Seqirus Inc. v ModernaTX, Inc
[2025] APO 21
•4 July 2025
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Seqirus Inc. v ModernaTX, Inc. [2025] APO 21
Patent Application: 2017326423
Title:High purity RNA compositions and methods for preparation thereof
Patent Applicant: ModernaTX, Inc.
Opponent:Seqirus Inc.
Delegate:M. Umehara
Decision Date: 4 July 2025
Hearing Date: Written submissions completed on 7 April 2025
Catchwords: PATENTS – opposition to the grant of a patent under s59 – no claims found to lack utility – novelty – citations do not disclose all features of the claims – inventive step – it would be a matter of routine to arrive at the claimed invention – clear enough and complete enough disclosure and support – technical contribution to the art does not extend to a general principle – opportunity to amend – costs awarded
Representation: Patent attorney for the applicant: RnB IP
Patent attorney for the opponent: FB Rice Pty Ltd
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2017326423
Title:High purity RNA compositions and methods for preparation thereof
Patent Applicant: ModernaTX, Inc.
Date of Decision: 4 July 2025
DECISION
The opposition is successful on the grounds of inventive step, clear enough and complete enough disclosure and support with regard to claims 1-8 and 11-20 and fails on the grounds of clarity, utility and novelty.
I allow the applicant two (2) months from the date of this decision to file amendments to overcome the deficiencies identified in this decision.
I award costs according to Schedule 8 against the applicant, Moderna TX, Inc.
REASONS FOR DECISION
Australian patent application no. 2017326423 (the opposed application) in the name of ModernaTX, Inc. (the applicant) was filed under the provisions of the Patent Cooperation Treaty on 14 September 2017 and claims priority from US provisional patent application 62/394711 filed on 14 September 2016. While nothing turns on this point, a divisional application, 2024200861 claiming priority from the opposed application was filed on 9 February 2024 and examination has commenced.
The acceptance of the opposed application was advertised on 9 November 2023. Seqirus Inc. (the opponent) filed a notice of opposition under section 59 of the Patents Act 1990 (the Act) on 9 February 2024. A statement of grounds and particulars (SGP) was subsequently filed on 9 May 2024. The SGP identified entitlement, manner of manufacture, novelty, inventive step, utility, sufficiency, clarity and support as grounds of opposition.
The evidence in support (EIS) was filed on 9 August 2024, consisting of a declaration by Professor Andre Gerber dated 8 August 2024 (Gerber) together with exhibits AG-1 to AG-13 and a declaration by Professor Thomas Preiss also dated 8 August 2024 (Preiss) together with exhibits TP-1 to TP-15.
No evidence in answer was filed and the matter was set for hearing by written submissions. The submissions were completed on 7 April 2025. The opponent’s submissions in support pressed novelty, lack of inventive step, lack of clear enough and complete enough disclosure, lack of utility and lack of support.
Onus and standard of proof
The opposed application was filed after 15 April 2013 and is governed by the Act and Patents Regulations 1991 as amended by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012. Thus, the standard of proof that applies in the present case is the balance of probabilities.
The onus rests with the opponent to satisfy me, on a balance of probabilities, that a ground of opposition to the grant exists. Under subsection 60(3A), if I am satisfied, on the balance of probabilities, that a ground of opposition to the grant of a patent exists, I may refuse the application. I note, however, that, under subsection 60(3B), I must not refuse an application without giving the applicant a reasonable opportunity to amend the relevant specification to remove any grounds of opposition.
The specification
The specification includes 110 pages of written description, 20 claims as accepted, 40 figures spanning 51 pages and 32 sequences. Before construing the specification, I note the comments of Middleton J:
“It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date.”[1]
The invention as described
[1] Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214 at [139].
Under the heading “Background of the Invention”, it is explained that mRNA has immense therapeutic potential by transiently expressing any desired protein while avoiding the downsides of viral and DNA-based nucleic acid delivery approaches.[2] However, mammalian cells contain sensors of nucleic acids including RNA as part of the innate immune system, which need to be avoided when developing mRNA therapeutics.[3]
[2] Specification at page 1 lines 15-17.
[3] Specification at page 1 lines 17-19.
Early work in the field showed that incorporation of modified nucleosides, in particular pseudouridine, reduced innate immune activation and increased translation of mRNA.[4] Further progress identified double stranded RNA contaminants as being at least partially responsible for the innate immune activation.[5] However, there remains a need for better understanding of the nature of contaminations and improved methods of preparing mRNA for therapeutic use.[6]
[4] Specification at page 1 lines 24-27.
[5] Specification at page 1 lines 27-29.
[6] Specification at page 2 lines 11-15.
Under the heading “Summary of Invention”, the invention is described as relating to in vitro RNA synthesis for producing RNA transcripts having enhanced properties resulting in qualitatively and quantitatively superior compositions.[7] In contrast to methods described in the art which attempt to remove contaminants following production, the described invention controls the nature and levels of contaminants produced in the in vitro-transcription (IVT) reaction.[8]
“Without being bound in theory, it is believed that preventing the production of unwanted contaminants in the IVT reaction from the outset provides for improved compositions having higher purity and potency, measurable, for example, in terms of increased translation from full-length, intact mRNA in the composition.”[9]
[7] Specification at page 2 lines 18-24.
[8] Specification at page 2 lines 25-30.
[9] Specification at page 2 line 30 – page 3 line 2.
The “Detailed Description” explains that the IVT methods of the invention involve a modification in the relative amounts of nucleotides and/or nucleotide analogues in the reaction mixture to produce a high yield product which is significantly more pure than products produced by typical IVT methods.[10] The typical IVT reaction is described as including the following:
“an RNA polymerase, e.g., a T7 RNA polymerase at a final concentration of, e.g., 1000-12000 U/mL, e.g., 7000 U/mL; the DNA template at a final concentration of, e.g., 10-70 nM, e.g., 40 nM; nucleotides (NTPs) at a final concentration of e.g., 0.5-10 mM, e.g., 7.5 mM each; magnesium at a final concentration of, e.g., 12-60 mM, e.g., magnesium acetate at 40 mM; a buffer such as, e.g., HEPES or Tris at a pH of, e.g., 7-8.5, e.g. 40 mM Tris HCl, pH 8.”[11]
[10] Specification at page 18 line 29 – page 19 line 8.
[11] Specification at page 21 lines 6-11.
Relative to typical IVT methods, the process of the invention involves modifying the relative amounts of nucleotides and/or nucleotide analogs in the reaction mixture.[12] For example, one or more nucleotides and/or one or more nucleotide analogs may be added in excess to the reaction mixture.[13] In particular, the following is noted:
“the methods of the invention involve the surprising finding that the presence of an excess amount of one or more nucleotides and/or nucleotide analogs can have significant impact on the end product.”[14]
[12] Specification at page 22 lines 11-12.
[13] Specification at page 22 lines 13-14.
[14] Specification at page 22 lines 6-9.
A nucleoside triphosphate (NTP) is in excess when it is it in a concentration that is 2-fold to 100-fold, or more, greater than any one or more of the other individual NTPs in the reaction mixture.[15] Alternatively, the excess of the selected NTP is in a concentration of 0.5 mM to 150 mM, or more, greater than the amount of any one or more of the other individual NTPs in the reaction mixture.[16] The excess may also be achieved by including a corresponding nucleoside diphosphate (NDP) where all NTPs are present in equimolar amounts.[17] In the broadest sense, the NTP in excess may be any one of GTP, ATP, UTP or CTP.[18] Otherwise, buffers, RNA polymerases and DNA templates to be used are typical for IVT reactions.[19]
[15] Specification at page 22 lines 24-29.
[16] Specification at page 23 lines 2-11.
[17] Specification at page 24 lines 24-26.
[18] Specification at page 24 lines 9-11.
[19] Specification at page 27 line 29 – page 28 line 31.
The RNA produced by using a NTP in excess is said to be “surprisingly pure and of high integrity.”[20] It is said to have fewer contaminants, including immune-stimulating contaminants, such as reverse complement transcription products, cytokine-inducing RNA contaminants and double-stranded RNA contaminants.[21] With regard to these contaminants, the following comment is provided:
“Without being bound in theory, it is believed that the removal of certain species or contaminants, for example, dsRNA species or contaminants, is important in the preparation of IVT RNA compositions for therapeutic use.”[22]
[20] Specification at page 29 lines 15-16.
[21] Specification at page 29 lines 17-22.
[22] Specification at page 36 lines 16-18.
The NTPs may include both natural and modified NTPs.[23] The modified NTPs may be chemically modified with respect to the natural adenosine (A), guanosine (G), uridine (U), thymidine (T) or cytidine (C) ribo- or deoxyribnucleosides in one or more of their position, pattern, percent or population and can include any useful modification, such as to the sugar, the nucleobase, or the internucleotide linkage.[24] An extensive list of modified nucleic acids is provided.[25]
[23] Specification at page 45 lines 1-2.
[24] Specification at page 45 lines 8-24.
[25] Specification at pages 46-65.
The highly pure RNA compositions may themselves be therapeutic or are used to produce polypeptides of interest.[26] Therapeutic proteins mediate a variety of effects in a host cell or a subject in order to treat a disease or ameliorate the signs and symptoms of a disease.[27] The polypeptides of interest may be selected from any of “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, targeting moieties or those proteins encoded by the human genome for which no therapeutic indication has been identified but which nonetheless have utility in areas of research and discovery.”[28]
[26] Specification at page 68 lines 23-25.
[27] Specification at page 68 lines 26-28.
[28] Specification at page 69 lines 25-31.
