mRNA vaccine encoding for an antigenic polypeptide, as immunity can be improved without delivering an antigenic polypeptide, for example, by delivering biologics, antibodies, therapeutic proteins or peptides etc.[109] The applicant submits that D1A is referring to mRNA that is antigenic per se, rather than mRNA that encodes an antigenic polypeptide for prophylaxis, and this is evidenced in D1 by the disclosure focused on mRNA having untranslatable regions that are antigenic as a nucleic acid.[110]

1. D1A further discloses the formulation of modified mRNA using lipidoids, including the synthesis of six cationic lipids, DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, 98N12-5, C12-200 and DLin-MC3-DMA.[111] D1A discloses the formulation of modified RNA nanoparticles by combining synthesised lipid solution with modified mRNA solution to formulate a LNP with a 50:10:38.5:1.5 molar ratio of cationic lipid:DSPC:Cholesterol:PEG-c-DOMG.[112]

1. D1A discloses that vaccines of the invention may be utilised to treat conditions or diseases in many therapeutic areas such as, but not limited to, cardiovascular, CNS, dermatology, endocrinology, oncology, immunology, respiratory, and anti-infective."[113] D1A also discloses vaccines of the invention encoding for viral pathogens which include influenza, parainfluenza and respiratory syncytial virus.[114] The opponent submits that this disclosure provides clear instructions to work a form of the invention providing mmRNA to encode for a viral pathogen within an LNP to induce an immune response.[115] The applicant disagrees submitting that D1A discusses a mmRNA encoding an anti-viral agent,[116] and this does not relate to an antigenic polypeptide that elicits an antigen-specific immune response, but rather a therapeutic polypeptide which performs its usual anti-viral function.[117]

1. D1A discloses that the mmRNA may be designed to encode polypeptides from several categories including, but not limited to biologics, antibodies, vaccines, therapeutic proteins or peptides, cell penetrating peptides, secreted proteins, plasma membrane proteins, cytoplasmic or cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease, and targeting moieties.[118] The applicant submits that the reference to vaccines in D1A occurs as part of a laundry list of 13 possible applications on page 21, lines 15-21.[119] Furthermore the applicant submits that D1A merely lists "infectious diseases" as one of 16 listed diseases,[120] disorders or conditions, and that D1A focusses on anti-microbial polypeptides (e.g. anti-bacterial or anti-viral), not an mRNA vaccine comprising mRNA encoding an antigenic polypeptide.[121]

1. The applicant further submits that the opponent's EIR specifically acknowledges that D1A does not disclose an mRNA vaccine comprising an mRNA encoding an antigenic polypeptide.[122] Prof. Leaf Huang in the EIR states:

"While there may be some difference in the specific polypeptides encoded for between D1A and the Opposed Application it is not my understanding that this is supposed to be the contribution which the Opposed Application puts forward as an invention."[123]

"Again, the only difference [between D1A and the Opposed Application] is the nature of the particular mRNA sequence and so the polypeptide encoded for. The Opposed Application and the claims, as I understand them, do not seem to suggest that the invention lies in the nature of the mRNA and so I don't understand how this can be seen to be in any way a significant point of differentiation."[124]

1. I consider that D1A fails to rectify the deficiencies in D1 with regards to novelty. That is, I do not consider that D1A provides clear and unmistakeable directions to make compositions comprising mRNA encoding an "antigenic polypeptide". D1A discloses therapeutic polypeptides, not antigenic polypeptides that elicit an antigen-specific immune response. This position appeared to be conceded by the opponent's own expert, Prof. Leaf Huang in the EIR where he suggested that there was a difference in the "polypeptide encoded for" between D1A and the opposed application. At best, D1A may disclose mRNA that is antigenic per se, rather than mRNA that encodes an antigenic polypeptide. Therefore D1A fails to disclose a polypeptide that is capable of eliciting an antigen specific immune response (i.e. an "antigenic polypeptide" within the meaning of my construction of that term). As a result, I consider claim 1 is novel in view of D1A. As claims 2-67 are dependent on claim 1, it follows that these claims are also considered novel in view of D1A.

1. WO 2014/136086 A1 (designated D2) was published on 12 September 2014 and has an earliest priority date of 8 March 2013. Consequently it is part of the prior art base in relation to whole of contents novelty.

1. D2 is titled "Lipids and lipid compositions for the delivery of active agents." D2 discloses cationic lipids useful in the delivery of biologically active agents to cells and tissues.[125] D2 also discloses a pharmaceutical composition (i.e. formulation) comprising a lipid composition in the form of a lipid nanoparticle.[126] Prof. Zhang notes that D2 mentions a large number of lipid compositions on pages 43-45 but that LNPs are but one alternative.[127]

1. D2 discloses a number of different lipid compositions including:

• "a lipid nanoparticle comprising a compound of formula (I) a helper lipid, for example cholesterol, a neutral lipid, for example DSPC, and a stealth lipid, for example PEG-DMG, S010, SO11 or SO24, and a biologically active agent, for example an mRNA."[128]

• "a lipid composition comprising a compound of formula (I), a helper lipid, for example cholesterol, a neutral lipid, for example DSPC, and a stealth lipid, for example PEG-DMG, S010, S011 or S024 in a lipid molar ratio of 55-40 compound of formula (I) / 55-40 helper lipid / 15-5 neutral lipid/ 10-1 stealth lipid."[129]

• encapsulation of mRNA in a cationic lipid,[130] DSPC, cholesterol and lapidated PEG or stealth lipid in molar ratios of 40:10:38:2 respectively.[131]

1. D2 further discloses that the lipid composition comprises a biologically active agent,[132] which may be mRNA.[133] The applicant submits that insofar as D2 mentions mRNA as a possible "biologically active agent", D2 lists mRNA as one of 41 possible alternatives.[134]

1. D2 does not use the words "vaccine" or "vaccinations". However, D2 discloses that the lipid compositions are suitable for immunisation purposes,[135] including immunising against pathogens which cause infectious disease.[136] More specifically, under the heading "Immunization according to the invention" D2 states:

"For immunization purposes, the invention involves delivering a RNA which encodes an immunogen. The immunogen elicits an immune response which recognizes the immunogen, and so can be used to provide immunity against a pathogen, or against an allergen, or against a tumor antigen."[137]

"A RNA molecule useful with the invention for immunization purposes will typically be single-stranded. Single-stranded RNAs can generally initiate an adjuvant effect by binding to TLR7, TLR8, RNA helicases and/or PKR."[138]

1. However, under the same heading D2 goes on to disclose that the preferred plus stranded RNAs are self-replicating.[139]

1. Examples 1-126 of D2 show various lipid compounds and synthesis steps. D2 then exemplifies LNPs formed by mixing equal volumes of lipids dissolved in alcohol with siRNA which is used to target mRNA encoding for Factor VII and PLK1-424.[140] The only immunisation studies in D2 disclose the immunisation of BALB/c mice with liposomes comprising DSPC, cholesterol, and various lipids of the invention, encapsulating a "vA317" self-replicating RNA replicon which encodes respiratory syncytial virus F protein.[141] Furthermore D2 exemplified a study involving mouse intravenous tail vein injection of modified synthetic leptin mRNA.[142]

1. The opponent submits that the accepted approach to assessing whole of contents novelty citations in Australia has been described in detail by the declaration of Dr. Declan McKeveney.[143] The opponent further submits that the assessment of whole of contents novelty must take into account information contained in the relevant document and whether or not that information, if in an actual or notional valid clam, anticipates the claims of the opposed application.[144] The McKeveney declaration drafts notional claims 1-3 based on the disclosure of D2 which the opponent submits is supported in accordance with Section 40(3) of the Patents Act, and discloses the opposed claimed invention.[145] The opponent submits that the applicant's experts comments on the disclosure of D2 are wholly irrelevant and should be dismissed as they are not placed to understand the assessment which is made in relation to the law on whole of contents novelty under Australian patent law.[146]

1. The applicant submits that the McKeveney declaration in the EIS, which attests to applicable legal principles and constructs notional claims, is not the proper subject of the EIS as this is not expert witness opinion on the disclosure of D2.[147] The applicant further submits that:

"the requirement to have regard to notional claims in the context of a "whole of contents" novelty allegation cannot be used to construct a basis for the disclosure of a combination of features which is not in fact disclosed, in accordance with the general principles of novelty, in the prior art specification in question."[148]

"The standard of disclosure required for lack of novelty is no less stringent in the case of a "whole of contents" allegation than a conventional novelty citation. If anything, it is more stringent, given the requirement for an actual or notional claim which is supported by the disclosure: see, in the context of the pre-Raising the Bar version of the Patents [2005] FCA 892; Act, E I Du Pont de Nemours & Co v ICI Chemicals & Polymers Ltd (2005) 66 IPR 462 at [85], [90]-[93]."[149]

1. The applicant submits that the notional claims proposed in the opponent's submissions are not valid in meeting the requirements under Section 40, and certainly do not meet the post-"Raising the Bar" requirements.[150]

1. The applicant submits that D2 does not disclose an mRNA-LNP vaccine encoding an antigenic polypeptide, and the process of constructing any possible notional claim involves an impermissible ex post facto "cherry picking" exercise of selecting the specific combination of features from multiple lists of possible alternatives.[151] For example, they argue that there are no clear and unmistakeable directions in D2 to use mRNA for immunization purposes, as the only specific form of RNA discussed in this context is self-amplifying RNA which is not a form of mRNA encoding an antigenic polypeptide. In this context, D2 discloses that self-amplifying RNA is advantageous, and therefore preferred, because it results in "a huge amplification in the number of the introduced replicon RNAs and so the encoded immunogen becomes a major polypeptide product of the cells."[152]

1. The applicant further submits that the skilled person would not have considered using a lipid nanoparticle as recited in the opposed claims in view of the plethora of alternatives provided in D2 and the unpredictability in the field at the time of the claimed invention.[153] The applicant further submits that D2 provides a laundry list of therapeutic agents to be administered with a composition that may comprise a range of different components in numerous different ratios.[154]

1. As Emmett J stated in Du Pont quoted at paragraph [81] above, the first step in satisfying the pre-requisite of paragraph (b)(ii)(A) of the definition of prior art for the purposes of novelty is to identify whether the information contained in D2 anticipates the claims.

1. In my view, D2 fails to provide clear and unmistakeable direction to make vaccines comprising mRNA nucleotides encoding an antigenic polypeptide, formulated in a cationic lipid nanoparticle comprising the components in the ratios defined in opposed claim 1. The only embodiments that disclose mRNA for immunisation purposes, including the examples, relate to self-amplifying mRNA, which I have construed previously as not falling within the scope of the term mRNA. While LNPs are mentioned in D2 as one possible lipid composition of the invention, one example used a LNP composition that encapsulates an siRNA which is used to target mRNA encoding for Factor VII and PLK1-424, and the second example used a lipid composition comprising a modified synthetic leptin mRNA. The former example uses siRNA which is not mRNA and the latter example uses leptin mRNA which does not encode an antigen specific polypeptide. I do not consider from reading the disclosure of D2 as a whole, that the information contained in D2 provides clear and unmistakeable directions to make the vaccines defined by opposed claim 1.

1. Therefore, I consider claim 1 is novel in view of D2. As claims 2-67 are dependent on claim 1, it follows that these claims are also considered novel in view of D2.

1. WO 2015/095346 A1 (designated D3) was published on 25 June 2015 and has an earliest priority date of 19 December 2013. Consequently it is part of the prior art base in relation to whole of contents novelty.

1. D3 is titled "Lipids and lipid compositions for the delivery of active agents." D3 discloses cationic lipids useful in the delivery of biologically active agents to cells and tissues.[155] D3 discloses a pharmaceutical composition (i.e. formulation) comprising a lipid composition in the form of a lipid nanoparticle.[156] D3 discloses that the lipid composition comprises a biologically active agent.[157]

1. With regard to the formulation of the lipid composition, D3 discloses:

• "Lipids (cationic lipid, DSPC, cholesterol and lipidated PEG or stealth lipid) are dissolved in ethanol. The molar ratios are 40:10:38:2, respectively" (under the heading "Packaging of mRNA").[158]

• "a lipid composition comprising a compound of formula (I), a helper lipid, for example cholesterol, a neutral lipid, for example DSPC, a stealth lipid, for example S010, S014, S027, S031, or S033 in a lipid molar ratio of about 45 compound of formula (I)/ about 44 helper lipid/ about 9 neutral lipid/ about 2 stealth lipid."[159]

1. With regard to disclosing a lipid composition eliciting an immune response, D3 discloses:

"this invention provides a method for inducing an immune response in a subject against an immunogen of interest comprising administering an immunologically effective amount of a lipid composition of the invention to the subject, in combination with a RNA or DNA that encodes the immunogen."[160]

"The term "immunologically effective amount" refers to the amount of the compound of the invention and of RNA which encodes an immunogen needed to elicit an immune response which recognizes the immunogen (e.g. in the context of a pathogen). The term "immunogen" refers to any substance or organism that provokes an immune response when introduced into the body. The phrase "RNA which encodes an immunogen" refers to a polynucleotide, such as a messenger RNA or a replicon (e.g., self-replicating RNA), that when administered to a cell or organism is capable of being translated into a polypeptide according to the codon sequence of such RNA."[161]

"[f]or immunization purposes ... the invention encompasses delivering a RNA that encodes an immunogen. The immunogen elicits an immune response which recognizes the immunogen, and so can be used to provide immunity against a pathogen, or against an allergen, or against a tumor antigen."[162]

1. Examples 1-142 of D3 show various lipid compounds and synthesis steps. D3 then exemplifies LNPs formed by mixing equal volumes of lipids dissolved in alcohol with siRNA which is used to target mRNA encoding for Factor VII and PLK1-424.[163] The immunisation studies in D3 disclose the immunisation of BALB/c mice with liposomes encapsulating a self-replicating replicon encoding RSV F protein.[164] Furthermore D3 exemplified a study involving mouse intravenous tail vein injection of modified synthetic leptin mRNA.[165]

1. The opponent in the SGP submits that Tables 2 and 3 of D3 provide examples of mRNA and lipid nanoparticles.[166] The applicant responds submitting that neither table illustrates mRNA vaccines with Table 2 directed to the percentage encapsulation of mRNA encoding the hormone leptin, and Table 3 directed to LNP measurements using mRNA encoding human leptin, human FIX protein, fluorescent luciferase, Gluc and murine EPO, none of which are antigenic polypeptides.[167]

1. The applicant submits that the SGP incorrectly asserts that D3 discloses mRNA vaccines formulated in LNPs, but rather D3 discloses examples of vaccines that are RNA and separately "mRNA therapy" with mRNA vaccines not being disclosed.[168] The applicant further submits that pages 241-247 of D3 do not teach an mRNA polynucleotide encoding an antigenic polypeptide in combination with a lipid nanoparticle.[169]

1. The applicant submits that the process of constructing any possible notional claim involves an impermissible ex post facto "cherry picking" exercise of selecting the specific combination of features from multiple lists of possible alternatives.[170] For example, they argue that there are no clear and unmistakeable directions in D3 to use mRNA for immunization purposes, as the only specific form of RNA discussed in this context is self-amplifying RNA which is not a form of mRNA encoding an antigenic polypeptide. In this context, D3 discloses that self-amplifying RNA is advantageous, and therefore preferred, because it results in "a huge amplification in the number of the introduced replicon RNAs and so the encoded immunogen becomes a major polypeptide product of the host cells."[171] The applicant further submits that self-amplifying RNA was shown in D3 to produce an immunological response to RSV.[172]

1. In the EIA, Prof. Zhang provides some evidence supporting the notion that the vaccines disclosed in D3 relate to self-amplifying RNA, noting that:

"D3 is focused on LNPs for delivering "active agents", one of which is listed as mRNA. However, in terms of using nucleic acids, the focus in D3 is clearly on self-amplifying RNA, not mRNA."[173]

1. The opponent submits that the applicant's experts comments on the disclosure of D3 are wholly irrelevant and should be dismissed as they are not placed to understand the assessment which is made in relation to the law on whole of contents novelty under Australian patent law.[174] As discussed above, the opponent reiterates that the accepted approach to assessing whole of contents novelty has been described in detail by Dr. Declan McKeveney. The McKeveney declaration drafts notional claim 1 based on the disclosure of D3 which the opponent submits is supported in accordance with Section 40(3) of the Patents Act, and discloses the opposed claimed invention.[175]

1. In my view, D3 fails to provide clear and unmistakeable direction to make vaccines comprising mRNA nucleotides encoding an antigenic polypeptide, formulated in a cationic lipid nanoparticle comprising the components in the ratios defined in opposed claim 1. The only embodiments that disclose mRNA for immunisation purposes, including the examples, relate to self-amplifying mRNA, which I have construed previously as not falling within the scope of the term mRNA. While LNPs are mentioned in D3 as one possible lipid composition of the invention, one example used a LNP composition that encapsulates an siRNA which is used to target mRNA encoding for Factor VII, and another example used lipid nanoparticles encapsulating mRNA encoding human leptin, human FIX protein, fluorescent luciferase, Gluc and murine EPO. The former example uses siRNA which is not mRNA and the latter example uses mRNA which do not encode an antigenic polypeptide. I do not consider from reading the disclosure of D3 as a whole, that the information contained in D3 provides clear and unmistakeable directions to make the vaccines defined by opposed claim 1.

