Sandoz AG v Leo Laboratories Limited
[2015] APO 41
•24 July 2015
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Sandoz AG v Leo Laboratories Limited [2015] APO 41
Patent Application: 2006325244
Title:Therapeutic compositions comprising ingenol-3-angelate
Patent Applicant: Leo Laboratories Limited
Opponent: Sandoz AG
Delegate: Dr S.D. Barker
Decision Date: 24 July 2015
Hearing Date: 25 and 26 May 2015, in Canberra
Catchwords: PATENTS – opposition to grant – ingenol angelate formulations – construction of the term "aprotic" – novelty – the citation does not disclose an aprotic solvent or a pH of no greater than 4.5 – inventive step – the evidence does not establish that it would have been a matter of routine to use an aprotic solvent or a pH of no greater than 4.5 – opposition fails on all grounds – costs awarded
Representation: Patent applicant: Ian Horak of counsel, assisted by Damian Slizys and Carol Burnton of Freehills Patent Attorneys
Opponent:Marco Fachini, a European Patent Attorney of Sandoz International
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2006325244
Title:Therapeutic compositions comprising ingenol-3-angelate
Patent Applicant: Leo Laboratories Limited
Date of Decision: 24 July 2015
DECISION
The opposition is unsuccessful.
Subject to appeal, I direct that the application proceed to grant.
I award costs according to Schedule 8 against Sandoz AG.
REASONS FOR DECISION
Patent application number 2006325244 was filed on 18 December 2006 as an application under the Patent Cooperation Treaty. The applicant at filing was Peplin Research Pty Ltd, and the application was subsequently assigned to Leo Laboratories Limited (Leo). The application was examined and accepted by the Commissioner, and subsequently opposed by Sandoz AG (Sandoz). A hearing was held on 25 and 26 May 2015 in Canberra to decide the opposition. Leo was represented by Ian Horak of counsel, assisted by Damian Slizys and Carol Burnton of Freehills Patent Attorneys. Sandoz was represented by Marco Fachini, a European Patent Attorney of Sandoz International. Also in attendance were Dorte Jenson and Thorsten Thormann from Leo Laboratories, and Daniel Wise from Carpmaels & Ransford LLP.
The opposition
The statement of grounds and particulars identified five grounds of opposition: entitlement of the applicant, novelty, inventive step, utility and section 40. At the hearing, the opposition was limited to the grounds of entitlement, novelty, inventive step and utility. I raised a matter of fair basis during the hearing.
The parties relied upon evidence by several declarants. Evidence in support consists of declarations by Peter Hersey, Giovanni Appendino, Roberta Cavalli, Marco Fachini, Kieran Williams and Emma-Louise Moore. Evidence in answer consists of declarations by Philip Andrew Marshall, Jacqueline Waterkeyn, Michael Edward Donald Crothers, Carol Margaret Burnton, Per-Ola Christian Arvidsson and Peter Gordon Parsons. Evidence in reply consists of declarations by Emma-Louise Moore, Kieran Williams, Giovanni Appendino and Roberta Cavalli. I will refer to the relevant parts of the evidence where appropriate. Where a declarant has provided more than one declaration, I will refer to the evidence as "Appendino 1" or "Appendino 2", for instance (with the earlier declaration designated 1, and the later declaration designated 2).
The specification
The specification states at page 1 that it relates to "compositions of compounds obtainable from Euphorbia species and which are useful in the treatment of skin cancers". The specification ends with 9 Figures and 49 claims.
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 background to the invention
The specification states at page 1 that ingenol angelates are known:
"The compound ingenol angelate can be isolated from various Euphorbia species, and particularly from Euphorbia peplus and Euphorbia drummondii. Ingenol angelate exists in three isoforms: ingenol-3-angelate (isoform 'b'), ingenol-5-angelate (isoform 'a') and ingenol-20-angelate (isoform 'c')."
and that they are toxic for skin cancer cells:
"Ingenol angelate has been found to be highly toxic for skin cancer cells via rapid mitochondrial disruption and cell death by primary necrosis, while leaving healthy cells unaffected."
At page 2 it is noted that there is a:
"tendency for isoform 'b' to undergo rearrangement to isoform 'a' and subsequently to isoform 'c'"
and also that:
"the different isoforms have different solubilities".
The structure of ingenol-3-angelate, showing the 3, 5 and 20 positions, is:
The 'b' isoform is the 3-angelate (shown above). The 'a' isoform is the 5-angelate, and the 'c' isoform is the 20-angelate. Ingenol-3-angelate is sometimes abbreviated to I3A.
At page 3 the specification says that:
"ingenol angelate is generally susceptible to rearrangement in protic solvents".
