Out With The In-Crowd – Gene Therapy For A Previously Excluded, Antibody-Positive Patient Group Ruled Non-Inventive

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

Introduction

The Australian Patent Office (APO) has refused to grant a patent on Australian Patent Application 2018299865 (the Application) in the name of uniQure IP B.V.  The Application sought to protect using known AAV5-based gene therapy for patients with pre-existing anti-AAV5 neutralizing antibodies, who were said by uniQure to have previously been thought to be unsuitable for this treatment.  While the claims were found to be clear, supported, and novel, they all failed for lack of inventive step.  Treating antibody-positive patients was considered an obvious extension of the prior art and common general knowledge.

Background

The Application was filed on 10 July 2018.  The invention related to a method of treating human genetic diseases, particularly haemophilia, using AAV5 viral gene therapy vectors.  Specifically, the invention was said to lie in the realisation that treatment could be efficacious even for patients with pre-existing neutralizing antibodies against the AAV5 vector.   The specification stated that the “general consensus in the field” was to avoid treating patients who had the neutralizing antibodies, and that current clinical practice was to screen patients and exclude from treatment those with these antibodies.

The case proceeded through multiple examination reports and amendments between December 2023 and July 2024, with objections being raised on a number of grounds.  On 11 December 2024, uniQure requested to be heard.  A hearing was conducted by written submissions, filed on 17 January 2025 accompanied by a declaration from Dr Sander van Deventer, and a set of further amendments.  The Delegate conducting the hearing expressed concerns with those amendments.  A final set of amendments was filed on 7 March 2025, including the deletion of the previous claims 1 and 2.

There were three independent claims to be considered.

Claim 1, former claim 3, as proposed to be amended, read:

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 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.

Claim 2, former claim 4, was in Swiss form, directed to the use of an “AAV5 gene therapy vector in the preparation of a medicament for treating a genetic disease or disorder” in a similar manner to that described in claim 1.

Proposed claim 12 read:

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.

Consideration

Clarity: The Delegate considered that the proposed amendments removed the examiner’s previous objection of lack of clarity.

Support: The examiner considered that the support in the specification did not extend to the general treatment method claimed, but was limited to the specific examples of treating haemophilia caused by blood-clotting factor IX deficiency by administration of a baculovirus-expressed AAV5 vector.  However, the evidence of Dr van Deventer was 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.”  The Delegate was therefore satisfied that the claimed invention, across its whole scope, was supported by the complete specification as effective treatment of patients could be plausibly extrapolated from the observations made in the experimental example and the description as a whole.

Novelty:  The deletion of former claims 1 and 2 disposed of some of the examiner’s novelty objections which were based on a number of prior art documents.  Although some of the prior art documents disclosed the use of AAV5 vectors for delivering gene therapy without discussing a selection process for candidate patients, the Delegate did not consider that this amounted to a disclosure of every single possible approach, nor did it amount to clear and unmistakable directions for a method of administering AAV5-based gene therapy to a treatment-naïve person who is also positive in a pre-screening assay for anti-AAV5 antibodies.

Inventive Step:  The objection based on a lack of inventive step was based on a subset of the prior art documents also considered in respect of novelty.  The Delegate noted that two of these documents were not commented on by uniQure but were referenced in a document provided to Dr van Deventer in preparing his evidence.  These documents related to early clinical trials for AAV2 gene therapy and did not mention exclusion of patients having pre-existing anti-AAV2 antibodies.  They included discussions of successful treatment of patients with pre-existing anti-AAV2 antibodies.  This was taken by the Delegate as directly contradicting uniQUre’s submission, supported by Dr van Deventer’s evidence, 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.  The Delegate held that although there may have been a preference for patients who were free of pre-existing antibodies against the AAV serotype used in the intended therapy, this preference did not translate to a universal acceptance of treatment failure in the presence of anti-AAV antibodies.

Outcome

The Application was refused on the grounds of lack of inventive step.  The Delegate observed that there was no subject matter that could be made the subject of a valid claim to overcome that conclusion so there would be no purpose in allowing any further opportunity to amend.  uniQure had previously filed and requested examination of a divisional application, which is currently yet to be examined by IP Australia.

Implications

A claim that there is an inventive step in identifying a new patient group for a method of treatment is likely to fail where the previous exclusion of that group was a matter of preference rather than a firm belief amongst skilled people that the treatment would fail in patients from that group.  This is especially the case where prior art includes examples of successful treatment of such patients.

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