1. Therefore, I consider claim 1 is novel in view of D3. As claims 2-67 are dependent on claim 1, it follows that these claims are also considered novel in view of D3.

1. The test for whether an invention is obvious is to ask whether it would have been a matter of routine to proceed to the claimed invention. In Wellcome Foundation Ltd v V. R. Laboratories (Aust.) Pty Ltd[176] Aickin J stated:

"The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they are the steps of the inventor or not."

1. More recently, the High Court in Aktiebolaget Hassle v Alphapharm Pty Ltd[177] referred with approval to this approach and further held:

"That way of approaching the matter has an affinity with the reformulation of the 'Cripps question' by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157. This court had been referred to Olin in the argument in Wellcome Foundation. Graham J had posed the question:

'Would the notional research group at the relevant date in all the circumstances directly be led as a matter of course to try [the claimed invention] in the expectation that it might well produce [the desired result]?'

1. The relationship between the matter of routine test in Wellcome Foundation and the reformulated Cripps question in Alphapharm was discussed in Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73; 222 FCR 336 at [71]:

"We do not think there is a divide here in terms of whether an expectation of success is relevant between a test which refers to routine steps to be tried as a matter of course and the reformulated Cripps question. It is difficult to think of a case where an expectation that an experiment might well succeed is not implicit in the characterisation of steps as routine and to be tried as a matter of course."

1. In Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2 at [89], Jagot J (with whom Besanko and Nicholas JJ agreed) further elaborated on the expectation of success:

"To my mind, these references suggest that the primary judge strayed from the test of steps taken in an expectation that they might well produce the invention or a useful result towards a test of an expectation of knowing that steps will produce a useful result based on predictive capacity."

1. Common general knowledge (CGK) is the background knowledge and experience available to all those working in the relevant art:

"The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge."[178]

1. The Full Federal Court in AstraZeneca state at [203] that:

"If the problem addressed by a patent specification is itself common general knowledge, or if knowledge of the problem is s 7(3) information, then such knowledge or information will be attributed to the hypothetical person skilled in the art for the purpose of assessing obviousness. But if the problem cannot be attributed to the hypothetical person skilled in the art in either of these ways then it is not permissible to attribute a knowledge of the problem on the basis of the inventor's "starting point" such as might be gleaned from a reading of the complete specification as a whole."

1. The "Background of the Invention" section of the specification, when providing a summary of the state of the art identifies a couple of different problems with vaccine production. Firstly, the time and expense associated with current technologies in antigen vaccine production:

"Vaccine production used in the art e.g., antigen vaccine production, has several stages, including the generation of antigens, antigen purification and inactivation, and vaccine formulation. First, the antigen is generated through culturing viruses in cell lines, growing bacteria in bioreactors, or producing recombinant proteins derived from viruses and bacteria in cell cultures, yeast or bacteria. Recombinant proteins are then purified and the viruses and bacteria are inactivated before they are formulated with adjuvants in vaccines. It has been a challenge to drastically reduce the time and expense associated with current technologies in vaccine development."[179]

1. Secondly, the constant evolution of most infectious agents results in difficulties in quickly providing vaccine protection against closely related subtypes:

"The biggest challenge for therapy and prophylaxis against influenza and other infections using traditional vaccines is the limitation of vaccines in breadth, providing protection only against closely related subtypes. In addition, today's length of the production process inhibits any fast reaction to develop and produce an adapted vaccine in a pandemic situation. It is of great interest to develop new vaccines as well as new approaches to combatting infectious disease and infectious agents."[180]

1. However, the "Detailed Description" of the opposed specification outlines the need in the art to develop new mRNA vaccines stating:

"Of particular interest, is the ability to design, synthesize and deliver a nucleic acid, e.g., a ribonucleic acid (RNA), for example, a messenger RNA (mRNA), which encodes an antigen, e.g., an antigen derived from an infectious microorganism, for the purposes of vaccination."[181]

1. It can be seen from a review of the current state of the art in the opposed specification that the need to deliver a mRNA to encode an antigen for the purposes of vaccination was clearly a problem that was recognised in the art. Therefore this is a problem that can be attributed to a PSA within the meaning of AstraZeneca, rather than an impermissible 'starting point' gleaned only from reading the opposed specification as a whole.

1. There appears to be no explicit formulation of the problem in the opponent's submissions. In the SGP, the opponent states "the Opposed Specification is directed to overcoming the problems associated with achieving improved functionality of mRNA vaccines."[182] Prof. Leaf Huang when commenting on the opposed specification, states that the "invention seems to be framed as providing new vaccines against infectious diseases."[183]

1. The applicant, including all three of its experts, defines the problem more narrowly as the formulation and delivery of a vaccine comprising an mRNA polynucleotide encoding an antigenic polypeptide in a manner that elicits a functional immune response.[184]

1. Both parties formulations of the problem are broadly consistent with the need in the art to deliver a mRNA to encode an antigen for the purposes of vaccination. Therefore, I consider the problem to be a need for mRNA vaccines encoding antigenic polypeptides.

1. While the parties agreed that lipid delivery technology had been used to successfully deliver nucleic acid, the applicant noted that many such delivery systems in addition to LNPs had been used including naked, protamine, liposomes and lipoplex formulations.[185] The parties also agreed that LNPs could be formulated from the four claimed lipid components and these could encapsulate nucleic acid.[186] However, the applicant adds that only certain lipids from each generic class can be employed successfully.[187]

1. Both parties agreed that there were a number of ways to obtain such lipid particles with microfluidic approaches (including those developed by the Cullis group) replacing previous methods (such as the approach of Jeffs L. B. et al., Pharm Res. 2005, Vol. 22, No. 3, pages 362-372).[188] With regard to the structure of LNPs, both parties agreed that the development of the ionisable cationic lipid was important in the use of LNPs as it allowed for complexation with a nucleic acid while charged at an acidic pH while then becoming neutral at a physiological pH to improve LNP circulation, delivery and endosomal release.[189] Similarly, the parties were in agreement that the non-cationic lipid, sterol and PEG lipid components of the LNP were important for LNP formulation and stabilisation.[190]

1. The opponent submits that a PSA, at the relevant date, would have been directly led, as a matter of course, to obtain a nucleic acid vaccine delivering mRNA polynucleotides encoding an antigen with a cationic lipid nanoparticle as defined in claim 1.[191] Furthermore, the opponent submits that any innate immune response could be addressed by modification of the mRNA, which would provide a strong expectation of success.[192] The opponent notes that the knowledge in the art, years before the priority date, that mmRNA could reduce the innate immune response and allow for improved protein expression is clearly highly relevant to the development of an mRNA vaccine.[193]

1. The applicant's experts, Dr. Cobaugh and Prof. Zhang submit that the same LNP approach used in siRNA and saRNA would not be expected to work for mRNA due to "... differences in size, structure, charge, chemistry, modifications, pH and hydrodynamic radius."[194] Dr. Cobaugh further acknowledges that the concept of modification was understood at the priority date but dismisses it as not having been successfully applied to an mRNA-LNP vaccine.[195]

1. In the discussion of the CGK, the applicant also references the experiences of the failed CureVac COVID-19 mRNA vaccine trial. Prof. Zhang summarises the CureVac trial as follows:

"CureVac is a spin off from University Tubingen, founded in 2000, and unlike most in the field at the time was indeed seeking to develop mRNA therapeutics. Specifically, CureVac has more recently been interested in using LNP technology to deliver mRNA for treatment of infectious diseases. However, as an indication of the significant difficulty in successfully formulating mRNA in LNPs, CureVac announced preliminary data on 16 June 2021 from a 40,000-person clinical trial showing that its two-dose COVID-19 mRNA vaccine was just 47% effective at preventing disease, and hence was considered a failure. This failure shows how difficult, even 7 years or so after the relevant date, it still is to successfully develop an mRNA-LNP vaccine."[196]

1. An important question to pose at this point is: Would the CGK directly lead a PSA, with the knowledge of success in formulating LNPs to encapsulate both small siRNA and large saRNA, to apply this knowledge to encapsulate mRNA with a reasonable expectation of success?

1. The opponent submits that no new LNP formulations or mRNA sequences were invented, but the applicant simply applied LNP delivery that was well known in the field to deliver smaller siRNA and larger saRNA, to deliver intermediate sized mRNA.[197] The opponent argues that the opposed application presents no new research and development or invention but rather applies a well-known LNP technology to the delivery of known mRNA, a purpose for which it was known to be suited.[198] The opponent further submits that because the size of mRNA falls between the size of siRNA and saRNA, the skilled person would then use LNPs to develop a mRNA vaccine with an expectation of success.[199]

1. The opponent, at the hearing, cited Weng Y. et al., Biotechnology Advances, 2020, Vol. 40, No. 107534 (Exhibit LZ-5)(Weng) as evidence of how siRNA and plasmid DNA delivery technologies have inspired mRNA delivery:

"In recent years, various, materials such as lipids, lipidoids, polymers, peptides, proteins, extracellular vesicles, etc, have been designed and explored for mRNA delivery in vitro and in vivo. Most of these materials are inspired by siRNA and plasmid DNA delivery technologies."[200]

1. The opponent cites Leung A. K. K. et al., Advances in Genetics, 2014, Vol. 88, pages 71-110 (Exhibit LH-21)(Leung) as providing some evidence of the broader potential application of LNPs, in particular to mRNA:

"It is important to note that technologies for the production of LNP systems are not restricted for siRNA but are also applicable to plasmid DNA, mRNA and potentially, clustered regularly interspaced short palindromic repeat (CRISPR) DNA."[201]

"In comparison to cationic polymers, lipid nanoparticles (LNP) are currently the most mature technology enabling the delivery of siRNA in vivo, with at least four formulations of LNP-siRNA in various phases of clinical trials for the treatment of hypercholesterolemia, transthyretin mediated amyloidosis and liver cancers."[202]

"The ionizable cationic lipid-based encapsulation technology for siRNA described above is fully applicable to other nucleic acid polymers such as plasmids and mRNA. A major challenge for LNP-plasmid systems is sufficient target gene expression since the nuclear envelope remains the barrier to the translocation of plasmid DNA into the nucleus. ... In contrast mRNA-LNP systems eliminate the need for nuclear translocation for gene expression. ... Recently, it has been demonstrated that chemically modified mRNA condensed by protamine can be encapsulated inside of preformed cationic vesicles (Wang et al., 2013). The microfluidic mixing method presented previously would eliminate the need for nucleic acid-condensing agents such as protamine and the need for the time-consuming extrusion process. As LNP-mRNA systems produced by microfluidic mixing would contain the same lipid components as used for the delivery of siRNA, it is expected that these LNP-mRNA would display biodistribution and pharmacokinetic properties similar to that of LNP-siRNA systems."[203]

1. In the EIS, Prof Leaf Huang, when asked about his understanding of the field of mRNA delivery at the earliest priority date, described LNP technology[204] and was familiar with the lipid components,[205] the manner of production and the leaders in the field at that time.[206] While Prof. Huang did assert that there were "many labs" or "a lot of groups" working on mRNA delivery using LNPs (with particular reference to the Pieter Cullis lab),[207] he did acknowledge that other delivery systems were being worked on at the relevant time:

"One of the most common approaches was to use liposomes or other types of lipid nanoparticles (LNPs), although other delivery systems such as polymeric particles and protamine cores encased in lipids were also being tested and developed."[208]

1. Prof. Huang notes the same LNP delivery platform had successfully been used for both siRNA and saRNA delivery, despite these different RNA molecules having "differences in size, structure, charge, chemistry, modifications, pH and hydrodynamic radius."[209] Prof. Huang concludes his EIS on this point stating:

"formulation of ... mRNA within ... LNPs and subsequent characterization could be carried out using published procedures which had been validated in siRNA formulation and which could be carried out in the lab in a straightforward manner and which had developed into the microfluidics approach."[210]

1. In response to this submission, Prof. Zhang states:

"I disagree that this was a "straightforward matter". The assertions made again draw upon knowledge that at the relevant time was based on siRNA formulation requirements, not mRNA requirements."[211]

"I do not agree with any suggestion that such formulations could be easily applied to mRNA."[212]

1. The applicant provides evidence that the combination of mRNA with LNPs did not occur until after the earliest priority date of the opposed application. For example, Wadhwa A. et al., Pharmaceutics, 2020, Vol. 12, No. 102 (Exhibit LZ-6)(Wadhwa) states:

"The first reported use of LNPs as delivery system for mRNA came in 2015, with the delivery system consisting of ionizable cationic lipid/phosphatidylcholine/cholesterol/PEG-lipid in the ratio of (50:10:38.5:1.5)[Pardi N. et al., J Control Release., 2015, Vol. 217, pages 345-351 (Exhibit CC-5)(Pardi 2015)]".[213]

1. Similarly, the review article Pardi N. et al., Nature Reviews Drug Discovery, 2018, Vol. 17, pages 261-279 (Exhibit CC-6)(Pardi 2018) states:

"Numerous studies have demonstrated efficient in vivo siRNA delivery by LNPs (reviewed in REF. 81), but it has only recently been shown that LNPs are potent tools for in vivo delivery of self-amplifying RNA [Geall A. J. et al., Proceedings of the National Academy of Sciences, 2012, Vol. 109, No. 36, pages 14604-14609 (Exhibit LH-10)(Geall) - D6] and conventional, non-replicating mRNA [Pardi 2015]."[214]

and Kulkarni J. A. et al., Nucleic Acid Therapeutics, 2018, Vol. 28, No. 3, pages 146-157 (Exhibit CC-4)(Kulkarni) states:

"The initial design of LNP systems (SPLP) for larger nucleic acid polymers was for the delivery of pDNA to express a therapeutic gene. As noted previously, low expression levels and an inefficient and nonscalable formulation technique precluded further development. Following the development of the ethanol loading technique for encapsulating siRNA into LNP, it was shown that this protocol could be used to encapsulate negatively charged macromolecules [61, 73]. This has led to significant advances to enable mRNA-based therapeutics."[215]

1. Even if it was accepted that the combination of mRNA with LNPs did not in fact occur until after the earliest priority date, this does not necessarily mean that the PSA would not be directly led to do it at that date, with a reasonable expectation of success.

1. The applicant submits, based on their EIA, that studies using siRNA were not thought to be applicable to using mRNA.[216] All three of the applicant's experts independently concurred that there was unpredictability in the field.[217] Prof. Zhang's evidence states that it could not be known at the relevant time what kind of delivery system would work with mRNA vaccines in order to produce a functional immune response based on what did or did not work with siRNA/ RNAi or self-amplifying RNA.[218] Similarly, Dr. Cobaugh states:

"Similarly to siRNA / RNAi, it was not considered at the time that delivery systems validated for saRNA could be used for mRNA, again because of differences in size, structure, charge, chemistry, modifications, pH and hydrodynamic radius."[219]

1. The applicant responds to Prof. Huang's submission that the same LNP platform had been used for saRNA and siRNA delivery despite differences in size, charge etc., by submitting that these considerations are entirely legitimate and clearly reflected in objective documentary evidence.[220] For example, Weng demonstrates that the size of mRNA when compared to siRNA was still seen as a significant challenge in the art in 2020:

"Efficient and safe delivery of mRNA is one of the biggest challenges in the development of mRNA-based therapeutics, which is more challenging than delivery of small oligonucleotides (Islam et al., 2015; Kowalski et al., 2019; Li et al., 2019). The size of mRNA (300-5,000 kDa, 1-15 kb, Fig. 3a) is significantly larger than siRNA".[221]

1. The applicant's experts further provide evidence on the difficulty and uncertainty surrounding adapting siRNA and saRNA LNP technology to mRNA. For example, the applicant refers to an online article in Chemical and Engineering News which states:

"siRNA molecules are like short rods, with two rows of about 20 nucleotides each ... mRNA, in contrast, can easily span thousands of nucleotides, wind into complex shapes, and change the properties of the LNP in ways that are hard to predict."[222]

1. The applicant further raises Geall as demonstrating that LNPs, while producing a good result with saRNA, did not produce a functional compound when formulated with plasmid DNA (per Fig. 3), which reinforced the belief that self-amplifying RNA, and not the LNP was responsible for the reported results.[223] Another example cited by Prof. Zhang was Wadhwa which Zhang said stood for the proposition that "significant difficulties in mRNA vaccine development were still notable in 2020, some 6 years after the relevant date, [providing] an indication as to the level of difficulties faced in the field before and leading up to 23 April 2014."[224] As stated in Wadhwa, some of these difficulties include:

"that (i) mRNA is a very large molecule, (ii) it is intrinsically unstable and prone to degradation by nucleases, and (iii) it activates the immune system ... intracellular delivery of mRNA still represents a major hurdle. The clinical translation of mRNA-based therapeutics requires delivery technologies that can ensure stabilization of mRNA under physiological conditions."[225]

1. The evidence of Dr. Eric Huang in the EIA reinforces this unpredictability. For example, Huang notes at [14] of his declaration that mRNA is relatively unstable and, as a result, in vivo mRNA delivery and expression was challenging. He further noted at [12] that the field of mRNA vaccines was highly unpredictable because the delivery of mRNA using lipid carriers, including liposomes and cationic lipid complexes, had faced challenges in producing therapeutic effects.