The aim of the invention
At page 2 the specification identifies two needs:
"There is a need for an effective, topical treatment for skin cancer, as systemic treatments involving other drugs necessarily result in exposure of susceptible healthy cells, in non-target parts of the body, to cytotoxic chemicals"
and:
"There is a need to provide a stable formulation of ingenol angelate, preferably for topical administration."
The nature of the invention
The specification goes on to state at page 2 that:
"It has now, surprisingly, been found that ingenol angelate can be solubilised, substantially without rearrangement between isoforms, in an acceptable, aprotic solvent in the presence of an acceptable, miscible acidic buffer."
This seems to be the essence of the invention.
The invention as described
The specification sets out the invention in general terms on page 2 as follows:
"Thus, in a first aspect, the present invention provides a formulation of ingenol angelate for use in therapy, wherein the ingenol angelate has been dissolved in a pharmaceutically acceptable, aprotic solvent, said formulation further comprising a pharmaceutically acceptable acidifying agent which is at least partially compatible with the solvent and which provides the formulation with an apparent pH of no greater than 4.5."
The specification proceeds to follow a normal layout, discussing aspects of the invention and Examples.
The major question in this opposition is the meaning of an aprotic solvent. This is a technical term, and there is evidence as to the meaning of the term. There is no doubt that aprotic is the opposite of protic. The evidence shows that there are two ways in which the term aprotic can be understood. First, it is a solvent that does not donate protons. Second, it is a solvent that does not participate in hydrogen bonding.
Hydrogen bonding is an attractive interaction between a hydrogen atom of a molecule and an atom or group within the same or a different molecule. Hydrogen bonding is a strong force when the hydrogen atom is attached to a highly electronegative atom (such as oxygen) and the other atom has available lone pairs of electrons (such as oxygen). The effect is well established in alcohols, as shown below with the hydrogen bond represented by a dotted line between the hydrogen of one molecule and the oxygen of another:
The evidence supporting the first interpretation of aprotic is as follows.
- Professor Appendino says at paragraph [69] of Appendino 1 that benzyl alcohol is not an aprotic solvent because it is able to donate a proton:
"As is clear from the chemical structure I have depicted above, benzyl alcohol contains a hydroxyl group, which would be capable of donating a proton. Therefore, benzyl alcohol is a protic solvent."
- Dr Crothers refers to a standard reference work at paragraphs [7] and [8] of his declaration:
"I understand this expression to be used in a conventional sense, in particular, in accordance with the definition given to this expression by the International Union of Pure and Applied Chemistry (IUPAC) in its Compendium of Chemical Terminology, informally known as the 'Gold Book'. The Gold Book is published by IUPAC and contains internationally accepted definitions for terms in chemistry. The Gold Book definition of aprotic solvent is annexed to this declaration and marked 'MC-2', and reads:
Non-protogenic (in a given situation). (With extremely strong Brønsted acids or bases, solvents that are normally aprotic may accept or lose a proton. For example, acetonitrile is in most instances an aprotic solvent, but it is protophilic in the presence of concentrated sulphuric acid and protogenic in the presence of potassium tert-butoxide. Similar considerations apply to benzene, trichloromethane, etc.)
According to this definition, an aprotic solvent is therefore one that is non-protogenic in a given situation. This means that the solvent is not capable of acting as a proton donor in its local environment. I understand the local environment defined in the claim to be a formulation with an apparent pH of no greater than 4.5. Accordingly, I understand the expression 'aprotic solvent' to mean a solvent that is non-protogenic under these pH conditions."
The evidence supporting the second interpretation of aprotic is as follows.
- The text book Organic Chemistry by Clayden, Greeves, Warren and Wothers (Exhibit GA-14) at page 333:
"they have either O-H or N-H groups. Solvents of this kind are described as protic solvents, that is, they are capable of forming hydrogen bonds in solution".
- Dr Marshall provides his understanding of aprotic solvents at paragraph [266] of his declaration:
"A more functional way to consider protic and aprotic solvents is that a protic solvent is a solvent that participates in hydrogen bonding. Consequently, an aprotic solvent is one that does not significantly participate in hydrogen bonding."
In the end I think that both definitions are saying the same thing. A solvent that can donate protons would be able to participate in hydrogen bonding. A solvent that is able to participate in hydrogen bonding would be able to donate a proton (e.g. from an O‑H group). It is clear that the degree of proton donation does not have to be that of an acid (since no declarant suggests that protic equates to acidic). The well-known text book Advanced Organic Chemistry – Reactions, Mechanisms and Structure by Jerry March (exhibit GA-24) lists some examples of protic and aprotic solvents at page 358:
"Examples of protic solvents are water, alcohols, and carboxylic acids, while some polar aprotic solvents are dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone, sulphur dioxide, and hexamethylphosphoramide [(Me2N)3PO], HMPA."
