EnGene IC Pty Ltd v Vaxiion Therapeutics, LLC
[2018] APO 6
•18 January 2018
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
EnGene IC Pty Ltd v Vaxiion Therapeutics, LLC [2018] APO 6
Patent Application: 2008201082
Title:Minicell compositions and methods
Patent Applicant: Vaxiion Therapeutics, LLC
Opponent: EnGene IC Pty Ltd
Delegate: K. Wagg
Decision Date: 18 January 2018
Hearing Date: 30 August 2017
Catchwords: PATENTS –Minicells which display an antibody or antibody fragment and comprise a biologically active compound- Section 40-Novelty-all grounds of opposition fail-costs awarded against the Opponent.
Representation: Counsel for the Applicant: David Logan QC
Patent attorneys for the Applicant: Mark Egerton of Fisher Adams Kelly Callinans
Counsel for the Opponent: Angus Lang
Patent attorneys for the Opponent: John Lee of Gilbert and Tobin
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2008201082
Title:Minicell compositions and methods
Patent Applicant: Vaxiion Therapeutics, LLC
Date of Decision: 18 January 2018
DECISION
All grounds of opposition fail.
Costs are awarded against the Opponent.
Subject to appeal, I direct the application proceed to grant.
REASONS FOR DECISION
Background
Patent application number 2008201082 was filed on 06 March 2008 (the application). The application claims divisional status from patent number 2002318168 and claims an earliest priority date of 25 February 2002. The request for examination in relation to the application was filed on 23 September 2008. Consequently, substantive amendments of the Patents Act 1990 brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Raising the Bar) do not apply to the present application. This includes the amendment to subsection 60 (3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition exists. Any subsequent references to sections of the Patents Act relate to the Patents Act 1990 prior to amendment by the Raising the Bar Act. A similar qualification applies to references to the Patents Regulations 1991.
The applicant is Vaxiion Therapeutics, LLC (the Applicant). The application was examined and advertised as accepted by the Commissioner on 15 September 2011. EnGene IC (the Opponent) filed a notice of opposition to grant on 15 December 2011. After evidence in support was filed, the Applicant sought leave to amend the specification, including the claims, on 6 December 2013. Those amendments were allowed on 16 June 2014.
A hearing was held on 30 August 2017 in Canberra to decide the opposition.
The Statement of Grounds and Particulars
The Statement of Grounds and Particulars identified 6 grounds of opposition. At the hearing the following grounds were pressed:
·Insufficiency (section 40(2)(a))
·Inutility (section 18(1)(c))
·Lack of Fair Basis (section 40(3))
·Lack of Best Method of Performance (section 40(2)(a))
·Lack of Novelty
·Lack of Clarity
Standard of Proof
The onus of proof in this opposition proceeding rests with the Opponent, who must demonstrate that it is clear that a valid patent cannot be granted (F.Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [67]; 50 IPR 305; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18]; 79 IPR 426).
Evidence
The evidence is summarised in the table below:
Evidence Declarant Date Reference Exhibits In Support Andrew Blattman 27 July 2012 Blattman #1 ANB-1 to ANB-25 Dr Renato Morona 13 September 2012 Morona #1 RM-1 to RM-6 Dr Renato Morona 24 April 2013 Morona #2 RM-7 to RM-9 Dr Renato Morona 12 September 2013 Morona #3 In Answer Dr David Bramhill 1 July 2014 Bramhill #1 DB-01 Dr David Bramhill 15 July 2014 Bramhill #2 DB-02 Mark Egerton 16 July 2014 Egerton MLE-01 to MLE-03 In Reply Dr Renato Morona 14 October 2014 Morona #4 Further Evidence by the Applicant Dr Giacalone 11 August 2015 Giacalone MG-01 to MG-11 Responding Further Evidence by the Opponent Dr Renato Morona 11 February 2016 Morona #4 RM AD RM1 to RM2 Dr Stephen Mahler 11 February 2016 Mahler SM1-SM11 Dr Himanshu Brahmbhatt 11 February 2016 Brahmbhatt #1 HB-01 to HB-12 Dr Himanshu Brahmbhatt 11 February 2016 Brahmbhatt #2 HB-13 to HB-14 What is the invention as described?
Before commencing to construe the specification, I note what Middleton J said in Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214, 100 IPR 451 at [139]:
"It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date.”
The Specification
The specification is entitled “Minicell compositions and methods”. The minicells which are the subject of the claims are fully intact eubacterial minicells and contain a biologically active compound. The minicells also display an antibody or antibody derivative. The minicells are useful in therapy where the antibody serves to target a disease and then deliver the biologically active compound. The specification ends with 15 claims.
The field of the invention
The field of the invention is drawn to (page 1 lines 10-14):
“The invention is drawn to compositions and methods for the production of achromosomal archaebacterial, eubacterial and anucleate eukaryotic cells that are used as, e.g. therapeutics and/or diagnostics, reagents in drug discovery and functional proteomics, research tools, and in other applications as well”
The person skilled in the art
The person skilled in the art (PSA) was considered in Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; 49 IPR 225 at [70]:
“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.”
However, the PSA is not a real person, but an artificial construct that is used as a tool of analysis by the Court to make a determination. This concept was established in AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30 at [23]:
“The notional person is not an avatar for expert witnesses whose testimony is accepted by the court. It is a pale shadow of a real person – a tool of analysis which guides the court in determining, by reference to expert and other evidence, whether an invention as claimed does not involve an inventive step.”
The understanding of the PSA is based on evidence from persons with knowledge of the relevant art, experts, as to the things they know and do, and what they understand to be commonly known and done. The weighing and evaluating of this evidence to decide the characteristics of the PSA is part of the normal work of a delegate of the Commissioner.