The specification concludes with 12 examples. Examples 1-3 describe the methods for the manufacture of polynucleotides using prior art methods, including methods for synthesis of chimeric polynucleotides and standard PCR procedures for the production of DNA templates. Example 4 describes the optimisation of IVT to synthesise short model “RNA-1” and uses specific IVT reaction mixtures referred to as “equimolar”, “alpha” and “GDP alpha” nucleotide formulations and assesses the induction of immune response associated with each product. Examples 5-12 all used the equimolar, alpha and/or GDP alpha IVT reaction processes and shows that RNA produced from the alpha and GDP alpha reaction mixtures had improved purity compared to the equimolar process.
The three reaction mixtures of Example 4 are as follows:
[29]
[29] Specification at page 95, Table 1.
The model transcript prepared using the equimolar IVT process had a higher IFN-β response than material prepared using the alpha IVT processes.[30] The equimolar process also showed the presence of reverse complements, which was not present in the alpha reactions.[31] Similarly, both alpha and GDP alpha reactions mitigated extraneous IFN-B inducing impurity formation, which was enhanced in the equimolar process.[32]
The claims
[30] Specification at page 95 lines 10-11.
[31] Specification at page 95 lines 13-15.
[32] Specification at page 100 line 10 – page 100 line 1.
The specification ends with 20 claims. Independent claims 1 and 16 read as follows:
1.A method of producing a messenger ribonucleic acid (mRNA) that is suitable for administration as a vaccine to a human subject, wherein the mRNA comprises an open reading frame encoding a vaccine antigen, the method comprising incubating a reaction mixture comprising a deoxyribonucleic acid (DNA), an RNA polymerase that initiates with a GTP or GDP, a buffer, adenosine triphosphate (ATP), cytidine triphosphate (CTP), uridine triphosphate (UTP), and guanosine triphosphate (GTP), thereby producing the mRNA, wherein:
(i)the concentration of GTP is greater than the concentration of one or more of ATP, CTP, and UTP, and two or more of ATP, CTP, and UTP are in equimolar concentrations; and/or
(ii)the reaction further comprises guanosine diphosphate (GDP), the concentration of GTP plus GDP is greater than the concentration of one or more of ATP, CTP, and UTP, and two or more of GTP, ATP, CTP, and UTP are in equimolar concentrations.
16.A method of producing a messenger ribonucleic acid (mRNA) that is suitable for administration as a vaccine to a human subject, wherein the mRNA comprises an open reading frame encoding a vaccine antigen, the method comprising incubating a reaction mixture comprising a deoxyribonucleic acid (DNA), a T7 RNA polymerase, a buffer, adenosine triphosphate (ATP), cytidine triphosphate (CTP), uridine triphosphate (UTP), and guanosine triphosphate (GTP), thereby producing the mRNA,
wherein the concentration of GTP is greater than the concentration of one or more of ATP, CTP, and UTP, and two or more of ATP, CTP, and UTP are in equimolar concentrations,
wherein the UTP is a modified UTP comprising 2’-O-methylribose, pseudouridine (ψ), N1-methylpseudouridine (m1ψ), 2-thiouridine, 4-thiouridine, 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, or 5-methoxyuridine.
Appended claims 2-15 and 17-20 further define the components and incubation conditions as well as the properties of the produced mRNA. The full claim set is reproduced at Annex A.
The person skilled in the art
It is well established that many of the issues in an opposition are answered by reference to the person skilled in the art:
“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.”[33]
[33] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70].
The hypothetical skilled person works in the field with which the invention is connected and is a non-inventive person or team likely to have a practical interest in the subject matter of the invention.[34] As noted by Nicholas J in ToolGen Incorporated v Fisher (No 2), the notional team for considering obviousness may have wider skills than the team required for sufficiency.[35]
[34] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70]-[72].
[35] ToolGen Incorporated v Fisher (No 2) [2023] FCA 794 at [81].
The opponent has characterised the relevant person as follows:
“In this case, the person skilled in the art is a person, or more likely a team of persons, comprising a PhD qualified molecular biologist, biochemist or molecular bioscientist with experience in RNA-mediated mechanisms and methods of RNA preparation, including IVT methods of RNA production. They would be likely to have a significant amount of laboratory experience in research and be working at research hospitals, universities and research institutes and/or be employed by medical and pharmaceutical companies with a focus on RNA biology and/or methods of RNA production, including protein therapeutics.”[36]
[36] Opponent submissions in support at [18].
The opponent’s evidence was obtained from independent experts Professor Preiss and Professor Gerber. The applicant did not provide any evidence in answer. However, the applicant submitted that neither Professor Preiss nor Professor Gerber have qualifications or experiences in relation to mRNA vaccine production or formulation at the relevant date and are therefore not relevant persons skilled in the art.[37]
[37] Applicant submissions in answer at [0137].
However, Professor Preiss is an expert in the field of RNA biology.[38] His postdoctoral work involved the investigation of the mechanisms of mRNA translation initiation in eukaryotes.[39] Since then, Professor Preiss has continued to study various aspects of gene regulation at the RNA level, becoming the Professor of RNA Biology at ANU.[40] Similarly, Professor Gerber is a Professor of RNA Biology at University of Surrey, a position held since 2012.[41] Professor Gerber’s field of interest lies in RNA-protein interactions.[42]
[38] Preiss at [6].
[39] Preiss at [4].
[40] Preiss at [1]-[5].
[41] Gerber at [1].
[42] Gerber at [1]-[3].
I therefore understand the applicant’s concerns to be specific to qualifications or experiences directly related to immunology and mRNA vaccines in the immunology sense. I acknowledge the applicant’s concerns insofar as the available evidence being relevant to the processes for preparing RNA products rather than to the therapeutic efficacy of mRNA vaccines.
The preparation of RNA products by IVT is a standard technique known in the art since at least the 1980s.[43] The nature of the RNA product or the peptide or protein encoded by the produced mRNA is not important to the process. As I understand the technology, whatever is encoded by the template DNA will be transcribed into mRNA during the IVT reaction and the host will produce the encoded peptide or protein following administration of the mRNA so produced. If the DNA template encodes a vaccine antigen, the product of the IVT reaction will be a mRNA encoding the target vaccine antigen.
[43] Gerber at [16] and Preiss at [20].
While neither declarant purport to be immunologists, contaminants triggering unintended immune and inflammatory responses was a known issue in IVT.[44] Professor Gerber stated that “Failure to effectively control contaminants was known to result in strong rejection reactions in patients during final clinical application.”[45] Therefore, controlling the contaminants during IVT reactions does not only address efficiency but also the safety of the RNA product and the declarants are familiar with this issue.
[44] Gerber at [19] and Preiss at [21]-[22].
[45] Gerber at [28].
As noted by the opponent, the opposed application generally relates to an improved IVT reaction.[46] The specification itself generally relates to the production of pure mRNA where the polypeptide of interest may relate to any biologic, antibody, vaccine, therapeutic protein or peptide of choice.[47]
[46] Opponent submissions in reply at [10].
[47] Specification at page 29 lines 5-7.
Therefore, I consider that the declarants are well placed to give evidence in relation to the opposed application.
Construction
The correct approach to the construction of claims was discussed by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd:
“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.” [48]
[48] H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at [118]-[120].
The claims are to be construed in light of the specification as a whole, but the plain and unambiguous meaning of a claim cannot be varied or qualified by reference to the body of the specification.[49] Further, a construction according to which the invention will work is to be preferred to one in which it may not.[50]
[49] Welch Perrin & Co Pty Ltd v Worrel [1961] HCA 91 at [610].
[50] Pfizer Overseas Pharmaceuticals v Eli Lilly & Company [2005] FCAFC 224 at [250].
The Full Court in Airco Fasteners Pty Ltd v Illinois Tool Works Inc.,[51] recently reiterated the principle that experts can give evidence on the meaning which those skilled in the art would give to technical or scientific terms and phrases and on any unusual or special meanings that would be given by skilled addressees to words which might otherwise bear their ordinary meaning,[52] and the Court is to place itself in the position of some person acquainted with the surrounding circumstances as to the state of the art and manufacture at the time.[53] However, it is for the Court, not for any witness however expert, to construe the specification.[54] A similar approach is taken in matters before the Commissioner.
A method of producing a mRNA that is suitable for administration as a vaccine
[51] Airco Fasteners Pty Ltd v Illinois Tool Works Inc. [2023] FCAFC 7 at [48].
[52] Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd [1994] FCA 1529 at [485]- [486].
[53] Kimberley-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 at [24].
[54] Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd [1994] FCA 1529 at [485]-[486].
Both independent claims 1 and 16 are directed to methods of producing mRNA that is suitable for administration as a vaccine to a human subject, wherein the mRNA comprises an open reading frame encoding a vaccine antigen. A vaccine antigen is defined in the specification as “a biological preparation that improves immunity to a particular disease or infectious agent.”[55] The opposed application does not purport to have invented new vaccine antigens. Instead, the opposed application states that “one or more vaccine antigens currently being marketed or in development may be encoded by the RNA of the present invention.”[56]
[55] Specification at page 21 lines 26028.
[56] Specification at page 71 lines 28-29.
The applicant stressed that the claimed subject matter is specific to mRNA vaccines where a vaccine antigen is encoded by the mRNA.[57] This was contrasted to the broader use of the term “vaccines” in the art which may include references to the delivery of non-antigenic therapeutic polypeptides, such as antibodies, which assist in boosting an immune response but do not comprise an antigen.[58] I agree with the applicant and nothing in the opponent’s submissions nor the expert evidence suggest non-antigenic polypeptides were considered relevant. For completeness, I will further add that the mRNA product itself does not elicit an immune response and it is the antigen expressed therefrom that vaccinates the host against the target pathogen.
[57] Applicant submissions in answer at [22].
[58] Applicant submissions in answer at [22].