From this I conclude that alcohols are protic solvents, and not aprotic solvents. I note that Dr Crothers states at paragraph [12] that benzyl alcohol is a weak acid but should be regarded as an aprotic solvent:
"benzyl alcohol (BnOH) is a weak acid that is capable of ionisation into protons (H+) and anions (BnO-). As a weak acid, this ionisation is not complete in the pH range 0 to 14. The degree of ionisation depends on the negative logarithm of its acid dissociation constant (pKa). The pKa of benzyl alcohol is > 14. When the pH of the local environment is at least 2 pH units lower than 14, benzyl alcohol will be 100% unionised. This means that benzyl alcohol will be 100% unionised at pH 12 or below. It follows that since the pH in claim 1 is no greater than 4.5, benzyl alcohol will not donate protons under the conditions of claim 1 of the Application. I therefore understood benzyl alcohol to be an aprotic solvent in the situation claimed in of [sic] claim 1 of the Application."
I am not sure that this degree of analysis is appropriate in order to decide whether a solvent is aprotic. However, to the extent that it is, it is worth remembering what every high school student knows - water has a pH of 7, and given that
pH = -log10 [H+]
the concentration of hydrogen ions in water is only 10-7 moles/litre. The concentration of water is 55.5 moles/litre (based on a density of 1 kg/litre and a molecular weight of 18), so it is clear that water is a very weak acid and far less than 1% is in an ionised form. However, there is no debating that water is a protic solvent. While I do not disagree with the calculations that Dr Crothers has done, I do not agree that the low level of ionisation of benzyl alcohol, or any other alcohol, means that they are not a protic solvent.
I am satisfied that the normal meaning of an aprotic solvent is one that does not participate in hydrogen bonding, and this necessarily excludes water, alcohols and acids.
The specification uses the language of the first interpretation, but expands it somewhat. At page 3 the specification says:
"In aprotic solvents, which are generally solvents that do not contribute protons to the solution, such as polyethylene glycol, dissolution can take some considerable time and this, together with the temperature required, can also lead to rearrangement to an extent above acceptable levels."
From this I conclude that the specification envisages that aprotic solvents "generally" do not contribute protons to the solution (so may be a broader group than normally understood). Further, the specification asserts that polyethylene glycol is an aprotic solvent. Polyethylene glycol is a polymer of ethylene oxide having the general formula
H – (O – CH2 – CH2 )n – OH
which clearly contains terminal hydroxyl groups as well as repeating ether groups.
The specification then discusses solvents further on the same page:
"Substances such as acetone and acetonitrile are capable of dissolving I3A, but are not generally pharmaceutically acceptable, and may not be suitable for long term storage. More acceptable may be substances such as methyl ethyl ketone, ethyl acetate, or diethyl ether, but benzyl alcohol is generally most preferred."
While the specification does not state that these solvents are aprotic solvents, this seems to be the clear implication. The significant point is that benzyl alcohol appears to be included as an aprotic solvent. Benzyl alcohol is an alcohol having the formula:
C6H5 – CH2 – OH
Previously I stated that benzyl alcohol is a protic solvent. However, it is totally clear that the specification treats benzyl alcohol, and also polyethylene glycol, as aprotic solvents. While this is unexpected, it is beyond doubt that the thrust of the specification is that aprotic solvents are understood as including polyethylene glycol and benzyl alcohol. However, there is no suggestion in the specification that any other alcohols (or other protic solvents) should be understood as being aprotic. I consider that it is appropriate to read the specification as asserting that aprotic is extended only to polyethylene glycol and benzyl, and not to any other solvents that would normally be considered to be protic.
On page 14 the specification lists a particularly preferred composition:
"a) 0.1% (w/w) I3A;
b) 30% (w/w) isopropyl alcohol;
c) 0.9% (w/w) benzyl alcohol;
d) 1.5% (w/w) hydroxyl ethyl cellulose; and
e) 67.5% (w/w) citrate buffer pH 3, preferably pH 2.75".Example 3 contains information on the ingenol-3-angelate compositions with a citrate buffer in the pH range of 2.5 to 4.0, in accelerated stability studies. Some of these involve benzyl alcohol.
Page 71 describes the preparation of stock ingenol-3-angelate in benzyl alcohol and a citrate buffer at pH 3.
Construction of claim 1
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".
The importance of construction in context cannot be doubted. In International Business Machines Corp v Commissioner of Patents (1991) 22 IPR 417 Burchett J found at page 422 that:
"When the present specification is read, the whole of the context rises up to insist that claim one is talking about the operation of computers. Almost the first words of the specification inform the reader that the invention 'relates to computer graphics and more specifically to a method and apparatus for generating curves on computer graphic displays'. The recital of the prior art reinforces the clear impression thus conveyed from the beginning of the document."
This is different to giving the claims a gloss from the description (which is not legitimate, see Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 at 610) because the limitation arises from the whole thrust of the specification as against mere comments in the description.