The key expert declarants in this opposition are Dr Morona, Dr Bramhill, Dr Giacalone, DrMahler and Dr Brahmbhatt. Each of the declarants has experience in the field and is able to comment on what would be known and understood by the PSA.
The Opponent took issue with Dr Giacalone’s ability to comment on matters before the priority date (25 February 2002), because he started work on the invention for Vaxiion in 2006 (Giacalone #1 at 1 and 3). Dr Giacalone did, however, have experience dating back to the priority date and would be able to provide evidence on the state of the art at that time as the other experts have done. I therefore accept his evidence but I will weigh it accordingly.
The invention described in the specification
Titled “Minicell compositions and methods”, the specification describes the field of the invention as being “drawn to compositions and methods for the production of achromosomal archaebacterial, eubacterial and anucleate eukaryotic cells that are used as, eg., therapeutics and/or diagnostics, reagents in drug discovery and functional proteomics, research tools, and in other applications as well” (page 1).
“Minicells’ are defined in the specification as “achromosomal cells that are products of aberrant cell division, and contain RNA and protein, but little or no chromosomal DNA” (page 2, lines 1-2). The term “minicells” encompasses derivatives of eubacterial cells that lack a chromosome; derivatives of archaebacterial cells that lack their chromosome(s), and anucleate derivatives of eukaryotic cells (page 4, lines 25-28). Minicells are however “capable of plasmid-directed synthesis of discrete polypeptides in the absence of synthesis directed by mRNA from the bacterial chromosome” (page 2, lines 6-7).
The specification states that prokaryotic (also known as eubacterial) minicells have been previously been used to produce various eubacterial proteins (page 2 lines 19-20) and to express immunogens from other prokaryotes (page 3, lines 17-18). The specification refers to a third party report of minicells containing genes from a pathogenic agent (cholera), in which the pathogenic antigens are carried on the surface of the minicells (page 3, lines 20-24). Also noted is a report of a non-native modified fusion protein lacking a transmembrane domain being expressed in a minicell and properly translocated through the cell membrane and secreted - in this report the authors note the difficulty in expressing viral membrane proteins in prokaryotes (page 3 line 25 to page 4 lines 2).
Consistent with the stated field of the invention, under the heading “Summary of the invention”, the specification states on page 4:
“The invention is drawn to compositions and methods for the production and use of minicells, including but not limited to eubacterial minicells, in applications such as diagnostics, therapeutics, research, compound screening and drug discovery, as well as agents for the delivery of nucleic acids and other bioactive compounds to cells.”
On page 5, the specification describes various embodiments of minicells. Relevant to the invention set out in the opposed claims, on page 5 the invention encompasses a prokaryote minicell comprising a membrane protein not naturally found in a prokaryote, for example, a membrane protein derived from a eukaryote or an archeabacterium, or a fusion protein generated in vitro. Such minicells may, but need not, comprise an expression element that encodes and expresses the membrane protein (page 5, para 1).
On page 6, one aspect of the invention is the display of membrane-associated proteins on the minicell surface - the word “display”, is explicitly defined as “exposure of the structure of interest on the outer surface of the minicell” (page 6, lines 3-5). The displayed membrane protein can be a fusion protein (page 7 lines 5-7) and the displayed domain may be a binding moiety (page 7, line 28). Furthermore,
“By way of non-limiting example, binding moieties used for particular purposes may be a binding moiety directed to a compound or moiety displayed by a specific cell type or cells found predominantly in one type of tissue, which may be used to target minicells and their contents to specific cell types or tissues; or a binding moiety that is directed to a compound or moiety displayed by a pathogen, which may be used in diagnostic or therapeutic methods; … a diseased cell; … By "diseased cell" it is meant pathogen-infected cells, malfunctioning cells, and dysfunctional cells, e.g., cancer cells.” (page 7 line 28 to page 8 line 6).
The specification goes on to discuss the addition of biologically active compounds to the minicell (pages 8 and 9). The term “biologically active” is defined on page 8 lines 8-22 of the specification:
“The term “biologically active (synomyous with “bioactive”) indicates that a composition or compound itself has a biological effect, or that it modifies, causes, promotes, enhances, blocks, reduces, limits the production or activity of, or reacts with or binds to an endogenous molecule that has a biological effect. A “biological effect” may be but is not limited to one that stimulates or causes an immunoreactive response; one that impacts a biological process in an animal; one that impacts a biological process in a pathogen or parasite; one that generates or causes to be generated a detectable signal; and the like. Biologically active compositions, complexes or compounds may be used in therapeutic, prophylactic and diagnostic methods and compositions. Biologically active compositions, complexes or compounds act to cause or stimulate a desired effect upon an animal. Non-limiting examples of desired effects include, for example, preventing, treating or curing a disease or condition in an animal suffering therefrom; limiting the growth of or killing a pathogen in an animal infected thereby; augmenting the phenotype or genotype of an animal; stimulating a prophylactic immunoreactive response in an animal; or diagnosing a disease or disorder in an animal.”
The specification then defines the meaning of “biologically active” in the context of therapeutic, diagnostic and prophylactic applications of the invention (page 8 line 19 to page 9 line 10). Broadly, for therapeutic applications, a biologically active composition, complex or compound has an activity that impacts an animal suffering from a disease or disorder in a positive sense and/or impacts a pathogen or parasite in a negative sense (page 8, lines 23-29). In a diagnostic application, “biologically active” indicates that the composition, complex or compound can be used for in vivo or ex vivo diagnostic methods and in diagnostic compositions and kits (page 8, line 30 to page 9, line 2). For prophylactic applications, a biologically active composition or compound induces or stimulates an immunoreactive response (page 9, lines 3-10).
