uniQure IP B.V. [2025] APO 14 (19 May 2025)

1. Examination of the application was requested on 26 May 2022 and a first examination report was issued on 19 December 2023 raising objections under section 40(3A), novelty and inventive step. This report also included additional comments pointing to additional grounds of objection including a lack of unity, further inventive step and a lack of patentable subject matter were the other objections to be addressed. A response to the examination report was filed on 26 February 2024, accompanied by amendments to the specification, and a second examination report formally raising objections to the lack of patentable subject matter, clarity, support and unity was issued on 29 February 2024. A response to the second examination report, again accompanied by amendments to the specification, was filed on 21 June 2024. A third examination report was issued on 18 July 2024 maintaining and adding further objection to the lack of patentable subject matter, maintaining support and clarity, as well as raising novelty and inventive step anew. On 11 December 2024, the applicant requested to be heard.

1. A delegate of the Commissioner issued a letter on 8 January 2025 indicating that the objections to the lack of patentable subject matter were not sustainable and that the applicant need not address these objections for the hearing. The matter was heard by written submissions filed on 17 January 2025, which was accompanied by further amendments under section 104 and a declaration by Dr Sander van Deventer dated 30 November 2024 together with Exhibit A.

1. I had concerns regarding the amendments filed with the submissions of 17 January 2025 and issued a letter on 27 February 2025 regarding the construction of the claims as proposed to be amended. A response was received on 7 March 2025, accompanied by further amendments under section 104.

1. This decision is based on the specification as formally proposed to be amended, up to and including the amendments filed with the letter of 7 March 2025. Any reference to the specification below is a reference to the specification as proposed to be amended with the letter of 7 March 2025.

1. The application was filed after 15 April 2013 and therefore is governed by the Patents Act 1990 (the Act) as amended by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012. The standard of proof that applies to examination is the balance of probabilities - if satisfied on the balance of probabilities that the application complies with the Act I must accept the application.[1] If I am not so satisfied, then I can refuse the application.[2]

1. The specification is comprised of a description, including a sequence listing, followed by 12 claims and 6 drawings. Before construing the specification, I note the comments of Middleton J in Eli Lilly and Company Limited v Apotex Pty Ltd:

"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."[3]

1. The field of the invention relates to Adeno-associated virus (AAV) based gene therapies in humans and more specifically to the treatment of human patients suspected of harbouring antibodies directed against the AAV serotype intended for use in said treatment.[4] The efficiency of AAV-based gene therapies can be reduced by previous exposure to wild-type AAV or AAV-based vectors wherein the patient develops neutralizing antibodies (NAb) directed towards the viral capsid proteins.[5]

1. The general consensus in the field, at the time of filing, is described as avoiding treating patients having NAb titers altogether.[6] In this regard, the general practice in the art is described as involving the screening of patients for exclusion, based on the presence of NAb against the AAV capsid.[7] Strategies to overcome pre-existing NAb, such as immunosuppressive regimens and plasma exchange, had achieved limited success.[8]

"The current inventors have now surprisingly found that in particular for AAV5 gene therapy vectors, and in contrast to the suggestions in the state of the art, human patients that have endemic pre-existing anti-AAV5 antibodies (i.e. pre-existing anti-AAV5 antibodies resulting from endemic exposure) can be considered to be eligible for treatment."[9]

1. This is contrasted to the belief that the presence of anti-AAV NAb should be considered as an exclusion criterion for treatment with AAV-based gene therapies, making the patient ineligible for this type of treatment.[10] The finding that human patients that have endemically acquired anti-AAV5 antibodies can be considered to be eligible for treatment is said to be surprising.[11]

1. In one aspect, the invention provides for an AAV5 gene therapy where the patient is not subjected to a pre-screening.[12] Alternatively, the patient may be subjected to a pre-screening with an assay for anti-AAV5 antibodies and tests positive.[13]

1. The AAV5 gene therapy vectors relate to an AAV5 vector capsid with a vector genome having a gene of interest comprised in between AAV5 inverted repeats.[14] The AAV5 vectors are delivery vehicles for a payload, which is a vector genome having a transgene to target cells.[15] Hence, AAV5 vectors are used in medical treatment of diseases which may be ameliorated by the delivery of a transgene.[16] Therapeutic nucleic acid sequences typically encode products, such as proteins or RNA, for administration and expression in a patient in vivo or ex vivo to treat a genetic defect, an epigenetic disorder, or a condition associated with dysregulation of a gene product by replacing or correcting the deficiency.[17] For example, the transgene can be Factor IX (FIX) for the treatment of hemophilia.[18]

1. The description concludes with an example describing a clinical trial.[19] Reference is made to NCT02396342 as the relevant record on the NIH clinicaltrials.gov website where further information can be obtained.[20] Briefly, the example relates to a dose-escalation study carried out with adult males having severe or moderate-severe hemophilia B who required either continuous FIX prophylaxis or on-demand FIX and have either 4 or more bleeds per year or hemophilic arthropathy.[21] An AAV5 vector incorporating a codon-optimised wildtype hFIX gene under the control of a liver-specific promoter LP1 was used in the study.[22]

1. The AAV5 vector was administered as a single, 30 minute, peripheral intravenous infusion of 5 x 1012 gc/kg or 2 x 1013 gc/kg and sera from the subjects were obtained for AAV5 NAb titer and TAb titer analyses.[23] The patients in both cohorts all presented meaningful improvements in FIX activity, resulting in a substantial reduction or even absence of use of prophylactic administration of FIX protein.[24] While there was variation observed between the FIX activity levels observed between patients and between cohorts, it did not correlate with the NAb or TAb status of the patients.[25] These and further observations are depicted in figures 1-3.[26]

1. The following conclusions are drawn from the study:

"To conclude, the presence of anti-AAV5 antibodies, detected in vitro either by the NAb assay or the TAb assay was not predictive nor indicative for impairing transduction in vivo. There was no evident correlation between presence of Nabs before therapy and FIX levels after therapy resulting from the AAV5 FIX gene transfer. ... Hence, it is considered feasible that testing for the presence or absence of anti-AAV5 antibodies in an untreated population is not required prior to treatment with an AAV5 gene therapy vector."[27]

1. The specification as proposed to be amended concludes with 12 claims as filed with the letter of 7 March 2025. These claims are annexed to this decision. I have considered the proposed amendments and they comply with section 102.

1. Proposed claims 1, 2 and 12 are independent claims and reproduced below. Proposed claims 3-11 are dependent claims appended to independent claims 1 and 2. The independent claims are presented below showing the amendments (additions in underline and deletions in strike-through) relative to the claims considered by the examiner in the third adverse report:

1. A method of treating a human genetic disease or disorder comprising administering an effective amount of an AAV5 gene therapy vector to a human in need thereof, wherein said human is subjected to a pre-screening with an assay to determine anti-AAV5 antibodies and wherein said human has not been subjected to a medical treatment with an AAV5 gene therapy vector prior to said medical treatment administering the effective amount of the AAV5 gene therapy vector, said human having an anti-AAV5 antibody level corresponding to at most the 95th percentile of anti-AAV5 antibody levels as observed in the human population, wherein said human tested tests positive for anti-AAV5 antibodies in the pre-screening assay;

wherein the method does not further comprise administering to said human a therapy to reduce or inhibit anti-AAV5 antibodies, and said human has not been subjected to a prior therapy to reduce or inhibit anti-AAV5 antibodies.