The applicant further submitted that the requirement for suitability for administration as a vaccine means that “methods to produce the mRNA must result in an mRNA that meets both safety and efficacy requirements as a human vaccine.”[59] However, the specification does not define any particular safety or efficacy requirements. Instead, the specification states as follows:
“… the methods of the invention arrive at mRNA compositions suitable for therapeutic use by controlling the nature and levels of contaminants produced in the IVT reaction, i.e., the contaminants are not made in the initial reaction, as contrasted to art-described methods which attempt to remove contaminants once they have been produced. Without being bound in theory, it is believed that preventing the production of unwanted contaminants in the IVT reaction from the outset provides for improved compositions having higher purity and potency, measurable, for example, in terms of increased translation from full-length, intact mRNA in the composition.”[60]
[59] Applicant submissions in answer at [019].
[60] Specification at page 2 line25 page 3 line 2.
In the context of the specification, both declarants associate the levels of contaminants with suitability of the product for administration as a vaccine.[61] Relative to standard IVT processes, the modified IVT process simply produces the same mRNA with reduced contaminants, thereby negating the need for post-synthesis purification. There is no ingenuity claimed in relation to any mRNA sequence for encoding a vaccine antigen in the opposed application.
Natural NTPs and modified NTPs
[61] Gerber at [88] and Preiss at [25].
The claims refer to NTPs without qualification, natural NTPs and modified NTPs. The specification provides the following explanations for NTPs:
“A nucleoside triphosphate, as used herein, refers to a molecule including a nucleobase linked to a ribose (i.e. nucleoside) and three phosphates (i.e. nucleotide). A nucleotide diphosphate refers to the same molecule, but which has two phosphate moieties. A nucleotide monophosphate refers to the same molecule, but which has one phosphate moiety.”[62]
“Natural nucleotide triphosphates include at least adenosine triphosphate (ATP), guanosine triphosphate (GTP), cytidine triphosphate (CTP), 5-methyluridine triphosphate (m5UTP), and uridine triphosphate (UTP).”[63]
“The nucleotide analogs useful in the invention are structurally simliar [sic] to nucleotides or portions thereof but, for example, are not polymerizable by T7. Nucleotide/nucleoside analogs as used herein (including C, T, A, U, G, dC, dT, dA, dU, or dG analogs) include for instance, antiviral nucleotide analogs, phosphate analogs (soluble or immobilized, hydrolyzable or nonhydrolyzable), dinucleotide, trinucleotide, tetranucleotide, e.g., a cap analog, or a precursor/substrate for enzymatic capping (vaccinia, or ligase), a nucleotide labelled with a functional group to facilitate ligation/conjugation of cap or 5' moiety (IRES), a nucleotide labelled with a 5' PO4 to facilitate ligation of cap or 5' moiety, or a nucleotide labelled with a functional group/protecting group that can be chemically or enzymatically cleavable. Antiviral nucleotide/nucleoside analogs include but are not limited to Ganciclovir, Entecavir, Telbivudine, Vidarabine and Cidofovir.”[64]
[62] Specification at page 19 lines 19-22.
[63] Specification at page 19 line 30 – page 20 line 2.
[64] Specification at page 20 lines 14-23.
A person skilled in the art would understand that where “natural” and “modified” NTPs are specified, the claimed subject matter is directed to the specified subgroup. Where it is not specified, the NTPs encompass both natural and modified NTPs.
NTP concentrations
The claims specify relative concentrations of the NTPs in the IVT reaction mixture. The following concentrations are defined in the claims:
(i)the concentration of GTP is greater than the concentration of one or more of ATP, CTP, and UTP, and two or more of ATP, CTP, and UTP are in equimolar concentrations;
(ii)the concentration of GTP plus GDP is greater than the concentration of one or more of ATP, CTP, and UTP, and two or more of GTP, ATP, CTP, and UTP are in equimolar concentrations.
As noted by the opponent, the IVT reaction mixture may comprise any amount of GTP or GTP plus GDP greater than another NTP.[65] When GTP alone is used, the claims require that two or more of ATP, CTP, and UTP are in equimolar concentrations. When GTP plus GDP are used, the claims require that two or more of GTP, ATP, CTP, and UTP are in equimolar concentrations. As long as there are two NTPs in equimolar concentrations, they need not be present in lower or greater concentrations than any other NTP.
[65] Opponent submissions in support at [77].
While not explicitly pressed as a specific ground of opposition, the opponent submitted that the claims were unclear because “there is no clear meaning, definition or boundary for what constitutes a concentration ‘greater than’ the concentration of a selected NTP.”[66] Professor Preiss was specifically asked to comment on this:
“I was asked what I understand the term ‘greater than’ to mean in the context of the above claim. In my view this is ANY amount greater than another amount. In particular, claim 1 does not limit the concentration of the particular NTPs, nor does it limit the extent to which the GTP can be ‘greater than’ another NTP.”[67]
[66] Opponent submissions in support at [79].
[67] Preiss at [125].
Professor Gerber gave a similar explanation.[68] Consequently, the concentration of GTP or GTP plus GDP may be only marginally greater than one or more of the other NTPs. Alternatively, the concentration of GTP or GTP plus GDP may be significantly greater than one or more of the other NTPs. There is no lower limit for how much the concentration of GTP or GTP plus GDP must be “greater” by in the specification. Similarly, there is no upper limit. The claims simply require that the concentration of GTP or GTP plus GDP is greater than one or more of the other NTPs.
[68] Gerber at [87].
Furthermore, I note that there is no requirement in the claims that GTP or GTP plus GDP to be present in the IVT reaction mixture at the highest concentration among all NTPs present. The concentration of GTP or GTP plus GDP need only be greater than one or more NTPs. While two or more NTPs must also be equimolar to one another, these conditions can be met as long as there is one NTP at a lower concentration than GTP or GTP plus GDP. This is reflected in the specification, which includes:
“For instance, an excess of a nucleotide and/or nucleotide analog may be a greater amount than the amount of each or at least one of the other individual NTPs in the reaction mixture or may refer to an amount greater than equimolar amounts of the other NTPs.”[69]
[69] Specification at page 22 lines 16-18.
I consider that a person skilled in the art would readily be able to determine whether any given IVT reaction mixture falls within the scope of the present claims by comparing the concentrations of each of the NTPs present therein.
Utility
Subsection 18(1)(c) of the Act requires that the invention, so far as claimed in any claim, is useful. The ground of utility was considered by the Full Court of the Federal Court in H Lundbeck A/S v Alphapharm Pty Ltd., where Emmett J stated:
“A claim is bad if it covers means that will not produce the desired result, even if a skilled person would know which means to avoid. That is to say, everything that is within the scope of a claim must be useful, otherwise the claim will fail for inutility.”[70]
[70] H Lundbeck A/S v Alphapharm Pty Ltd. [2009] FCAFC 70 at [247].
In Apotex Pty Ltd v AstraZeneca AB (No 4), Jagot J pointed out that lack of utility requires evidence, not just speculation:
“Ultimately, an asserted lack of utility must be established by appropriate evidence, not be mere speculation that the invention will not work or meet the promise set out in the specification.”[71]
[71] Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162 at [352].
A summary of relevant principles was provided by the Full Court of the Federal Court:
“It is ‘no objection’ to the validity of an innovation patent granted under the Act that it is ‘commercially impracticable’. The utility of the patent depends upon whether, by following the teaching of the specification, the result claimed is produced...
The ‘basic principle’ of inutility is that if an invention ‘does what it is intended by the patentee to do, and the end attained is itself useful, the invention is a useful invention’... What the invention is ‘intended’ to do is a matter to be gathered from the ‘title and the whole of the specification’.
Put another way, the two questions are: first, what is the promise of the invention derived from the whole of the specification?; second, by following the teaching of the specification, does the invention, as claimed in the patent, attain the result promised for it by the patentee?... Further, ‘everything’ that is within the scope of a claim must be useful, that is, attain the result promised for the invention by the patentee.”[72] [citations omitted]
[72] Artcraft Urban Group Pty Ltd v Streetworx Pty Ltd [2016] FCAFC 29 at [118]- [121]. (Artcraft)
However, I note Beach J’s observation regarding construction of the specification:
“…the specification (including the claims) must be construed from the perspective of a skilled person, but not in a way that such a person would appreciate would lead to unworkability when by construction it could be given a more limited but workable meaning.”[73]
[73] Sequenom, Inc. v Ariosa Diagnostics, Inc. [2019] FCA 1011 at [799]. (Sequenom)
For completeness, I also note that Section 7A states that an invention is taken to not be useful unless a specific, substantial, and credible use for the invention (so far as claimed) is disclosed in the complete specification. However, this requirement is additional to the requirement that the claimed invention must achieve the promised benefit[74] and the opponent’s submissions relate only to a failure to achieve the promised benefit.
What is the promise of the invention?
[74] Explanatory Memorandum, Intellectual Property Laws Amendment (Raising the Bar) Bill 2011 (Cth) at page 44.
As noted by the opponent, the specification promises methods for in vitro RNA synthesis wherein the RNA transcripts produced “have enhanced properties which result in qualitatively and quantitatively superior compositions”.[75] Although the applicant submitted that utility should be assessed with reference to the invention as claimed, I note that the first question in Artcraft above seeks the promise of the invention derived from the whole of the specification.
Does the claimed invention attain the result promised?
[75] Specification at page 2 lines 18-21.
