Seqirus Inc. v ModernaTX, Inc

[2025] APO 15

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

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

Patent Application:                2015249553

Title:Nucleic Acid Vaccines

Patent Applicant:                   ModernaTX, Inc.

Opponent:  Seqirus Inc.

Delegate:  Damian Triffett

Decision Date:  23 May 2025

Hearing Date:  3 April 2024, by Video Conference

Catchwords:  PATENTS – section 59 opposition to the grant of a patent – a lipid nanoparticle mRNA vaccine – grounds of lack of novelty, inventive step, clear enough and complete enough disclosure, support and utility – opposition successful – claims lack inventive step in view of D1 – description is not clear and complete enough with respect to all cationic lipids – claims not supported with respect to all cationic lipids – grounds of novelty and utility not established – opportunity to amend – costs awarded against applicant

Representation:  Counsel for the applicant: Mr Christian Dimitriadis  

Patent attorney for the applicant: Dr Vaughan Barlow from RnB IP, Mr Robert Finzi from RnB IP 

Patent attorney for the opponent: Dr Declan McKeveney from FB Rice, Dr Patrick McManamny from FB Rice

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application:                2015249553

Title:Nucleic Acid Vaccines

Patent Applicant:                   ModernaTX, Inc.

Date of Decision:                   23 May 2025

DECISION

The opposition succeeds on the grounds of inventive step, section 40(2)(a) and section 40(3).

I award costs according to Schedule 8 against ModernaTX, Inc.

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

REASONS FOR DECISION

Background

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).

The opposition

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.

2. 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).

3. 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.

4. 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).

The specification

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.

What is the invention as described?

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.”

The background to the invention

1. The application is titled “Nucleic Acid Vaccines”.

2. The Field of the Invention:

   “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]

Summary of Invention

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]

Detailed Description of the Invention

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]

2. 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.

Examples

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

2. 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]

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

4. 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]

5. 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]

6. 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.

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

The Person Skilled in the Art

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.”

2. 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]

Characterisation of the PSA

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]

2. 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] 

3. 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.

Suitability of expert witnesses

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] 

2. 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.  

Construction

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.”

Construction of claim 1

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

“A nucleic acid vaccine, comprising:
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.”

Vaccine

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.

2. 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]

1. Prof. Huang further states:

“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]

1. Dr. Cobaugh in the EIA disagrees stating:

“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.

mRNA

1. The specification defines mRNA as:

   “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]

2. 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.

Antigenic polypeptide

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”.

2. 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]

2. 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.

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

Cationic lipid

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

2. 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] 

3. 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]

4. 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.

5. 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. 

Non-cationic lipid

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.

Sterol

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

2. Prof. Leaf Huang states:

   “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.

PEG-modified lipid

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]

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

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

Novelty

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] 

2. 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.”

2. 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”.

Whole of contents novelty

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.

2. 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.  

3. At [80] to [81], Emmett J said:

   “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.”

4. 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]

WO 2013/151736 A2

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

2. 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]

2. 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]

3. 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”.

4. In the EIA, Prof. Zhang states that:

   “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]

and

“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.  

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

and

“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.

WO 2014/136086 A1

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.

2. 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] 

3. 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]   

2. 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]

1. The applicant goes on to state:

“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 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]

2. 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]

2. 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.

2. 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.

WO 2015/095346 A1

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.

2. 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]

3. 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]

2. 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]

3. 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]

2. 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.

Inventive Step

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 BiorexLaboratories 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]?’

That approach should be accepted.”

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.”

Common general knowledge

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]

Problem

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.”

2. 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.

2. 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]

3. 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]

4. 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.

Inventive step in light of the CGK

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]

2. 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]

3. 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]

4. 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]

5. 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]

Adapting siRNA/saRNA delivery to mRNA

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?

2. 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]

3. 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]

and Dr. Cobaugh states:

“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]

Damian Triffett
Delegate of the Commissioner of Patents

ANNEX

1. A nucleic acid vaccine, comprising:

   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.