Claim 1 is the key claim. It reads:
"A formulation of ingenol angelate for use in therapy, wherein the ingenol angelate has been dissolved in a pharmaceutically acceptable, aprotic solvent, said formulation further comprising a pharmaceutically acceptable acidifying agent which is at least partially compatible with the solvent and which provides a formulation with an apparent pH of no greater than 4.5."
The claim is directed to a formulation of ingenol angelate. There is no limitation that the substance must be the 3-angelate, or even that there is any 3-angelate present. The other components of the formulation are:
- a pharmaceutically acceptable, aprotic solvent;
- a pharmaceutically acceptable acidifying agent;
- the acidifying agent is "at least partially" compatible with the solvent; and
- the apparent pH of the formulation is no greater than 4.5.
As already discussed, an aprotic solvent is one that does not have the capacity to engage in hydrogen bonding. However, the whole thrust of the specification is that aprotic solvents include polyethylene glycol and benzyl alcohol. While the specification does not set up a simple dictionary to this effect, I believe that it is part of the clear context of the specification that must be recognised when reading the claims. Consequently, when reading claim 1 the term aprotic solvent is understood to include polyethylene glycol and benzyl alcohol (and no other protic solvents).
Novelty
It is a requirement of subsection 18(1) of the Patents Act (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.
It is well established that the 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 at [20], 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".
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 [1972] RPC 457 at 486).
Sandoz relied on a single citation to allege lack of novelty: "Antitumor Activity of 3-Ingenyl Angelate: Plasma Membrane and Mitochondrial Disruption and Necrotic Cell Death", Ogbourne, S et al, Cancer Research 2004, 64, 2833 – 2839 (the Ogbourne article).
The Ogbourne article
The Ogbourne article carries a date on its face of 15 April 2004. It was not disputed that the article is part of the prior art base.
The Ogbourne article discloses investigations into the activity of ingenol-3-angelate against various tumours. The article states at page 2837:
"This report describes the preclinical activity of a new topical anticancer agent, PEP005 (ingenol-3-angelate) that was capable of regressing a wide range of established s.c. tumors in mice after three daily treatments".
The article concludes at page 2838:
"Only three topical applications of PEP005 were required for tumor cure in mouse models, and to date, the only significant finding from formal toxicology studies evaluating topical treatment with PEP005 was local inflammation (data not shown). PEP005, thus, represents a novel topical chemotherapeutic agent, which induces primary necrosis and is, therefore, unlikely to have its activity compromised by the development of apoptosis resistance in tumor cells (48, 49). Despite this mode of action, PEP005 treatment is associated with a very favorable cosmetic outcome (Fig. 3D), a feature that was also noted after the use of E. peplus sap to treat human skin lesions (21). Overall, PEP005 may be less traumatic to patients and less demanding on clinical resources than current treatments for nonmelanoma skin cancer and may deliver significantly improved outcomes. Clinical-grade PEP005 is currently being manufactured in preparation for human clinical trials."
The article states at page 2834 that the composition that was used in the test was:
"PEP005 was dissolved in an isopropanol-based gel composed of 25% w/w isopropyl alcohol and 25% w/w propyl alcohol in water (pH 4 – 6)."
There are two features that need to be carefully considered: what is the solvent, and what is the pH of the composition.
What is the solvent in the Ogbourne article?
All that we know of the solvent used in the Ogbourne article is that it contains water, isopropyl alcohol and propyl alcohol. Due to the presence of water, this cannot be considered to be an aprotic solvent system. Propyl alcohol and isopropyl alcohol are both alcohols, and thus are protic (the present specification has only extended the concept of aprotic to polyethylene glycol and benzyl alcohol, and not alcohols generally). Consequently, Ogbourne does not disclose the use of an aprotic solvent. Evidence was filed as to the true nature of the solvent used in the Ogbourne article. I do not believe it is appropriate to supplement the Ogbourne article in this way, so I will not refer to this evidence. There is no disclosure of an aprotic solvent.
What is the pH in the Ogbourne article?
The pH of the formulation is listed as "4 – 6". While this range overlaps with a pH of no greater than 4.5, the critical question is whether this is a disclosure of a pH of no greater than 4.5. It is impossible to discern the exact composition of the formulation in the Ogbourne article, and as a consequence its pH is uncertain. While the pH lies in the range of 4 – 6, it cannot be said that a person carrying out the (limited) directions in Ogbourne would inevitably have made a formulation with a pH of no greater than 4.5.
Conclusion
The Ogbourne article does not render claim 1 lacking in novelty. Consequently, it does not render any of the other claims lacking in novelty.
Inventive step
It is a requirement of subsection 18(1) of the Act that the invention, so far as claimed in any claim, involves an inventive step. Subsection 7(2) states that an invention is taken to involve an inventive step unless it would have been obvious to a person skilled in the art in the light of the common general knowledge, considered alone or together with the prior art. A document is prior art for this purpose if "a skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded [the document] as relevant" (subsection 7(3)).