The opponent pressed that “at least claim 1 lacks utility because, the claim encompasses reaction mixtures and reaction conditions which will not work or indeed, will not produce mRNA suitable for administration as a vaccine to a human subject (i.e., with less contaminants than the art-described methods).”[76] To this end, the opponent relied on the following quotes from the experts:
“I note that Example 4 showed that for both the equimolar process and alpha process low temperature IVT reactions (< 30°C) produce a larger abundance of reverse complement RNAs than IVT reactions at 37°C.”[77]
“…there will be upper and lower limits to all NTP concentrations, and the disparity between GTP and the remaining NTPs, beyond which the reaction will no longer be efficient in producing (full-length) transcripts. The upper limit of NTPs will also be driven by the solubility of NTPs in solution.”[78]
“…there will be NTP concentrations that fulfil the criteria of the NTP concentrations of the claims but will be outside the useful range for efficient IVT and consequently could result in a higher proportion of immunogenic contaminants.”[79]
“…I would not expect to achieve the same result (i.e., less than 1% of the total mass of RNA in the reaction mixture is a reverse complement transcription product) with any concentration of GTP that is at a concentration greater than the concentration of one or more of ATP, CTP and UTP, wherein two or more of ATP, CTP and UTP are in equimolar amounts. One can envisage NTP concentrations that fulfil these criteria but will be outside the useful range for efficient IVT and could result in higher proportions of immunogenic contaminants.”[80]
[76] Opponent submissions in support at [254].
[77] Gerber at [74].
[78] Preiss at [134].
[79] Preiss at [138].
[80] Preiss at [141].
The statements by the two experts relate to their comments in relation to the examples of the opposed application. The examples of the opposed application showed only that the alpha and GDP alpha outperformed the equimolar starting mixture. Consequently, the experts are unable to extrapolate these results across the claimed scope without any certitude. I note that the concerns are couched in possible outcomes, such as “could result in”, rather than absolute terms. There is no evidence as to any particular embodiment properly within the scope of the claims that does not work.
A person skilled in the art would understand the invention to operate within generally accepted limits of IVT reactions. While failure may be achieved by intentionally operating outside known limits, the promise of the opposed application does not extend beyond known limits of IVT reaction conditions. It follows that I consider this a case as alluded to by Beach J in Sequenom where a skilled person would construe the claims in a manner that does not give rise to unworkability.
Conclusion on utility
The opponent has raised doubts and concerns in relation to the likely outcomes of the claimed IVT process. However, the opponent has only provided mere speculation rather than any evidence to show that the claims include within their scope any particular embodiment that would not be useful or would not achieve at least some aspect of the benefits promised in the specification. Consequently, this ground of opposition fails.
Novelty
It is a requirement of subsection 18(1) of the Act that the invention, so far as claimed in any claim, is novel. Subsection 7(1) provides that an invention is taken to be novel unless it is not novel in light of the prior art base. Prior art information made publicly available in a document or through the doing of an act forms part of the prior art base for the purpose of novelty if it was published before the priority date of a claim.
It is well established that the general test for lack of novelty is the reverse infringement test, as set out by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd:
“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.” [81]
[81] Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; 137 CLR 228 at 235, [20].
This test is satisfied if the alleged anticipation discloses all the essential features of the invention as claimed.[82] The level of disclosure required is set out in General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd:
“If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. …if carrying out the directions contained in the prior inventor’s publication will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.
If, on the other hand, 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 which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee’s claim the prior publication 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.” [83] (citations omitted)
[82] Nicaro Holdings Pty Ltd v Martin Engineering Co [1990] FCA 40;(1990) 91 ALR 513 at 517.
[83] General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd [1972] RPC 457 at 485-486.
The requirement for clear and unmistakable directions in the prior publications from General Tire is well known. General Tire also states that if carrying out the directions in the prior art leads inevitably to doing something within the scope of the claim in suit, then there will be a lack of novelty. This inevitable consequence of carrying out the directions in the prior art was considered in Novozymes v Danisco[84] with Jessop J providing the following guidance (with Yates J and Greenwood J concurring):
“In my view, the General Tire approach, if taken at all, may be taken only with respect to the whole of any claim asserted to have been anticipated. The ‘precise destination’ at which the flag must have been planted is one which includes every integer of the claim. The approach cannot, in my view, be taken for some integers only, leaving others to be dealt with by reference to the understanding of the skilled addressee.”[85]
[84] Novozymes A/S v Danisco A/S [2013] FCAFC.
[85] Novozymes A/S v Danisco A/S [2013] FCAFC at [145].
More recently, the Full Court considered where the prior art discloses the invention in hypothetical manner without concrete confirmation of the results and emphasised as follows:
“We do not accept that a documentary disclosure containing an hypothesis cannot be an anticipatory disclosure that deprives an invention of novelty. In such a case the question, simply put, remains: what does the prior document disclose? The occasion on which, or the context in which, a particular documentary disclosure is made may well inform the interpretation of the document’s content. But if, as a matter of interpretation, the document nonetheless discloses that which is later claimed as an invention, that disclosure will anticipate the invention and deprive it of novelty.”[86]
[86] Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd [2020] FCAFC 116 at [104].
With that in mind, I will now look at the disclosures of the prior art. The Opponent pressed that claims 1-3, 5-8 and 11-13 are not novel in light of D2, D4 or D5.[87]
D2: Triana-Alonso et al.: “Self-coded 3’-Extension of Run-off Transcripts Produces Aberrant Products during in Vitro Transcription with T7 RNA Polymerase”, Journal of Biological Chemistry, 1995, vol. 270, iss. 11, pp. 6298-6307
D4: Kariko et al.: “Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA”, Immunity, 2005, vol. 235, no. 2, pp. 165-175
D5: WO 2011/005799 A2 (NOVARTIS AG) 13 January 2011
[87] Opponent submissions in support at [84].
Professor Gerber was asked to consider each of these documents and provide general comments as well as whether he thought that the claimed invention was new given the disclosures of these documents.[88] Professor Preiss was asked a similar task for eight documents, including D2, D4 and D5.[89]
Novelty in light of D2
[88] Gerber at [35].
[89] Preiss at [29] and [70].
The opponent pressed that claims 1, 2, 5-8 and 11-13 lack novelty in light of D2. According to Professor Preiss, “D2 generally discusses synthesis of incorrect products during RNA transcription with T7 RNA polymerase as a result of run-off transcription.”[90] Professor Preiss goes on to note that D2 identifies the following parameters that influence the extent of false transcription: incubation time; RNA polymerase concentration; and UTP concentration.[91] Professor Gerber took particular interest in the last parameter:
“In summary, the key finding of D2 was that the number of false products formed during IVT depends on NTP concentration. That is, if all NTPs are used in the same concentration then the transcript will be extended and false products will be produced. However, if the concentration of UTP was lowered, then the production of false products is reduced.”[92]
[90] Preiss at [43].
[91] Preiss at [44].
[92] Gerber at [37].
Indeed, the abstract of D2 concludes with the following:
“Surprisingly, a reduction of the UTP concentration to 0.2-1.0 mM in the presence of 3.5-4.0 mM of the other NTPs leads to faithful transcription and good yields, irrespective of the nucleotide composition of the template.”
A person skilled in the art may expect the modified IVT process of D2 to result in faithful transcription of whatever DNA template used. Neither expert suggested that D2 discloses a method for producing mRNA comprising an open reading frame encoding a vaccine antigen and is suitable for administration as a vaccine.
According to the applicant, the use of 32P labelled mRNA “cuts against the requirement in the present claims that the mRNA must be suitable for administration as a vaccine to a human subject.”[93] The applicant went on to submit that “given the increased risk of cell death and mutation resulting from radiation exposure”, therapeutics and vaccines do not typically contain radioactive material.[94] However, I note that neither expert had any concerns with using 32P labelled mRNA as a model for studying the transcription fate.
[93] Applicant submissions in answer at [054].
[94] Applicant submissions in answer at [056].
Irrespective of whether D2 included studies using 32P labelled mRNA, in the absence of any disclosure of producing mRNA comprising an open reading frame encoding a vaccine antigen D2 cannot be said to anticipate the present claims. All claims are novel in light of D2.
Novelty in light of D4
The opponent pressed that claims 1-3, 5-7 and 11-13 lack novelty in light of D4. According to Professor Preiss, D4 generally describes the effects of incorporating modified nucleosides into RNA on toll-like receptor (TLR) signalling and on dendritic cell activation.[95]
[95] Preiss at [54].
D4 describes materials and methods used to produce mRNA by IVT, including the use of DNA templates and T7 RNA polymerase.[96] Professor Gerber noted that the methods of D4 describe the following RNA transcripts with functional coding regions: RNA-1866 (NdeI-linearized pTEVluc) which encodes firefly luciferase and a 50 nt-long polyA-tail; RNA-1571 (SspI-linearized pSVren) which encodes Renilla luciferase; RNA-730 (HindIII-linearized pT7T3D-MART-1) which encodes the human melanoma antigen; RNA-713 (EcoRI-linearized pT7T3D-MART-1) which corresponds to antisense sequence of MART-1; and RNA-497 (BglII-linearized pCMV-hTLR3) which encodes a partial 5’ fragment of hTLR3.[97]
[96] D4 at page 174 left column paragraph 2.
[97] Gerber at [50].
The applicant submitted that “While there is some disclosure in D4 of an mRNA produced using T7 RNA polymerase and encoding MART-1, this is not in the context of vaccination.”[98] Given that the claims of the opposed application are directed to methods of producing mRNA that is suitable for administration as a vaccine and comprises an open reading frame encoding a vaccine antigen, there is no need for D4 to have disclosed a vaccination protocol using the mRNA. The question is whether the mRNA encoding for MART-1 produced by the method of D4 would be suitable for administration as a vaccine. While D4 does not mention vaccinations, as noted by the applicant, MART-1 is an antigen that can be recognised by the immune system and is used as a cancer vaccine.
[98] Applicant submissions in answer at [0162].