1. The description defines AAV vector as referring to "a recombinant adeno-associated virus (AAV) vector which is derived from the wild type AAV by using molecular methods."[28] In an AAV vector, at least a part of the viral genome has been replaced with a transgene, which is a non-native nucleic acid with respect to the wild type AAV nucleic acid sequence.[29] The AAV vector, including combinations of AAV capsid and AAV genome inverted terminal repeat sequences, can be produced using methods known in the art, such as using mammalian cells or in insect cells using a baculovirus expression system.[30]

1. The specification further defines gene therapy as the insertion of nucleic acid sequences into an individual's cells and/or tissues to treat a disease.[31] The transgene can be a functional mutant allele that replaces or supplements a defective one or any nucleic acid suitable for use in gene therapy.[32] In the above claim, there is no limitation on the nature of the transgene or disease to be treated.

1. Patients who have previously undergone a medical treatment with an AAV5 gene therapy vector are excluded from the treatment scope. Furthermore, the patient is treated only if they also test positive for anti-AAV5 antibodies in a pre-screening assay. Given it is a pre-screening assay, I understand this to mean a test performed before deciding whether to give AAV5 gene therapy to said patient. Similar tests, or even identical tests, may be performed at a later date but it is the result of the pre-screening that would determine whether the patient receives treatment or not. Consequently, if the patient is negative on the pre-screen, they are excluded from the method of proposed claim 1.

1. I also note that the method of proposed claim 1 specifically excludes prior or additional therapy to reduce or inhibit anti-AAV5 antibodies. Such strategies have been used in the prior art, such as immunosuppressive regimens and plasma exchange, to force a positive patient back to negative status before commencing the AAV based gene therapy.[33] The invention is not directed to these prior art strategies.

1. Use of an AAV5 gene therapy vector in the preparation of a medicament for a medical treatment of treating a genetic disease or disorder in a human in need thereof, wherein said human is has been subjected to a pre-screening with an assay to determine anti-AAV5 antibodies and wherein said human has not been subjected to a medical treatment with an AAV5 gene therapy vector prior to said medical treatment medicament being administered, said human having an anti-AAV5 antibody level corresponding to at most the 95th percentile of anti-AAV5 antibody levels as observed in the human population, wherein said human tested positive for anti-AAV5 antibodies in the pre-screening assay;

wherein the medicament is not for administration with a therapy to reduce or inhibit anti-AAV5 antibodies, and said human has not been subjected to a prior therapy to reduce or inhibit anti-AAV5 antibodies_._

1. Yates J described the generalised form of a Swiss type claim as being "the use of compound X in the manufacture of a medicament for a specified (and new) therapeutic use".[34] The novelty and inventiveness of Swiss claims derives from the new medical use, not from the manufacture of the medicament.

1. I am prepared to accept that claim 2 as proposed to be amended is a Swiss type claim. As a Swiss type claim, the same eligibility criteria for treatment-naïve patients harbouring anti-AAV5 antibodies would apply to proposed claim 2 in the same manner as in proposed claim 1. If I am wrong and it is not a Swiss claim, proposed claim 2 would be directed to the use of an AAV5 gene therapy vector in the preparation of a medicament which is suitable for use with patients meeting the eligibility criteria. Given that the AAV5 gene therapy vector is a known delivery platform for gene therapy, the latter would lack novelty and inventiveness on the face of the specification alone.

1. A method for determining human patients eligible for a medical treatment with an AAV5 gene therapy vector, the method comprising selecting a human patient that has: (i) not been subjected to a prior AAV5 gene therapy treatment and that has (ii) not been subjected to a prescreening with an assay to determine anti-AAV5 antibodies, and identifying the human patient as eligible for the medical treatment.

1. Proposed claim 12 is directed to a method for determining the eligibility for treatment and does not include the AAV5 gene therapy itself. A patient is identified as being eligible for the medical treatment if they have not previously undergone a medical treatment with an AAV5 gene therapy vector and they have not already been subjected to a pre-screening with an assay to determine the presence or absence of anti-AAV5 antibodies. As long as the patient has not been subjected to pre-screening, the patient may have had endemic exposure to wild type AAV5 or be completely naïve to AAV. Irrespective of their actual anti-AAV5 antibody titers, if the patient has already been subjected to pre-screening, they are not eligible for AAV5 gene therapy according to proposed claim 12. After the initial eligibility determination, the patient may also be subjected to additional testing, including assays for determining anti-AAV5 antibody titers.

1. Although claim 12 does not include the additional exclusion of patients who have not been subjected to a prior therapy to reduce or inhibit anti-AAV5 antibodies, it is understood that such additional therapy would only be carried out after confirming they harbour anti-AAV5 antibodies. Consequently, similar to the other claims, the method of claim 12 would consider such patients as being ineligible for treatment with an AAV5 gene therapy.

1. As provided for in section 40(3) of the Act, the claims must be clear and succinct. As cited with approval in Austal Ships Sales Pty Ltd v Stena Rederi Aktiebolag [2008] FCAFC 121, it was noted in Flexible Steel Lacing Company v Beltreco Ltd:

"Lack of precise definition in claims is not fatal to their validity, so long as they provide a workable standard suitable to the intended use ... The consideration is whether, on any reasonable view, the claim has meaning ... In determining this, the expressions in question must be understood in a practical, common sense manner ... Absurd constructions should be avoided ... and mere technicalities should not defeat the grant of protection..."[35]

1. In particular, the claims are considered to provide a workable standard if a third party could, without difficulty, determine whether an act falls within the scope of the claim, as noted in Monsanto Company v Commissioner of Patents:

"There will, I think, in the present case be no difficulty in a third party ascertaining whether or not what he proposes to do falls within the ambit of the claim ... For these reasons I do not regard the use of the adjective 'substantial' as giving rise to any uncertainty."[36]

1. More recently, Beach J said in Meat & Livestock Australia Limited v Cargill, Inc:

"A valid claim is required to define with sufficient certainty the scope of the monopoly being claimed (s 40(3)). Given that a patent is a public instrument, the claim must be defined in such a way that it is not reasonably capable of being misunderstood so that others know the 'exact boundaries of the area within which they will be trespassers': Electric & Musical Industries Ld v Lissen Ld (1939) 56 RPC 23 at 39 per Lord Russell of Killowen. A claim will lack clarity if a person skilled in the relevant art cannot ascertain whether what he proposes to do falls within the claim's ambit."[37]

1. After considering the other authorities cited above, Beach J went on to say:

"Finally, if a claim is clear, it is not to be made obscure or treated as obscure by taking elements of a preferred embodiment not referred to in the claim and artificially creating obscurity."[38]

1. The examiner objected to the lack of clarity relating to the use of NAb and TAb cut-off values of previous claims 12 and 13 as well as the percentile values in previous claims 3 and 4.[39] Previous claims 12 and 13 have been removed from the claims as proposed to be amended but proposed claim 11 has been added with similar features.