The test for whether an invention is obvious is to ask whether it would have been a matter of routine to proceed to the claimed invention. In Wellcome Foundation Ltd v V.R. Laboratories (Aust.) Pty Ltd [1981] HCA 12 at [45], 148 CLR 262 at 286 Aickin J stated:
"The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not."
The High Court in Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59, 212 CLR 411 approved this approach.
The problem
In the present case the parties took different views as to the problem addressed by the specification. Both rely upon different statements on page 2 of the specification (quoted previously). Sandoz relied on the statement:
"There is a need to provide a stable formulation of ingenol angelate".
Leo preferred the more general statement:
"There is a need for an effective, topical treatment for skin cancer".
Leo relied upon the decision of the Full Court of the Federal Court in AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99. At [203] the majority said that it is not appropriate to take as the starting point information that was known to the applicant but was not either common general knowledge or information available under section 7(3) (see paragraph [203] for instance).
In this case the issue is resolved by considering what the specification says on its face. While the specification speaks at length about ingenol-3-angelate, there is a clear statement on page 2 that there is a need for “an effective, topical treatment for skin cancer”. There can be no doubt about the correctness of this statement. While this statement appears after a general discussion of ingenol angelates, it seems to me that it should be understood as the most general statement of the background to the invention. The inventor is aware of ingenol angelate as a possible solution, and the limitations that it has in terms of stability. I think that the fair way to read the first two pages of the specification is that the inventor has addressed the desire for a topical treatment of skin cancer by turning its mind to ingenol angelates and the stability problem that lies in the way of their use. Ingenol angelates are part of the inventive journey of the applicant, not a part of the problem.
As I do not consider that the specification presents ingenol-3-angelate as part of the problem, it is not necessary to see whether reliance on ingenol-3-angelate would have been impermissible. However, it will be clear from what is said below that ingenol-3-angelate was not part of the common general knowledge, but would have been part of the section 7(3) information.
Obviousness in the light of the common general knowledge
Common general knowledge is "the background knowledge and experience which is available to all in that field in considering the making of new products or making of improvements in old products" (ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc [1999] FCA 345, 45 IPR 577 at [111]), or "part of their common stock of knowledge relating to the art" (British Acoustic Films Ltd v Nettlefold Productions (1936) 53 RPC 221, cited with approval in Aktiebolaget Hässle v Alphapharm Pty Ltd [1999] FCA 628, 44 IPR 593 at [39]).
The evidence shows that the structure of ingenol was first reported in 1970 (Appendino 1 at [28]). The anticancer activity of ingenol esters was reported in 1976 (Appendino 1 at [29]). Acyl migration of ingenol-3-esters was reported in 1975 (Appendino 1 at [45]).
The Ogbourne article describing the successful trial of ingenol-3-angelate as a topical treatment for skin cancer was published in 2004 (Appendino 1 at [50]). Professor Appendino became aware of the article through the regular literature searches that he conducted (paragraph [50] of Appendino 1). At paragraph [53] of Appendino 1 he concludes:
"by December 2005, I understood, and to my observation others working in the field of bioactive products and/or cancer research around the world, including Australia, knew about ingenol esters, particularly ingenol angelate and its utility as a treatment for skin cancer."
It is undoubtedly true that ingenol-3-angelate and its anticancer properties were part of the public knowledge. The question is how widely was that knowledge distributed. Dr Marshall states at paragraph [366] in response to paragraph [53] of Professor Appendino's evidence:
"it is not reasonable to expect everyone in these fields knew about ingenol esters, particularly ingenol angelate and its utility as a treatment for skin cancer by December 2005".
Professor Hersey gave evidence about the Ogbourne article, and the publicity that followed its publication. He said at paragraph [25]:
"Peplin was very active in publicising the work that it was undertaking and the clinical trials it was undertaking. There was a considerable amount of interest in the press relating to Peplin's activities, given that it was a successful Biotech Australian company."
At paragraph [26] he concludes:
"Given the publicity that Peter Parsons and Peplin were receiving, given that a number of different medical researchers from different research institutes had been involved in working with PEP-005 [i.e. ingenol 3-angelate], and given the various publications in leading technical journals relating to ingenol 3-angelate, I believe that by December 2005, there was an awareness within the Australian medical community of ingenol 3-angelate and its potential use for the treatment of cancer, particularly its use as a topical treatment for skin cancer."
Dr Marshall commented on the Ogbourne article at paragraph [373]:
"The Ogbourne Article was reported in the Cancer Research Journal. This journal would be read by those working in cancer research. However, those in cancer research, if similar to workers in my field, are likely to review the contents of each issue of the journal for articles of interest and read those rather than read every article within the entire journal. Thus, the Ogbourne Article would not be universally read by those in Cancer Research, particularly given the very large number of articles produced in this field each month."