1. As a result of all this unpredictability in the field, the applicant contends that when siRNA LNP technology was in fact applied to mRNA, the success was surprising to those in the art. For example, Dr. Cobaugh in the EIA notes that:

"[t]he subsequent ability to apply LNP delivery systems to mRNA that had previously been validated only in siRNA was very surprising [emphasis added]."[226]

"In this study we review the challenges involved in extending LNP technology to nucleic acid polymers, the critical factors that have enabled progress to this point, and the remarkable [emphasis added] way in which LNP technology for siRNA can be applied to much larger payloads such as mRNA and pDNA."[227]

1. The applicant submits that when the combination of mRNA with LNPs was later demonstrated, the result was considered "remarkable" by the very same person, Pieter Cullis, that is relied on in the EIS as "one of the best known" labs supposedly working on mRNA at the relevant time.[228]

1. To assist me to assess what was the state of the CGK at the time, and address the modified Cripps question I posed above, I will consult two review articles that were published before the earliest priority date of the opposed application. The first is Sahin U. et al., Nature Reviews Drug Discovery, 2014, Vol. 13, pages 759-780 (Exhibit LZ-4)(Sahin) and the second is Deering R. P. et al., Expert Opin. Drug Deliv., 2014, Vol. 11, No. 6, pages 885-899 (Exhibit LH-19)(Deering). Both of these articles were the subject of much discussion both at the hearing and from the experts.

1. Prof. Zhang submits that Sahin, while providing "a comprehensive overview of the current state of mRNA-based drug technologies and their applications",[229] "makes no mention whatsoever of any research having been undertaken in relation to the use of LNPs as a delivery system for mRNA vaccines, or even consideration of such research."[230] Zhang says that Sahin also questions whether improvements in the delivery of siRNA could even be applied to mRNA:[231]

"The extensive but moderately successful efforts and difficulties experienced with siRNA and pDNA deliveries are predictive of what to expect for similar efforts in the mRNA field. However, it is important to consider the conceptual differences among these three platforms. In particular, the lessons learnt and improvements made in the delivery of siRNA and pDNA need to be considered when deciding whether these improvements can similarly be adopted to advance mRNA delivery or whether novel mRNA-tailored approaches have to be explored".[232]

1. The applicant further notes the difficulties discussed in Sahin in relation to mRNA technology such as targeted delivery, pharmacology, rapid mRNA degradation, cellular uptake, sufficient protein expression, cellular reach and accessibility, mRNA and protein product half-life, and dosing,[233] with Sahin concluding:

"[u]nder the shadow of disappointments and failures in the neighbouring fields of gene therapy and siRNA, the mRNA field has been advanced with due caution."[234]

1. More specifically, Sahin discusses some difficulties encountered when considering mRNA delivery technology:

"Irrespective of whether the IVT mRNA is delivered to the cells in vitro or in vivo, two key factors determine its cytoplasmic bioavailability. One is rapid degradation by the highly active ubiquitous RNases, which are abundant in the extracellular space. The other is the cell membrane, which hampers the passive diffusion of the negatively charged large mRNA molecule into the cytoplasm."[235]

"As discussed above, it is still unclear how to accurately deliver the IVT mRNA to the target cell type and how to achieve the right therapeutic dose level".[236]

1. At the hearing the opponent considered these extracts from Sahin to represent a direction for the PSA to implement the lessons learnt and improvements made with siRNA and pDNA delivery technology to mRNA delivery. Conversely, the applicant considers this is not a direction but rather, when read in context, details the difficulties faced in adapting siRNA and pDNA delivery to mRNA and outlines the conceptual differences among these three delivery methods.

1. As Sahin does not mention any research having been undertaken in relation to the use of LNPs as a delivery system for mRNA vaccines, I consider that this article does not provide any evidence that LNPs as a delivery system for mRNA vaccines forms part of the CGK. To my mind, Sahin merely teaches that problems using mRNA delivery technology were known in the art, and that any adaption of siRNA and pDNA technologies to mRNA should be proceeded with cautiously. This is hardly a direction.

1. I consider that Sahin teaches that in the art at the relevant date, potential difficulties were known in adapting siRNA technology to mRNA, and although advances in siRNA would be considered by a PSA, there was still much uncertainty as to how this would be translated to mRNA.

1. The opponent cites Deering as evidence that there was significant work into mRNA vaccines being undertaken at the relevant time, and that data from both siRNA and saRNA was regarded as applicable to mRNA:

"Recently, there have been major research efforts to optimize the delivery of short nucleic acids (e.g., siRNA) into the cytoplasm of cells. Since siRNA is active in the cytoplasm, the complications associated with nuclear delivery are circumvented. Advances in delivery that have been made in therapeutic delivery of siRNA have the potential to advance the RNA vaccine field."[237]

1. The applicant responds by submitting that there is no specific suggestion in Deering to use LNPs with mRNA vaccines, but rather an acknowledgement of many different delivery options:[238]

"Though the initial barriers for this nucleic acid vaccine approach seem to be overcome, in our opinion, the future and continued success of this approach lies in a more extensive evaluation of the many non-viral delivery systems described in the literature and gaining a better understanding of the mechanism of action to allow rational design of next generation technologies."[239]

1. Prof. Leaf Huang further commented that Deering discusses unpublished results indicating mRNA vaccines for prostate cancer and NSCLC to be "... safe, well-tolerated and immunogenic."[240]

1. The applicant submits that Prof. Leaf Huang's comments need to be put in context of the full reference in Deering:

"Unpublished findings in ongoing or recruiting clinical trials using conventional mRNA vaccines to target prostate cancer and NSCLC have also demonstrated mRNA vaccines to be safe, well-tolerated and immunogenic [18,37]. At the time of this publication, there are no published clinical data on any of the more advanced mRNA vectors or non-viral delivery systems that have shown great potential in preclinical testing. Currently, there are no published human data using mRNA vaccines for prevention against infectious diseases."[241]

and that this disclosure is unpublished and refers to cancer immunotherapy.[242]

1. The applicant further points out that Table 2 which summarises published data for non-viral delivery of conventional mRNA in preclinical models for prophylactic vaccine approaches has a single reference for delivery systems using liposomes, lipopolyplex, DC-targeted lipopolyplexes and lipoplex, but not a single reference relating to mRNA used in combination with LNPs as an mRNA-LNP vaccine.[243] This does not suggest that there was "a lot" of work at the relevant date in relation to mRNA-LNP vaccines.[244] In fact, page 5 of Deering states that "[m]uch effort has been put into delivering naked mRNA" which the applicant submits is done in relation to protamine mRNA and that this shows that many different options were being pursued, and LNPs do not feature.[245]

"Currently, there are two major forms of RNA vaccines based on the auto-replicative capacity of the mRNA: conventional, non-amplifying mRNA molecules and self-amplifying mRNA or replicons that maintain replicative activity derived from an RNA virus vector (Figure 1),"[246]

Deering provides no reference to LNPs under either of the headings "Conventional, non-amplifying mRNA molecules" or "Self-amplifying mRNA".

1. The applicant argues that page 6 of Deering warns that the undesirable inflammatory immune responses previously seen with complexed RNA (e.g. siRNA) may affect mRNA vaccines, thereby explicitly teaching against the applicability of siRNA results to mRNA.[247] The applicant further submits that page 6 of Deering teaches against using cationic lipids to deliver mRNA as per the opposed claims but rather suggests using neutral liposomes.[248]

1. Prof. Leaf Huang refers to pages 7 and 11 of Deering to assert that because siRNA data had been relied upon to develop the much larger saRNA vaccines, siRNA data was considered appropriate to develop mRNA vaccines as their size falls between siRNA and saRNA.[249] However, the applicant submits that this is inconsistent with (i) the lack of any published studies, let alone CGK, evidencing the use of mRNA vaccines comprised of mRNA with LNP to induce an antigen specific immune response as a vaccine platform, and (ii) the pre-existing knowledge in the art that LNPs used with siRNA gave an undesirable inflammatory response associated with a transient IgM response, which taught against using LNPs with mRNA for vaccines.[250] Furthermore, contrary to Prof. Huang's statement that Deering evidences knowledge of applicability of siRNA data for mRNA, Deering states:

"It is important to bear in mind that vaccine-delivered mRNA might interact with a different set of cellular proteins than those that regulate siRNA movement and location."[251]

1. The applicant concludes by submitting that Deering cannot be relied on to say that it was CGK to come to the vaccine of claim 1 with a reasonable expectation of success as Deering discusses a number of different delivery systems for non-amplifying mRNA but does not provide a single reference relating to mRNA used in combination with LNPs.[252]

1. I consider that Deering merely teaches that advances in therapeutic delivery of siRNA have the potential to advance the RNA vaccine field, but Deering suggests the CGK at the relevant time relates to vaccines using self-amplifying RNA or naked protamine-complexed RNA rather than mRNA-LNP, which are not specifically referenced.

1. Another related question is: Would there be a reasonable expectation of success that a vaccine comprising a mRNA encoding an antigenic peptide encapsulated in a LNP would produce an antigen specific immune response i.e. act as a vaccine?

1. Prof. Leaf Huang submits that it was well-known at the time to immunologists that if the delivery aspect could be appropriately achieved then expression and a suitable immune response would be expected.[253] Prof. Huang also provided that:

"It was also understood that it was generally preferable to use modified mRNA (mmRNA) as this would reduce the innate immune response to the mRNA and would often result in better expression of the protein and so was considered more efficient."[254]

1. The applicant's experts disagreed, instead suggesting that the CGK at the time was less clear on whether a functional immune response could be achieved. For example, Prof. Zhang submits that it was known in the art at the relevant time that stabilisation and the ability to elicit a functional immune response to mRNA vaccines were significant obstacles to overcome.[255] Dr. Eric Huang also submitted that it was

"unclear in the art whether formulations, including cation lipid complexes described in the art as transfection reagents, would be useful in delivery of an RNA vaccine that would produce a meaningful immune response."[256]

1. Furthermore, Dr. Eric Huang references Petsch B. et al., Nature Biotechnoogy, 2012, Vol. 30, No. 12, pages 1210-1216 (Exhibit EH-4)(Petsch) which noted at the time that:

"successful mRNA immunization resulting in protection from infectious disease has never been reported ... whether mRNA vaccines induce protective antibody responses and are efficacious in infectious disease is not clear."[257]

1. The applicant submits that to generate a functional immune response, an mRNA vaccine needed to both (i) express sufficient levels of protein, and (ii) generate sufficient immune stimulation.[258] The applicant's experts provide some evidence to support the fact that there were doubts whether mRNA could produce sufficient protein expression and immune stimulation. Prof. Leaf Huang references Deering which notes that "due to the short half-life and instability of RNA, only a transient and low level of expression can be achieved in vivo"[259] Dr. Eric Huang also references Kallen K.-J, et al., Human Vaccines & Immunotherapeutics, 2013, Vol. 9, No. 10, pages 2263-2276 (Exhibit EH-3)(Kallen) which indicates that there was not a strong relationship between protein expression and immunogenicity:

"ways to elicit a balanced, long lasting immune response comprising strong humoral and cellular responses" are distinct from "measures to increase protein expression encoded by a given mRNA".[260]

1. The applicant submits that in order to solve these two problems or requirements for a functional immune response, the prior art taught away from the present invention by pursuing two alternate strategies, firstly saRNA vaccines, and secondly, mRNA vaccines with protamine not LNP. For example, Geall and Hekele A. et al., Emerging Microbes and Infections, 2013, Vol. 2, e53 (Exhibit LH-11)(Hekele) - D7, teach the use of saRNA rather than mRNA for the ability of saRNA to produce higher transcript numbers, and Petsch teaches a two component influenza vaccine containing free mRNA for antigen expression and protamine-complexed mRNA for immune stimulation.[261] See also Sahin which states:

"two different strategies using IVT mRNA as prophylactic influenza vaccines are currently undergoing preclinical investigation ... The first is based on an intradermally injected two-component vaccine containing an mRNA adjuvant [protamine] and naked IVT mRNA encoding influenza haemagglutinin antigen alone or in combination with neuraminidase encoding IVT mRNA. Both regimens induced protective immune responses against the corresponding influenza strains in aged and newborn mice, as well as long-lasting protective immunity in ferrets and pigs. The second strategy uses self-amplifying IVT mRNA containing sequences of positive-stranded RNA viruses".[262]

1. The applicant submits that these solutions attempted to solve the problems of (1) producing high levels of protein expression and (2) inducing sufficient immunostimulation in different ways. Self-amplifying RNA vaccine technology addressed these problems by replacing mRNA with an RNA replicon in order to boost expression and immunogenicity, whereas protamine-complexed mRNA vaccines used protamine to stabilise the mRNA and act as an adjuvant.[263]

1. Self-amplifying RNA vaccines had several benefits. This is highlighted by Deering which states:

"[s]elf-amplifying RNA vaccines have several attractive features that are lacking in conventional mRNA vaccines, namely, that their autoreplicative ability maintains a high expression of the encoded GOI in host cells, regardless of cell division. Additionally, the duration of expression from self-amplifying RNA molecules can extend to almost 2 months in vivo".[264]

"self-amplifying vectors are ideally suited for vaccine development because they provide transient expression and inherent adjuvant effects."[265]

1. The applicant submits that self-amplifying RNA is not a like-for-like replacement of mRNA as the RNA replicon within saRNA is considered critical for achieving the requisite antigen production and immunogenicity in vivo.[266] As a result, the applicant submits that a PSA would not be directly led as a matter of course and with an expectation of success to try and develop an mRNA-LNP vaccine because it was understood from the CGK that self-amplifying RNA technology was critical.[267] The CGK was that that mRNA could not match the high levels of expression or induce the same immune response as saRNA.[268] Furthermore, Geall demonstrates that LNP carriers, while producing a good result with self-replicating RNA, did not produce a functional compound when formulated with plasmid DNA which reinforced the belief that self-amplifying RNA, and not the LNP was responsible for the reported results.[269]

1. The applicant further submits that in order for mRNA to be a viable vaccine candidate, the prior art proposed complexing mRNA with protamine.[270] The use of protamine had two perceived benefits. Firstly, protamine was known to protect RNA vaccines from degradation, thereby boosting expression. Secondly, the protamine could contribute a strong immunostimulatory signal as an adjuvant.[271] The importance of protamine was raised by Dr. Eric Huang by citing Petsch which states:

"the improved efficiency and duration of antigen expression in vivo and complexation with protamine are necessary for the sustained protective immune responses observed in this study."[272]

1. The applicant submits that the PSA would not have been directly led as a matter of course and with an expectation of success to replace protamine with LNPs as there was no motivation in the CGK to do so.[273] To the contrary, it was known that LNPs used with siRNA gave an undesirable inflammatory response associated with a transient IgM response. This taught against using LNPs with mRNA for vaccines, as discussed in the opposed application:[274]

"In view of the observations made in association with the siRNA delivery of LNP formulations, the fact that LNP is useful in vaccines is quite surprising. It has been observed that therapeutic delivery of siRNA formulated in LNP causes an undesirable inflammatory response associated with a transient IgM response, typically leading to a reduction in antigen production and a compromised immune response."[275]

1. The applicant concludes by submitting that there was no reasonable expectation that the presently claimed vaccines would be effective.[276]

1. After consideration of all the evidence, I do not consider that a PSA, in light of the problem and in view of the CGK alone, would be directly led as a matter of course to formulate a nucleic acid vaccine comprising a mRNA encoding an antigenic polypeptide, formulated in a LNP having the four components in the defined ratios, as defined in claim 1 of the opposed application, with a reasonable expectation of success.

1. I come to this conclusion for a number of reasons.

1. Firstly, I consider that the CGK teaches away from using mRNA LNP vaccines, instead teaching that either saRNA or mRNA and protamine was required to achieve an immune response. For example, Deering teaches that much effort has been put into delivering naked mRNA with protamine and Sahin teaches that only two approaches were currently undergoing preclinical investigation, one of which was an mRNA adjuvant [protamine] and naked IVT mRNA encoding influenza haemagglutinin antigen and the other was self-amplifying IVT mRNA containing sequences of positive-stranded RNA viruses. Furthermore, Hekele teaches the use of saRNA rather than mRNA to produce higher transcript numbers.

1. Secondly, I do not consider that there was any motivation in the CGK for the PSA to replace protamine with LNPs. As it was known in the CGK that LNPs used with siRNA gave an undesirable inflammatory response associated with a transient IgM response, I do not think a PSA would be directly led as a matter of course to combine the use of mRNA with an LNP in a vaccine.