The description amounts to 354 pages and describes more specific embodiments of the minicells, their preparation, structural features and applications. It ends with 25 examples, describing the preparation and isolation of minicells according to the invention.
The specification ends with 15 claims. The correct approach to the construction of claims was discussed by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70, 81 IPR 228 at [118] – [120]:
“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”
Claim 1
Claim 1 is the only independent claim and it reads:
“A fully intact eubacterial minicell derived from a eubacterial parent cell, wherein the minicell comprises a biologically active compound and displays an antibody or antibody derivative, wherein the biologically active compound and the antibody or antibody derivative are exogenous to the parent cell and distinct from each other.”
The claim is to a minicell per se. This minicell is derived from a eubacterial parent cell. Minicells were well known to the experts and to the field (Morona #1 at 27) and being derived from eubacteria is self-explanatory (Morona #3 at 14).
The minicell is said to be “fully intact”. The body of the specification does not use the term “fully intact” but it does refer to an “intact” minicell on pages 53-54. Here intact minicells are said to have an “intact” outer membrane.
Bramhill (in Bramhill #2 at 38) states that this meaning of “intact” is the same as “fully intact” with little weight given to the positive modifier, “fully”:
“there is no ambiguity in meaning implied by “fully intact”. Intact is a word, like “dead” “complete” “unique” etc., that retains the same meaning despite any number of positive modifiers: “fully absolutely totally utterly intact” has the same meaning as “intact”.
Accordingly, in my view the use of the word “fully” in front of the term “intact” serves to make it clear to the person skilled in the art that there is no room for compromise on the meaning of “intact”. It is not partially intact in any way, but fully, or completely, intact.
In Brahmbhatt #1 at 12 the declarant construes “fully intact” with his knowledge of the outer membranes and adds what he thinks must be present in the membrane for it to be considered fully intact:
“By “fully intact” I understand (and would at 2002 have understood) that the minicell must have an uncompromised outer membrane that has not been destabilised (whether wholly or partly), and in particular all proteins, phospholipids and lipopolysaccharides (LPS) must be present.”
Dr Mahler makes a similar statement in Mahler at 33 in that he notes that it is the outer membrane which is indeed what makes the minicell cell intact:
“I understand this to mean the outer membrane of the minicell must not be degraded in any way.”
Brahmbhatt goes further to state that loss of LPS would result in a loss of structural integrity and a loss of intactness (Brahmbhatt #1 at 15).
When the term “fully intact” is read in the context of the specification, including the use of the term “intact”, which refers to the outer membrane, and in view of the evidence by Drs Bramhill, Brahmbhatt and Mahler it is clear to me that term refers to the structural integrity of the outer membrane. It is indeed the outer membrane of the minicell which holds it together, i.e., which makes it intact. If the outer membrane is not intact such as by being degraded, or compromised, then the minicell would not be intact.
Claim 1 requires the minicell to comprise “a biologically active compound” which is exogenous to the parent cell. The specification defines “biologically active” as synonymous with “bioactive” and indicating that the compound itself has a biological effect; or that it alters in some way the activity of an endogenous molecule that has a biological effect (page 8 lines 8-11). The specification goes on to state that the biologically active compounds “act to cause or stimulate a desired effect upon an animal” and that this effect has uses in therapeutic, prophylactic and diagnostic applications (page 8 lines 15-22).
Dr Bramhill referred to this definition in Bramhill II (at 40) and stated that:
“There is no ambiguity in this description”
Dr Mahler does not appear to have trouble with this term either stating (Mahler at 35) that:
“a biologically active compound must achieve a biological effect”.
Drs Morona and Brahmbhatt discuss this term (Morona V at 22 and Brahmbhatt I at 27) and attempt to distinguish it from a term later used in the application, “biologically active in a cell”. They then go on to state that a compound being biologically active in vitro has a different meaning to one that is biologically active in vivo. In this context they are discussing experiments done by the Applicant and they are arguing that a compound, which has a known biological activity, is not shown to be biologically active on its target.
In my view the term “biologically active compound” is clear and in its broad meaning the compound merely has to demonstrate any biological activity capable of causing or stimulating a desired effect in an animal which is of use for therapeutic, prophylactic or diagnostic purposes. Whether or not the specific compound used in the minicell exerts its biological activity when it reaches its target is not a question of construction but a question of utility.
The next feature of the claim is that the minicell displays an antibody or antibody fragment. The opponent submitted that the word “display” is used so that the purpose of the antibody or antibody derivative in targeting a cell and delivering the biologically active compound can be carried out. I accept this construction, the antibody or antibody derivative is “displayed” so that it can bind antigen external to the minicell. It therefore would be read as being in the outer membrane in order to do this.
The Opponent also submitted that the biologically active compound could have an effect on the minicell itself and includes DNA in the minicell. In a broad sense DNA is a biologically active compound. However, in the context of claim 1, if the biologically active compound were DNA, that DNA must be exogenous to the parent cell and be capable of causing or stimulating a desired effect in an animal which is of use for therapeutic, prophylactic or diagnostic purposes.
Clarity
It is a requirement of subsection 40(3) of the Act that the claims must be clear. This requirement is understood to be satisfied if a person could ascertain "whether or not what he proposes to do falls within the ambit of the claim"(Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59).
The Opponent submitted that the term “fully intact” was unclear if it were suggested by the Applicant to have any meaning otherthan that the minicell must have an uncompromised outer membrane that has not been destabilised. I have construed this term above and I agree that “fully intact” requires the outer membrane to maintain structural integrity of the minicell and to hold the minicell together so that it is fully intact. It does not lead to position where a PSA would not be able to determine if something, such as a minicell, falls within the scope of the claim or not. Therefore this feature of the claims is clear.