1. Previous claims 3 and 4 related to the use of percentile values of anti-AAV5 antibody levels as observed in the human population. In particular, the examiner explained as follows:

"With respect to the population features, the applicant submits that the skilled worker can identify the appropriate percentile of any given reference population. I totally agree. However the nature of the reference population is unspecified. In a reference population of, say, infants without AAV exposure, the 95th percentile will be completely different to that of an adult population. The value of the 95th percentile may also vary between different geographical locations, or even over time based on different levels exposure to AAV5. Therefore the skilled worker cannot objectively determine whether any patient is below the 95th percentile or not, without defining the reference population."

1. Previous claims 3 and 4 have now been amended to proposed claims 1 and 2. The proposed amendment removes the reference to the 95th percentile. As noted by the applicant, the claims now recite that the patient is determined as treatment-eligible if they test positive for anti-AAV5 antibodies, regardless of the titer range or the precise assay used to determine the antibody titer.[40] I also note that the reference population is no longer relevant.

1. I consider that a pre-screening assay to determine the presence of anti-AAV5 antibodies would give a clear positive or negative result that a person skilled in the art would have no difficulty interpreting. This also accords with the evidence of Dr van Deventer:

"Therefore, at the priority date, individuals who were to receive systemic administration of AAV-based gene therapies would be routinely screened for the presence of anti-AAV antibodies using standard assays to detect the antibody titre, such as total anti-AV antibody (TAb) assays and neutralising anti-AAV antibody (NAb) assays."[41]

1. The nature of the assay carried out and the sensitivities of the screening protocol would impact on patient eligibility. For example, in proposed claim 11, the patient is considered to be "positive" where they have:

"a total-anti-AAV5 antibody titer with a value in the range of 0.02-5 as determined with a TAb assay, wherein the TAb assay is an ELISA assay and total antibody titre is calculated as a serum dilution with 5-fold higher absorbance than a negative control; or

an anti-AAV5 antibody titer with a value in the range of 3-5,000 as determined by a NAb assay, wherein the NAb assay is a luciferase reporter assay comprising expression of an AAV5 luciferase reporter construct, and neutralising antibody titre is calculated by 'point-based' titer analysis performed on neutralisation percentage values obtained by comparison of a serum dilution to positive and negative controls."

1. Altering the nature of the test or the lower limit for the positive threshold could mean that the same patient may be considered "positive" under one test yet "negative" under another. For proposed independent claims 1, 2 and 12, the person skilled in the art need only consider whether the patient has undergone pre-screening for any anti-AAV5 antibody prior to being assigned eligibility for AAV5-gene therapy. This is irrespective of the patient's actual anti-AAV5 antibody titer. The patient's eligibility hinges on the pre-screening process, not on the abundance of anti-AAV5 antibodies actually present in the patient. A person skilled in the art can readily determine whether a patient has been subjected to a pre-screening assay and whether they were assigned a positive or a negative result. With regard to proposed claim 11, the relevant assay and cut-off are made abundantly clear. Therefore, the claims as proposed to be amended are clear.

1. Section 40(3) requires that the claims are supported. At the heart of this consideration is the principle that the "extent of the patent monopoly, as defined by the claims, should correspond to the technical contribution to the art in order for it to be supported, or justified."[42] Delegates of the Commissioner have adopted the following approach to determine whether the claimed matter is supported by the matter disclosed in the specification:

a) Construe the claims to determine the scope of the invention claimed.

b) Construe the description and the technical contribution to the art, that is how far the concept has carried forward the state of the art.

c) Decide whether the claims are supported by the technical contribution to the art.[43]

1. The Federal Court has approved of this approach.[44] Burley J explored the requirement of support in Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) and added:

"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 breadth of the monopoly claimed".[45]

1. Similarly, Nicholas J considered the ground of support and affirmed the approach taken by Burley J.[46] Nicholas J also referred to UK Supreme Court's decision regarding speculative claiming:

"The concept of plausibility originates in the case law of the EPO as a response to over-broad claims, in particular claims to whole classes of chemical compounds supported by a description which fails to show which compounds can be expected to work. The Technical Board of Appeal treats the condition of sufficiency under EPC article 83 as satisfied if it is possible to work the invention across the scope of the claim from the information in the specification, interpreted in the light of common general knowledge at the priority date. It addresses the broader question whether the disclosed contribution to the art is commensurate with the monopoly claimed under EPC article 56, in the context of inventive step. In that context, its case law requires the formulation of a problem which the claims of the patent could be said to solve: see T 939/92 AGREVO/Triazole sulphonamides [1996] EPOR 171. It imports a requirement that the patent should disclose not just what the invention is and how to replicate it, but some reason for expecting that it will work. Plausibility was the standard to which the patentee was expected to demonstrate this."[47]

1. More recently, the Full Court in in Jusand considered sufficiency and support for an invention which could be performed in a range of ways:

"The invention as claimed was a Safety System able to be constructed from a range of materials but the specification showed only how to make it from steel. Thus the monopoly defined by the claims exceeded the technical contribution made to the art. Effectively, if this patent were upheld it would confer upon the Appellant a monopoly over a range of Safety Systems which it has simply not invented. This would reward the patentee for something it has not done and it would prevent others of an inventive disposition from discovering how to make ingenious systems of anchor and impact reduction members from other materials including materials not yet known."[48]

1. The examiner raised an objection to the lack of support at the second report, which was maintained with the third adverse report. The key points raised are as follows:

• - "... it appears to me that the actual technical contribution of the application is the [sic] that AAV5 expressing factor IX, when produced in insect cells, can effectively deliver factor IX to patients with pre-existing antibodies to AAV5. Therefore only claim 11, which reflects this technical contribution, satisfies the support requirement."[49]
• - "The applicant submits that the specification teaches the general principle that a patient with anti-AAV5 antibodies may be effectively treated with an AAV5 gene therapy. However, according to my reading of the specification, this conclusion has been inferred from a total of three patients who (contrary to the exclusion criteria for the NCT02396342 trial) demonstrated factor IX activity after administration of a baculovirus-expressed AAV5 vector in the presence of preexisting antibodies.