Professor Preiss was specifically asked to consider whether the methods disclosed in D4 would potentially produce a viable mRNA vaccine and responded that “if the template was switched to a template encoding an mRNA vaccine candidate, the conditions used in D4 could have produced an mRNA that was functional as a prototype mRNA vaccine.”[99] From this, I understand that Professor Preiss does not consider RNA-730 encoding the human melanoma antigen to be a vaccine antigen and/or that it would not be suitable for administration to a human subject as a vaccine. The evidence of Professor Gerber is also silent with respect to any of the model mRNA of D4 being suitable as a vaccine antigen.
[99] Preiss at [87].
However, as repeatedly stressed by the applicant, neither declarant is an expert in the field of vaccines. It is therefore unsurprising that they did not recognise a potential antigen of interest.
Initially, Professor Preiss stated that each IVT reaction in D4 used equimolar concentrations of all four nucleotides.[100] Upon comparing the claimed invention with D4, Professor Preiss reasoned that the concentration of GTP was greater in instances where one or more of the other natural NTPs were substituted with a modified equivalent.[101] As D4 disclosed substituting one natural NTP at a time, as well as GTP being present in greater concentration than the natural NTP with modified substitution, there were also two other NTPs in equimolar amounts. Professor Gerber made a similar observation for D4.[102]
[100] Preiss at [55].
[101] Preiss at [81].
[102] Gerber at [52].
As explained in the construction section above, where the claims do not specify “natural” or “modified” NTPs, they encompass both natural and modified NTPs. Therefore, I understand the claims to be defining the relative concentrations of the sums of both natural and modified NTPs. This is consistent with the examples of the opposed application and the initial reading of D4 given by Professor Preiss before being asked to compare the disclosures of D4 specifically to the claims. Moreover, D4 explicitly states that “In each transcription reaction, all four nucleotides or their derivatives were present in equimolar (7.5 mM) concentration.”[103]
[103] D4 at page 174 left column paragraph 2.
Therefore, given my construction of the claims, D4 does not disclose an IVT process where GTP, or GTP plus GDP, is in greater concentration than one or more of ATP, CTP and UTP where the molar concentration is calculated on the sum of natural and modified NTPs. All claims are novel in light of D4.
Novelty in light of D5
The opponent pressed that claims 1-3 and 11-13 lack novelty in light of D5. According to Professor Gerber, “D5 describes the synthesis and transfection of self-replicating RNAs using cell based assays and their immunogenicity in mice.”[104] In particular, attention is drawn to example 9, where self-replicating RNA vaccines were produced through IVT with modified nucleosides.[105] Similar to D4, the example uses equimolar NTPs, where difference in concentrations between natural NTPs occur only when a portion of one NTP is substituted for a modified NTP.[106]
[104] Gerber at [60].
[105] Gerber at [61] and Preiss at [89].
[106] Gerber at [61] and Preiss at [89].
While the experts draw direct analogy to the claimed features, they do not suggest that self-replicating RNAs fall within the scope of mRNAs. Even if self-replicating RNA was equated to mRNA, D5 discloses the use of equimolar NTPs in the IVT reactions. Therefore, the claims are novel in light of D5.
Conclusion on novelty
None of the prior art documents provide clear and unmistakable directions to the claimed invention. The opponent has not made out this ground of opposition.
Inventive step
Subsection 7(2) states that an invention is taken to involve an inventive step unless it would have been obvious to a person skilled in the art in light of the common general knowledge (whether in or out of the patent area) before the priority date of the relevant claim when considered alone or together with the information mentioned in subsection 7(3).
Nicholas J provided a statement of principles relevant to assessing inventive step:
“Section 7(2) of the Act uses the word ‘obvious’ in the course of describing what must be established before an invention can be held not involve an inventive step. Something may be ‘obvious’ in light of the common general knowledge, or the common general knowledge coupled with the relevant s 7(3) information, if it is ‘plain or open to the eye or mind, something which is perfectly evident to the person thinking on the subject’ or something which ‘would at once occur to anyone acquainted with the subject and desirous of accomplishing the end’.
An invention may also be obvious in light of the common general knowledge if the person skilled in the art faced with the same problem as the inventor would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not or (using the language of the ‘modified Cripps question’) if the person skilled in the art would be directly led as a matter of course to take such steps in the expectation that doing so might well produce a useful or better alternative to the prior art. However, a claimed invention is not obvious merely because the person skilled in the art would consider that it was ‘worthwhile to try’.”[107]
[107] Hood v Bush Pharmacy Pty Ltd [2020] FCA 1686 at [116]-[117] (citations omitted).
It is important to note the requirement for a reasonable expectation of success. This is explicit in the expectation that an approach “might well” succeed, and implicit in the characterisation of steps as those to be taken as a matter of routine.[108] However, success need not be guaranteed: “the relevant test is not knowing that steps will or would or even may well work, but merely expecting that the steps may well work.”[109] Further, it is possible that the skilled person might be directly led to try more than one alternative expecting that each may well produce a useful or desired result.[110]
[108] Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73; 314 ALR 91 at [71].
[109] Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2 at [99].
[110] Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2 at [91]-[93].
Importantly, where a claim is directed to a combination of known integers obviousness is not established merely by identifying each of those features in the prior art or the common general knowledge – the question is whether the combination of those features is obvious.[111] In a similar vein, the High Court said that the question of whether it would be obvious to add one integer to a combination of other integers:
“…will turn on what a person skilled in the relevant art, possessed with that person’s knowledge would have regarded, at the time, as technically possible in terms of mechanics, and also as practical. … Even if an idea of combining integers, which individually may be considered mere design choices, is simple, its simplicity does not necessarily make it obvious.”[112]
Common general knowledge
[111] Minnesota Mining and Manufacturing Co v Beiersdorf (Aust) Ltd [1980] HCA 9; 144 CLR 253 at 293, Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; 212 CLR 411 at 429, [41].
[112] Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21 at [111].
Common general knowledge 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.”[113]
[113] Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; 144 CLR 253 at 293.
However, it is not enough that information is recorded in a document, even if that document is widely circulated. It is only part of the common general knowledge when it is generally known and accepted in the art:
“…information does not constitute common general knowledge merely because it might be found, for example, in a journal, even if widely read by persons in the art … Reference in this regard is made to the words of Luxmoore J in British Acoustic Films (1936) 53 RPC 221 at 250, cited by Lehane J in Aktiebolaget Hässle v Alphapharm Pty Ltd (1999) 44 IPR 593; [1999] FCA 628 at 605 [39]:
In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art.”[114]
[114] Ranbaxy Laboratories Limited v AstraZeneca AB [2013] FCA 368; 101 IPR 11 at [217].
The opponent provided a summary of matters that were common general knowledge before the priority date, as explained by Professor Gerber and Professor Preiss:
“(i)Methods of synthesising mRNA encoding a protein of interest, including use of IVT.
(ii)Key properties of a functional mRNA, including therapeutic mRNA, such as coding sequence and humanised codon choice, optimised untranslated region (UTR) sequences, cap structures, polyadenylation and internal nucleoside modifications.
(iii)Components of IVT reactions and the role of each component, including a DNA template, an RNA polymerase, nucleotide triphosphates (i.e., ATP, GTP, UTP, GTP), reagents for capping such as a capping dinucleotide (if performing co-transcriptional capping), modified nucleotides if used, an RNase inhibitor, a buffer, a reducing agent, and optionally a bulking agent. A number of commercial IVT kits were available before the claimed priority date, such as MEGAscript™ and RiboMAX™, included standard reagents and troubleshooting manuals.
(iv)Effect of IVT reaction conditions on the resultant mRNA transcript that could cause issues with the mRNA produced, including therapeutic use, such as generation of double-stranded RNA, generation of degradation products, incomplete capping and incomplete transcription.
(v)Effect of excess and/or unincorporated nucleotides in IVT reactions on RNA produced, including purity, yield and quality, and persistence in a mRNA IVT product, which can potentially activate the neuroinflammatory mechanisms in the central nervous system.
(vi)Methods of optimising IVT reaction conditions to control the nature, or amount, of unwanted contaminants, include [sic] optimising nucleotide triphosphate concentrations and ratios, and enzyme concentrations.
(vii)Advantages of using modified nucleotides (e.g., pseudouridine (Ψ), 2-thiouridine, 5-methylcytidine, etc.) in IVT reaction mixtures titrated with the corresponding natural nucleotide to achieve improved yield and purity, and to reduce immune recognition and stimulation.
(viii)Importance of reducing immune system stimulation when producing mRNA therapeutics, including vaccines, such as those caused by contaminants, including double-stranded RNA.”[115]
[115] Opponent submissions in support at [25]. (citations omitted)
The applicant was in agreement with the above, except for (viii) including reference to vaccines.[116] The applicant stressed that neither declarant was specifically qualified to give evidence in relation to mRNA vaccines.[117] However, I note that the applicant did not provide any contradictory evidence.
[116] Applicant submissions in answer at [0136].
[117] Applicant submissions in answer at [0137].
In any event, the opposed application itself makes apparent that various vaccine antigens were already well known in the art. It is suggested that vaccine antigens currently being marketed or in development may be used.[118] As well as personalised cancer vaccines,[119] a long list of infectious diseases that RNA vaccines may treat, such as hepatitis, measles, influenza, cholera, rabies, amoebiasis, rubella, mumps and polio, is given as suitable treatment targets.[120]
The problem
[118] Specification at page 71 lines 28-29.
[119] Specification at page 71 line 30 – page 72 line 2.
[120] Specification at page 73 line 4 – page 74 line 13.
As noted by the opponent,[121] the problem to be solved according to the opposed application is:
“a need for better understanding of the nature of contaminants in IVT-generated mRNA preparations, in order to better control for levels and nature of contaminants in IVT preparations. There further exists a need for improved methods of preparing mRNA for therapeutic use and for high purity compositions produced according to such methods.”[122]
[121] Opponent submissions in support at [154].
[122] Specification at page 2 lines 11-15.