The Opponent further argues that the term “biologically active compound” is unclear because the reference in the description refers to biological effects. There are terms in that definition that the Opponent believes are open-ended and therefore unlimited. Specifically the terms are that the biological effect “may be but is not limited to” followed by a list, then it is one that generates or causes to be generated a detectable signal which is followed by “and the like”.
I have construed the term “biologically active compound” above and have been able to give it a meaning. The term is also known to all the witnesses. The parts of the description the opponent refers to merely provide examples of what a PSA would already consider to be a biological effect, and do not render the claims unclear.
In conclusion, I find the claims are clear.
Sufficiency
The test for sufficiency of description is set out in the High Court decision in Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 at [25]:
"… will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions of prolonged study of matters presenting initial difficulty?"
The Opponent argued that there were no examples within the scope of the claims in the specification and that the prophetic disclosures required undue experimentation by the person skilled in the art to produce something within the scope of each claim.
Dr Morona commented on the examples stating that many were prophetic in nature (Morona III at 67) and stated at 68:
“…the experimental procedures set out in the Opposed application allegedly managed to produce exogenous GFP in the cytoplasm of minicells, and an exogenous bacterial protein (T-PhoA) on the inner membrane of minicells. There are however no directions in the Opposed application that a person of ordinary skill in the field could have used to achieve the expression of any exogenous protein on the outer membrane of a minicell. This represented a significant and unsolved technical difficulty that the Opposed application provides no tangible solution for. In my opinion, the significant lack of guidance and directions in the Opposed application means that an ordinarily skilled person in the relevant field in February 2002 would not have had any reasonable expectation of achieving a useful result when attempting to prepare minicells having the claimed features.”
Dr Bramhill responds to this issue of displaying the antibody in the outer membrane stating (Bramhill #2 at 29):
“there are two general approaches to engineer this arrangement, one is to conjugate the antibody or antibody derivative to the minicell surface either chemically or via very tight non-covalent association, while the second is to use one of the fusion strategies cited in the opposed application.”
Dr Bramhill then goes on to cite the disclosure in the specification on pages 183-186 to means of attaching binding moieties or other compounds to minicells.
Dr Giacalone provided further evidence on work he did using methods disclosed in the specification in which he followed the following disclosures (Giacalone at 3):
“I conducted or supervised, in the course of my work at Vaxiion, a number of procedures by following specific disclosures of methods of displaying antibodies or antibody derivatives on the surface of minicells as taught by the opposed patent application. These methods include:
a)Chemical cross-linking of antibodies to the surfaces of eubacterial minicells, for
example the use of cross-linking reagent N-ε-maleimidocaproyloxysulfosuccinimide ester (Sulfo-EMCS) (e.g. see pages 183-185 and particularly page 185 lines 10-25 of the opposed patent application);
b)Use of bi-specific antibodies to display antibodies on the surfaces of eubacterial minicells, for example using succinimidyl 3-(2-pyridyldithio) propionate (e.g. see page 178 lines 15-17 and page 185 lines 12-13 of the opposed patent application);
c)Fusion of an scFv antibody derivative (single chain variable :fragment; e.g. see p177 line 23 and p. 178 lines 26-30 of the opposed patent application) to form a chimeric Lpp-OmpA (Lpp-OmpA-scFv) construct using the procedures disclosed and cited at pages 177-181, 214, 225, 232 and particularly at page 181 lines 5-13
of the opposed patent application with regard to the Lpp-OmpA display system(see expression system described in Daugherty et al. referenced at page 181 lines 11-13 of the opposed patent application);
d)Use of streptavidin/biotin to link antibodies to the surfaces of eubacterial minicells (e.g. see p. 25 lines 3:--5 of the opposed patent application).”Dr Giacalone then provided examples of the experiments he undertook. In their submissions, the Opponent went through each example and discussed the issues with it. Rather than attempting to find fault in Dr Giacalone’s work, I will instead deal with the question set out by the High Court in Kimberly Clark.
Will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions of prolonged study of matters presenting initial difficulty?
The Opponent argued that to perform the invention would require undue experimentation for three reasons. I will deal with these in turn.
1. Determining whether the minicell is “fully intact”
The Opponent submitted that the specification does not provide a method of determining whether the minicell is intact or not. In some of Dr Giacalone’s experiments reducing agents are used on the minicells. The Opponent’s declarants expressed concern that the use of reducing agents, such as EDTA, 2-MEA and DTT would lead to minicells that were leaky (Brahmbatt #1 at 22-26). However, the opponent’s evidence does not establish, as a matter of fact that this would happen and that it would require new invention or prolonged study to overcome.
In his experiments, Dr Giacalone uses red fluorescence to indicate that doxorubicin is present in the minicells (Figure 1C). The witnesses do have a discussion as to whether or not doxorubin is a biologically active compound. It is used in a minicell in an experiment presented by Dr Giacalone in evidence. They argued that if doxorubin was not released from the minicell in Dr Giacalone’s example then it would not be exerting a biological effect and would not be a biologically active compound. This is not a question of clarity but related to the experiments and in my view this was speculative and I have evidence, other than speculation, that this occurred. Furthermore, doxorubin is a well-known drug and is a biologically active compound.
Both Drs Mahler and Morona comment on the background red fluorescence present in the figure. They say this could be due to leakage but acknowledge that it is not clear whether that is the case (Mahler at 34 and Morona V at 20). The fact that leakage is a possibility does not satisfy me to the level of practical certainty that Dr Giacalone has not been able to produce something within the scope of the claim. Both Drs Mahler and Morona do, however, appear to propose a method for measuring whether a minicell is intact. Dr Mahler states at 34:
“There is, however, no evaluation of the minicells over time, for example by recording and observing red fluorescence over time or comparing the minicells with a population with known leakage characteristics.”