I accept that there was an awareness of ingenol-3-angelate within the Australian medical community, but it is not clear from the evidence that the awareness was sufficiently widespread to have become part of the common stock of knowledge of the art. The evidence fails to establish that ingenol-3-angelate was part of the common general knowledge. Consequently, it has not been established that the invention lacks inventive step in the light of the common general knowledge alone.
Obviousness in the light of information available under section 7(3)
Sandoz relies on four documents:
"Antitumor Activity of 3-Ingenyl Angelate: Plasma Membrane and Mitochondrial Disruption and Necrotic Cell Death", Ogbourne, S et al, Cancer Research 2004, 64, 2833 – 2839 (the Ogbourne article)
"The Dermatitis-Producing Constituents of Euphorbia Hermantiana Latex", Lin, L et al, Journal of Natual Products, 46, 723, 1983 (the Lin article)
"Synthesis of Modified Ingenol Esters", Appendino, G et al, Eur J Org Chem 1999, 3413 – 3420 (the Appendino article)
"Studies on the stability of corticosteroids VI. Kinetics of the rearrangement of betamethasone-17-valerate to the 21-valerate ester in aqueous solution", Bundgaard, H and Hansen, J, Int J Pharmaceutics 7 (1981) 197 - 203 (the Bundgaard article)
Was the Ogbourne article part of the section 7(3) information?
Leo submitted that there was no evidence that the Ogbourne article would have been ascertained. In their written summary of submissions they state:
"There is no evidence that the Ogbourne Paper or any of the other publications would have been retrieved in a search for efficacious skin cancer treatments. The Opponent's experts impermissibly started with I3A."
It is true that Professor Appendino was aware of the Ogbourne article in 2004 as a part of his normal work (paragraph [50] of Appendino 1), and Professor Cavalli was provided with a copy of the Ogbourne article by Shelston IP (paragraph [13] of Cavalli 1). However, despite the lack of direct evidence I think this is a case where there is a strong inference that the Ogbourne article would have been ascertained. Both parties appeared to accept that workers in the art carried out literature searches using electronic databases. Dr Marshall said that the Cancer Research Journal was routinely consulted. The Ogbourne article would have been found in a search for treatments of skin cancer, since the Abstract of the article says:
"Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005)".
The better question posed by Leo is whether the Ogbourne article would have been regarded as relevant. The Ogbourne article reports the results of early investigations into the activity of ingenol-3-angelate. The investigations involve tests on mice, and the article concludes with an indication that human clinical trials will be undertaken next. It is clear that a person would have understood that ingenol-3-angelate was a promising compound, but it was far from certain that it could become a practical treatment option. It was clearly a possible starting point for further investigation. Does this make the Ogbourne article relevant for the purposes of section 7(3)?
In Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; 235 ALR 202 at [152] the High Court said:
28381190 "the phrase 'relevant to work in the relevant art' should not be construed as meaning relevant to any work in the relevant art, including work irrelevant to the particular problem or long-felt want or need, in respect of which the invention constitutes an advance in the art. The phrase can only be construed as being directed to prior disclosures, that is publicly available information (not part of common general knowledge) which a person skilled in the relevant art could be expected to have regarded as relevant to solving a particular problem or meeting a long-felt want or need as the patentee claims to have done."
At [153] the Court offers the following guidance:
"The question of what a person skilled in the relevant art would regard as relevant, when faced with the same problem as the patentee, is to be determined on the evidence. The starting point is the subject matter of the invention to be considered together with evidence in respect of prior art, common general knowledge, the way in which the invention is an advance in the art, and any related matters."
The evidence is not helpful to the opponent. At paragraph [50] of Appendino 1, Professor Appendino says that he was already aware of the Ogbourne article:
"In 2004, I became aware through the scientific literature that a group of researchers in Australia had isolated the ingenol 3-angelate from Euphorbia peplus and had conducted successful trials of that drug in vitro and as a topical application for the treatment of skin cancer in mice. Annexed to this declaration and marked 'GA-21' is a copy of a paper titled ‘Antitumor Activity of 3-Ingenyl Angelate: Plasma Membrane and Mitochondrial Disruption and Necrotic Cell Death’ (‘the Ogbourne paper’), which was published in 2004 in Cancer Research. I became aware of this paper through the regular literature searches that I conduct, as discussed in paragraph 11, above."
In paragraph [11] of Appendino 1, Professor Appendino says he conducts regular searches to identify recently published articles relating to topics in which he has an interest or is conducting research.
Professor Cavalli says at paragraph [14] of Cavalli 1:
"I have reviewed these documents. Given the matters I have set out in paragraph 12, I consider the information in each of these documents to be very relevant to the exercise of developing a stable formulation of ingenol 3-angelate and to confirm the information that is mentioned in paragraph 8 above."