In the absence of any theory, it seems difficult to conclude that the technical contribution of the application extends any further than the specific observation from the examples - that is the combination of a baculovirus expression system for AAV5 for the treatment of hemophilia."[50]

1. The examiner also noted that the FDA approval of ROCTAVIAN in 2023 was restricted to the treatment of patients who test negative for anti-AAV5 antibodies during screening. This exclusion of positive patients from the approval of ROCTAVIAN was said to be inconsistent with the applicant's contribution to the art and the claimed invention. The examiner's conclusion was that "Since none of the claims are directed to the specific combination, it follows that all claims lack support."[51]

1. According to the applicant, "the specification as filed provides a general principle whereby patients who were previously excluded from AAV5-based gene therapy due to testing positive for anti-AAV5 antibodies can now be treated successfully by AAV5-based gene therapy."[52]

1. In relation to the present application, Dr van Deventer reviewed the experimental results and agree with the following observations made therein:

• - "I note that the application explicitly states that the presence of anti-AAV5 antibodies, detected in vitro either by the NAb assay or the TAb assay was not predictive nor indicative for impairing transduction in vivo."[53]
• - "Further, the application also states, contrary to the prevailing conviction in the field at the time, that there was no evident correlation between the presence of anti-AAV5 antibodies before therapy and FIX levels after therapy resulting from the AAV5-mediated FIX gene transfer."[54]
• - "...the application concludes that the result of the sample patient population can be readily applicable to the broader healthy population, such that AAVS-based gene therapy of 'positive' anti-AAV5 individuals can be reasonably expected to be successful even when an individual has a high anti-AAV5 antibody load."[55]

1. Dr van Deventer opined that the present application "significantly increases the patient population that may be effectively treated with AAV5-based gene therapy."[56] He also added:

"Patients can be treated regardless of whether they have, or are suspected of having, anti-AAV5 antibodies with the same expectation of successful AAV5-based gene therapy treatment as those that are confirmed to have low-to-none anti-AAV5 antibodies."[57]

1. The following points were stressed in the applicant's submissions:

• - "The skilled person would not have expected AAV5-based gene therapy to successfully work in a patient having neutralising anti-AAV5 antibodies."[58] (emphasis in original)
• - "Patients were previously excluded because of predicted failure of treatment and expectation of AAV5 gene therapy vectors being neutralised by anti-AAV5 antibodies, not simply a desire to avoid negative trial results."[59] (emphasis in original)
• - "Secondly, under Australian law, the applicant is not required to provide experimental data for each and every embodiment in order for claims to be supported and enabled. See, eg Evolva SA [2017] APO 57 at [67-68]."[60] (emphasis in original)
• - "Moreover, the applicant submits that the proposed claims are enabled, because the skilled person, armed with the specification as filed and their knowledge of the art, would be able to perform the invention across its full scope without undue experimental burden."[61]

1. The applicant also submitted that the 2023 FDA approval information for ROCTAVIAN[62] discussed by the examiner was irrelevant for being "a regulatory document published long after the priority date for this application"[63] and that it "does not speak to a technical expectation (or rather a lack of expectation) to be able to successfully treat patients with an AAV5-based gene therapy if they had existing anti-AAV5 antibodies, as of the priority date."[64] (emphasis in original)

1. The applicant's contribution to the art is said to reside in expanding the cohort of candidate patients who may be eligible to receive gene therapy using AAV5 vectors. Other than the eligibility of patients, the AAV-based gene therapy itself has not been altered in any way to accommodate the expanded cohort.

1. I do not consider the invention to relate to a new mode of therapy using AAV5 gene therapy vectors. There is no indication in the specification that a new platform for gene therapy has been invented or that AAV5 gene therapy vectors are intended to be used in treatment of diseases where they would not have been deployed before. Rather, the invention lies in allowing previously excluded patients to receive the same treatment.

1. According to the applicant, a person skilled in the art would not have expected AAV5-based gene therapy to successfully work in a patient having anti-AAV5 NAb and would therefore exclude these patients from treatment. Dr van Deventer echoes this and explains that, at the priority date, a person skilled in the art would screen for the presence of anti-AAV antibodies and only proceed to administer AAV-based gene therapy to patients without pre-existing immunity.[65]

1. In spite of this prevailing expectation of failure, observations were made during a clinical study into the use of AAV5 gene therapy to deliver factor IX to hemophilia patients, as recorded in the worked example. Firstly, that all patients who received treatment presented meaningful improvements in FIX activity.[66] Secondly, that there were variations in responses between patients and between dosing level cohorts but there was no correlation with the NAb or TAb profiles of these patients.[67] Thirdly, that the NAb prevalence in the treatment group was in line with that of a healthy control group.[68] These observations are statistically verified in the application and the experimental section concludes that the presence of anti-AAV5 antibodies was neither predictive nor indicative of impaired transduction of the therapeutic gene in vivo and makes the following final statement:

"Hence, it is considered feasible that testing for the presence or absence of anti-AAV5 antibodies in an untreated population is not required prior to treatment with an AAV5 gene therapy vector."[69]

1. The experimental example in the specification refers to the NIH clinicaltrials.gov website, specifically to the record of NCT02396342, for further details of the trial. According to the information on the website, "Neutralizing antibodies against AAV5 at Visit 1" was one of the 19 exclusion criteria.[70] I have checked the record history as well and "Neutralizing antibodies against AAV5 at Visit 1" was always part of the exclusion criteria from 2015 when the study was first recorded through to its completion in 2022. However, the experimental example in the specification does not refer to any exclusion criteria at all.

1. In any event, the NAb prevalence in the treatment group in the experimental example was similar that of a healthy control group. Regardless of the prevailing hurdle for AAV-based gene therapy eligibility being the presence of anti-AAV NAb, the pre-screening for anti-AAV5 NAb was essentially ineffective, allowing the same population profile in the treatment group as a healthy control group.

1. Fortuitously, this allowed for the critical observation that the presence of anti-AAV5 antibodies was neither predictive nor indicative of impaired transduction of the therapeutic gene in vivo and that testing for anti-AAV5 antibodies may not be required prior to treatment with an AAV5 gene therapy vector. Where there is no correlation between pre-screening results and treatment outcome, subjecting the patients to such testing is not necessary.[71] The AAV5 gene therapy was nevertheless effective, despite the assumption that the treatment would be ineffective in such patients.

1. To my mind, whether the patients were subjected to pre-screening or their pre-treatment sera were studied in greater detail at a later time, the observation of effective treatment response in patients with pre-existing anti-AAV5 antibodies remains true. A person skilled in the art is given guidance that there is no correlation between pre-treatment AAV5 antibody profile and treatment outcome. I therefore consider that it would be reasonable to extrapolate the observation to the treatment of patients with pre-existing anti-AAV5 antibodies.

1. The examiner was also concerned that the experimental example covers only a small group of patients and only one type of AAV5 gene therapy, specifically a baculovirus expression system for AAV5 with FIX transgene for the treatment of hemophilia. However, the AAV5 gene therapy itself is unchanged by the present invention. The only difference is that the same therapy should also be effective in patients who were previously excluded based on their pre-treatment anti-AAV5 antibody profile. Therefore, I find compelling Dr van Deventer's alternative view that:

"This discovery is not limited to a specific disease or condition, the expression system used to manufacture the AAV vector, nor is it specific to the therapeutic transgene expressed by the AAVS gene therapy vector."[72]

1. I am satisfied the claimed invention, across its whole scope, is supported by the complete specification. Effective treatment of patients with pre-existing anti-AAV5 antibodies with AAV5 gene therapy can be plausibly extrapolated from the observations made in the experimental example and the description as a whole.