Dr Morona makes a similar comment (Morona V at 21):
“there is no time course data in relation to the retention by minicells of doxorubicin measured at time intervals in the Giacalone Declaration.”
In view of this evidence, the Opponent has not established that the person skilled in the art would not be able to produce fully intact minicells based on the specification nor have they established that determining whether minicells are intact would require new invention or additions of prolonged study.
2. Displaying the antibody or antibody derivative in a way that it remains functional
On this alleged difficulty, the Opponent noted three problems.
The first problem was that in order to cross-link antibodies to the minicell surface the disulphide bonds on the antibodies need to be reduced. However, this step is unpredictable and can lead to toxic aggregates of antibodies (Mahler at 52, Brahmbhatt I at 40).
The Applicant argued that aggregation was not a real concern and cited Exhibit HB-12, a paper by Dr Brahmbhatt, in which a similar reduction step is carried out and this problem is not discussed. The Applicant submitted that there was no evidence that aggregation occurred in the experiments conducted by Dr Giacalone which displayed antibodies citing the FACS data in MG-02 which is fluorescent-activated cell sorting and showed the signal from the monoclonal antibody displayed on the surface of the minicells with doxorubicin inside the minicell. The Applicant further stated thatthe fact that in MG-03 the minicells were able to kill A549 tumour cells despite having been treated with the reducing agent DTT demonstrated that the antibodies were displayed to be able to target the tumour cells.
Furthermore, a reduction step is not a feature of claim 1 and Applicant submitted that Dr Giacalone (in MG-07) had produced minicells comprising the Lpp-OmpA-scFv fusion protein using a method that did not require a reduction step. Although the Opponent alleged that the Lpp-OmpA-scFv fusion technology would not have been available at the priority date, the specification refers to the display of fusion proteins with a transmembrane domain (anchoring domain) and another display domain (page 12 line 27 to page 13 line 27). In my view the specification emcompases the strategy used by Dr Giacalone albeit the particular fusion protein. Therefore the Opponenthas not demonstrated that something within the scope of the claim could not be done, as a result of antibody aggregation.
The issue of aggregation, was not demonstrated in the experiments presented by Dr Giacalone and instead the Opponent appears to be seeking to have the Applicant repeat its experiments until there is a statistical significant sample of positive experiments to prove this is not an issue. The burden of proof in opposition proceedings is on the Opponent and therefore it is not the Applicant’s burden to prove repeatability or statistical signifcance. The problem of aggregation was not reported by Dr Giacalone or by Dr Brahmbhatt in his evidence (HB-12).and in my view the opponent has not established that aggregation represents an initial difficulty or be something that would require prolonged study or experimentation to overcome. It has therefore not been established that the description is insufficient as a consequence of antibody aggregation.
The second problem identified by the Opponent is that there is no data to indicate whether cross-linking of the antibodies to the minicell surface was stable in Dr Giacalone’s experiments. This submission is based on Dr Mahler’s (Mahler at 32) evidence where he stated:
“There is nothing in the Giacalone Declaration or the Additional Documents which indicates whether the linkages between the antibody and the minicell surface were stable.”
The declarant then states why this would be a problem:
“The consequence of unstable linkages would be a loss of targeting capability of the minicells.”
While this could be a potential issue the experiments conducted by Dr Giacalone were able to target tumour cells in MG-03 and I therefore do not consider the stability of the cross linking of the antibodies to the minicell surfaceto represent an initial difficulty that requires an undue burden on the person skilled in the art. Dr Mahler, proposes further methodology that could measure if this were a potential issue (Mahler at 32). In my view these further experiments are not required when there is no evidence that there was a loss of targeting capability actually occurring in the first place. The Opponent has not discharged its burden of proof.
Thirdly, the Opponent argued that there is no way of controlling the orientation of the antibody citing a concern raised by Dr Mahler (at 37) that the antigen-binding portion of the antibody may be oriented in a manner that reduces or precludes ligand binding. In response, the Applicant submitted that this conclusion is not based on experimental evidence and that scFv antibodies would have solved this problem.Single chain Fv fragments are disclosed in the specification at page 177 line 23 and page 178 lines 26-30 and used by Dr Giacalone in his experiments (MG-07, MG-10 and MG-11). In this regard, Dr Mahler’s concerns have not been experimentally demonstrated nor has the opponent established that they would require new invention, additions or prolonged study to overcome them as an initial difficulty. To the contrary, Dr Giacalone has conducted experiments (MG-07, MG-10 and MG-11) where this was not presented as an issue.
3. Ensuring that there is a biologically active compound having a biological effect on the target.
The Opponent noted that doxorubicin, the compound used in Dr Giacalone’s experiments, was not listed as a biologically active compound. However, doxorubicin is a known anthracycline DNA binding anticancer drug and the Applicant cited HB-7. HB-7 is an article entitled Structural Studies of atom-specific anticancer drugs acting on DNA (Pharmacology and Therapeutics 83, 1999, 181-215). It discusses the action of doxorubicin on pages 183-185. This demonstrates to me that doxorubicin was a well-known drug99 and a lot of its biological activity and mechanism of action had been elucidated.. I therefore accept that doxorubicin is a biologically active compound.
The experiments by Dr Giacalone show minicells containing doxorubicin killing lung cell carcinoma cells. Dr Mahler criticises this to say that it is not statistically significant and not in vivo (Mahler at 38). I note that the bar for sufficiency is not that of clinical medicine, and instead it only requires that the PSA be able to do something within the scope of each claim; in vivo experiments are not a requirement for sufficiency of a product claim. In my view Dr Giacalone’s evidence demonstrates that the PSA could determine the biological effect of a biologically active compound on its target.