It seems clear that the declarants for the opponent do not assist me to decide whether the Ogbourne article would have been regarded as relevant to the problem as I have formulated it.
However, despite the absence of direct evidence I believe it is appropriate to consider whether or not there is a sound inference that is open to me. Returning to the words of the High Court, the question is whether the article contains information that a person:
"could be expected to have regarded as relevant to solving a particular problem"
Taken at its broadest, "relevant" simply means "bearing upon or connected with the matter in hand; to the purpose; pertinent" (Macquarie Dictionary), so the question is whether the Ogbourne article is connected with the problem of an effective, topical treatment for skin cancer. The Ogbourne article relates to a substance that is reported as "may deliver significantly improved outcomes" in the treatment of non-melanoma skin cancer. This in itself provides a clear logical connection to the problem. Success is not guaranteed, and may not be quick. But that does not mean that there is not a logical connection to the problem. Rather, such considerations seem more appropriate to the question of whether it would have been a matter of routine.
Despite the absence of clear evidence from the opponent, I believe that the inference is very strong that the Ogbourne article would have been ascertained and regarded as relevant. Since the Ogbourne article is a document under section 7(3), the information that it contains about ingenol‑3-angelate is section 7(3) information.
Obviousness in the light of the Ogbourne article
The Ogbourne article discloses ingenol-3-angelate as a compound with useful activity. Previously I stated that the article does not disclose the use of an aprotic solvent, or a pH of no greater than 4.5.
Sandoz submitted at paragraph [164] of their written submissions that there was no evidence that there is any advantage over the Ogbourne article:
"the Applicant has not justified why the formulation details not explicitly disclosed in the Ogbourne paper would influence the stability of the formulation. Nothing in the Opposed Application suggests that such details would have any effect on stability".
This appears to be an attempt to classify the features of the claims as non-essential. I do not accept that the features can be ignored, and it is essential that the opponent establish that all of the features would have been a matter of routine. Sandoz can only succeed in the opposition if they can show that these changes would have been a matter of routine.
The instability of ingenol 3-esters was known in the art since 1975 (Appendino 1 at [45]), but there is no evidence that this was common general knowledge. Professor Cavalli said at paragraph 18 of Cavalli 1:
"I expect that it would be best to formulate ingenol 3-angelate in solution with a mildly acidic pH".
The reason for adopting a mildly acidic pH is to reduce transesterification reactions. However, Professor Cavalli was instructed that transesterification was an issue (see paragraph 8 of Cavalli 1):
"I have been informed by Shelston IP that: …
(b) the ester naturally occurs at the 3 position, but that when isolated and manipulated there is a tendency for the compound to isomerise by way of transesterification of the ester group from the 3 position to the 5 position and then eventually to the 20 position".
I consider that Professor Cavalli has been led to the solution, and I give no weight to her evidence on this point.
When Dr Marshall was asked whether there would be any stability risks associated with ingenol‑3-angelate based on its structure, he said (at paragraphs [137] to [142] of his declaration) that there were several parts of the molecule that need to be considered. One of the possibilities that he raised is transesterification. To my mind, the matters raised by Dr Marshall are all logical and would likely occur to any person skilled in the art. This suggests a person would anticipate transesterification, but only as one of a number of possible instability risks. Dr Marshall said that in order to control these risks he would (paragraph [145]):
"take care to avoid excessive exposure to UV light, for example, by the use of opaque packaging and enclosed manufacture"
and also (paragraph [146]):
"I would probably avoid water, amines, low molecular weight alcohols and other nucleophiles and acid and base altogether in the formulation of this compound".
This suggests an avoidance of both protic solvents and acidic pH. As the claims require a pH of no greater than 4.5 and an aprotic solvent, the evidence does not establish that the claims lack inventive step in the light of the Ogbourne article.
Obviousness in the light of the Lin article
The Lin article discusses dermatitis producing constituents of the plant Euphorbia hermentiana. I can see no reason why a person would have considered this document relevant to the problem of an effective, topical treatment for skin cancer. Thus the Lin article is not available under section 7(3).
Obviousness in the light of the Appendino article
The Appendino article describes the synthesis of ingenol esters. The article summarises the outcome of the work in this way (page 3416):
"In summary, synthetic protocols for the manipulation of the polyhydroxylated southern region of ingenol have been developed, paving the way to the preparation of C-20 modified analogues. Their evaluation for antitumour activity and PKC activation showed that chemical manipulation can effectively dissect cytotoxicity and tumour-promoting activity (or potential), affording more optimal candidates for further development."
It appears that the article focusses on benzoate esters, and there seems to be no reference to angelate esters. I do not see any reason to believe that the Appendino article would have been regarded as relevant to the problem of an effective, topical treatment for skin cancer. Thus the Appendino article is not available under section 7(3). Even if it were available, I cannot see why it would have been a matter of routine to proceed to angelate esters.