The claimed invention is directed at the mRNA vaccine subset of the broader field of RNA production. That is, the problem addressed by the opposed application does not reside in providing a new vaccine antigen or even a new mRNA vaccine. The problem lies simply in providing improved IVT methods for preparing RNA.
Inventive step in light of common general knowledge alone
I understand the broad strokes of the opponent’s case on obviousness in light of the common general knowledge alone to be along the lines of RNA synthesis through IVT being well known and the production of mRNA vaccines through such methods being a mere choice of what is encoded.[123] Of particular relevance to the present claims, Professor Gerber summarised the process of carrying out IVT reactions using commercially available kits:
“At 14 September 2016, these kits, and others, were commonly used for IVT with linearised DNA templates derived from plasmids or upon annealing of single stranded DNA (ssDNA) synthetic fragments (30-60 nucleotides) bearing a minimal T7 promotor sequence. Following incubation, DNAse I digest is performed in the same reaction buffer and then EDTA is added to stop the reaction and complex Mg2+.
Following the IVT reaction, RNA precipitation and/or purification is typically undertaken using an RNA isolation kit to ensure contaminants are removed that could induce inflammatory responses when used in vivo.
The mRNA produced using IVT normally comprises of 5’ UTRs, 3’ UTRs, the coding sequence, 3’ polyA tail and 5’ cap. Typically, the 3’ polyA tail and 5’ cap components can be added either co-transcriptionally or post-transcriptionally.”[124]
[123] Opponent submissions in support at [164].
[124] Gerber at [18]-[20].
The evidence convincingly establishes that those in the field knew, as a matter of common general knowledge, that IVT methods could be used to produce RNA products. The evidence also establishes that IVT reaction conditions, such as excess and/or unincorporated NTPs, can impact on the on the resultant mRNA transcript that could cause issues with the mRNA produced. For example, generation of double-stranded RNA, generation of degradation products, incomplete capping and incomplete transcription could potentially activate inflammatory mechanisms and cause issues in therapeutic use.
In the present case, although IVT methods were known and it was also known that many factors could affect the resulting product, there is nothing to suggest that the modified method itself was common general knowledge. Irrespective of the RNA product being encoded, the opponent has not established that the claims lack inventive step in light of the common general knowledge alone.
Common general knowledge plus D2
The opponent submitted that a person skilled in the art looking for an IVT method to produce mRNA suitable for use as a vaccine would follow the IVT method of D2:
“In particular, it is clear that the person skilled in the art, desirous of controlling for levels and the nature of contaminants in IVT preparations to thereby produce high purity mRNA, ) [sic] would have been directly led, if not driven, as a matter of course to follow the IVT method taught in D2 and reduce the concentration of UTP in the IVT reaction mixture relative to the remaining NTPs (i.e., GTP, ATP and CTP), to arrive at the method of claim 1 and with a reasonable expectation of successfully producing a high quality mRNA suitable for therapeutic use.”[125]
[125] Opponent submissions in support at [170].
The applicant was concerned by the lack of disclosure of mRNA suitable for administration as a vaccine to a human and the presence of 32P radioactive label in the model experiments as teaching away from such a use.[126] However, both Professor Gerber and Professor Preiss answered positively to the hypothetical task of using the technique of D2 to produce mRNA encoding a vaccine antigen for therapeutic use.[127] Given the weight of the evidence, I am confident that a person skilled in the art would not share the same concerns as the applicant.
[126] Applicant submissions in answer at [0156].
[127] Gerber at [47] and Preiss at [78].
Whether an IVT method is described as using an excess of GTP or a reduction of UTP, they both fulfil the requirement of GTP concentration being greater than one or more of the other NTPs (UTP) and two or more NTPs (ATP and CTP) being in equimolar concentrations. The only difference is in the product to be encoded by the mRNA, which is determined by the DNA template used in the IVT process. According to the expert evidence, replacing one template with another known template does not require further invention.
With regard to the presence of 32P radioactive label in the model experiments in D2, it was simply used for visualisation of the mRNA products, not for any therapeutic purpose.[128] In a similar fashion, the opposed application also used 32P radioactive label in Example 11 to determine the sample purity of model RNA constructs.[129]
[128] Gerber at [44].
[129] Gerber at [82].
The present claims are directed to methods of producing mRNA by IVT where the reaction mixture has been modified to reduce the production of contaminants. As noted by the opponent, D2 teaches that the preferential reduction of UTP concentration relative to the other NTPs “leads to faithful transcription and good yields, irrespective of the nucleotide composition of the template.”[130] In this context, I am satisfied that the expert evidence supports a conclusion that simply encoding a known vaccine antigen in place of the model peptides of D2 does not require further invention.
[130] D2 abstract.
Therefore, claims 1-8 and 11-20 of the opposed application lack inventive step in light of D2. Features of the IVT process, such as the use of modified NTPs, choice of polymerase and reaction temperature, are routinely chosen by the person skilled in the art depending on the nature of the desired product and components used in the reaction mixture. There are well defined reaction conditions and components known in the art.[131]
[131] Gerber at [14]-[20 and Preiss at [20]-[28].
Claims 9 and 10 of the opposed application are inventive over common general knowledge plus D2 as this document teaches maintaining GTP, CTP and ATP in equimolar concentrations.
Common general knowledge plus D4
The opponent submitted that a person skilled in the art looking for an IVT method to produce mRNA suitable for use as a vaccine would have been directly led, if not driven, to follow the IVT method of D4.[132] Similar to D2, at least Professor Preiss also hypothesised that switching the template with one encoding for a mRNA vaccine antigen candidate would produce a prototype mRNA vaccine.[133]
[132] Opponent submissions in support at [178].
[133] Preiss at [87].
As noted by the applicant, D4 discloses an IVT process using modified UTPs to produce mRNA including an embodiment encoding MART-1, which is a peptide suitable for use as a therapeutic cancer vaccine.[134] The document itself is silent with respect to the potential use of MART-1 as a cancer vaccine and neither professor picked up on this antigen.
[134] Applicant submissions in answer at [0162].
Regardless of the nature of the template, the IVT process employs equimolar amounts of GTP, CTP, ATP and UTP. The concentration of the natural NTPs may vary from experiment to experiment as modified NTPs replace portions of their natural cousins. However, the combination of the natural and modified NTP is equivalent to the other NTPs. Consequently, D4 does not teach an IVT method where the concentration of GTP or GTP plus GDP is greater than another NTP and where two or more NTPs are present in equimolar amounts.
Therefore, it has not been established that claims 1-20 of the opposed application lack inventive step in view of common general knowledge plus D4.
Common general knowledge plus D5
According to the opponent, a person skilled in the art looking for an IVT method to produce mRNA suitable for use as a vaccine would have been directly led, if not driven, to follow the IVT method of D5 as well.[135] However, whilst Professor Preiss could identify some features of the invention disclosed in D5, he does not suggest that the method of D5 could be used to produce mRNA vaccines.[136] Professor Gerber was put to a similar task and responded:
“I was also asked whether I would expect the methods of D5 to work for an mRNA comprising an antigen for therapeutic use (i.e., vaccine). Overall, I consider that the methods look promising when looking to produce IVT mRNA for use in vaccines and therapeutic use.”[137]
[135] Opponent submissions in support at [184].
[136] Preiss at [88]-[94].
[137] Gerber at [69].
The IVT process of D5 may provide a good starting point for producing mRNA vaccines. However, as with D4, the IVT process of D5 employs equimolar amounts of GTP, CTP, ATP and UTP where variations in concentrations can only be found where a modified NTP is subtracted from the total.
Therefore, it has not been established that claims 1-20 of the opposed application lack inventive step in view of common general knowledge plus D5.
Conclusion on inventive step
The opponent has not established that the claims lack inventive step in light of the common general knowledge alone or in combination with D4 or D5.
The evidence does however establish that claims 1-8 and 11-20 lack inventive step in light of common general knowledge plus D2. The opposition is successful on this ground.
Clear enough and complete enough disclosure and support
Section 40, as amended by the Raising the Bar Act, relevantly requires that the complete specification disclose the invention in a manner that is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art (section 40(2)(a)) and that the claim or claims be supported by matter disclosed in the specification (section 40(3)). Such enablement must be across the whole breadth of the claims, without undue burden or the need for further invention and the claim scope must not exceed the applicant’s contribution to the art. Delegates of the Commissioner have adopted the following stepped approach to assessing whether there is a clear enough and complete enough disclosure:
a) Construe the claims to determine the scope of the invention as claimed;
b) Construe the description to determine what it discloses to the person skilled in the art; and
c) Decide whether the specification provides an enabling disclosure of all the things that fall within the scope of the claims.[138]
1.Is it plausible that the invention can be worked across the full scope of the invention?
2.Can the invention be performed across the full scope of the claims without undue burden?[139]
[138] CSR Building Products Limited v United States Gypsum Company [2015] APO 72.
[139] Evolva SA [2017] APO 57.
These principles have been confirmed by the Federal Court.[140] Similarly, the requirement of support was discussed by Burley J:
“In CSR Building Products Ltd v United States Gypsum Company [2015] APO 72, Dr S D Barker adopted the summary provided by Aldous J in Schering Biotech at 252 – 253, which has been often followed in the United Kingdom (emphasis added):
...to decide whether the claims are supported by the description it is necessary to ascertain what is the invention which is specified in the claims and then compare that with the invention which has been described in the specification. Thereafter the court’s task is to decide whether the invention in the claims is supported by the description. I do not believe that the mere mention in the specification of features appearing in the claim will necessarily be a sufficient support. The word ‘support’ means more than that and requires the description to be the base which can fairly entitle the patentee to a monopoly of the width claimed.