1. Furthermore, I agree with the applicant that the 2023 FDA approval information for ROCTAVIAN is irrelevant to the present consideration. What is described in a patent application does not confine the direction for future development by anyone in the field, including the applicant themselves. Not all patents necessarily translate to becoming a commercial embodiment. Comparing the patent application with what the applicant has chosen to go forward with commercially does not make the described subject matter any less adequately disclosed in the present application.

1. For the purposes of subsection 7(1) of the Patents Act, an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the pieces of prior art information. It is well established that the general test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aickin J:

"The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement."[73]

1. This test is satisfied if the alleged anticipation discloses all of the essential features of the invention as claimed with clear and unmistakable directions to do what the patentee claims to have invented:

"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 ... To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented." [74]

1. This was further explained by the Full Court more recently:

"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.

It is important to stress that validation of the ACCORD Protocol's hypothesis was certainly not required in order to achieve the equality of disclosure referred to in Hill v Evans. Looked at from a different perspective, it is not a requirement for a patentable invention that the invention, as claimed, be based on scientific proof or substantiation. That being so, no greater requirement is imposed on a prior documentary disclosure in order for it to be anticipatory. What is required is that the prior document discloses that which is subsequently claimed as an invention. If that is disclosed, the invention cannot be new. If it should also be proved that the invention is not useful (for example, a claimed method of medical treatment is wholly or partly ineffective), then the patent can be challenged on that basis as well. But that raises a separate and distinct ground of invalidity."[75] (citations omitted)

1. The following documents appear in the third report:

D1: BIOMARIN: "A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study of BMN 270, an Adenovirus-Associated Virus Vector- Mediated Gene Transfer of Human Factor VIII in Patients With Severe Haemophilia A (NCT02576795)", 14 June 2017

D2: LEEBEEK F.W.G. et al.: "Interim Results from a Dose Escalating Study of AMT-060 (AAV5-hFIX) Gene Transfer in Adult Patients with Severe Hemophilia B", BLOOD, 2016, vol. 128, no. 22, abstract 2314

D3: DOLGIN E.: "Early clinical data raise the bar for hemophilia gene therapies", NATURE BIOTECHNOLOGY, 2016, vol. 34, no. 10, pp. 999-1001

D4: MINGOZZI F. et al.: "Immune responses to AAV vectors: overcoming barriers to successful gene therapy", BLOOD, 2013, vol. 122, no. 1, pp. 23-36

D5: BOUTIN S. et al.: "Prevalence of Serum IgG and Neutralizing Factors Against Adeno-Associated Virus (AAV) Types 1, 2, 5, 6, 8, and 9 in the Healthy Population: Implications for Gene Therapy Using AAV Vectors", HUMAN GENE THERAPY, 2010, vol. 21, no. 6, pp. 704-712

D6: SEN D. et al.: "Improved adeno-associated virus (AAV) serotype 1 and 5 vectors for gene therapy", SCIENTIFIC REPORTS, 2013, vol. 3, article 1832

D7: NATHWANI A.C. et al.: "Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates", BLOOD, 2007, vol. 109, no. 4, pp. 1414-1421

D8: HILDINGER M. et al.: "Hybrid vectors based on adeno-associated virus serotypes 2 and 5 for muscle-directed gene transfer", JOURNAL OF VIROLOGY, 2001, vol. 75, no. 13, pp. 6199-6203

D9: SRIVASTAVA A.: "In vivo tissue-tropism of adeno-associated viral vectors", CURRENT OPINION IN VIROLOGY, 2016,vol. 21, pp. 75-80

D10: MANNO C.S. et al.: "AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B", BLOOD, 2003, vol. 101, no. 8, pp. 2963-2972

D11: MANNO C. et al.: "Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response", NATURE MEDICINE, 2006, vol. 12, no. 3, pp. 342-347

1. The examiner's objection is reproduced here in its entirety:

"After more detailed consideration of the facts involved, I am now of the opinion that at least claims 1-2 lack novelty and claim 3 and the remaining claims do not involve an inventive step.

The canonical definition of anticipation, from the 19th century Hill v Evans UK precent [sic], is that the skilled worker would be able to practically apply the claimed invention based on the prior art without the need for further experiments or gaining further information.

In view of this, I am of the opinion that claims 1-2 lack novelty in view of the general concept of AAV5 gene therapy, as seen in e,g. D3 (of record) or D9 (newly cited).

It is not in dispute that the concept of AAV5 gene therapy was not new as of the priority date. The Applicant's alleged invention is based on the discovery in three patients from the NCT02396342 trial that efficacy and safety of the AAV5-based FIX gene therapy was irrespective of preexisting antibodies to AAV5. Based on this, the applicant claims a method in which AAV5 antibodies are either not measured before therapy (claims 1-2) or AAV5 gene therapy is intentionally given to patients with antibodies (claims 3-4).

D3 and D9 are both review articles which speak to the utility of AAV5 in gene therapy. Unlike D1 and D2, neither of them say anything about any need to modify therapy based on antibody titres. Although AAV5 was a relatively new serotype with little clinical development when the present application was filed, early clinical trials for AAV2 (discussed in D10 and D11) for haemophilia did not mention exclusion criteria based on vector antibodies for either im or iv delivery respectively.

The Applicant has submitted that in the relevant literature before the priority date 'the general consensus in the clinic with regard to pre-existing immunity involves the screening of human patients for exclusion should patients have neutralising antibodies against the AAV capsid'. The Applicant then asserts that based on this, it was deemed technically impossible to treat patients with AAV5 without knowing whether they had pre-existing immunity or not.

However, D4 of record acknowledges that screening patients for preexisting antibodies was only one of a range of possible strategies to deal with the problem of vector immunity (see Table 1).

Furthermore, Australian claim construction has no requirement for efficacy to be demonstrated by the prior art for there to be anticipation (Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd [2020] FCAFC 116). Neither does Australian law give any special weight to 'identification of new patient populations' unlike before the EPO.

Indeed the scope of the claims encompasses AAV5 gene therapy for all diseases and also extends beyond the clinical trial context. It is clear to me that the skilled worker, before the priority date, would have envisioned giving AAV5 gene therapies to the whole population regardless of antibody titer. Doing so would have infringed the claims on file.

Any decision not to do so would only have been influenced by regulatory considerations or the desire to remove false negatives from the trial results.

Therefore the skilled worker already had enough information from D3 and D9, against the background of common general knowledge, to carry out the claimed invention. In the words of Hill v Evans, there is no room for a further invention since no more work needed to be done to carry out the claimed methods.