This ground of opposition fails.
Utility
It is a requirement of subsection 18(1)(c) of the Act that the invention, so far as claimed in any claim, must be useful:
Subject to subsection (2), an invention is a patentable invention for the purposes of a standard patent if the invention, so far as claimed in any claim: …
(c) is useful.The issue of utility was considered by the Full Court of the Federal Court in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70, 81 IPR 228. Emmett J at 247 [81] 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."
In Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162; (2013) 100 IPR 285 at [352] 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."
I will therefore determine the desired result of the specification (promise of the invention) and then look to see if the evidence shows whether there is something within the scope of the claim that does not produce that desired result.
What is the promise of the invention?
The Opponent stated that the benefit of the invention promised by the Applicant is that the antibody or antibody derivative on the surface of the minicell will bind to a target and enable the biologically active compound, carried by the minicell, to produce a useful biological effect. To support this submission the Applicant cited the example experiments conducted by Giacalone (at 8-10 and 12) and the discussion of claim 1 by Bramhill (in Bramhill #2 at 10).
The Applicant responded that the promise suggested by the Opponent is an overly narrow interpretation and that the summary of the invention in the specification does not specifically relate to antibodies, target cells or application. The Applicant submitted that it is not essential part of the promised result that the antibody displayed on the surface of the minicell will bind to a target cell and that the therapeutic, diagnostic or prophylactic effect is not an essential feature of the claim.
I have reviewed the summary of the invention the Applicant has taken me to above. I noted that this passage must be read in the context of the amended claims and therefore one must look at this broad passage and the narrower claims to determine what is promised.Indeed the specific minicell as claimed displays an antibody and comprises a biologically active compound. Both of these must have a use, the antibody or antibody derivative is displayed for a reason and the biologically active compound is present for a reason. I therefore accept the Opponent’s construction of the promise of the invention in that the antibody or antibody derivative is displayed so it can bind a target and then the biologically active compound is delivered.
Does the evidence establish that something within the scope of the claim will not achieve the promise?
The Opponent did not provide evidence of an expert making something within the scope of the claim and showing that it did not meet the promise. Instead they looked at the experiments which were conducted by the Applicant’s witness, Dr Giacalone, and criticised them. In that criticism they state potential problems which I have discussed earlier under sufficiency.
The issues raised by the opponent included the possible binding of doxorubicin to the plasmid DNA and therefore making it incapable of exerting a biological effect on the target cell, that the antibodies will form toxic aggregates in the membrane of the minicell leading to unrepeatable results, that the conjugation method of example 4 (MG-04) conducted by Dr Giacalone will activate complement in vivo resulting in destruction of the minicell and toxic effects and fourthly that the expression-fusion methods might not produce correctly folded antibodies or that they will be unstable.
The Opponent’s submissions are a want of more experiments and a demonstration of repeatability. The opponent has not demonstrated in evidence that these issues will occur. Therefore the evidence does not establish a lack of utility.
This ground of opposition fails.
Fair Basis
It is a requirement of subsection 40(3) of the Act that the claims must be fairly based on the matter described in the specification.
The Opponent, in their submissions, applied the test from Olin Mathieson Chemical Corporation v Biorex Laboratories Limited [1970] RPC 157, a case decided under the UK Act of 1949. This case provides a test for fair basis where the specification must provide a “sound prediction” for what is claimed. The Applicant stated that there is no authority for this case to be law in Australia.
The Opponent also cited Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd (1987) 15 FCR 382 (Coopers) claiming that the specification lacked an essential feature of the claims. The Applicant noted that relying on Coopers is also problematic as that case relates to external fair basis rather than internal fair basis.
The High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58 at [69], [2004] HCA 58; 217 CLR 274 (Lockwood) at 300 approved the words of Gummow J in Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 at 95:
"the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification".
In my view, the question of fair basis in this particular case can be answered by using the principles established in Lockwood, rather than relying on other principles and authorities that are further away from the question put forward by the High Court.
The first aspect of the Opponent’s argument relies on the issues their experts had with the experiments conducted by Dr Giacalone. In short, they believe that the experiments posed a range of potential problems and that they would not be repeatable. The Opponent states that because of these issues the PSA would not be able to make a “sound prediction” that all embodiments of claim 1 would achieve the desired benefit and accordingly there is no real and reasonably clear disclosure of the claimed invention.
In my view, these are not issues based on what is described in the body of the specification but instead relate to potential problems with the experiments conducted Dr Giacalone. These experiments are not in the specification. Fair basis is a question about the internal consistency of the patent specification itself and therefore these experiments cannot result in a lack of fair basis.
The second aspect is the term “fully intact”. As the Opponent puts it, this is an “essential feature of the minicell, however, this term is not used in the specification” and consequently is not fairly based.
I note that using “essential features” in Coopers, occurred before Lockwood and that the High Court stated in Lockwood at 68:
“The comparison which s 40(3) calls for is not analogous to that between a claim and an alleged anticipation or infringement. It is wrong to employ “an over meticulous verbal analysis”. It is wrong to seek to isolate in the body of the specification “essential integers” or “essential features” of an alleged invention and to ask whether they correspond with the essential features of the claim in question.”
Instead of determining whether or not the term “fully intact” is an essential feature, I will determine if there is a real and reasonably clear disclosure of the claimed invention. A feature of that invention is the fully intact eubacterial minicell.
The Opponent has set out parts of the specification which relate to poroplasts, spheroplasts, and protoplasts (page 49 lines 11-23). Indeed these have their membranes disrupted and are mentioned as preferred embodiments.