1. Thirdly, I consider that while it was known in the art that an LNP formulation comprising the four lipid components defined in claim 1 could be used to encapsulate siRNA, I consider that there was still much uncertainty in the CGK at the relevant date as to whether such an LNP could successfully encapsulate mRNA encoding an antigenic polypeptide and produce a meaningful antigen specific immune response. Geall provides some evidence that an LNP encapsulating plasmid DNA failed to produce any meaningful immune response. While there was some evidence in Leung that this failure was due to the nuclear envelope being a barrier to the translocation of plasmid DNA into the nucleus which would not present the same problems with mRNA-LNP systems, much uncertainty remains. Due to this uncertainty, I do not consider that there would be a reasonable expectation of success that an LNP could successfully encapsulate mRNA encoding an antigenic polypeptide and produce a meaningful antigen specific immune response.

1. Fourthly, when siRNA/LNP technology was in fact applied to mRNA it was considered surprising to those in the art. For example, Dr. Cobaugh found it surprising and I consider his opinion carries weight as his expertise is in mRNA. Also, Pieter Cullis, who the opponent acknowledges to be a prominent researcher in the mRNA-LNP space, himself found it "remarkable" that this LNP technology could be applied to mRNA given the structural differences between siRNA and mRNA.

1. The disclosure of D1 was discussed with regards to novelty above. D1 fails to provide clear and unmistakable directions that the mRNA LNP vaccines disclosed in D1 have an open reading frame encoding an "antigenic polypeptide". The question now is: Would the PSA seeking mRNA vaccines encoding antigenic polypeptides and in possession of D1 and the CGK, be directly led to the claimed vaccine?

1. The opponent submits that a PSA, desirous of producing an efficacious vaccine, would be directly led as a matter of course to replace the mCherry, EPO or Factor IX modified mRNA of D1 with a different mRNA known for encoding an antigen to prepare a vaccine, with a reasonable expectation of success.[277]

1. The opponent relies on the evidence of Prof. Leaf Huang to support this argument who states:

"The only difference between Examples of the respective documents is the nature of the mRNA itself. The Opposed Application describes a very large range of mRNA and mmRNA which are said to be suitable for formulation and does not claim any surprising effect in the use of certain types of mRNA and so this difference would appear to be nothing more than a choice based on the desired antigenic protein to be encoded for. Since D1 and D1A demonstrated exactly the same LNP formulation as in the Opposed Application encapsulated mRNA and mmRNA, which could be transcribed, I can't see that there is any invention in simply using the same approach with a different mRNA."[278]

1. In response the applicant submits that there is a clear difference between encoding a therapeutic (non-antigenic) polypeptide that performs its usual function when administered (e.g. an antibody, an anti-viral molecule), versus encoding an antigenic polypeptide that must elicit a functional, antigen-specific immune response.[279] The applicant submits that an antigenic polypeptide is intended to elicit an antigen-specific immune response, whereas a non-antigenic polypeptide is specifically intended not to elicit an immune response.[280]

1. To support the applicant's assertion, Prof. Zhang states:

"Antigenic polypeptides perform a very different role to non-antigenic polypeptides. For example, in order to be successful, antigenic polypeptides must be formulated in such a way that a functional immune response is elicited. This requires a very nuanced approach in formulation, as a functional immune response requires a certain level of translation from mRNA to antigen, and suitable recruitment of host immune cells. In contrast, a non-antigenic polypeptide is not subject to such constraints. The suggestion that simply replacing non-antigenic mRNA with antigenic mRNA would result in an effective vaccine underestimates the technical demands in successful formulation."[281]

"There is no data in D1 demonstrating that delivery of an antigenic polypeptide resulted in generation of a functional immune response, and so I cannot see how it would be obvious to do so. The experience of CureVac as discussed above shows it is not obvious as to how to develop a successful mRNA vaccine, and if it were so easy to do so, I would have thought there would be many more successful examples of such technology by now, but there are not."[282]

1. The applicant also argues that formulating a mRNA-LNP vaccine comprised of a mRNA polynucleotide encoding an antigenic polypeptide requires several challenges to be overcome, such as correct targeting of cells, and sufficient expression of an antigen so as to elicit a functional immune response.[283]

1. Having considered the evidence, I consider that in light of the problem of the need for mRNA vaccines encoding antigenic polypeptides, and in view of D1, a PSA would be directly led as a matter of course and with a reasonable expectation of success, to develop a mRNA LNP vaccine encoding an antigenic polypeptide. It is apparent that a PSA would be aware of a number of antigenic polypeptides used in the well-trodden art of protein vaccines. While Prof. Zhang notes that a functional immune response requires a certain level of translation from mRNA to antigen, as I have construed the word "vaccine" broadly as merely a composition that improves immunity, I consider that there would be the requisite expectation of success as the level of translation would be sufficient to produce an antigen specific immune response. This expectation of success does not require an immune response such as required for a commercially successful vaccine, such as what was being sought after with the CureVac vaccine. While I do accept Prof. Zhang's evidence that a nuanced formulation may be required to produce a commercially successful vaccine, I do not consider that the scope of the claims require that level of success.

1. The same can be said for Prof. Leaf Huang's comments in the EIR at [91] that:

"it is certain that the production of a new vaccine is a significant task. However, much of that relates to the production of mRNA encoding appropriately for a suitable antigenic polypeptide and balancing the innate immune response with achieving a suitable overall immune response."

1. Balancing the innate immune response with achieving a suitable overall immune response is not a feature of claim 1. That level of success is not mandated by claim 1. Therefore, I consider claim 1 lacks an inventive step in view of D1.

1. Dependent claims 2-59 define different components, ratios of components and modifications that could be used in the nucleic acid vaccine defined in claim 1. The opponent submits that claims 2-59 are directed to known routine components of compositions for inducing an immune response, with known routine proportions of those components, and/or known routine desiderata or properties.[284] The applicant failed to provide any submissions in defence of a novelty or inventive step attack on these claims. I agree with the opponent that these claims merely define routine features that would be part of the CGK. The ratios of lipid components, mRNAs encoding antigenic polypeptides and mRNA modifications defined in claims 2-59 are routine modifications that would be obvious to a PSA in view of the CGK.

1. Dependent claims 60-65 define methods of inducing an antigen specific immune response in a subject, comprising administering the vaccine of any one of claims 1-34 to the subject in an effective amount to produce an antigen specific immune response. I consider that claims 60-65 lack inventive step because in light of the problem and in view of D1, a PSA would be directly led as a matter of course to use the vaccine defined in claim 1 to induce an antigen specific immune response as that is the purpose of vaccination.

1. Dependent claim 66 defines a vaccine of any one of claims 1-34 suitable for use in a method of inducing an antigen specific immune response. Dependent claim 67 defines a Swiss style claim where the vaccine of any one of claims 1-34 is used in the manufacture of a medicament with the intention of using that vaccine to induce an antigen specific immune response. Given my findings above regarding claims 60-65, it follows that these claims also lack inventive step.

1. WO 2013/185069 A1 (designated D5) was published on 12 December 2013. Consequently it is part of the prior art base.

1. D5 is titled "Pulmonary Delivery of mRNA to Non-Lung Target Cells". D5 discloses compositions comprising mRNA formulated for pulmonary administration and related methods for the delivery of mRNA.[285] D5 discloses that a suitable lipid carrier vehicle includes a lipid nanoparticle.[286] In addition D5 discloses an IT spray experiment in mice with firefly luciferase (FFL) mRNA lipid nanoparticle formulation of HGT5001:DOPE:Cholesterol:DMG-PEG2K at a molar ratio of 40:20:35:5.[287]

1. The applicant submits that Table 1 of D5 discloses an extremely long list (spanning 49 pages) of polypeptides encoded by a mRNA, but not one of these polypeptides is an antigenic polypeptide.[288] The same can be said of Table 2 and Table 3.[289]

"A range of mRNAs are discussed in D5, as is the case in the Opposed Application, and they include proteins that would be designed to produce an immune response such as those in table 4 including infectious diseases."[290]

1. Table 4 discloses mRNAs encoding therapeutic proteins and, along with other components, their use in treating 376 diseases or disorders (i.e. indications).[291] Included in the long list of diseases is "infectious disease vaccines" with "infectious antigen" being listed as a therapeutic protein.[292] The only other disclosure of vaccination in D5 is at [0009] which discloses "[c]linical trials involving vaccination against tumor antigens by intradermal injection of naked or protamine-complexed mRNA have demonstrated feasibility, lack of toxicity and promising results." The applicant submits that while there are references in D5 to "therapeutic applications", treatment of "infectious diseases", an mRNA encoding an antibody, and "conferring immunity to a subject", none of these references equates to disclosure of a mRNA-LNP vaccine encoding for an antigenic polypeptide.[293]

1. Paragraphs [0096] and [0100] of D5 disclose mRNA encoding an antibody. The applicant submits that an "antibody" is not an antigenic polypeptide for the following reason.[294] The way in which immunity is conferred in this manner is through activity of the encoded antibody once it is expressed in a host which is entirely different to the way an antigenic polypeptide, once expressed in a host, acts to stimulate an adaptive, antigen-specific immune response in a host.[295] The former is used as a treatment, whereas the latter is used for prevention.[296] The applicant further submits that the only examples in D5, Examples 1 and 2, involve an mRNA encoding a luciferase which is a bioluminescent reporter system, a surrogate for a therapeutic protein to which an immune response was not desired.[297]

1. D5 fails to disclose a mRNA LNP vaccine having an open reading frame encoding an "antigenic polypeptide". The opponent submits that the difference of the nature of the peptide for which the mRNA encodes is considered an obvious alternative in light of the CGK.[298] The applicant disagrees submitting that D5 is focussed on delivering RNA-mediated therapies that do not aim to elicit an immune response and hence do not involve delivering a vaccine.[299] The applicant further notes that D5 relates exclusively to pulmonary delivery which involves use of an inhaler for adsorption into the bloodstream via the lungs using lyophilised or dry powder formulations, which is distinct from attempting to elicit a functional immune response.[300]

1. For the same reasons given for D1 above, I consider that in light of the problem of the need for mRNA vaccines encoding antigenic polypeptides, and in view of D5's disclosure of mRNA LNP formulations, a PSA would be directly led as a matter of course and with a reasonable expectation of success, to develop a mRNA LNP vaccine encoding an antigenic polypeptide.

1. Therefore, I consider claim 1 lacks an inventive step in view of D5. Claims 2-67 also lack inventive step in view of D5 for the same reasons given above for D1.

1. Geall (designated D6) and Hekele (designated D7) were published in 2012 and 2013 respectively. Consequently these documents are part of the prior art base.

1. D6 teaches the delivery of saRNA specifically for vaccine purposes using DLinDMA:DPSC:cholesterol:PEG-DMG 2000 LNP formulation at molar ratios of 40:10:48:2.[301] D6 discloses the formulation and delivery of the RSV-F glycoprotein gene as an example viral antigen and demonstrates a protective immune response in mice.[302]

1. D7 disclosed an identical formulation to D6 with the key difference being the delivery of saRNA for the production of an influenza H1 HA antigen from the H1N1 virus.[303]

1. The opponent submits that D6 and D7 indicate that the LNP delivery approach is applicable to both siRNA, which is significantly smaller than mRNA, and to saRNA, which is significantly larger, and shows that appropriate LNP escape and expression is possible to provide for a protective immune response to vaccinate for infectious disease.[304]

"Recently, there has been an exponential growth in the development of clinically suitable nonviral delivery systems for siRNA (19, 20); we have taken advantage of these innovations".[305]

1. The opponent submits here that the authors are clearly stating that they believed, and proved, that siRNA-LNP delivery technology could be employed for considerably larger saRNA to achieve a protective immune response to a viral antigen.[306] This was confirmed by Prof. Leaf Huang's comments regarding the clearly expressed views of Deering on which Andrew Geall is an author.[307]

"The same approach was considered appropriate for conventional mRNA which, while undoubtedly different to both siRNA and saRNA as a molecular entity, is intermediate in size between both of those forms of RNA".[308]

1. The applicant submits that insofar as D6 describes "mRNA-based vaccines", this is done using self-amplifying RNA.[309] D6 also teaches away from RNA vaccines that are not self-replicating:

"... for infant RSV vaccine development, safety considerations favour replicating (or self-amplifying) vaccine candidates over subunit approaches."[310]

1. The applicant submits that a PSA would not have been directly led as a matter of course and with a reasonable expectation of success to try and develop an mRNA-LNP vaccine in light of D6 because it was understood from both D6 and the CGK that self-amplifying RNA technology was critical for achieving the requisite antigen production and immunogenicity in vivo. Based on the CGK, it was believed that mRNA could not match the high levels of expression or induce the same immune response as saRNA and hence combinations of mRNA with adjuvanating protamine were being explored, not mRNA with LNPs.[311]

1. The applicant submits that D7 summarises the benefits of using self-amplifying RNA vaccines, which were found to avoid some of the pitfalls identified in D7, with the authors concluding that self-amplifying mRNA vaccines were immunogenic in mice and that the platform may be feasible for numerous pathogens.[312] The applicant submits that there is no teaching in D7 that mRNA should be formulated in LNPs in order to generate an immune response, or that mRNA delivered in LNPs would be an effective vaccine.[313]

1. I have already considered earlier in this decision that mRNA and saRNA are different (at paragraph [53]). Therefore D6 and D7 fail to disclose a mRNA LNP vaccine having an open reading frame encoding an antigenic polypeptide. The relevant question here is: In light of the problem of a need for mRNA vaccines encoding antigenic polypeptides, would the PSA be directly led as a matter of course (and with a reasonable expectation of success) to substitute the saRNA LNP vaccine disclosed in either of D6 or D7, with mRNA? I consider the answer to this question is no as D6 explicitly teaches away from RNA vaccines that are not self-replicating and notwithstanding this explicit instruction, as discussed previously, the CGK taught away from mRNA LNP vaccines but rather taught towards using either saRNA or mRNA and protamine.

1. Therefore, I consider claim 1 provides an inventive step in view of either of D6 or D7. As claims 2-67 are dependent on claim 1, it follows that these claims are also considered inventive in view of either of D6 or D7.

1. WO 2011/140627 A1 (designated D9) was published on 17 November 2011. Consequently it is part of the prior art base.

1. D9 is titled: "Nucleic Acid-Containing Lipid Particles and Related Methods". D9 discloses a method for preparing nucleic acid-lipid nanoparticles comprising the cationic lipid DLinKC2-DMA using a microfluidic mixing device.[314] D9 teaches encapsulating siRNA with an LNP formulation including DLin-KC2-DMA, DSPC, cholesterol, and PEG-c-DMA in a 40:11.5:47.5:1 ratio.[315]

1. The opponent submits that D9 further reinforces the knowledge that siRNA-LNP delivery approaches were considered to be applicable to mRNA delivery given that it refers to mRNA delivery on page 34.[316]

1. The applicant submits that D9 is clearly focussed on delivery of siRNA to reduce protein expression, not mRNA to express an antigenic polypeptide.[317] The applicant supports this submission by quoting the single reference to mRNA at page 34 of D9 in the context of the page as a whole:

"Typical applications include using well known procedures to provide intracellular delivery of siRNA to knock down or silence specific cellular targets. Alternatively applications include delivery of DNA or mRNA sequences that code for therapeutically useful polypeptides. In this manner, therapy is provided for genetic diseases by supplying deficient or absent gene products.

In related embodiments, the present invention provides a method of treating a disease or disorder characterized by overexpression of a polypeptide in a subject, comprising providing to the subject a pharmaceutical composition of the present invention, wherein the therapeutic agent is selected from an siRNA, a microRNA, an antisense oligonucleotide, and a plasmid capable of expressing an siRNA, a microRNA, or an antisense oligonucleotide, and wherein the siRNA, microRNA, or antisense RNA comprises a polynucleotide that specifically binds to a polynucleotide that encodes the polypeptide, or a complement thereof."

1. The applicant submits that when this passage is read in context, D9 does not call out mRNA specifically, but equally suggests using DNA.[318] D9 also teaches encoding therapeutic (i.e. non-antigenic) polypeptides for protein replacement therapy, not antigenic polypeptides to elicit an immune response as a vaccine.[319] Furthermore the related embodiments taught in the passage above teach the use of other types of RNA, namely siRNA, a microRNA and an antisense oligonucleotide, but do not teach the use of mRNA.[320]

1. D9 fails to disclose a mRNA LNP vaccine having an open reading frame encoding an antigenic polypeptide. I consider that a PSA would not be directly led as a matter of course (and with a reasonable expectation of success) to substitute the siRNA LNP disclosed in D9, with a mRNA LNP vaccine encoding an antigenic polypeptide. I have already discussed at length above in relation to the CGK, why a PSA would not adapt the siRNA LNPs known in the art to a mRNA vaccine. The same reasoning above applies here.

1. I consider claim 1 provides an inventive step in view of D9. As claims 2-67 are dependent on claim 1, it follows that these claims are also considered inventive in view of D9.