Obviousness in the light of the Bundgaard article
The Bundgaard article relates to the stability of betamethasone 17-valerate in aqueous solution at various pH levels. Betamethasone is an anti-inflammatory and immune-suppressive. There is no discussion of ingenol compounds, and betamethasone is structurally quite different to ingenol. I can see no reason that the Bundgaard article would have been regarded as relevant to the problem of an effective, topical treatment for skin cancer. Thus the Bundgaard article is not available under section 7(3).
Conclusion on obviousness
It has not been established that any of the claims lack inventive step.
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 High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58 at [69], 217 CLR 274 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"
At the hearing I asked whether claim 38 is fairly based. Claim 38 reads:
"A process for preparing a formulation of ingenol angelate, comprising dissolving the ingenol angelate in a pharmaceutically acceptable, aprotic solvent, said process comprising the addition of a pharmaceutically acceptable acidifying agent which is at least partially compatible with the solvent and which provides the formulation with an apparent pH of no greater than 4.5, said agent being added with, before, or after the ingenol angelate."
The aspect that concerned me was the reference to acidification "after" addition of the ingenol‑3‑angelate. The reason why I raised this matter is because the specification says at page 2 (quoted previously):
"It has now, surprisingly, been found that ingenol angelate can be solubilised, substantially without rearrangement between isoforms, in an acceptable, aprotic solvent in the presence of an acceptable, miscible acidic buffer."
This clearly implies that stability is achieved by the presence of the acid at the time of dissolution (and thus the acid is not added "after" the ingenol-3-angelate). This seems to be supported by the text at page 7:
"It is preferred to add the acid, or buffer, sufficiently soon after addition of the I3A to ensure that no more than about 1%, and preferably no more than about 0.5%, of the 'b' isoform rearranges into the 'a' isoform."
It seems that additional of the acid "after" the ingenol-3-angelate will allow rearrangement to begin, and the extent of rearrangement depends on how long after acid is added. However, there is a disclosure of addition of the acid "after", even though that is less than optimal. I accept that there is a fair basis for the claim.
Utility
It is a requirement of subsection 18(1) of the Act that the invention, so far as claimed in any claim, must be 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".
Sandoz alleged that there is a lack of utility because the claims include any pH below 4.5, and the ingenol-3-angelate would decompose at a pH below 3. The specification says at page 3:
"Suitable acids are generally organic acids, as it has been established that I3A can decompose much below about a pH of 3, while rearrangement is likely to occur at above a pH of about 4.5."
Leo submitted that this was a reference to stability in solution, and that stability in a formulation can be different. It is not clear to me that the specification is drawing this distinction.
100. Leo also submitted that claim 1 commences:
A formulation of ingenol angelate for use in therapy …
and a composition in which ingenol-3-angelate is unstable is not suitable for use in therapy. I agree that it is not reasonable to construe claim 1 as including formulations that are not suitable for use in therapy due to instability of the ingenol-3-angelate. It follows that since the claim does not include formulations that are unstable, that it does not lack utility in this way.
Entitlement
101. The written summary of submissions on this ground reads:
"To the extent that the alleged invention of the Opposed Application is said to include the choice of ingenol angelate for therapeutic use, then the list of named inventors does not include each person who materially contributed to the alleged invention. Accordingly, the Applicant is not entitled to a grant of a patent for the Opposed Application.
To the extent that the alleged invention is said to include the choice of ingenol angelate for therapeutic use, the Opponent denies that such choice is inventive. However in the alternative, at least James Harrison Aylward should be listed as an inventor of the Opposed Application, by reason of the fact that he is listed as the inventor on PCT/AU1998/000656 which discloses that certain ingenane compounds may be used in the treatment of skin cancer."
102. I am not aware of any authority for the proposition that a person who places information in the public domain is the inventor of anything that is developed based on that information. This is because an inventor may "consider and adopt ideas and materials derived from many sources … [such as] a suggestion by an employee, or hired consultant … or adopt a material suggested by a friend … as long as he maintains intellectual domination of the work of making the invention down to the successful testing, selecting or rejecting as he goes … and he does not lose his quality as inventor by reason of having received a suggestion or material from another even if such suggestion proves to be the key that unlocks his problem" (Morse v Porter, 155 USPQ 280 (Bd Pat Inter, 1965)).
103. It follows that the inventor of the prior art is not thereby the inventor of the present application. The ground of lack of entitlement is not made out in this situation.
Conclusion
104. I conclude that Sandoz have not made out any of the grounds of opposition.
Costs
105. The parties submitted that costs should follow the event. I see no reason to depart from that result. Costs should be awarded against Sandoz.
Dr S.D. Barker
Delegate of the Commissioner of Patents
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