The eubacterial minicell disclosed on pages 55, lines 1-3 states:
“minicells are produced which contain an intact outer membrane, inner membrane, cell wall and all of the cytoplasm components but do not contain chromosomal DNA.”
In their submissions the Applicant cited this passage as the real and reasonably clear disclosure of “fully intact.”
To establish a lack of utility, the Opponent relied on several passages which refer to protoplasts and poroplasts and the examples which are not within the meaning of “fully intact” as I have construed the term. This does not, however, satisfy me that there is no real and reasonably clear disclosure of fully intact minicells but rather that there is also a disclosure of minicells which are not fully intact. The Opponent has therefore not discharged its onus in relation to this ground and I am not practically certain that the claims are not fairly based.
This ground of opposition fails.
Best Method of Performance
The specification, in addition to fully describing the invention, must include the best method of performing the invention. In American Cyanamid Company v Ethicon Limited [1979] RPC 215 at page 269, it was stated:
"The Act is intending to protect the public against a patentee who deliberately keeps to himself something novel and not previously published which he knows of or has found out gives the best results, with a view to getting the benefit of a monopoly without giving to the public the corresponding consideration of knowledge of the best method of performing the invention."
In Expo-Net Danmark A/S v Buono-Net Australia Pty Ltd (No 2) (Expo-Net) [2011] FCA 710 Bennett J stated (at 15-16):
"it must be established that there was a better method known to the applicant at the date of filing the patent than the one described in the specification. This is clearly a subjective question."
"To that end it is necessary first to understand what the invention is. Indeed, this is perhaps the first question that needs to be answered".
Consequently, even if a manner of performing an invention is self-evident from the common general knowledge, applicants are nevertheless required to set out the best method of performing the invention known to them. This requirement was confirmed by the Full Court of the Federal Court in Les Laboratoires Servier v Apotex Pty Ltd [2016] FCAFC 27:
"It can be accepted that there are cases where the claim is to a product or class of products and the best method requirement is satisfied by a description of the best embodiment known to the patentee at the relevant time. It can also be accepted that there are cases where the claim is to a product and there is no requirement to provide a method of using that product. It is also the case that there is no requirement actually to have carried out the best method and that a prediction will suffice. However, it is necessary to understand the invention itself”…”The nature of the invention will determine what is 'best' in the circumstances."
The best method requirement is assessed on the basis of the applicant’s knowledge at the time of filing the complete specification (Rescare Ltd. v Anaesthetic Supplies Pty. Ltd., 25 IPR 119). If the applicant identifies a better method at a time subsequent to filing, there is no obligation to amend the specification to include that method.
The specification will fail for want of best method if it can be shown that the best method known to the applicant at the date of filing is not included, PfizerOverseas Pharmaceuticals v Eli Lilly [2005] FCAFC 224 at [366]-[379] (Pfizer). Section 102 allows for amendments to overcome a ground of objection and this includes adding the best method known at the filing date, Pfizer at [368].
100. It is clear that I need to consider three matters:
1. What is the invention for which a best method must be provided
101. The invention for which a best method must be provided for is the invention defined by the claims. This has been discussed above, but it is a method to produce a fully intact eubacterial minicell, derived from a eubacterial parent cell comprising a biologically active compound and displaying an antibody or antibody derivative. The biologically active compound and antibody or antibody derivative is exogenous to the parent cell and distinct from each other.
2. What method is described in the specification?
102. The Opponent submitted that there is no method described for this particular invention; it is not provided for by way of an embodiment or worked example. Their expert, Dr Morona, stated (Morona #3 at 59):
“In essence, the Examples of the Opposed application provide evidence of producing two exogenous proteins in minicells, green fluorescence protein (Example 16) and T-PhoA (Example 17). The discussion relating to rat neurotensin receptor is limited to the production of sequences that might be incorporated into a vector (see Example 21), and detailed means for the expression and localisation of an encoded protein is in no way described or demonstrated.”
103. He goes on to say (at 60):
“None of these exogenous proteins are displayed on an outer surface of an intact minicell containing an uncompromised outer membrane. The Opposed application provides no direction as to how this could be achieved, nor any experimental demonstration (prophetic or otherwise of an intact minicell that expresses an exogenously introduced prokaryotic or eukaryotic protein on its outer surface.”
104. In response to this the Applicant is of the view that there is no requirement to provide a best method other than what is required for full description. They set out what I have previously found to provide sufficiency as set out by Dr Giacalone when he set out working on the examples provided in evidence. They are as follows (Giacalone at 3):
“a)Chemical cross-linking of antibodies to the surfaces of eubacterial minicells, for example the use of cross-linking reagent N-ε-maleimidocaproyloxysulfosuccinimide ester (Sulfo-EMCS) (e.g. see pages 183-185 and particularly page 185 lines 10-25 of the opposed patent application);
b)Use of bi-specific antibodies to display antibodies on the surfaces of eubacterial minicells, for example using succinimidyl 3-(2-pyridyldithio) propionate (e.g. see page 178 lines 15-17 and page 185 lines 12-13 of the opposed patent application);
c)Fusion of an scFv antibody derivative (single chain variable :fragment; e.g. see p177 line 23 and p. 178 lines 26-30 of the opposed patent application) to form a chimeric Lpp-OmpA (Lpp-OmpA-scFv) construct using the procedures disclosed and cited at pages 177-181, 214, 225, 232 and particularly at page 181 lines 5-13
of the opposed patent application with regard to the Lpp-OmpA display system(see expression system described in Daugherty et al. referenced at page 181 lines 11-13 of the opposed patent application);
d)Use of streptavidin/biotin to link antibodies to the surfaces of eubacterial minicells (e.g. see p. 25 lines 3-5 of the opposed patent application).”