1. US 8,691,966 B2 (designated D13) was published on 8 April 2014. Consequently it is part of the prior art base.

1. D13 discloses the use and potential benefits of modified polynucleotides.[321] D13 is focussed on the use of modified mRNA with a pseudouridine residue as a means to reduce immunogenicity of RNA.[322]

1. The opponent submits that a PSA trying to produce a mRNA vaccine would have immediately considered the use of mmRNA to improve the transcription efficiency and control innate immunogenicity.[323] The applicant submits that the mRNA in D13 is non-antigenic and that the aim in D13 is to reduce immunogenicity of RNA in the context of providing for expression of therapeutic proteins, whereas the aim of the opposed application is to elicit a functional, antigen-specific immune response.[324]

1. D13 fails to disclose an LNP mRNA vaccine having an open reading frame encoding an antigenic polypeptide. For similar reasons as those given above, I do not think a PSA, in light of the problem and in view of D13, would be directly led as a matter of course (and with a reasonable expectation of success) to produce the nucleic acid vaccine as defined in claim 1 of the opposed application.

1. I further consider that any possible combination of D13 with any other prior art document will not rectify any deficiencies of such documents with regard to inventive step.

1. I consider claim 1 provides an inventive step in view of D13. As claims 2-67 are dependent on claim 1, it follows that these claims are also considered inventive in view of D13.

1. Paragraph 40(2)(a) as amended by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth) (the Raising the Bar Act) requires that the claimed invention be described in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art.

1. It is clear that this provision requires that the PSA must be able to perform the invention across the scope of the claim without undue burden or inventive skill.[325] In Evolva SA[326] (Evolva), the Deputy Commissioner considered paragraph 40(2)(a), and having drawn guidance from European and UK decisions, adopted the following approach to assessing a clear and complete enough disclosure:

What does the specification disclose to the skilled person?

Does the specification provide an enabling disclosure of all the things that fall within the scope of the claims, and in particular:

Is it plausible that the invention can be worked across the full scope of the claim?

Can the invention be performed across the full scope of the claim without undue burden?

1. This approach has subsequently been adopted by delegates of the Commissioner,[327] and the approach of the Deputy Commissioner was affirmed by the Federal Court in Cytec Industries Inc. v Nalco Company [2021] FCA 970. I will adopt the Deputy Commissioner's approach to considering this ground.

1. More recently, the Full Federal Court considered issues of support and sufficiency on appeal in Jusand Nominees Pty Ltd v Rattlejack Innovations Pty Ltd [2023] FCAFC 178. With regard to the use of ranges in a claimed invention, the Full Court noted that:

"A good place to start is with the invention as it is claimed but the inquiry can

extend into the invention's essence or core. An assessment of that essence or

core is likely to include a consideration of the patent's technical contribution to

the art and may involve an assessment of what it is that makes the invention

What is the scope of the invention as claimed?

1. The claimed invention defines a nucleic acid vaccine (or a composition that improves immunity) comprising one or more mRNA polynucleotides having an open reading frame encoding a polypeptide that is capable of stimulating an antigen specific immune response, formulated in a cationic lipid nanoparticle having a molar ratio of about 20-60% cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol: and about 0.5-15% PEG-modified lipid.

What does the specification disclose to the skilled person?

1. I consider that the specification broadly discloses mRNA vaccine compositions. The specification discloses the formulation of modified mRNA using lipidoids The specification further discloses mRNA LNP vaccines having a molar ratio of 50% cationic lipid (DLin-KC2-DMA or DLin-MC3-DMA), 10% non-cationic lipid (DSPC), 38.5% sterol (Cholesterol) and 1.5% PEG-modified lipid (PEG-DOMG), and the use of those vaccines to express antigenic polypeptides (influenza haemaglutinin antigen and MRSA). I note here that that none of the LNP examples disclosed varied the composition of the LNP other than varying the cationic lipid between KC2 and MC3. While the specification discloses a number of examples analysing the immunogenicity of mRNA vaccines encoding a variety of antigenic polypeptides (See Example 17-21), none of these examples disclosed the use of a LNP.

1. The first limb of the test outlined in Evolva asks: Is it plausible that the invention can be worked across the full scope of the claim?

1. With regard to the threshold of plausibility, I note the comments made by Lord Sumption (with whom Lords Reed and Briggs agreed) in Warner-Lambert Company LLC v Generics (UK) Limited (t/a Mylan) and ors[328] who stated:

"The principle is that the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true."

1. In Gary B Cox v MacroGenics, Inc. [2019] APO 13, the Delegate considered the U.K cases on plausibility as well as Evolva and considered that the consideration of plausibility is:

"one of technical credibility or believability. Plausibility may be a low threshold, but it is a threshold nonetheless, and is not satisfied by mere speculation or assertion."[329]

1. The opponent argues that it is simply not technically credible that all combinations of all four broadly defined lipid classes, within the recited ranges, could provide for an efficacious vaccine.[330] They argue that all that has been provided by the applicant's experts is speculation and assertion in their comments indicating their belief that the two formulation data points provided in the opposed application represent a 'platform technology'.[331]

1. Prof. Leaf Huang in the EIS, describes in detail why at least not all non-cationic and PEG-modified lipids, and the claimed ranges thereof, could be expected to result in a successful mRNA LNP vaccine. These factors include resulting variations in stability, particle size, charge etc.[332] Prof. Huang's evidence doubts whether successful encapsulation of mRNA could occur across the full scope of the claims stating:

"I believe it would not have been possible to formulate an LNP which can successfully encapsulate and deliver mRNA for vaccine purposes which has, for example, 60 molar % cationic lipid and/or 15 molar % PEG-modified lipid."[333]

1. The applicant responds submitting that the exemplified ranges of LNP components are shown in the opponent's own prior art to go beyond what the opponent's own EIS asserts is plausible.[334] The EIA points out that D11[335] teaches an amount of cationic lipid, D10[336] teaches an amount of non-cationic lipid, D6, D7 and D9 all teach an amount of sterol, and D8[337] and D10 teach an amount of PEG-lipid that is outside the ranges asserted in the EIS to be reasonable or plausible.[338]

1. On the question of plausibility, the opponent notes that the applicant has previously formed a view that such claims could not be plausible based on the evidence presented in D14[339] by their U.S. expert, Dr. Andrew S, Janoff, in a challenge by Moderna Therapeutics Inc. against a Provita Biotherapeutics, Inc U.S. patent.[340] The opponent contends that Dr. Janoff, on behalf of the applicant, submitted evidence regarding the chemical structure of the cationic lipid having a major impact on transfection efficiency.[341] Prof. Leaf Huang agreed with this statement:

"as the charge, linker and tail structure can have a major impact on the ability of the cationic lipid to adopt the necessary conformation to trigger endosomal escape which is an essential step for transcription."[342]

1. Prof. Zhang states in relation to the opponent's submissions that D14 is evidence of the opposed claims being overly broad:

"There is nothing in D14 that makes me think the % molar ratios of lipid components shown in the claims of the opposed application are unjustified or that they could not be achieved as part of a successful mRNA-LNP vaccine formulation. D14 is focused on an analysis of lipid components and formulations in relation to siRNA as of 2008, which was not considered relevant to mRNA vaccine formulation."[343]

1. While Prof. Leaf Huang provides evidence doubting whether successful encapsulation of mRNA could occur across the full scope of the claims, a mere "doubt" is not sufficient to establish a lack of plausibility.

"Certainly at levels of 10 molar % and above [for the molar ratio of the PEG-lipid in the LNP] I doubt [emphasis added] that the LNP could be functional in vivo".[344]

1. However, D6 and D7 both teach a protective immune response in mice by using a saRNA LNP with a 10% molar ratio of the PEG-lipid. These documents provide evidence of where an immune response was achieved with an LNP vaccine with components outside the concentration range Prof. Leaf Huang said would be functional.

1. Furthermore, while the chemical structure of the cationic lipid may have an impact on transfection efficiency, to my mind this potential shortcoming is insufficient evidence to meet the threshold that the LNP mRNA vaccine over the scope of claim 1 would not be "technically credible" or "believable" in its ability to produce an immune response. Therefore, I consider that it is at least plausible that the invention can be worked across the full scope of claim 1.

1. The second limb of the test outlined in Evolva asks: Can the invention be performed across the full scope of the claim without undue burden?

1. The concept of an undue burden was discussed in Evolva. Having considered UK and European authorities the Deputy Commissioner concluded:

"My understanding of these authorities is that the emphasis in relation to undue burden has been on the nature of the work that is required by the skilled person in view of the guidance in the specification. To this end, one approach has been to ask whether the skilled person would be required to undertake a 'research programme' in order to perform the invention."[345]

1. The consideration of what constitutes an undue burden is necessarily dependent upon the nature of the technology, and factors relevant to the consideration include the level of predictability in the art and the level of guidance in the specification.[346]

1. The opponent argued that the development of nucleic acid vaccines with significantly different formulation ratios of lipids or employing different cationic or non-cationic lipids (for example) would require an extensive program to develop in addition to the use of different mRNA to ascertain whether or not an efficacious vaccine providing for a protective immune response [emphasis added] was ultimately delivered.[347]

1. Prof. Leaf Huang elaborated on the amount of work needed to formulate the LNPs defined in opposed claim 1:

"While I might avoid some extremes in the molar ratios to give a better chance of success, that does not assist with the significant uncertainty that comes from the use of the broad lipid terms. Focussing on the cationic lipid alone, it would be a huge amount of work to synthesize/obtain all cationic lipids in the LNP formulation, even assuming you kept the other 3 components the same in nature and relative amount, and formulate them with mRNA and then run efficacy tests which, again, would at least involve some sort of mammalian challenge experiments to assess survival rates and form a view on the protective effect [emphasis added] of that vaccine formulation."[348]

1. The applicant submits that once the present invention determined that LNPs previously used with siRNA could be used for mRNA vaccines, the previous validation of the same LNPs in siRNA vastly reduced any experimental burden, well below that which could reasonably be considered "undue".[349] This argument was well summarised by Prof. Zhang:

"Prof Huang has asserted throughout his declaration that the knowledge existing at the relevant time in relation to siRNA is applicable to mRNA vaccines. While I disagree that this was known as of 23 April 2014, once it then did become known from the studies in the opposed application, that knowledge substantially contributed to the ease with which mRNA vaccines according to claim 1 of the opposed application can be formulated. I do not believe that formulating the mRNA vaccines across the ranges shown in claim 1 of the opposed application would be overly difficult, once the knowledge flowing from the studies in the opposed application was known. The discovery in the opposed application that formulations previously used for siRNA could work with mRNA substantially reduced the "scientific burden" in then formulating mRNA vaccines."[350]

1. The opponent disagrees submitting that there is no principle of general application, rather, the opposed application only demonstrates that a specific LNP formulation already demonstrated to be successful in siRNA delivery and delivery of mRNA encoding for therapeutic and other proteins could be used for delivery of certain modified mRNA encoding an antigen.

1. The Delegate in CSR Building Products Ltd v United States Gypsum Company [2015] APO 72 (CSR) at paragraph [97] quotes Kitchin J in Eli Lilly at [243]:

"Even though a reasonable amount of trial and error is permissible, when it comes to sufficiency of disclosure, for example in an unexplored field or where there are many technical difficulties, the skilled person has to have at his disposal, either in the specification or on the basis of his common general knowledge, adequate information leading necessarily and directly towards success through the evaluation of failures."

1. The opponent argues that the specification "... does not provide clear guidance telling the person skilled in the art how to adjust the process and materials so as to achieve with certitude the full combination of properties."[351] The opposed application does not teach how to select within the broad parameters and vast combinations encompassed by claim 1 to obtain in every instance a vaccine which provides for a protective immune response to the relevant disease as it would involve more than mere trial and error in light of the number of alternative components of the LNP and ratios of those components.

1. The opponent submits that the opposed application provides an invitation to further extensive research rather than any roadmap to success, which amounts to a research program rather than mere trial and error. Therefore, this is an undue burden on the skilled person.

1. The opponent's attack for lack of clear and complete enough disclosure is multifaceted. The first attack is that there is not clear and complete enough disclosure for a mRNA LNP vaccine encoding any antigenic peptide. The second attack relates to the scope of the four LNP components and the undue burden placed on the PSA to work the invention. The third attack is more targeted and relates to the potential toxicity of a particular cationic lipid component. I will outline the respective arguments in turn.

1. Prof. Leaf Huang notes the apparent discrepancy between the breadth of the claims and the disclosure in the specification in relation to the mRNA encoding an antigenic polypeptide:

"the mRNA polynucleotide can be one that encodes for literally any [emphasis added] antigenic peptide, even though only influenza and MRSA are demonstrated in the Examples as pathogens against which an LNP vaccine is trialled and the MRSA formulation did not appear to work".[352]

"the Examples of the Opposed Application demonstrate experiments to develop an LNP vaccine formulation against influenza and MRSA and no benefit whatsoever was observed against MRSA. I don't see how these results justify claim 1 covering the delivery of any [emphasis added] mRNA polynucleotide which encodes for an antigen when one of two Examples didn't work."[353]

1. The applicant responds to this criticism submitting that the opposed application discusses a range of different antigenic polypeptides and associated pathogens including H1N1 haemaglutinin, Dengue, Tuberculosis, H10N8 haemaglutinin, and H7N10 haemaglutinin, and that expression of different antigens is shown across a number of different models, including mice, monkeys and ferrets.[354] The applicant further notes that Prof. Leaf Huang states that D5 "teaches a wide range of mRNA encoding for a similarly wide range of proteins can be delivered for therapy"[355] despite the fact that the opposed application shows mRNA-LNP mediated polypeptide expression of a larger range of different antigens.[356]

1. The applicant's experts suggest that the invention is a platform technology, however only two LNP formulations are disclosed with variations only in the substitution of one cationic lipid for another closely related one.[357] Example 16 demonstrated no survival benefit whatsoever for the vaccinated mice versus the vehicle-vaccinated group which casts doubt on the efficacy of the exemplified vaccine against this antigen.[358] Example 15 is essentially the only example in which an LNP is defined, and which is shown to result in some improvements in titres but only versus an in vitro transfection vehicle.[359] The opponent argues that this is not the demonstration of a platform technology or a credible basis from which the claimed vaccine could be obtained across the entire scope of claim 1.[360]

1. In response to the accusation that not all antigenic polypeptides could plausibly work, the applicant argues that the assessment of Example 16 made by the opponent is speculative and directly contradicts the statements made in the opposed application regarding the difficulty in developing appropriate animal models to test vaccine efficacy.[361] The applicant argues the failure of the experiment in Example 16 cannot be attributed to a failure of the efficacy of the mRNA-LNP vaccine, but rather, the MRSA mouse model that was developed was too severe. Dr. Cobaugh states:

"[t]he fact that this data was included in the opposed application indicates to me a good level of transparency, and I see no reason to doubt the reasoning provided. Development of bacterial models is much more difficult than viral models."[362]

"I do not believe that the results seen in Example 16 call into question the merit of the mRNA vaccines shown in the opposed application, but reflect the difficulty in validating in different animal models."[363]

1. The applicant's own expert, Prof. Zhang, noted the difficulty CureVac had in successfully formulating mRNA in LNPs, achieving just 47% effectiveness at preventing Covid-19, seven years after the current priority date.[364] This highlights the difficulty in merely switching one mRNA encoding antigen for another and still trying to obtain an effective vaccine.

1. In relation to the apparent failure of the CureVac vaccine, Prof. Leaf Huang states:

"Again, my understanding is that Curevac used an LNP approach like that claimed in the Opposed Application and yet this knowledge and approach did not prevent failure in clinical trials due to the approach they took on their mRNA."[365]

1. I consider that the specification provides evidence of two LNP mRNA formulations (DLin-KC2-DMA or DLin-MC3-DMA) encoding a viral antigen (HA) that improves immunity. Example 16 was the only example in the specification which used a LNP mRNA formulation encoding a non-viral antigen (bacterial antigen MRSA) and the results from this example were inconclusive (no indication of improving immunity) due to the severe nature of the mouse model. Therefore, I consider that the specification fails to provide any evidence that the LNP mRNA vaccine works with any antigen other than a viral antigen.

1. The question here is: Would a PSA be able to work the invention as defined in claim 1 with any antigenic polypeptide without undue burden? Another way of putting it is: Does the success in improving immunity with a viral antigen represent a principle of general application that can be extrapolated to any antigenic polypeptide?

1. There is little evidence on this point. While the CureVac vaccine (which used a LNP mRNA approach encoding a Covid-19 antigenic polypeptide) was ultimately not successful at clinical trials, the efficacy of a vaccine required to pass clinical trials is set at a far higher bar than a vaccine merely needing to improve immunity (as I have construed opposed claim 1). The submissions of the opponent appear to discuss the amount of experimentation required to test for an "efficacious vaccine" or providing for a "protective immune response". Indeed, Prof. Leaf Huang referred to testing for a "protective effect". I have construed the word "vaccine" in claim 1 broadly as only implying that the composition needs to "improve immunity" in an antigen specific manner. This is a lower threshold for the PSA to test than producing an efficacious vaccine in practice.

1. On the evidence before me, I consider that the amount of experimentation required to test whether the LNP vaccine produces an immune response on different antigens, would not be undue. Although the field of mRNA LNP vaccines is relatively new, once sufficient expression of the antigen was demonstrated, a PSA would know how to test for an immune response using a variety of well-known tests and models. Furthermore, I consider that this testing is not an undue burden, as there is a principle of general application given the indication that one antigen is able to demonstrate an immune response in the defined LNP vaccine, there is no reason to think that other antigens will not be able to produce an immune response.