Regarding claims 3-4, although the specific choice of treatment algorithm is new, there does not appear to be any significant advantage associated with that choice assuming that the skilled worker intends to give treatment to the broad patient population anyway. The doses or routes of administration mentioned in the dependent claims are also known in the art e.g. from D1-D2."[76] (emphasis in original)

1. D3 highlights the promising early results of gene therapies for haemophilia with AAV vectors for delivering therapeutic genes. Twelve gene therapy products in clinical development are discussed. These products include various AAV vectors as well as lentivirus vectors delivering Factor IX, for haemophilia A or Factor VIII for haemophilia B. Of the AAV vectors, these include AAV8, engineered AAV, AAV5, recombinant AAV10 and AAV6 vectors. The article discusses their various challenges, successes and outlook for future development by those who have been involved in developing the products to date.

1. For example, D3 covers an AAV8 based therapy achieved curative levels of sustained expression of Factor IX, which is considered curative for hemophilia B but immune reactions against the AAV8 capsid occurred in the highest dose cohort. D3 also covers the applicant's work, including an AAV5 platform generated in a baculovirus-insect cell expression system and requiring high doses to obtain a response. A similar expression system has been used for generating an AAV6 platform for delivering genome-editing nucleases to stably insert a corrective Factor IX into the albumin gene locus.

1. D9 provides a review of the historical perspective of the discovery of cellular receptors and co-receptors for AAV2 and additional AAV serotypes and their impact on the use of AAV vectors in human gene therapy. AAV1-AAV6 serotype vectors transduce tissue culture cells to various degrees of efficacy while AAV7-AAV13 serotype vectors transduce tissue culture cells poorly in vitro but efficiently transduce various tissues and organs in vivo. Numerous glycan receptors and co-receptors for AAV serotype vectors have been identified and linked to tissue tropism. AAV1, AAV2, AAV5, AAV8 and AAV9 serotype vectors have been used in numerous phase I/II clinical trials in humans, including AAV5 vectors for gene therapy of haemophilia A. The article concludes with a call for ongoing research into the basic molecular biology of AAV in general and AAV vectors.

1. The applicant understood the objection to be indicating "that claims 1 and 2 lack novelty in view of D3 or D9"[77] and has proposed to delete previous claims 1 and 2. In relation to the claims as proposed with the submissions, the applicant says that:

"The skilled person, with their knowledge of the art, would hypothesise that if a patient having anti-AAV5 antibodies is treated with an AAV5-based gene therapy, treatment would not be successful (eg Declaration, paragraph 11). Therefore, the prior art fails to disclose even an unsubstantiated hypothesis that would destroy the novelty of the invention."[78] (emphasis in original)

1. With regard to D3 and D9, the applicant noted as follows:

"... discussing AAV5-based gene therapy treatment in a general way and describing the challenges of anti-AAV humoral immunity may encompass contemplation of treating anti-AAV5 antibody positive patients. But this mere contemplation does not provide clear and unmistakable directions to the skilled person to treat an anti-AAV5 antibody positive patient with an AAV5-based gene therapy with an expectation of success."[79] (emphasis in original)

1. In short, none of the cited prior art documents disclose administering AAV5-based gene therapy to a patient who has tested positive in a pre-screen for anti-AAV5 antibodies.

1. Proposed claim 1 requires the step of subjecting a treatment-naïve person to pre-screening with an assay to determine the presence or absence of anti-AAV5 antibodies. As noted by the examiner, D3 and D9 are both review articles which speak to the utility of AAV vectors in gene therapy. Both documents include discussions of AAV5 platforms amongst other serotypes. Neither document discusses the selection process of candidate patients.

1. D3 and D9 make plain that different strategies are employed by different teams for different reasons in implementing AAV-based gene therapy. However, this does not mean that every possible approach was therefore disclosed in these documents. While it may have been within the grasp of the person skilled in the art to envision giving AAV5 gene therapy to the whole population regardless of the antibody titer or disease, it remains that D3 and D9 themselves do not provide clear and unmistakable directions for a method of administering AAV5-based gene therapy where the treatment-naïve person is also positive in a pre-screening assay for anti-AAV5 antibodies.

1. For completeness, I have also reviewed the remaining documents cited and confirmed that none provide a clear and unmistakable disclosure for a method of administering AAV5-based gene therapy where the treatment-naïve person is also positive in a pre-screening assay for anti-AAV5 antibodies. Therefore, I consider proposed independent claims 1 and 2, and proposed claims 3-11 appended thereto, are novel over D3 or D9.

1. Proposed claim 12 is directed to a method for determining eligibility for medical treatment with AAV5-based gene therapy where the patient is treatment-naïve and has not been subjected to a pre-screening with an assay to determine anti-AAV5 antibodies. None of the cited prior art documents disclose, neither explicitly nor implicitly, such a method for determining eligibility for AAV5-based gene therapy.

1. Therefore, I consider proposed claims 1-12 satisfy the requirements for novelty.

1. 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).

1. 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."[80]

1. 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 to 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'."[81]

"The reformulated Cripps question does not require certainty of outcome. It requires that the skilled addressee be directly led as a matter of course to try the claimed invention in the expectation that a particular research path 'might well produce' a useful result. It does not require the skilled addressee to know that the steps will produce a useful result."[82]

1. It is also possible that the person skilled in the art might be directly led to try more than one alternative expecting that each may well produce a useful or desired result.[83]

1. The examiner raised an objection to the lack of inventive step against all of the claims in light of each of the disclosures of D3 and D9 discussed above. Of relevance to the proposed claims, "the specific choice of treatment algorithm" was considered to be new over the cited prior art for novelty but the examiner went on to say that "there does not appear to be any significant advantage associated with that choice assuming that the skilled worker intends to give treatment to the broad patient population anyway."[84]

1. The applicant misunderstood the objection as being raised in light of D1 and D2.[85] The applicant nevertheless provided submissions in relation to the inventiveness of the present claims in light of each of D1-D9. As an overarching theme, the following was stressed:

"Based on the skilled person's knowledge of the art in the context of the whole technical field, the skilled person would, at the priority date, only be directed to treat a patient with AAV5-based gene therapy after confirming the patient returned a negative result for anti-AAV5 antibodies."[86] (emphasis in original)

1. Dr van Deventer opined that this would permit a new patient group to receive AAV5-based gene therapy, rendering the "anti-AAV5 positive subpopulation newly eligible for treatment with AAV5-based gene therapy."[87] (emphasis in original) He goes on to state:

"The practical, clinical benefit of the present invention is that it significantly increases the patient population that may be effectively treated with AV5-based gene therapy. This is crucial for patients where AAV5-based gene therapy is their only treatment option."[88]

"Patients can be treated regardless of whether they have, or are suspected of having, anti-AAVS antibodies with the same expectation of successful AAV5-based gene therapy treatment as those that are confirmed to have low-to-none anti-AAV5 antibodies."[89]

1. According to the applicant, each of the documents teach away from the claimed invention: D1 and D2 include pre-existing anti-AAV5 antibodies as an explicit exclusion criteria; D3 prefers using lentiviral vectors instead; D4 teaches strategies for suppressing the anti-AAV5 NAb prior to AAV5-gene therapy; D5, D6, D7 and D9 point towards switching AAV serotypes; and D8 is predicated on there being a low prevalence of anti-AAV5 antibodies in human population.[90] With regard to D9, additional comment is made that there is no mention of whether patients were pre-screened for anti-AAV5 antibodies but the applicant concludes: "Given the state of the art at the priority date (discussed above), the skilled person would presume that AAV5-treated patients were screened, and that they tested negative."[91]

1. As the examiner had raised only D3 and D9 as the relevant prior art documents against the claimed invention, it is perhaps not unexpected that many of the documents discussed by the applicant do not relate to the problem or teach away from the claimed solution. The other documents were mentioned in the objections as evidence of common general knowledge relating more broadly to AAV-based gene therapies.