Although the protocols used by Dr Giacalone did not follow one of the explicit worked examples in the specification, he nonetheless used methods disclosed in the specification. The methods he used were presented as examples or protocols. The Sulfo-EMCS, disclosed on page 185 is presented to the person skilled in the art as a “non-limiting example” (page 185 line 10). Similarly, the the use of the single chain antibodies (scFv) is also presented by way of “non-limiting example (page 187 lines 26-27). I accept that these disclosures are general in nature, however, they do represent a method of performing the invention.
I am satisfied that the method specification discloses a method of performing the invention claimed.
3. Was a better method known?
105. The Opponent did not provide submissions or evidence on this question. There is no evidence on the state of mind of the Applicant at the time of filing nor is there any evidence on what would be a “better method”. As a consequence of this, the Opponent has not discharged its onus of proof and I cannot be satisfied that a better method was known.
106. In summary, the specification provides a best method for performing the invention as claimed and I am not satisfied that there was a better method known to the Applicant at filing.
107. This ground of opposition fails.
Novelty
108. 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) states that an invention is taken to be novel unless it is not novel in the light of the prior art. A citation is part of the prior art base for the purposes of novelty if it was published before the priority date of the claim. However, subsection 7(1)(c) includes the prior art base which is defined as:
“information contained in a published specification filed in respect of a complete application where: the information is, or were to be, the subject of a claim of the specification, the claim has, or would have, a priority date earlier than that of the claim under consideration; and the specification was published after the priority date of the claim under consideration; and the information was contained in the specification on its filing date when it was published”
109. In other words a patent application that is published after the opposed application can be cited for novelty if the citation has an earlier priority date. This is known as “whole of contents” novelty.
110. The Opponent raised one document as a whole of contents novelty citation:
D1: WO2002/072759
111. In order to use a whole of contents novelty citation it must be possible to draft a notional claim (assuming there is not an actual claim to the relevant subject matter) that is fairly based on the disclosure of the prior specification relied upon (Danisco A/S v Novozymes A/S (No 2) [2011] FCA 282;(2011) 91 IPR 209 at [178]). However, in order to determine if a claim can be drafted from a disclosure the usual tests for novelty is to be applied.
112. The well-established general test for lack of novelty is the reverse infringement test. The classic formulation of this test is that given by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; 137 CLR 228 at 235:
"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".
113. This test is satisfied if the alleged anticipation discloses all the essential features of the invention as claimed (see Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 at 517). In order to meet this requirement, the prior art must “contain clear and unmistakeable directions to do what the patentee claims to have invented” (The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited (General Tire) [1972] RPC 457 at 486).
114. The Opponent contended that D1 claims priority from US 60/274,039 and US 60/306,946 which were filed on 7 March 2001 and 20 July 2001. The earliest priority date claimed for the current application is 25 February 2002.
115. The Applicant purported that the subject matter the Opponent relies on in D1 is not fairly based on either priority document and thereby making that subject matter a later disclosure.
116. I will first look at the disclosure of D1 and determine if it provides clear and unmistakable directions which, if followed, would fall within the scope of the current claims.
117. D1 discloses minicell display technology which can be used for peptide screening (Morona III at 36). An exogenous plasmid (page 6 line 29 to page 7 line 8) is introduced into the minicell (page 8 lines 1-5), which then expresses a gene from the plasmid which codes for a peptide which is displayed on the outer surface of the minicell (page 6 lines 29 to page 7 line 1).The displayed peptides are then used to identify “target molecules” which bind and interact with a displayed peptide. Relevantly, the target molecule-peptide pairs includesantibody-antigen pairs and IgG-protein A. (D1 page 19, lines 8-13).
118. The Opponent has argued that this screening technology would be within the scope of the claims if the plasmid construct is considered to be the biologically active compound. They say that the plasmid is capable of elucidating a biological effect on the minicell itself. This construction is broad and would encompass the biological effect elucidated by the compound not to be targeted but rather include a biological action, such as to carry out gene expression itself. Indeed one could consider a plasmid, and DNA generally, to be a biologically active compound. However, above I have construed the term “biologically active compound” in claim 1 as defining either a compound having a biological effect, or a compound capable of modifying the activity of an endogenous molecule having a biological effect, which in either case produces a desired effect upon an animal.
119. The plasmid DNA in D1 has a biological function in the minicell in that it acts as an expression vector. However, it does not elucidate a biological activity capable of causing or stimulating a desired effect upon an animal, as is required by claim 1 as I have construed it. It follows that D1 does not anticipate opposed claim 1.
120. The Applicant’s submissionsfocussed instead on the requirement in claim 1 that the minicell displays an antibody or antibody derivative, whereas the evidence establishes that in D1 it is shortpeptides (possibly antigen), which is displayed on the minicell surface (Bramhill 2 at 16.1.3, 16.2 and 16.2.1; and not inconsistent with Morona IV at 22-23 and 37).
121. In conclusion, D1 does not provide clear and unmistakable directions to generate a minicell comprising a biologically active compound as I have construed this term in claim 1, nor does it disclosea minicell displaying an antibody or antibody derivativeIt follows that this ground of opposition has not been successful.
122. Given my decision, I do not need to decide the priority of D1.
Conclusion
123. All grounds of opposition fail. Subject to appeal, I direct the application proceed to grant.
Costs
124. The parties submitted that costs should follow the event. I see no reason to depart from that result. Costs should be awarded against the Opponent under Schedule 8.
K. Wagg
Delegate of the Commissioner of Patents
1
15
0