1. The opponent submits that given the vast number of combinations encompassed by the four lipid components, coupled with each being recited only as a generic class, the scale of the task to produce the vaccine defined in claim 1 would be enormous placing undue burden on the PSA.[366]

1. The applicant notes that in the EIS, Prof. Leaf Huang indicates the straightforward nature of preparing the relevant LNP components:

"[t]hese four LNP lipid components could be formulated in differing relative amounts but within generally understood limits."[367]

"[t]he materials for LNP formation were either readily available or were easily synthesised and so it was relatively straightforward to prepare and characterise LNPs".[368]

"I was asked about typical methods to actually formulate LNPs encapsulating a nucleic acid immediately prior to 23 April 2014. In my opinion this was a straightforward matter well before that date, at least on a laboratory scale, and at that time a skilled graduate student could perform the encapsulation and formulation tasks. The formulations, in terms of molar ratios, and a number of individual lipids within each lipid class which had been shown to form LNPs were described in the literature and generally fell within well-defined ranges."[369]

"it was not particularly problematic to make and test such LNPs for encapsulation efficiency, morphology etc. immediately prior to 23 April 2014."[370]

1. However, Prof. Leaf Huang further states that while the physical bringing together of the components is straightforward enough, the amounts of structural lipids within those ranges could be reduced so significantly that a stable particle with an appropriate outer layer supporting the PEG-lipid and encapsulating the cationic lipid/mRNA could not form.[371]

1. The applicant submits that the principle, as shown in the examples of the opposed application, can be used to generally apply the full ranges of LNP components recited in the opposed claims to the present invention.[372] The applicant cites Prof. Leaf Huang's comments in relation to the adaptation of LNP components developed for siRNA to mRNA vaccines:

"I believe formulations highly validated in siRNA and, to an extent, in saRNA delivery would have a very high expectation of working with mRNA delivery at the relevant date ..."[373]

1. This quote from Leaf Huang is however, taken out of context as he goes on to say:

"... but proof of a single [emphasis added] formulation delivering mRNA encoding an antigen cannot remove scientific concerns around all other aspects of the formulation with very different lipid structures".[374]

1. Prof. Huang in the EIR concludes on this point:

"I also disagree that with this same knowledge around the narrowly validated siRNA-LNP formulations it could then be reasonably expected that variations across broad mol% ranges of each lipid type as well as changes of the actual lipids themselves within any of the broad "cationic", "non-cationic", "sterol" and "PEG-modified lipid" terms, would all be successful in both formulation and delivery steps."[375]

1. When discussing the opposed application, Prof. Zhang takes the contrary view:

"I believe that the molecular ranges for the LNP components shown in the claims of the opposed application are reasonable and justified, and encompass ranges that may be expected to provide a successful mRNA vaccine delivery system."

"In answer to Paragraph 131 of the Huang declaration, I disagree with the suggestion that the molar ratio ranges of LNP components that are taught in the opposed application are overly broad. Again, the lack of consensus in the "common general knowledge" at the relevant time as to how to successfully formulate nucleic acids in lipid delivery systems meant that different formulations for different applications were reasonable to pursue. I reiterate my assessment as set out above in relation to Paragraph 115 of the Huang declaration, and I believe that the molar ranges for the LNP components shown in the opposed application are reasonable and justified."

1. Both Zhang and Cobaugh appear to indicate that formulation of the mRNA vaccines across the ranges shown in claim 1 would not amount to undue burden:

"I disagree with the suggestion that formulating mRNA vaccines across the ranges shown in claim 1 of the opposed application would require "very intensive and expensive work", "a very large undertaking", or "a large team and a lot of resources over an extended period of time."[376]

"I do not agree that claim 1 is overly broad when compared to the data shown in the opposed application."[377]

1. Prof. Leaf Huang contests Dr. Cobaugh's evidence:

"Dr Cobaugh expresses his view that he expects the lipid component ranges of claim 1 would work and that they do not stand out as unusual or unachievable in light of the common general knowledge at the relevant date. This seems to contradict many of Dr Cobaugh's earlier statements on the common general knowledge or the knowledge imparted by some of the documents I have discussed. For example: ... "I disagree it was "common general knowledge" that the relative amounts of the four lipid classes for LNP delivery generally fell within fairly narrow ranges which were found in the literature" and "I do not believe that there was any particular expectation, or any particular upper or lower limits at the relevant time of 23 April 2014, because the ability to formulate mRNA into LNP delivery systems had not yet been characterised." Dr Cobaugh's views appear different in relation to expressing uncertainty for mRNA-LNP formulation in the common general knowledge and based upon the disclosure of documents disclosing siRNA and mRNA delivery within LNPs but a high degree of certainty that all formulations within claim 1 of the Opposed Application would have been expected to work at the relevant date."[378]

"At paragraph 151 Prof. Zhang says there was a high degree of unpredictability and lack of knowledge as to what nucleic acids paired with what delivery systems might work. I would have thought this view would also influence his thoughts on the broad lipid component ranges and generic class titles as creating uncertainty that they would all work with mRNA delivery."[379]

1. The opponent argues that the applicant's experts, when discussing the CGK and the prior art, attempt to create an air of uncertainty over the ability to successfully formulate a functional vaccine, even where the only difference between a vaccine of the prior art and the opposed application is the delivery of a mRNA encoding a therapeutic peptide rather than an antigenic peptide. However, when considering claim 1 of the opposed application, they consider such vaccine formulation to be a highly predictable field and are untroubled by their concerns in relation to inventive step.

1. The opponent asks: Why was there such alleged difficulty in the field at 2020 when Wadhwa was published some six years after the priority date of the opposed application if the opposed application provided for a technology platform?[380] Leaf Huang in his EIR thought if Prof. Zhang's view is correct that success should be straightforward for a PSA to formulate a vaccine as defined in claim 1, then why was there still difficulty in the field of mRNA vaccine formulation in 2020 as evidenced in Wadhwa?[381]

1. The opponent argues that Prof. Zhang has no explanation for these seemingly contrary views regarding the case of mRNA vaccine development based upon "knowledge flowing" from the limited studies in the opposed application and the deficit of success in the field in 2020 in obtaining such vaccine formulations.[382]

1. The applicant submits that the opponent's submissions that assert a "deficit of success in the field in 2020", has little to no bearing on the assessment of enablement as this could be due to any number of reasons that have nothing to do with enablement, such as financial or other commercial considerations, higher priorities, or other solutions perceived as more attractive (e.g. saRNA).[383] The applicant further argues that even if difficulties were faced by others in the field after the priority date, this does not mean that the opposed claims are not enabled.[384]

1. The applicant submits that the opponent's attempt to exert an inventive step/ enablement "squeeze", ignores the "step change" in the CGK as a result of the present invention, whereby knowledge on LNPs previously gained with siRNA was for the first time determined to be applicable to mRNA vaccines.[385] The applicant argues that the arguments made by Prof. Zhang are made in the context of the CGK prior to the present invention, i.e., the earliest priority date, when there was no appreciation that LNPs used with siRNA could also be used for mRNA.[386] The applicant argues that the opponent is conflating expert opinion of what was known as part of the CGK at the earliest priority date, with expert opinion of what the opposed specification plausibly discloses, and that these are different considerations and not inconsistent, especially given the "step change" in knowledge.[387]

1. Hassett discloses a mRNA LNP vaccine formulation comprising a molar ratio of 50:10:38.5:1.5 (cationic lipid:DSPC (being the non-cationic lipid):cholesterol:PEG lipid)[388] Hassett further discloses a H10N8 influenza hemagglutinin mRNA in which uracils were substituted with N1-methyl-pseudouridine (this being mRNA encoding for an 'antigenic polypeptide' within the scope of opposed claim 1) incorporated into the LNPs to allow for immunogenicity to be evaluated and was co-formulated with a firefly luciferase mRNA which allowed expression to be evaluated.[389] Furthermore, Hassett discloses that consistent with their previous publications, MC3 (cationic lipid)- formulated mRNA yielded robust titres and protein expression at a low dose (0.001 mg per kg) but in contrast, no detectable protein expression or immunogenicity was observed for DOTAP (cationic lipid)-containing LNPs.[390]

1. The opponent submits that the data and discussion in Hassett indicates there is a significant degree of uncertainty regarding what cationic lipids will produce an immune response.[391] Hassett states that:

"one strong determinant of immunogenicity was the lipid pKa, with a range of 6.6-6.9 being optimal for IM immunogenicity (Figure 2C)".[392]

1. The opponent submits that while the best performing lipids in Figure 2A are somewhat clustered within what presumably represents the optimal pKA range described, lipid L falls within this range and yet has no detectable immunogenicity.[393] Even general trends are not indicative of success.

1. With regard to DOTAP, Hassett et al. states that:

"we observed no detectable protein expression or immunogenicity for DOTAP-containing LNPs (Figure 2A)."[394]

"If MC3 is taken as a comparator ionizable lipid of Hassett et al. then this statement tells me the data obtained from administration of the DOTAP LNPs can be viewed as an example of data indicating no immune response at all."[395]

1. The applicant submits that non-ionisable cationic lipids such as DOTAP differ from ionisable cationic lipids because they have a higher pKa and are charged at physiological pH.[396]

"In respect of DOTAP (a non-ionizable cationic lipid), it should be noted that the experiments in Hassett were devised specifically for the identification of ionizable cationic lipids and therefore involved formulations optimised for those lipids (see page 8, right hand column, of Hassett). It is therefore unsurprising that the non-ionizable DOTAP formulation, deliberately included as a comparator, showed "no detectable protein expression or immunogenicity" per Figure 2A."[397]

1. The applicant submits that in view of this it is not possible to conclude that LNP formulations comprising DOTAP are not capable of working as a vaccine.[398] The skilled person wanting to prepare an LNP comprising DOTAP would appreciate that formulations with more suitable molar ratios for non-ionisable cationic lipids were available in the art (see the Zhang declaration, at paragraph [18]).[399] The results in Figure 2A for DOTAP were achieved using a formulation optimised for a different type of lipid, and are therefore not suitable for concluding that an LNP comprising DOTAP is not capable of working as a vaccine.[400]

1. The opponent further notes that of the five lead lipids selected for further testing in Hassett, lipid Q did not perform as well as the MC3 comparator despite very similar structures.[401] This further indicates a high degree of unpredictability. A similar variation in immunogenicity can be observed between lipid P and MC3 despite lipid P having a generally similar structure to lipid H (the ionisable lipid present in the applicant's Spikevax COVID-19 vaccine).[402]

"Even structurally similar ionizable lipids, when formulated into mRNA-LNPs, can result in quite large differences in immunogenic response and so it is necessary to run trials identifying the optimal formulation."[403]

1. The opponent submits that Hassett discloses that cationic lipids A, L, X, A', B', E', C, E, S and D' (as well as DOTAP from 30 cationic lipids tested) did not produce any detectable immunogenicity.[404] As put by Prof. Leaf Huang:

"these ionizable lipids, when formulated in the LNPs with mRNA encoding for an antigen, did not result in a functional immune response or indeed any immunogenic response that could be detected."[405]

1. The opponent submits that Hassett demonstrates that a number of mRNA-LNPs within the scope of the opposed claims do not provide for a functional immune response and there is significant unpredictability surrounding how the cationic lipids should be selected, meaning that the PSA would require a clear teaching as to how to avoid those embodiments which cannot be made to work.[406] The opponent concludes by submitting that the opposed specification only provides mRNA LNPs comprising two different but very closely structurally related cationic lipids (MC3 and KC2) and therefore there is nothing to lead the PSA directly towards success through the evaluation of initial failures.[407]

1. The applicant submits that even if there was evidence of some formulations performing better than others, this does not equate to an undue experimental burden, rather this is reflective of the standard practice of optimisation.[408]

1. Even the opponent's own expert, Prof. Leaf Huang, indicates the "straightforward nature" of encapsulating and formulating the relevant LNP components. However, the undue burden potentially comes from having to test which lipid components will result in an effective LNP in encapsulating the mRNA, rather than merely synthesising the LNPs once the correct ones are known.

1. Prof. Leaf Huang's evidence, which I consider representative of the PSA, provided an in-depth discussion surrounding the bounds of lipid delivery platforms that had proven successful in siRNA delivery.[409] Prof. Huang makes the following comments in his evidence regarding the state of the art at the earliest priority date of the opposed specification:

"In simple terms, the principle was well-known to immunologists that if you could deliver mRNA encoding for an antigen to, for example, dendritic cells and have that mRNA express the antigenic protein for presentation on the dendritic cell surface then you would have a chance of achieving an immune response. The challenge was largely in the delivery."[410]

"the general characteristics of the ionizable lipids were well-known immediately prior to 23 April 2024"[411]

"Many groups and companies are still running large research projects trying to develop ionizable cationic lipids for different applications due to the variability in results."[412]

"These four LNP lipid components could be formulated in differing relative amounts but within generally understood limits."[413]

1. Prof. Leaf Huang's evidence provides that although ionisable lipids were "well-known" before the earliest priority date, many groups and companies were trying to develop further ionisable lipids due to variability in results. With regard to the four LNP lipid components, Prof. Huang's evidence outlines generally understood limits for these components to formulate a successful LNP. This evidence suggests that it may be merely routine optimisation to test which components within the broad bounds of these ranges would formulate a successful LNP.

1. However, I consider that Hassett provides evidence of further ionisable cationic lipids which, according to Prof. Leaf Huang, do not provide an immune response (cationic lipids A, L, X, A', B', E', C, E, S and D'). Notwithstanding the fact that the non-ionisable cationic lipid DOTAP did not result in an immune response, I have evidence before me that ten out of thirty ionisable cationic lipids tested in Hassett did not provide an immune response. This evidence was not contested by the applicant's expert evidence. The applicant merely asserted that in Figure 2A of Hassett, the formulation was optimised for a different type of (ionisable) lipid. This submission does not explain the uncertainty surrounding the fact that several ionisable lipids, some with similar structures, did not result in an immune response. On the evidence before me, I do not consider that a PSA would have at their disposal, either from the specification or in the CGK, adequate information to lead to success through the evaluation of failures. Cationic lipids are a very large class of chemical compounds and if even the use of closely structurally related lipids does not result in an antigen specific immune response (as evidenced by Hassett), there is insufficient information for the PSA to predict which particular cationic lipids will be successful. In my opinion, the testing required amounts to a research program.

1. Therefore, I consider that it would amount to an undue burden on a PSA to test which cationic lipids would result in an LNP comprising mRNA encoding an antigenic polypeptide which results in an antigen specific immune response. Therefore claim 1 is not clearly and completely enough disclosed.

1. Claims 3-67 are dependent on claim 1 and fail to introduce any features that rectify this lack of clear enough and complete enough disclosure. Claim 2 is considered clearly and completely enough disclosed with respect to the ionisable cation lipids, as this claim is limited to DLin-KC2-DMA and DLin-MC3-DMA which are established in the specification to provide suitable LNPs.

1. Prof. Leaf Huang in his EIR, notes that DLinDMA is mentioned in D1 as being potentially toxic due to accumulation in tissues.[414] The opponent submits that this places an undue burden on a PSA seeking to work the invention to ascertain which cationic lipids may or may not accumulate in tissues or otherwise present potential toxicity challenges.[415]

1. In response, the applicant submits that the preamble of claim 1 which recites a "nucleic acid vaccine", would be understood by the skilled person as inherently excluding components that are toxic, and inherently requiring suitability for administration.[416] The applicant further argues that even if the opposed claims included embodiments involving toxic cationic lipid nanoparticles, this would not affect enablement as regardless of toxicity, such vaccines would still elicit an immune response. Formulations such as chemotherapeutic agents for example, which while carrying some level of toxicity, nevertheless contribute to treating cancers.[417]

1. I have found previously in this decision that the word "vaccine" implies that the mRNA LNP must result in an immune response. It is important to note here that D1 merely states that DLinDMA is potentially toxic as it accumulates in tissues. I consider that a PSA would exclude cationic lipids known in the art to be toxic and agree with the applicant that even if a cationic lipid is 'potentially' toxic, and may not pass clinical trials for example, such a lipid would still fall within the scope of claim 1 if it was able to produce an immune response.

1. As a result, on the question of potential toxicity alone, I consider that claim 1 is clearly and completely enough disclosed.

1. In summary, I consider claims 1 and 3-67 to lack clear and complete enough disclosure.

1. Section 40(3) as amended by the Raising the Bar Act requires that the claims must be supported by matter disclosed in the specification.

1. The requirement of support was discussed by Burley J in Merck Sharp & Dohme Corporation v Wyeth LLC[418]:

"In CSR Building Products Ltd v United States Gypsum Company [2015] APO 72, Dr S D Barker adopted the summary provided by Aldous J in Schering Biotech at 252 - 253, which has been often followed in the United Kingdom (emphasis added):

...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.

That approach encapsulates broadly the claim support obligation under s 40(3). To it may be added the requirement that the technical contribution to the art must be ascertained. Where it is a product, it is that which must be supported in the sense that the technical contribution to the art disclosed by the specification must justify the breath of the monopoly claimed".