2. 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).

3. 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.

4. 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.

5. 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.

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

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

8. 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.

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

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

11.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.

12.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.

13.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.

14.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.

15.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.

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

17.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.

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

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

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

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

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

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

24.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.

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

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

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

28.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.

29.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.

30.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.

31.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.

32.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.

33.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.

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

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

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

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

38.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.

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

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

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

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

43.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.

44.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.

45.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.

46.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.

47.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.

48.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.

49.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.

50.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.

51.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.

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

53.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.

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

55.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.

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

57.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.

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

59.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.

60.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.

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

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

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

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

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

66.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.

67.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.

[38] L Huang-1 at [21].

[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.

[55] L Huang-1 at [123].

[56] L Huang-1 at [155].

[57] Cobaugh at [61].

[58] L Huang-2 at [51].

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

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

[61] L Huang-1 at [67].

[62] L Huang-2 at [17].

[63] Zhang at [23].

[64] Zhang at [25].

[65] Zhang at [110].

[66] Cobaugh at [24].

[67] Cobaugh at [46].

[68] Zhang at [100].

[69] Eleanor Lawrence (ed), Henderson’s Dictionary of Biology, (13^th 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.

[77] L Huang-1 at [155].

[78] Specification at Page 4, line 4.

[79] Specification at Page 876, line 24.

[80] L Huang-1 at [155].

[81] Specification at Page 4, line 5.

[82] Chemical Entities of Biological Interest Database, CHEBI:15889 – sterol < at 7 March 2025.

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

[84] L Huang-1 at [155].

[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.

486.

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

[89] Du Pont at [85].

[90] D1 at [000134].

[91] D1 at [000147].

[92] D1 at [000536].

[93] D1 at [000514].

[94] D1 at [000524].

[95] D1 at [000530].

[96] D1 at [000522]-[000523].

[97] D1 at [000523]

[98] L Huang-1 at [53].

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

[100] D1 at Example 14.

[101] D1 at Page 431-438.

[102] Zhang at [86].

[103] Zhang at [91].

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

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

[106] D1A at Page 24, line 21.

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

[108] D1A at Page 24, lines 22-23.

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

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

[111] D1A at Page 259, lines 29-31.

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

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

[114] D1A at Page 183, lines 12-19.

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

[116] D1A at Page 182, lines 24-28.

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

[118] D1A at Page 21, lines 15-21.

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

[120] D1A at Page 172, lines 15-29.

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

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

[123] L Huang-2 at [68].

[124] L Huang-2 at [71].

[125] D2 at Abstract.

[126] D2 at Page 3, lines 9-13.

[127] Zhang at [178].

[128] D2 at Page 43, lines 21-24.

[129] D2 at Page 43, lines 33-37.

[130] D2 at Page 53, lines 34-35.

[131] D2 at Page 197, lines 23-24.

[132] D2 at Page 3, lines 2-3.

[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.

[136] D2 at Page 50, line 29.

[137] D2 at Page 61, lines 26-29.

[138] D2 at Page 63, lines 28-30.

[139] D2 at Page 62, line 10.

[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].

[145] McKeveney at [46].

[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].

[152] D2 at Page 62, lines 21-22.

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

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

[155] D3 at Abstract.

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

[157] D3 at Page 3, lines 18-20.

[158] D3 at Page 247, lines 10-11.

[159] D3 at Page 56, lines 2-6.

[160] D3 at Page 4, lines 17-20.

[161] D3 at Page 61, lines 4-11.

[162] D3 at Page 61, lines 26-29.

[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.

[166] SGP at Page 21.

[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].

[171] D3 at Page 76, lines 3-5.

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

[173] Zhang at [182].

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

[175] McKeveney at [74].

[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.

[182] SGP at Page 34.

[183] L Huang-1 at [114].

[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].

[196] Zhang at [73].

[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.

[201] Leung at Page 73.