That approach encapsulates broadly the claim support obligation under s 40(3). To it may be added the requirement that the technical contribution to the art must be ascertained. Where it is a product, it is that which must be supported in the sense that the technical contribution to the art disclosed by the specification must justify the breath of the monopoly claimed.”[141]
[140] Cytec Industries Inc. v Nalco Company [2021] FCA 970.
[141] Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) [2020] FCA 1477 at [546]-[547].
The opponent also points to the matter in Jusand[142] where the Full Court applied principles entirely consistent with those above and also considered the concept of a relevant range for the purpose of assessing enablement across the scope of the claims. There it was noted that whether a range is a relevant range is to be:
“...judged against the invention as claimed and, where appropriate, against its essence or core where that is understood to be related to the technical contribution the specification makes to the art and/or its inventive concept.”[143]
[142] Jusand Nominees Pty Ltd v Rattlejack Innovations Pty Ltd [2023] FCAFC 178 at [217].
[143] Jusand Nominees Pty Ltd v Rattlejack Innovations Pty Ltd [2023] FCAFC 178 at [191].
The Full Federal Court considered issues of support and sufficiency and noted:
“In many cases these obligations may tend to be the same since they are describing the same relationship although viewed from the differing perspectives of the claims and the specification. As Burley J has observed in Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) [2020] FCA 1477; 155 IPR 1 (‘Merck Sharp’) at [543], they may often be viewed as two sides of the same coin.”[144]
Opponent submissions
[144] Jusand Nominees Pty Ltd v Rattlejack Innovations Pty Ltd [2023] FCAFC 178 at [155].
The opponent submitted that claim 1 is overly broad and encompasses any amount of GTP or GTP plus GDP that is greater than that of another NTP.[145] It is their view that “Claim 1 of the Opposed Application encompasses ranges and combinations of nucleotide concentrations that would not successfully produce an mRNA product that would be suitable for administration as a vaccine.”[146] Claims 8 and 9 introduce ratio values but remain broader than the exemplified embodiment but claim 10 is recognised as reflecting the ratios of NTPs used in the exemplified embodiment.[147] Claims 14 and 15 introduce further functional limitations directed to the desired outcomes of the mRNA transcript produced by the methos of the invention.[148]
[145] Opponent submissions in support at [201].
[146] Opponent submissions in support at [203].
[147] Opponent submissions in support at [213].
[148] Opponent submissions in support at [216].
As explained by Professor Gerber and Professor Preiss, the claimed invention encompasses any amount of GTP or GTP plus GDP greater than the amount of another NTP.[149] For example, Professor Preiss explained:
“There will be upper and lower limits to all NTP concentrations, and the disparity between GTP and the remaining NTPs, beyond which the reaction will no longer be efficient in producing (full-length) transcripts.”[150]
[149] Opponent submissions in support at [216].
[150] Preiss at [127].
Professor Gerber also explained:
“In addition, the error rate of RNA polymerase may pose a problem depending on the concentration of NTPs in the reaction. In particular, if the NTP concentration is too low, it may lead to aberrant transcripts, whilst if the NTP concentration is too high it may lead to aberrant transcripts and inefficient transcription.”[151]
[151] Gerber at [88].
The opponent submitted that although the specification references a wide range of NTP concentrations and ratios for the modified IVT reactions, there is no guidance on how to make appropriate selections to successfully produce a mRNA that is suitable for administration as a vaccine to a subject across the very broad scope of the claims.[152] Throughout the specification, only 3 reaction mixtures are provided: the equimolar (1:1:1:1 ratio of GTP:ATP:CTP:UTP), alpha (4:2:1:1 ratio of GTP:ATP:CTP:UTP) and GDP alpha (4:2:2:1:1 ratio of GDP:GTP:ATP:CTP:UTP) reactions.[153] In comparison to the equimolar reaction, the alpha and GDP alpha processes demonstrated increased RNA integrity and purity, and reduced reverse complements, double stranded and run-on transcripts.[154]
[152] Opponent submissions in support at [206].
[153] Opponent submissions in support at [207].
[154] Opponent submissions in support at [208].
The opponent describes the applicant’s technical contribution to the art as being:
“to exemplify a reaction mixture comprising a 4:2:1:1 ratio of GTP:ATP:CTP:UTP or 2:2:1:1 ratio of GTP:ATP:CTP:UTP when GDP is present.”[155]
[155] Opponent submissions in support at [214].
The opponent submitted that the breadth of the subject matter claimed is “nothing more than mere speculation derived from the two exemplified reaction mixtures provided in the Opposed Application.”[156] Furthermore, the experts also noted additional differences between the equimolar and alpha processes:
“However, I note that there are additional difference between the equimolar process and the alpha process (see page 95, Table 1). For example, the alpha process comprises more polymerase (i.e., 14 U/μl) than the equimolar process (i.e., 7 U/μl). The alpha process also comprises more phosphate (i.e., effective phosphate 180 or 195, for the alpha or alpha GDP processes respectively) than the equimolar process (i.e., effective phosphate 90). Accordingly, I cannot attribute any improvements conferred by the alpha process solely to the different concentrations of NTPs.”[157]
[156] Opponent submissions in support at [210].
[157] Gerber at [75].
The opponent submitted that there is therefore “an absence of teaching in the opposed application as to how an appropriate reaction mixture is obtained in order to achieve a mRNA product with enhanced properties suitable for administration to a subject as a vaccine.”[158] Given the limited range of conditions and reaction mixtures shown to produce any mRNA product, the opponent submitted that it “places a significant undue burden on the skilled person seeking to successfully work the invention to ascertain which incubation times and reaction temperatures achieve a mRNA having enhanced properties that is suitable for administration as a vaccine to a human subject.”[159]
Applicant submissions
[158] Opponent submissions in support at [212].
[159] Opponent submissions in support at [224].
The applicant submitted that the “breadth of claim scope cannot automatically be equated with undue experimental effort” and the specification must be considered as a whole in the context of the common general knowledge in the art at the relevant time.[160] The applicant does not consider Professor Gerber and Professor Preiss to be relevant persons skilled in the art and submitted that their evidence in relation to the specification should be discarded.[161]
[160] Applicant submissions in answer at [0196].
[161] Applicant submissions in answer at [0205].
Instead, it was submitted that the examples in the opposed application provided a proof of concept showing B cell activation in an animal model following the administration of mRNA encoding human erythropoietin prepared by the alpha method.[162] It is further submitted that “This proof of concept is irrefutable and together with the other examples taught in the opposed application, would be understood by the skilled person as evidence of the ability to produce an mRNA that is suitable for administration as a vaccine to a human subject, wherein the mRNA encodes a vaccine antigen, using the claimed method.”[163]
[162] Applicant submissions in answer at [0206].
[163] Applicant submissions in answer at [0206].
With regard to the breadth of the reaction conditions in the claims, on the understanding that the person skilled in the art is motivated to make the claimed invention work, the applicant submitted that “it is clearly well established precedent that method claims do not require prescriptive recitation of every possible parameter such as the concentration of reaction constituents, temperatures, dosing regimes, etc.”[164]
Consideration
[164] Applicant submissions in answer at [0208].
At the outset, I will stress that the applicant did not provide any evidence. All submissions made by the applicant lack any evidentiary backing, unless relevant reference could be drawn from the evidence given by Professor Gerber or Professor Preiss. Although, the applicant held a strong view that both declarants lacked relevant skills and experiences to be giving evidence in relation to mRNA vaccines, in recognition of their qualifications and experiences in RNA biology as a whole, the opponent’s expert evidence will be preferred where the applicant’s submissions stray into technical matters.
The specification of the opposed application relates generally to mRNA production and there is no specific disclosure directed at the production of mRNA vaccines. The specification treats all mRNA products equally and does not single out mRNA vaccines as requiring any process that would differ from the others. The opposed application simply suggests that “one or more vaccine antigens currently being marketed or in development may be encoded by the RNA of the present invention.”[165] Furthermore, both declarants, who are experts in RNA synthesis through IVT, have not identified any difficulties with preparing mRNA encoding vaccine antigens relative to any other peptide sequence. Instead, both declarants attribute the lower levels of contaminants achieved through the modified IVT process with suitability of the product for administration as a vaccine.[166]
[165] Specification at page 72 lines 24-29.
[166] Gerber at [88] and Preiss at [25].
Other than the use of model sequences which do not encode vaccine antigens, the alpha and GDP alpha reactions of the opposed application fall within the scope of the claimed IVT method where the concentration of GTP or GTP plus GDP is greater than one or more NTPs and two or more of ATP, CTP and UTP are in equimolar concentrations. Both experts agree that the alpha and GDP alpha IVT process produces an improved mRNA product.[167] However, both experts also agree that the modified IVT reactions would not work across the full breadth of the claimed scope to produce mRNA suitable for administration as a vaccine:
“There will be upper and lower limits to all NTP concentrations, and the disparity between GTP and the remaining NTPs, beyond which the reaction will no longer be efficient in producing (full-length) transcripts. The upper limit of NTPs will also be driven by the solubility of the NTPs in solution.”[168]
“For example, with some concentrations the IVT reaction would possibly be less efficient and produce contaminants (e.g., no longer produce mRNA suitable for administration as a vaccine). In addition, the error rate of RNA polymerase may pose a problem depending on the concentration of NTPs in the reaction. In particular, if the NTP concentration is too low, it may lead to aberrant transcripts, whilst if the NTP concentration is too high it may lead to aberrant transcripts and inefficient transcription.”[169]
[167] Gerber at [88] and Preiss at [140].
[168] Preiss at [127].
[169] Gerber at [88].