1. To determine whether the requirements of support are satisfied the following steps were set out in CSR:[419]

(i) construe the claims to determine the scope of the invention as claimed,

(ii) construe the description to determine the technical contribution to the art, and

(iii) decide whether the claims are supported by the technical contribution to the art.

1. The Federal Court has approved of this approach.[420]

1. The opponent submits that the description does not provide a base which could fairly entitle the patentee to a monopoly of the breadth claimed.[421] The opponent submits that this case is analogous to CSR insofar as claim 1 is limited to a product which must show the espoused properties (i.e. the vaccine must be efficacious and result in a protective immune response) and yet the evidence shows this cannot be achieved with all lipid combinations claimed.[422]

1. The opponent argues that the applicant's technical contribution to the art is a 50:10:1.5:38.5 molar ratio formulation of cationic lipid:DSPC:PEG-DOMG:cholesterol, with the cationic lipid being either DLin-KC2-DMA or DLin-MC3-DMA and delivery of mRNA encoding an antigen.[423] The art has only been advanced, if at all, to the extent that a small number of lipid combinations in tightly defined molar ratios will at least deliver certain mRNA encoding an antigen.[424] The opponent notes further that the same formulation had already been exemplified in D1 for the encapsulation and delivery of modified mRNA.[425] They argue that if indeed the applicant's technical contribution to the art is in demonstrating that an identical LNP formulation known to be successful in delivering siRNA and mRNA encoding for therapeutic proteins could be used to deliver mRNA encoding an antigen then the scope of the claims should be limited to such formulation or at least be commensurate in scope with them.[426]

1. The applicant submits that prior to the present invention, it was not considered that LNP formulations developed in relation to siRNA would be applicable to mRNA vaccines.[427] Exemplification of the LNPs shown in the opposed application therefore opened up the ability to transfer the substantial body of knowledge gained with siRNA over a significant period of time to the formulation of mRNA vaccines.[428] As Prof. Zhang stated:

"Once the studies in the opposed application surprisingly demonstrated that LNP formulations previously used for siRNA could also be used to successfully deliver mRNA, the knowledge base shifted accordingly, and the benefit of knowledge previously acquired in relation to siRNA could then be used to assist in formulating mRNA vaccines."[429]

1. Therefore, the applicant submits that it follows that there is nothing in the opposed specification to suggest that the claims encompass matter that owes nothing to the teachings or principles disclosed.[430]

1. I consider the applicant's technical contribution to the art is demonstrating that LNP formulations developed in relation to siRNA, with the cationic lipid being either DLin-KC2-DMA or DLin-MC3-DMA, would be applicable to mRNA vaccines. While I agree that the opposed specification merely exemplifies a 50:10:1.5:38.5 molar ratio formulation of cationic lipid:DSPC:PEG-DOMG:cholesterol, with the cationic lipid being either DLin-KC2-DMA or DLin-MC3-DMA and delivery of mRNA encoding an antigen, I do not consider that the applicant's technical contribution to the art with regard to the components other than the cationic lipid and the molar ratios, is so narrowly limited. Once the knowledge was gained that formulations developed in relation to siRNA would be applicable to mRNA vaccines, this moved the art forward and a PSA would be able to optimise the components (other than the cationic lipid for the reasons given under clear and complete enough disclosure) and the molar ratios of those components in the LNP using previously established limitations in the art. I further note that there is evidence of mRNA LNP vaccines that provide immunity with non-cationic lipids, sterols and PEG-lipids outside the ranges that Prof. Leaf Huang considered would be required to successfully encapsulate mRNA and produce an immune response.[431] Therefore I consider that there is not enough evidence to conclude that the applicant's technical contribution to the art should be limited to the particular ranges that Prof. Huang says are required for successful encapsulation.

1. As a result, I consider that claim 1 lacks support as the scope of the cationic lipid component extends beyond the applicant's technical contribution to the art. Claims 3-67 are dependent on claim 1 and fail to introduce any features that rectify this lack of support. Claim 2 is considered to be supported with respect to the cationic lipid, as this claim is limited to DLin-KC2-DMA and DLin-MC3-DMA which are established in the specification to provide suitable LNPs that provide an immune response.

1. Section 18(1)(c) of the Patents Act requires that for an invention to be patentable it must be useful. This requirement was expressed in the following manner at [141] of Ranbaxy Australia Pty Ltd (CAN 110 781 826) v Warner-Lambert Company LLC [2008] FCAFC 82:

"Under ss 138 and 18(1)(c) of the 1990 Act, it is a ground of invalidity if the claimed invention is not useful "so far as claimed in any claim". If the claimed invention does what it is intended by the patentee to do and the end obtained is itself useful, the invention is useful within the meaning of s 18(1)(c) (see Rehm Pty Limited v Webster's Security Systems (International) Pty Limited (1981) 81 ALR 79 at 96; Welcome Real-Time SA v Catuity Inc [2001] FCA 445; (2001) 113 FCR 110 at 144; and Fawcett v Homan (1896) 13 RPC 398 at 405). As to the first aspect, the invention as claimed must attain the result promised by the patentee (Advanced Building Systems Pty Limited v Ramset Fasteners (Aust) Pty Limited [1998] HCA 19; (1998) 194 CLR 171 at 187)."

1. The principles of utility were summarised by the Full Court of the Federal Court in Artcraft Urban Group Pty Ltd v Streetworx Pty Ltd [2016] FCAFC 29 at [120]- [121] (with references omitted):

"The 'basic principle' of inutility is that if an invention 'does what it is intended by the patentee to do, and the end attained is itself useful, the invention is a useful invention'. What the invention is 'intended' to do is a matter to be gathered from 'title and the whole of the specification'.

Put another way, the two questions are: first, what is the promise of the invention derived from the whole of the specification?; second, by following the teaching of the specification, does the invention, as claimed in the patent, attain the result promised for it by the patentee? Further, 'everything' that is within the scope of a claim must be useful, that is, attain the result promised for the invention by the patentee."

1. As noted by Jagot J in Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162 at [352], lack of utility requires evidence, not just speculation:

"Ultimately, an asserted lack of utility must be established by appropriate evidence, not by mere speculation that the invention will not work or meet the promise set out in the specification."

1. The opponent submits that since the CureVac vaccine used a "...practically indistinguishable..." LNP approach, as stated in the Nature article referenced by Prof. Zhang it is clear that at least claim 1 of the opposed application encompasses nucleic acid vaccines which are not useful.[432] Prof. Zhang commented on CureVac's failure in developing a COVID-19 mRNA vaccine and put this forward as "...an indication of the significant difficulty in successfully formulating mRNA in LNPs...".[433] The applicant responds by submitting that the fact that difficulties may have been faced by others in the field does not mean that the present claims are not useful as failure by one (e.g. CureVac) does not mean it is not possible to produce a vaccine, as the applicant has done.[434]

1. The opponent further refers to the comments of inventor Dr Giuseppe Ciaramella, as clearly evidencing that an mRNA vaccine employing DLin-MC3-DMA as the cationic lipid did not work effectively as a functional, protective commercial vaccine.[435] The opponent further argues that the tissue accumulation and associated potential toxicity of members of the DLin family of cationic lipids would preclude their use as an effective vaccine.[436]

1. The applicant submits that the opposed application teaches nucleic acid vaccines comprising mRNA encoding an antigenic polypeptide, which when formulated with LNPs, can elicit enhanced, functional immune responses, more rapidly and with lower doses, when compared with other nucleic acid formulations.[437] These effects are explicitly demonstrated in the examples section using several different antigens across several different animal models.[438] Favourable comparisons are demonstrated against other mRNA vaccines with different lipid carriers (lipoplex) and also compared to vaccines with protein antigens, therefore the claimed invention clearly achieves the promised benefit given that the data presented in the specification clearly demonstrates clinical efficacy of the claimed nucleic acid vaccines.[439] Furthermore, the applicant submits that any assertion that the claims encompass known toxic LNPs and therefore embodiments that are not useful is unfounded and contrary to the specific teaching in the opposed application.[440]

1. The opponent submits that the data presented in Hassett clearly shows quite a number of mRNA-LNPs falling within the scope of the claims of the opposed application which do not work, therefore the claims do not deliver on the promise of the invention and the claims do not disclose a specific, substantial and credible use.[441]

1. I consider that the promise of the invention derived from the specification as a whole is that a composition comprising a mRNA encoding an antigenic polypeptide formulated in a LNP having the components in the molar ratios as defined in claim 1, will function as a vaccine (i.e. will produce an antigen specific immune response). An assertion of lack of utility requires evidence not just speculation. The opponent has failed to provide any evidence of a formulation within the scope of claim 1 that fails to attain the result promised for the invention by the patentee. While the opponent does submit that CureVac failed in developing a COVID-19 mRNA vaccine, as discussed above, the word "vaccine" in claim 1 has only been construed as implying that the formulation needs only to produce an immune response which is a much lower bar to meet than developing a commercial vaccine. Similarly, potentially toxic members of the DLin family of cationic lipids does not impact on the vaccine formulation's ability to produce an immune response and any cationic lipids that do not work (as some previously described in Hassett), would be outside the scope of claim 1. Therefore, claim 1 and all claims dependent on claim 1 are considered useful.

1. The opposition succeeds on the grounds of inventive step in relation to claims 1-67, and section 40(2)(a) and section 40(3) in relation to claims 1 and 3-67. The opposition fails on all other grounds.

1. I consider that these matters can be overcome by amendment. I will allow the applicant an opportunity to propose amendments.

1. It is normal in matters before the Commissioner that costs should follow the event. I see no reason to depart from that approach in the present case. I will award costs according to Schedule 8 against the applicant.

one or more mRNA polynucleotides having an open reading frame encoding an antigenic polypeptide, formulated in a cationic lipid nanoparticle having a molar ratio of about 20-60% cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol; and about 0.5- 15% PEG-modified lipid.

1. The vaccine of claim 1, wherein the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleylmethyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (L319).

1. The vaccine of claim 1 or 2, wherein the cationic lipid nanoparticle comprises a molar ratio of about 50% cationic lipid, about 1.5% PEG-modified lipid, about 38.5% cholesterol and about 10% non-cationic lipid.

1. The vaccine of claim 1 or 2, wherein the cationic lipid nanoparticle comprises a molar ratio of about 55% cationic lipid, about 2.5% PEG lipid, about 32.5% cholesterol and about 10% non-cationic lipid.

1. The vaccine of claim 1, wherein the cationic lipid is an ionizable cationic lipid and the non-cationic lipid is a neutral lipid, and the sterol is a cholesterol.

1. The vaccine of any one of claims 1-5, wherein the open reading frame is codon-optimized.

1. The vaccine of any one of claims 1-6, wherein the antigenic polypeptide is derived from an infectious agent.

1. The vaccine of claim 7, wherein the infectious agent is selected from a member of the group consisting of strains of viruses and strains of bacteria.

1. The vaccine of any one of claims 1-6, wherein the one or more RNA polynucleotides encode a further antigenic polypeptide.

1. The vaccine of claim 1-6, wherein the one or more RNA polynucleotides comprise at least one chemical modification.

1. The vaccine of any one of claims 1-6, wherein the antigenic polypeptide is selected from those proteins listed in Tables 6-14, Tables 29-30, or antigenic fragments thereof.

1. The vaccine of any one of claims 1-6, wherein the open reading frame of the one or more mRNA polynucleotides encodes an antigenic polypeptide selected from Tables 6-11 or antigenic fragments thereof.

1. The vaccine of any one of claims 1-6, wherein each of the open reading frame of the one or more mRNA polynucleotides is selected from any of the mRNA sequences from Table 28, or antigenic fragments thereof.

1. The vaccine of any one of claims 7-8, wherein the infectious agent is a strain of Influenza A or Influenza B or combinations thereof.

1. The vaccine of claim 14, wherein the strain of Influenza A or Influenza B is associated with birds, pigs, horses, dogs, humans or non-human primates.

1. The vaccine of any one of claims 1-14, wherein the antigenic polypeptide encodes a hemagglutinin protein or fragment thereof.

1. The vaccine of claim 16, wherein the hemagglutinin protein is H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, H18, or a fragment thereof.

1. The vaccine of claim 16 or 17, wherein the hemagglutinin protein does not comprise a head domain (HA1).

1. The vaccine of claim 16 or 17, wherein the hemagglutinin protein comprises a portion of the head domain (HA1).

1. The vaccine of any one of claim 16-19, wherein the hemagglutinin protein does not comprise a cytoplasmic domain.

1. The vaccine of any one of claim 16-19, wherein the hemagglutinin protein comprises a portion of the cytoplasmic domain.

1. The vaccine of any one of claims 16-21, wherein the truncated hemagglutinin protein.

1. The vaccine of any one of claims 16-21, wherein the truncated hemagglutinin protein comprises a portion of the transmembrane domain.

1. The vaccine of any one of claims 16-23, wherein the amino acid sequence of the hemagglutinin protein or fragment thereof comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, or 99% identify with any of the amino acid sequences provided in Table 14- 16.

1. The vaccine of claim 16, wherein the virus is selected from the group consisting of H1N1, H3N2, H7N9, and H10N8.

1. The vaccine of claim 16, wherein the antigenic polypeptide is selected from those proteins listed in Tables 6-12, or fragments thereof.

1. The vaccine of any one of claims 1-26, wherein the nucleic acid vaccine is multivalent.

1. The vaccine of claim 27, wherein the open reading frame of the one or more RNA polynucleotides encode at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 antigenic polypeptides.

1. The vaccine of claim 27, wherein the open reading frame of the one or more RNA polynucleotides encode at least 10, 15, 20 or 50 antigenic polypeptides.

1. The vaccine of claim 27, wherein the open reading frame of the one or more RNA polynucleotides encode 2-10, 10-15, 15-20, 20-50, 50-100 or 100-200 antigenic polypeptides.

1. The vaccine of any one of claims 1-30, wherein the RNA polynucleotide includes a chemical modification and the chemical modification is selected from any of those listed in Tables 22 and 23.

1. The vaccine of claim 31, wherein the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4'-thiouridine, 5- methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2- thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, and 2'-Omethyl uridine.

1. The vaccine of claim 32, further comprising a second chemical modification wherein said second chemical modification is selected from any of those listed in Tables 22 and 23.

1. The vaccine of claim 33, wherein the combination of first and second chemical modification is selected from those listed in Table 25.

1. The vaccine of claim 1, wherein 100% of the uracil in the open reading frame have a chemical modification.

1. The vaccine of claim 1 or 35, wherein the chemical modification is in the 5-position of the uracil.

1. The vaccine of any of claim 1 or 35, wherein the chemical modification is a N1-methyl pseudouridine.

1. The vaccine of claim 1, wherein the vaccine further comprises at least one 5' terminal cap, optionally wherein the at least one 5' terminal cap is 7mG(5')ppp(5')NlmpNp.

1. The vaccine of claim 16, wherein the hemagglutinin protein is selected from HA1, HA7 and HA 10.

1. The vaccine of any one of claims 16 or 39, wherein the RNA polynucleotide further encodes neuraminidase protein.

1. The vaccine of claim 14, wherein the Influenza virus is selected from H1N1, H3N2, H7N9, and H10N8.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises SEQ ID NOs 2459-2621.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide having at least 80% sequence identity to SEQ ID NOs 2459-2621.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 2254.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 2254.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 2259.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 2259.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 2192.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 2192.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 2200.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 2200.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises SEQ ID NO 2046.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 2046.

1. The vaccine of any one of claims 1-41, wherein them RNA polynucleotide comprises SEQ ID NO 2119.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 2119.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises SEQ ID NO 2054.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 2054.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises SEQ ID NO 2127.

1. The vaccine of any one of claims 1-41, wherein the mRNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 2127.

1. A method of inducing an antigen specific immune response in a subject, comprising administering a vaccine of any one of claims 1-34 to the subject in an effective amount to produce an antigen specific immune response.

1. The method of claim 60, wherein the antigen specific immune response comprises a T cell response.

1. The method of claim 60, wherein the antigen specific immune response comprises a B cell response.

1. The method of claim 60, wherein the method of producing an antigen specific immune response involves a single administration of the vaccine.

1. The method of claim 60, further comprising administering a booster dose of the vaccine.

1. The method of claim 60, wherein the vaccine is administered to the subject by intradermal or intramuscular injection.

1. A vaccine of any one of claims 1-34 for use in a method of inducing an antigen specific immune response in a subject, the method comprising administering the vaccine to the subject in an effective amount to produce an antigen specific immune response.

1. Use of a vaccine of any one of claims 1-34 in the manufacture of a medicament for use in a method of inducing an antigen specific immune response in a subject, the method comprising administering the vaccine to the subject in an effective amount to produce an antigen specific immune response.

[1] [2013] FCA 214, 100 IPR 451 at [139] (Eli Lilly).

[2] Specification at Page 1, lines 8-10.

[3] Specification at Page 3, lines 6-10.

[4] Specification at Page 3, lines 20-24.

[5] Specification at Page 18, lines 20-22.

[6] Specification at Page 19, lines 4-6.

[7] Specification at Page 19, lines 6-22.