[202] Leung at Page 77.

[203] Leung at Page 100.

[204] L Huang-1 at [25]-[29].

[205] L Huang-1 at [30]-[37].

[206] L Huang-1 at [38]-[39].

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

[208] L Huang-1 at [25].

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

[210] L-Huang-1 at [40].

[211] Zhang at [84].

[212] Cobaugh at [40].

[213] Wadhwa at Page 15.

[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].

[218] Zhang at [24] and [25].

[219] Cobaugh at [25].

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

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

[224] Zhang at [35].

[225] Wadhwa at Abstract.

[226] Cobaugh at [21].

[227] Kulkarni at Page 148.

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

[229] Sahin at Abstract.

[230] Zhang at [33].

[231] Zhang at [30] and [31].

[232] Sahin at Page 766.

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

[234] Sahin at Page 766.

[235] Sahin at Page 760.

[236] Sahin at Page 776.

[237] Deering at Page 5.

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

[239] Deering at Page 1.

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

[241] Deering at Page 4.

[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].

[246] Deering at Page 3.

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

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

[249] L Huang-2 at [11] and [12].

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

[251] Deering at Page 7.

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

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

[254] L Huang-1 at [28].

[255] Zhang at [27].

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

[257] Petsch at Page 1211.

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

[259] Deering at Page 3.

[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].

[264] Deering at Page 4.

[265] Sahin at Page 771.

[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.

[272] Petsch at Page 1215.

[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].

[278] L Huang-1 at [195].

[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].

[281] Zhang at [100].

[282] Zhang at [98].

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

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

[285] D5 at Abstract.

[286] D5 at [0103].

[287] D5 at [0145]-[0150].

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

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

[290] L Huang-1 at [198].

[291] D5 at [0093].

[292] D5 at Page 83.

[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].

[308] L Huang-2 at [12].

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

[310] D6 at Page 14606.

[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].

[314] D9 at Abstract.

[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].

[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].

[332] L Huang-1 at [161]-[167]. 

[333] L Huang-1 at [168].

[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].

[341] L Huang-1 at [107].

[342] L Huang-1 at [107].

[343] Zhang at [144].

[344] L Huang-1 at [167].

[345] Evolva at [33].

[346] Evolva at [34] and [35].

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

[348] L Huang-1 at [169].

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

[350] Zhang at [172].

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

[352] L Huang-1 at [155].

[353] L Huang-1 at [170].

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

[355] L Huang-1 at [61].

[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].

[362] Cobaugh at [62].

[363] Zhang at [158].

[364] Zhang at [73].

[365] L Huang-2 at [130].

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

[367] L Huang-1 at [37].

[368] L Huang-1 at [38].

[369] L Huang-1 at [39].

[370] L Huang-1 at [39].

[371] L Huang-1 at [168].

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

[373] L Huang-2 at [128].

[374] L Huang-2 at [128].

[375] L Huang-2 at [131].

[376] Zhang at [163]-[165].

[377] Cobaugh at [65].

[378] L Huang-2 at [54].

[379] L Huang-2 at [119].

[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].

[388] Hassett at Page 8.

[389] Hassett at Page 2, right hand column.

[390] Hassett at Figure 2A.

[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.

[395] L Huang-3 at [10].

[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.

[403] L Huang-3 at [15].

[404] Opponent’s Written Submissions on Reg 5.23 at Page 3; Hassett at Figure 2A.

[405] L Huang-3 at [11].

[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.

[409] L Huang-1 at [27]-[40].

[410] L Huang-1 at [28].

[411] L Huang-1 at [30].

[412] L Huang-1 at [31].

[413] L Huang-1 at [37].

[414] L Huang-2 at [69].

[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].

[429] Zhang at [172].

[430] Applicant’s Written Submissions at [0663].

[431] See D6-D10.

[432] L Huang-2 at [94]; Opponent’s Written Submissions at [251].

[433] Zhang at [73].

[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.