1. D3 and D9 are review articles which speak to the utility of various AAV vectors in gene therapy and AAV5 is mentioned among various serotypes used in the art. As noted by the applicant, D3 and D9 simply show AAV5 vectors and their use in gene therapy were known in the art. This is consistent with the use of these documents in the examiner's objection.

1. The applicant submitted that D3 and D9 do not directly motivate the skilled person towards a method of AAV5-based gene therapy that successfully treats patients that test positive for anti-AAV5 NAb. I note that these documents also do not express any blanket prejudice against the treatment of patients harbouring anti-AAV antibodies prior to the commencement of treatment. An invention may be considered obvious if the person skilled in the art faced with the same problem as the inventor, and in light of the common general knowledge, 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.

1. D10 and D11 are the only documents mentioned in the inventive step objection that the applicant did not comment on. I note that both D10 and D11 are referenced in D4, which was provided to Dr van Deventer for discussion of common general knowledge.[92] As noted by the examiner, D10 and D11 relate to early clinical trials for AAV2 gene therapy and do not mention exclusion of patients having pre-existing anti-AAV2 antibodies. I have reviewed these documents and further add that they include discussions of successful treatment of patients with pre-existing anti-AAV2 NAb.[93]

1. These observations in D10 and D11 directly contradict Dr van Deventer's statement that "Treatment failure was the expected outcome in the presence of anti-AAV antibodies, regardless of the serotype."[94] Moreover, according to the applicant, there was a prevailing belief across the whole field that any AAV gene therapy would necessarily fail if the patient harboured pre-existing antibodies against the AAV serotype intended. D10 and D11 show it was known in the art that not all AAV serotypes are prone to total neutralisation by pre-existing antibodies.

1. Despite the applicant's submissions, the observation that pre-existing anti-AAV5 antibodies does not necessarily lead to treatment failure is not unique among AAV serotypes. I accept that pre-existing anti-AAV antibodies was of concern in the art. However, I do not accept that there was a prevailing belief that any AAV gene therapy would necessarily fail in patients with pre-existing antibodies for the AAV serotype intended for use in the gene therapy. There may have been a preference for patients who were free of pre-existing antibodies against the AAV serotype used in the intended therapy. However, this preference does not translate to a universal acceptance of treatment failure in the presence of anti-AAV antibodies.

1. In the absence of a prevailing belief in the field that pre-existing anti-AAV antibodies would necessarily lead to treatment failure, a person skilled in the art would consider any of the known strategies may well lead to a useful result. I note that the person skilled in the art might be directly led to try more than one alternative expecting that each may well produce a useful or desired result.[95] As noted in Mylan, a person skilled in the art does not need to be certain that AAV5 gene therapy would not be rendered ineffective by pre-existing anti-AAV5 antibodies. The person skilled in the art need only have expected that treatment without regard to the pre-treatment anti-AAV5 antibody profile might well produce a useful result.[96]

1. I consider that a person skilled in the art faced with the problem of treating human patients with AAV-based gene therapy where the patient is suspected of having anti-AAV5 antibodies would investigate the feasibility of treatment with AAV5 gene therapy with an expectation that it might well result in useful treatment in these patients. Where possible, administering the intended AAV gene therapy vector without regard for pre-existing anti-AAV antibodies would be an obvious choice. It provides for a simplified patient selection process with obvious advantages such as convenience and timeliness of commencement of therapy, as noted by Dr van Deventer.[97]

1. Therefore, proposed claims 1-12 lack inventive step in light of D3 or D9, together with common general knowledge.

1. Having reviewed the specification in detail, I can see no subject matter that could be made the subject of a valid claim to overcome the findings on inventive step above. It follows that there would be no useful purpose in allowing any further opportunity to amend and the application should be refused. In any event, the applicant has filed and requested examination of a divisional application through which it appears that prosecution will be continued. I consider it appropriate to refuse the application to avoid any uncertainty.

Annex - claims as proposed to be amended with the letter of 7 March 2025

1. A method of treating a genetic disease or disorder comprising administering an effective amount of an AAV5 gene therapy vector to a human in need thereof, wherein said human is subjected to a pre-screening 5 with an assay to determine anti-AAV5 antibodies and wherein said human has not been subjected to a medical treatment with an AAV5 gene therapy vector prior to administering the effective amount of the AAV5 gene therapy vector, wherein said human tests positive for anti-AAV5 antibodies in the pre-screening assay;

wherein the method does not further comprise administering to said human a therapy to reduce or inhibit anti-AAV5 antibodies, and said human has not been subjected to a prior therapy to reduce or inhibit anti-AAV5 antibodies.

1. Use of an AAV5 gene therapy vector in the preparation of a medicament for treating a genetic disease or disorder in a human in need thereof, wherein said human has been subjected to a pre-screening with an assay to determine anti-AAV5 antibodies and wherein said human has not been subjected to a medical treatment with an AAV5 gene therapy vector prior to said medicament being administered, wherein said human tested positive for anti-AAV5 antibodies in the pre-screening assay;

wherein the medicament is not for administration with a therapy to reduce or inhibit anti-AAV5 antibodies, and said human has not been subjected to a prior therapy to reduce or inhibit anti-AAV5 antibodies.

1. A method in accordance with claim 1, wherein said AAV5 gene therapy vector is administered at a dosage corresponding with at least 1012 capsids/kg; or a use in accordance with claim 2, wherein said medicament is adapted for administration at a dosage corresponding with at least 1012 capsids/kg.

1. A method in accordance with claim 1 or 3, wherein said AAV5 gene therapy vector is administered at a dosage corresponding with at least 1012 gc/kg of body weight; or a use in accordance with claims 2 or 3, wherein said medicament is adapted for administration at a dosage corresponding to at least 1012 gc/kg of body weight.

1. A method or use in accordance with any one of claims 1 to 4, wherein said human has a disease selected from the group consisting 5 of Hemophilia A or Hemophilia B.

1. A method in accordance with any one of claims 1, 3-5, wherein said AAV5 gene therapy vector is administered to a human having Hemophilia, wherein the AAV5 gene therapy vector encodes a FIX protein or variant thereof; or a use in accordance with any one of claims 2-5, wherein said medicament is adapted for treating Hemophilia, wherein the AAV5 gene therapy vector encodes a FIX protein or variant thereof.