[8] Specification at Page 21, lines 18-27.

[9] Specification at Page 24, lines 27-28.

[10] Specification at Page 883, lines 3-6.

[11] Specification at Page 875-884; Zhang at [51].

[12] Specification at Page 880, lines 10-15.

[13] Specification at Page 883, lines 3-9.

[14] Specification at Pages 884-886; Zhang at [52].

[15] Specification at Page 886, lines 8-11.

[16] Specification at Page 886, line 16 - Page 888, line 4.

[17] Specification at Page 888, line 5 - Page 889, line 9.

[18] Specification at Page 889, lines 10-15.

[19] Specification at Page 889, line 17 - Page 890, line 12.

[20] Specification at Page 890, lines 14-19.

[21] Specification at Page 890, line 21 - Page 891, line 8.

[22] Specification at Page 890, lines 27-29.

[23] Specification at Page 891, line 10 - Page 893, line 14.

[24] Specification at Page 894, lines 2-20.

[25] Specification at Page 894, line 21 - Page 896, line 2; Zhang at [56].

[26] Specification at Page 896, line 4 - Page 898, line 2; Zhang at [57].

[27] Specification at Page 898; Zhang at [58].

[28] Specification at Page 898, lines 5-6.

[29] Specification at Page 898, lines 8-9.

[30] Specification at Page 899, line 2 - Page 903, line 8; Zhang at [59].

[31] Specification at Page 899, lines 6-12.

[32] Specification at Page 900, lines 7-9.

[33] Specification at Page 901, lines 12-14.

[34] Specification at Page 903, lines 1-2.

[35] [2000] FCA 980; 49 IPR 225 at [70].

[36] AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30; 257 CLR 356 at [23].

[37] Opponent's Written Submissions at [36]; SGP at Page 26.

[39] Applicant's Written Submissions at [0223]; Zhang at [39] and [68]; Cobaugh at [29] and [33]; E Huang at [16].

[40] Opponent's Written Submissions at [24].

[41] Opponent's Written Submissions at [25].

[42] Opponent's Written Submissions at [25].

[43] Applicant's Written Submissions at [0225].

[44] Applicant's Written Submissions at [0229].

[45] Applicant's Written Submissions at [0230].

[46] Opponent's Written Submissions at [27].

[47] Opponent's Written Submissions at [29].

[48] Applicant's Written Submissions at [0234].

[49] Applicant's Written Submissions at [0234].

[50] Opponent's Written Submissions at [28].

[51] Applicant's Written Submissions at [0228]; Cobaugh at [5]-[6]; Zhang at [2].

[52] [2009] FCAFC 70, 81 IPR 228 at [118]- [120].

[53] Specification at Page 852, lines 21-23.

[54] Specification at Page 27, lines 14-17.

[59] Specification at Page 505, lines 23-26.

[60] Specification at Page 32, lines 9-10.

[69] Eleanor Lawrence (ed), Henderson's Dictionary of Biology, (13th ed, 2005) 42.

[70] Specification at Page 3, lines 27-30.

[71] Specification at Page 641, lines 11-13.

[72] Specification at Page 642, line 32.

[73] Specification at Page 643, lines 8-12.

[74] Specification at Page 643, lines 12-20.

[75] Specification at Page 648, lines 19-25.

[76] Specification at Page 648, line 25 - Page 651, line 5.

[79] Specification at Page 876, line 24.

[82] Chemical Entities of Biological Interest Database, _CHEBI:15889 - stero_l at 7 March 2025.

[83] Specification at Page 644, lines 24-28.

[85] Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; 137 CLR 228 at 235.

[86] Nicaro Holdings Pty Ltd v Martin Engineering Company [1990] FCA 40; 16 IPR 545 at 549.

[87] The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 485-

[88] (1930) 47 RPC 69, 90.

[99] D1 at [0001172]; L Huang-1 at [53].

[104] D1A at Page 59, line 15 - Page 80.

[105] Applicant's Written Submissions at [0135].

[107] D1A at Page 187, line 1 - Page 188, line 3.

[109] Applicant's Written Submissions at [0128].

[110] Applicant's Written Submissions at [0124].

[112] D1A at Page 260, line 21 - Page 261, line 11.

[113] D1A at Page 24, line 29 - Page 25, line 2.

[115] Opponent's Written Submissions at [75].

[117] Applicant's Written Submissions at [140].

[119] Applicant's Written Submissions at [0125].

[121] Applicant's Written Submissions at [0132] and [0133].

[122] Applicant's Written Submissions at [0135].

[133] D2 at Page 3, line 17; Page 42, lines 8-9 and 15-16; Page 59, line 9.

[134] D2 at Page 41, line 29 - Page 42, line 16; Applicant's Written Submissions at [0151]; Zhang at [178].

[135] D2 at Page 3, lines 6-8, lines 17-19 and lines 29-35.

[140] D2 at Page 187, line 26 - Page 194, line 9.

[141] D2 at Page 194, line 10 - Page 195, line 1.

[142] D2 at Page 198, line 18 - Page 200, line 5.

[143] Opponent's Written Submissions at [83].

[144] Opponent's Written Submissions at [83].

[146] Opponent's Written Submissions at [81].

[147] Applicant's Written Submissions at [0146].

[148] Applicant's Written Submissions at [0148].

[149] Applicant's Written Submissions at [0148].

[150] Applicant's Written Submissions at [0158].

[151] Applicant's Written Submissions at [0149].

[153] Applicant's Written Submissions at [0152].

[154] Applicant's Written Submissions at [0154].

[156] D3 at Page 3, lines 20-21; D3 at Page 73, lines 30-31.

[163] D3 at Page 235, line 10 - Page 247, line 3.

[164] D3 at Page 258, line 11 - Page 259, line 6.

[165] D3 at Page 255, line 22 - Page 256, line 24.

[167] Applicant's Written Submissions at [0171].

[168] Applicant's Written Submissions at [0169]; D3 at Page 1.

[169] Applicant's Written Submissions at [0170].

[170] Applicant's Written Submissions at [0167].

[172] Applicant's Written Submissions at [0170].

[174] Opponent's Written Submissions at [115].

[176] [1981] HCA 12 at [45]; 148 CLR 262 at 286 (Wellcome Foundation).

[177] [2002] HCA 59; 56 IPR 129 at 142-143 (Alphapharm).

[178] Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; 144 CLR 253 at 292.

[179] Specification at Page, lines 1-9.

[180] Specification at Page 2, line 22 - line 26.

[181] Specification at Page 18, lines 7-10.

[184] Applicant's Written Submissions at [0210]; Zhang at [20]; Cobaugh at [12]; E Huang at [11].

[185] Opponent's Written Submissions at [160], [163] and [167]; Applicant's Written Submissions at [0423] and [0256]; L Huang-1 at [25]-[27].

[186] Opponent's Written Submissions at [161] and [166]; L Huang-1 at [30]-[37].

[187] Opponent's Written Submissions at [32].

[188] Opponent's Written Submissions at [32], [163] and [166]; L Huang-1 at [38], [39] and [129].

[189] Opponent's Written Submissions at [162]; L Huang-1 at [28]-[31] and [34].

[190] Opponent's Written Submissions at [32].

[191] Opponent's Written Submissions at [164].

[192] Opponent's Written Submissions at [165]; Leaf Huang-1 at [28].

[193] Opponent's Written Submissions at [171].

[194] Opponent's Written Submissions at [170].

[195] Opponent's Written Submissions at [171].

[197] Opponent's Written Submissions at [164] and [165].

[198] Opponent's Written Submissions at [164].

[199] Opponent's Written Submissions at [169] and [170].

[200] Weng at Page 5, left hand column.

[207] Opponent's Written Submissions at [160]; L Huang-1 at [25] and [38].

[209] Opponent's Written Submissions at [170]; L Huang-2 at [25].

[214] Pardi 2018 at Page 266, right hand column.

[215] Kulkarni at Page 154, left hand column; Note that [61] is a reference to Leung which was published in 2014.

[216] Applicant's Written Submissions at [0287].

[217] Applicant's Written Submissions at [0285].

[220] Applicant's Written Submissions at [0267].

[221] Weng at Page 4, right hand column, 1st paragraph.

[222] Applicant's Written Submissions at [0257]; Ryan Cross, Without these lipid shells, there would be no mRNA vaccines for COVID-19 (2021) Chemical and Engineering News at 3 February 2025.

[223] Applicant's Written Submissions at [0258].

[228] Applicant's Written Submissions at [0309].

[233] Applicant's Written Submissions at [0253].

[238] Applicant's Written Submissions at [0318].

[240] Deering at Page 4; L Huang-2 at [11].

[242] Applicant's Written Submissions at [0321].

[243] Applicant's Written Submissions at [0324].

[244] Applicant's Written Submissions at [0324].

[245] Applicant's Written Submissions at [0325].

[247] Applicant's Written Submissions at [0326].

[248] Applicant's Written Submissions at [0326].

[250] Applicant's Written Submissions at [0327].

[252] Applicant's Written Submissions at [0332] and [0333].

[253] Opponent's Written Submissions at [160]; L Huang-1 at [28].

[256] Applicant's Written Submissions at [0281]; E Huang at [12].

[258] Applicant's Written Submissions at [0403].

[260] Applicant's Written Submissions at [0419]; Kallen at Page 2264.

[261] Applicant's Written Submission at [0408].

[262] Applicant's Written Submissions at [0408]; Sahin at Page 770.

[263] Applicant's Written Submissions at [0409].

[266] Applicant's Written Submissions at [0414].

[267] Applicant's Written Submissions at [0415].

[268] Applicant's Written Submissions at [0415].

[269] Applicant's Written Submissions at [0415]; Geall at Figure 3.

[270] Applicant's Written Submissions at [0415].

[271] Applicant's Written Submissions at [0416]; See also Kallen at Page 2275.

[273] Applicant's Written Submissions at [0418].

[274] Applicant's Written Submissions at [0418].

[275] Specification at Page 21, lines 19-27.

[276] Applicant's Written Submissions at [0421].

[277] Opponent's Written Submissions at [177] and [178].

[279] Applicant's Written Submissions at [0443]; See also Zhang at [91], [98], [100] and [101]; Cobaugh at [42], [55] and [56]; E Huang at [24], [32] and [33].

[280] Applicant's Written Submissions at [0433].

[283] Applicant's Written Submissions at [0435].

[284] Opponent's Written Submissions at [55].

[288] Applicant's Written Submissions at [0466].

[289] Applicant's Written Submissions at [0466].

[293] Applicant's Written Submissions at [0461].

[294] Applicant's Written Submissions at [0469].

[295] Applicant's Written Submissions at [0469].

[296] Applicant's Written Submissions at [0469].

[297] Applicant's Written Submissions at [0470].

[298] Opponent's Written Submissions at [182].

[299] Applicant's Written Submissions at [0464].

[300] Applicant's Written Submissions at [0471].

[301] L Huang-1 at [63]; D6 at Figure 1.

[302] L Huang-1 at [64]-[65]; D6 at Pages 14605-14606.

[303] Opponent's Written Submissions at [187]; L Huang-1 at [69]-[70]; D7 at Results, Immunogenicity of the SAM (H1/LNP) vaccine.

[304] Opponent's Written Submissions at [185]; L Huang-2 at [40]-[42] and [109]-[110].

[305] D7 at Page 14608, left hand column.

[306] Opponent's Written Submissions at [186].

[307] Opponent's Written Submissions at [186]; L Huang-2 at [11].

[309] Applicant's Written Submissions at [0492]; D6 at Page 14604.

[311] Applicant's Written Submissions at [0502].

[312] Applicant's Written Submissions at [0512]; D7 at Pages 5-6; Zhang at [118].

[313] Applicant's Written Submissions at [0514].

[315] Opponent's Written Submissions at [188]; L Huang-1 at [219]; D9 at Page 7, line 30- Page 9, line 18.

[316] Opponent's Written Submissions at [188]; D9 at Page 34, lines 2-4.

[317] Applicant's Written Submissions at [0524].

[318] Applicant's Written Submissions at [0525].

[319] Applicant's Written Submissions at [0525].

[320] Applicant's Written Submissions at [0525].

[321] Opponent's Written Submissions at [191]; L Huang-1 at [101] and [231]-[233].

[322] Applicant's Written Submissions at [0540]; D13 at column 26, lines 22-29.

[323] Opponent's Written Submissions at [192].

[324] Applicant's Written Submissions at [0540] - [0541].

[325] Novartis AG v Johnson & Johnson Medical Limited [2010] EWCA Civ 1039 at [74].

[326] [2017] APO 57 at [45].

[327] See, e.g. Rimfrost AS v Aker BioMarine Antarctic AS [2018] APO 34; Cytec Industries Inc. v Nalco Company

[2018] APO 4; Grant Fisher v ToolGen Incorporated [2018] APO 65; Gary B Cox v MacroGenics, Inc. [2019] APO 13.

[328] [2018] UKSC 56 at [36].

[329] Gary B Cox v MacroGenics, Inc at [63].

[330] Opponent's Written Submissions at [209].

[331] Opponent's Written Submissions at [209]; L Huang-2 at [55].

[334] Applicant's Written Submissions at [0596].

[335] WO 2011/005799 A2 (NOVARTIS AG) 13 January 2011 (Exhibit LH-15).

[336] WO 2012/170930 A1 (SHIRE HUMAN GENETIC THERAPIES, INC) 13 December 2012.

[337] WO 2013/149141 A1 (SHIRE HUMAN GENETIC THERAPIES, INC.) 3 October 2013.

[338] Applicant's Written Submissions at [0596].

[339] Declaration of Andrew S. Janoff (Exhibit LH-17).

[340] Opponent's Written Submissions at [210].

[347] Opponent's Written Submissions at [213].

[349] Applicant's Written Submissions at [0600].

[351] CSR [2015] APO 72 at [102].

[354] Applicant's Written Submissions at [0634].

[356] Applicant's Written Submissions at [0637].

[357] L Huang-1 at [145], [148] and [153].

[358] L Huang-1 at [148]-[149]; L Huang-2 at [52] and [124].

[359] Opponent's Written Submissions at [219].

[360] Opponent's Written Submissions at [219].

[361] Applicant's Written Submissions at [0638].

[366] Opponent's Written Submissions at [211] and [218].

[372] Applicant's Written Submissions at [0630].

[380] Opponent's Written Submissions at [222].

[381] Opponent's Written Submissions at [223].

[382] Opponent's Written Submissions at [224]; Zhang-1 at [172].

[383] Applicant's Written Submissions at [0598].

[384] Applicant's Written Submissions at [0598].

[385] Applicant's Written Submissions at [0589].

[386] Applicant's Written Submissions at [0591]-[0593].

[387] Applicant's Written Submissions at [0595].

[389] Hassett at Page 2, right hand column.

[391] Opponent's Written Submissions on Reg 5.23 at Page 4.

[392] Hassett at Page 3, left-hand column.

[393] Opponent's Written Submissions on Reg 5.23 at Page 4.

[394] Hassett at Page 2, right hand column.

[396] Applicant's Written Submissions on Reg 5.23 at Page 9.

[397] Applicant's Written Submissions on Reg 5.23 at Page 10.

[398] Applicant's Written Submissions on Reg 5.23 at Page 10.

[399] Applicant's Written Submissions on Reg 5.23 at Page 10.

[400] Applicant's Written Submissions on Reg 5.23 at Page 14.

[401] Opponent's Written Submissions on Reg 5.23 at Page 4.

[402] Opponent's Written Submissions on Reg 5.23 at Page 4.

[404] Opponent's Written Submissions on Reg 5.23 at Page 3; Hassett at Figure 2A.

[406] Opponent's Written Submissions on Reg 5.23 at Page 4.

[407] Opponent's Written Submissions on Reg 5.23 at Page 4.

[408] Applicant's Written Submissions on Reg 5.23 at Page 14.

[415] Opponent's Written Submissions at [214].

[416] Applicant's Written Submissions at [0615] - [0617].

[417] Applicant's Written Submissions at [0620].

[418] (No 3) [2020] FCA 1477 at [546]- [547].

[419] [2015] APO 72 at [115].

[420] See for example, Cytec Industries Inc v Nalco Company [2021] FCA 970; (2021) 162 IPR 202.

[421] Opponent's Written Submissions at [239].

[422] Opponent's Written Submissions at [244].

[423] Opponent's Written Submissions at [213].

[424] Opponent's Written Submissions at [244].

[425] Opponent's Written Submissions at [213].

[426] Opponent's Written Submissions at [242].

[427] Applicant's Written Submissions at [0658].

[428] Applicant's Written Submissions at [0658].

[430] Applicant's Written Submissions at [0663].

[432] L Huang-2 at [94]; Opponent's Written Submissions at [251].

[434] Applicant's Written Submissions at [0576].

[435] Opponent's Written Submissions at [252].

[436] Opponent's Written Submissions at [252]; E Huang at [30].

[437] Applicant's Written Submissions at [0568].

[438] Applicant's Written Submissions at [0569].

[439] Applicant's Written Submissions at [0569].

[440] Applicant's Written Submissions at [0577].

[441] Opponent's Written Submissions on Reg 5.23 at Page 3.