Therefore, some parameters, such as NTP concentrations in the IVT reaction mixture, may require some attention on the part of the person skilled in the art. Based on the evidence at hand, it is apparent that the art of IVT has certain bounds within which a person skilled in the art would operate. That is, a person skilled in the art can anticipate the consequences of altering some reaction parameters and how to modify the reaction to suit their needs. For example, the opposed application shows that low temperature IVT reactions (< 30 °C) produce a larger abundance of reverse complement RNAs than IVT reactions at 37 °C.[170] The overall concentrations of NTPs, choice of RNA polymerases, reaction temperature and incubation duration are routinely adjusted and a person skilled in the art would expect to work through some fine tuning.
[170] Gerber at [91].
The opposed application provides a “typical” IVT reaction as including: an RNA polymerase at a final concentration of 1000-12000 U/mL; the DNA template at a final concentration of 10-70 nM; NTPs at a final concentration of 0.5-10 mM each; magnesium at a final concentration of 12-60 mM; a buffer at a pH of 7-8.5.[171]
[171] Specification at page 21 lines 6-11.
The specification broadly describes IVT reaction mixtures where any given NTP may be in excess.[172] The excess of the selected NTP is 0.5 mM to 150 mM greater than the other individual NTPs.[173] This is in line with the claimed invention extending to where the concentration of GTP or GTP plus GDP is simply greater than any one of the other NTPs and where two or more other NTPs are equimolar. Marginally increasing the GTP concentration or marginally dropping the concentration of just one of ATP, CTP or UTP in the IVT reaction mixture is all that is required to fall within the claimed scope.
[172] Specification at page 24 lines 9-11.
[173] Specification at page 22 lines 24-26 and page 23 lines 2-6.
In contrast to this, the only effective suppression of contaminants has been shown with the alpha and GDP alpha reactions performed with 30 mM GTP, 15 mM ATP, 7.5 mM CTP and 7.5 mM UTP (4:2:1:1 ratio of GTP:ATP:CTP:UTP) or 30 mM GDP, 15 mM GTP, 15 mM ATP, 7.5 mM CTP and 7.5 mM UTP (4:2:2:1:1 ratio of GDP:GTP:ATP:CTP:UTP). Professor Gerber stated that “it is not possible to know what other concentrations encompassed by the claim would work and certainly not every variation encompassed by the claim would work.”[174] Similarly, Professor Preiss does not expect an IVT reaction where GTP concentration is only marginally greater than the other NTPs to achieve the desired reverse complement transcription suppression.[175]
[174] Gerber at [88].
[175] Preiss at [141].
The opposed application does not provide any guidance, beyond the examples, with regard to appropriately choosing the relative amounts of the NTPs to ensure improved RNA products are obtained. Armed only with the guidance of using a selected NTP, GTP or GTP plus GDP in the case of the claimed invention, in a greater concentration than at least one of the other NTPs and two or more other NTPs are equimolar, the person skilled in the art is expected to work within the general bounds of IVT reactions to produce mRNA products with improved purity.
Professor Gerber opines that an IVT reaction of claim 8, where the reaction mixture comprises an at least 2:1 ratio of GTP concentration to any one of ATP, CTP or UTP concentrations, “may in principle work” but continues on to say that “it is not possible to know what would work and certainly not every variation encompassed by the claim.”[176] Professor Preiss considers that the ratios recited in claim 9 (at least 2:1 GTP:ATP, at least 2:1 or at least 4:1 GTP:CTP and at least 4:1 GTP:UTP) and claim 10 (2:1 GTP:ATP, 2:1 or 4:1 GTP:CTP and 4:1 GTP:UTP) reflect the alpha and GDP alpha reactions.[177]
[176] Gerber at [96].
[177] Preiss at [132].
While there is no certitude of product purity with deviation from the alpha and GDP alpha reactions, given the expert evidence, I am prepared to accept that the opposed application provides sufficient disclosure to enable a person skilled in the art to perform the invention of claims 9 and 10. Accordingly, the applicant’s contribution to the art resides in providing modified IVT reactions which have been shown to produce RNA with effective suppression of contaminants, thereby providing a better product. The modified IVT reaction is particularly well represented by the alpha and GDP alpha reactions. The applicant’s contribution to the art is a modified IVT reaction where GTP or GTP plus GDP is in excess by at least 2-fold of ATP and by at least 4-fold of CTP and UTP.
However, the alpha and GDP alpha reactions do not extend to a general principle where the concentration of the GTP or GTP plus GDP need only be greater than one or more of the other NTPs and two or more of the other NTPs are in equimolar concentrations. There is insufficient disclosure to enable a person skilled in the art to perform the inventions of claims 1-8 and 11-20, where the claims extend beyond the applicant’s contribution to the art.
The opposition is successful on these grounds.
Conclusion
The opponent has not made out the grounds for clarity, utility and novelty. The opposition is successful on the grounds of inventive step, clear enough and complete enough disclosure and support. Based on the evidence at hand, claims 1-8 and 11-20 lack inventive step and support and are not sufficiently described.
Despite my determination, I consider that the specification includes patentable subject matter and these issues can be overcome by amendment. I therefore allow the applicant two (2) months from the date of this decision to propose amendments to overcome the issues identified.
Costs
The normal approach is that costs should follow the event. I see no sufficient reason to depart from this approach. The opposition is successful. Accordingly, I award costs in accordance with Schedule 8 against the applicant, Moderna TX, Inc.
M. Umehara
Delegate of the Commissioner of Patents
Annex A – claims
1.A method of producing a messenger ribonucleic acid (mRNA) that is suitable for administration as a vaccine to a human subject, wherein the mRNA comprises an open reading frame encoding a vaccine antigen, the method comprising incubating a reaction mixture comprising a deoxyribonucleic acid (DNA), an RNA polymerase that initiates with a GTP or GDP, a buffer, adenosine triphosphate (ATP), cytidine triphosphate (CTP), uridine triphosphate (UTP), and guanosine triphosphate (GTP), thereby producing the mRNA, wherein:
(i)the concentration of GTP is greater than the concentration of one or more of ATP, CTP, and UTP, and two or more of ATP, CTP, and UTP are in equimolar concentrations; and/or
(ii)the reaction further comprises guanosine diphosphate (GDP), the concentration of GTP plus GDP is greater than the concentration of one or more of ATP, CTP, and UTP, and two or more of GTP, ATP, CTP, and UTP are in equimolar concentrations.
2.The method of claim 1, wherein the UTP is a natural UTP.
3.The method of claim 1, wherein the UTP is a modified UTP comprising 2’-O-methylribose, pseudouridine (ψ), N1-methylpseudouridine (m1ψ), 2-thiouridine, 4-thiouridine, 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, or 5-methoxyuridine.
4.The method of claim 1 or 3, wherein the UTP is an N1-methylpseudouridine triphosphate (N1-methylpseudo-UTP).
5.The method of any one of claims 1-4, wherein the amount of the GTP is greater than an amount of the UTP.
6.The method of any one of claims 1-5, wherein the amount of the ATP is greater than the amount of the UTP.
7.The method of any one of claims 1-6, wherein the amount of the CTP is greater than the amount of the UTP.
8.The method of any one of claims 1-7, wherein the reaction mixture comprises an at least 2:1, at least 3:1, at least 4:1, at least 5:1, and/or at least 6:1 ratio of GTP concentration to any one of ATP, CTP, or UTP concentrations.
9.The method of any one of claims 1-8, wherein the reaction mixture comprises an at least 2:1 ratio of GTP concentration to ATP concentration, an at least 2:1 or at least 4:1 ratio of GTP concentration to CTP concentration, and an at least 4:1 ratio of GTP concentration to UTP concentration.
10.The method of any one of claims 1-9, wherein the reaction mixture comprises a 2:1 ratio of GTP concentration to ATP concentration, a 2:1 or 4:1 ratio of GTP concentration to CTP concentration, and a 4:1 ratio of GTP concentration to UTP concentration.
11.The method of any one of claims 1-10, wherein the RNA polymerase is selected from T7 polymerase, T3 polymerase, and SP6 polymerase.
12.The method of claim 11, wherein the RNA polymerase is T7 polymerase.
13.The method of any one of claims 1-12, wherein the reaction mixture is incubated at 25 degrees Celsius or at 37 degrees Celsius.
14.The method of any one of claims 1-13, wherein the produced mRNA is less immunogenic and/or has fewer double-stranded impurities than an mRNA made by a comparable method but with equimolar amounts of the GTP, ATP, CTP and UTP in the reaction mixture.
15.The method of any one of claims 1-14, wherein less than 1% of the total mass of RNA in the reaction mixture is a reverse complement transcription product.
16.A method of producing a messenger ribonucleic acid (mRNA) that is suitable for administration as a vaccine to a human subject, wherein the mRNA comprises an open reading frame encoding a vaccine antigen, the method comprising incubating a reaction mixture comprising a deoxyribonucleic acid (DNA), a T7 RNA polymerase, a buffer, adenosine triphosphate (ATP), cytidine triphosphate (CTP), uridine triphosphate (UTP), and guanosine triphosphate (GTP), thereby producing the mRNA,
wherein the concentration of GTP is greater than the concentration of one or more of ATP, CTP, and UTP, and two or more of ATP, CTP, and UTP are in equimolar concentrations,
wherein the UTP is a modified UTP comprising 2’-O-methylribose, pseudouridine (ψ), N1-methylpseudouridine (m1ψ), 2-thiouridine, 4-thiouridine, 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, or 5-methoxyuridine.
17.The method of claim 16, wherein the UTP is an N1-methylpseudouridine triphosphate (N1-methylpseudo-UTP).
18.The method of claim 16 or 17, wherein the amount of the GTP is greater than an amount of the UTP.
19.The method of any one of claims 16-18, wherein the amount of the ATP is greater than the amount of the UTP.
20.The method of any one of claims 16-19, wherein the amount of the CTP is greater than the amount of the UTP.
0
24
0