1. A method in accordance with any one of claims 1, 3-6, wherein the method comprises administering the AAV5 gene therapy vector into the bloodstream; or a use in accordance with any one of claims 2-6, wherein said medicament is adapted for administration into the bloodstream.

1. A method in accordance with any one of claims 1, 3-7, wherein said AAV5 gene therapy vector is delivered to the liver via the bloodstream; or a use in accordance with any one of claims 2-7, wherein said medicament is adapted to be delivered to the liver via the bloodstream.

1. A method or use in accordance with any one of claims 1 to 8, wherein said AAV5 gene therapy vector is produced in insect cells.

1. A method or use in accordance with any one of claims 1 to 9, wherein the assay to determine anti-AAV5 antibodies is a total anti-AAV5 (TAb) assay or a neutralising anti-AAV5 antibody assay (NAb) assay, wherein the assay is performed on a serum sample obtained from the human.

1. The method or use in accordance with claim 10, wherein the human considered positive for anti-AAV5 antibodies has:

a total-anti-AAV5 antibody titer with a value in the range of 0.02-5 as determined with a TAb assay, wherein the TAb assay is 5 an ELISA assay and total antibody titre is calculated as a serum dilution with 5-fold higher absorbance than a negative control; or

an anti-AAV5 antibody titer with a value in the range of 3-5,000 as determined by a NAb assay, wherein the NAb assay is a luciferase reporter assay comprising expression of an AAV5 luciferase reporter construct, and neutralising antibody titre is calculated by "point-based" titer analysis performed on neutralisation percentage values obtained by comparison of a serum dilution to positive and negative controls.

1. A method for determining human patients eligible for a medical treatment with an AAV5 gene therapy vector, the method comprising selecting a human patient that has: (i) not been subjected to a prior AAV5 gene therapy treatment and (ii) not been subjected to a prescreening with an assay to determine anti-AAV5 antibodies, and identifying the human patient as eligible for the medical treatment

[2] The Explanatory Memorandum, Intellectual Property Laws Amendment (Raising the Bar) Bill 2011 at page 54.

[3] Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214 at [139].

[5] Specification at page 1 lines 21-25.

[6] Specification at page 1 lines 30-31.

[7] Specification at page 1 line 31 - page 2 line 2.

[9] Specification at page 2 lines 16-20.

[10] Specification at page 2 lines 20-25.

[11] Specification at page 2 lines 25-31 and page 12 lines 8-11.

[12] Specification at page 2 line 32 - page 3 line 3.

[13] Specification at page 3 lines 11-18.

[14] Specification at page 9 lines 29-32.

[15] Specification at page 9 line 32 - page 10 line 2.

[16] Specification at page 10 lines 2-7.

[17] Specification at page 14 line 32 - page 15 line 3.

[18] Specification at page 15 lines 3-20.

[20] Specification at page 20 lines 7-8.

[21] Specification at page 20 lines 4-7.

[22] Specification at page 20 lines 14-17.

[23] Specification at page 20 line 28 - page 21 line 3.

[24] Specification at page 24 lines 28-31.

[25] Specification at page 24 lines 31-33.

[26] Specification at page 3 line 22 - page 4 line 7.

[27] Specification at page 25 line 22 - page 26 line 2.

[28] Specification at page 4 lines 26-30.

[29] Specification at page 5 lines 14-15.

[30] Specification at page 4 line 31 - page 5 line 13.

[31] Specification at page 7 lines 4-5.

[33] Specification at page 2 lines 2-10.

[34] Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd (No 4) [2015] FCA 634 at [101].

[35] Flexible Steel Lacing Company v Beltreco Ltd [2000] FCA 890 at [81].

[36] Monsanto Company v commissioner of Patents (1974) 48 ALJR 59 at [60]-[61].

[37] Meat & Livestock Australia Limited v Cargill, Inc [2018] FCA 51 at [932].

[38] Meat & Livestock Australia Limited v Cargill, Inc [2018] FCA 51 at [937].

[39] Examiner's third adverse report at objection 12.

[40] Applicant submissions at paragraph bridging pages 3-4.

[42] EXXON/Fuel Oils (T409/91) [1994] OJ EPO 653.

[43] CSR Building Products Limited v United States Gypsum Company [2015] APO 72 at [115].

[44] See for example, Cytec Industries Inc v Nalco Company [2021] FCA 970; (2021) 162 IPR 202.

[45] Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) [2020] FCA 1477 at [546]- [547].

[46] ToolGen Incorporated v Fisher (No 2) [2023] FCA 794 at [391]- [395].

[47] Warner-Lambert LLC v Generics (UK) Ltd t/a Mylan [2018] UKSC 56 at [23].

[48] Jusand Nominees Pty Ltd v Rattlejack Innovations Pty Ltd [2023] FCAFC 178 at [222].

[49] Examiner's second report at objection 7.

[50] Examiner's third report at objection 11.

[51] Examiner's third report at objection 11.

[52] Applicant submissions at page 1 paragraph 8.

[58] Applicant submissions at page 1 paragraph 9.

[59] Applicant submissions at page 1 paragraph 11.

[60] Applicant submissions at page 2 paragraph 8.

[61] Applicant submissions at page 3 paragraph 8.

[62] https://www.fda.gov/vaccines-blood-biologics/roctavian

[63] Applicant submissions at page 3 paragraph 5.

[64] Applicant submissions at page 3 paragraph 6.

[66] Specification at page 24 lines 27-31.

[67] Specification at page 24 lines 31-33.

[68] Specification at page 25 lines 5-7.

[69] Specification at page 25 line 31 - page 26 line 2.

[70] https://clinicaltrials.gov/study/NCT02396342

[73] Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1997] HCA 19 at 20.

[74] The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 485-486

[75] Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd [2020] FCAFC 116 at [104]- [106].

[76] Examiner's third report at objection 13.

[77] Applicant submissions at page 4 paragraph 7.

[78] Applicant submissions at page 5 paragraph 3.

[79] Applicant submissions at page 5 paragraph 6.

[80] Minnesota Mining and Manufacturing Co v Beiersdorf (Aust) Ltd [1980] HCA 9 at 293.

[81] Hood v Bush Pharmacy Pty Ltd [2020] FCA 1686 at [116]- [117] (citations omitted).

[82] Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd [2020] FCAFC 116 at [502] (citations omitted). (Mylan)

[83] Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2 at [91]- [93].

[84] Examiner's third report at objection 13.

[85] Applicant submissions at page 6 paragraph 2.

[86] Applicant submissions at page 6 paragraph 3.

[90] Applicant submissions at page 6 paragraph 5 - page 9 paragraph 1.

[91] Applicant submissions at page 8 paragraph 7.

[93] D10 at abstract, page 2966 right column paragraph 2 and page 2970 right column paragraph 2; D11 at page 343 right column paragraph 2.

[95] Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2 at [91]- [93].

[96] Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd [2020] FCAFC 116 at [502].