Ever Neuro Pharma v Britannia Pharmaceuticals Limited
[2022] APO 37
•23 May 2022 (Corrected on 24 May 2022)
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
EVER Neuro Pharma v Britannia Pharmaceuticals Limited [2022] APO 37
Patent Application: 2015295817
Title:Composition containing apomorphine and a divalent metal cation
Patent Applicant: Britannia Pharmaceuticals Limited
Opponent:EVER Neuro Pharma
Delegate:Leslie F. McCaffery
Decision Date: 23 May 2022 (Corrected on 24 May 2022)
Hearing Date: 24 February 2022, by videoconference.
Catchwords: PATENTS – section 59 – opposition to the grant of a patent – grounds of clarity, support, clear enough and complete enough disclosure, utility, best methods, novelty, inventive step – opposition successful – description is not clear enough and complete enough, claims not supported – opportunity to amend – costs not awarded.
Representation: Patent attorney for the applicant: Charles Tansey, Michael Christie and Jon Wright of Spruson & Ferguson
Patent attorney for the opponent: Davies Collison Cave
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2015295817
Title:Composition containing apomorphine and a divalent metal cation
Patent Applicant: Britannia Pharmaceuticals Limited
Date of Decision: 23 May 2022 (Corrected on 24 May 2022)
DECISION
The opposition has been successful.
The specification does not disclose the invention in a manner that is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art in relation to the definition of divalent metal cations.
Claims 1 to 7 and 11 to 20 lack support.
I allow the applicant two (2) months from the date of this decision to propose amendments to attempt to overcome the identified deficiencies.
Costs not awarded.
REASONS FOR DECISION
Australian application 2015295817 was filed by Britannia Pharmaceuticals Limited (the applicant) on 31 July 2015 and claims an earlier priority from European application 14002689. The application was accepted on 13 March 2020.
Ever Neuro Pharma (the opponent) filed a notice of opposition on 2 July 2020. The statement of grounds and particulars was filed on 2 October 2020. The opponent relied on the following grounds:
(a)Subsection 59(b): The invention is not a patentable invention pursuant to Section 18 of the Act.
a.The alleged invention, so far as claimed in each claim of the Application, is not novel when compared to the prior art base as it existed before the priority date of each claim (subparagraph 18(1)(b)(i)).
b.The alleged invention, so far as claimed in each claim of the Application, does not involve an inventive step when compared to the prior art base as it existed before the priority date of each claim (subparagraph 18(1)(b)(ii)).
c.The alleged invention, so far as claimed in each claim of the Application, is not useful (paragraph 18(1)(c)).
(b)Subsection 59(c): The specification filed in respect of the Application does not comply with subsection 40(2) or subsection 40(3) of the Act.
a.The complete specification filed in respect of the Application does not disclose the alleged invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the art (paragraph 40(2)(a)).
b.The Application does not disclose the best method known to the Applicant of performing the alleged invention (paragraph 40(2)(aa)).
c.The claims of the Application are not clear and succinct (subsection 40(3)).
d.The claims of the Application are not supported by matter disclosed in the complete specification filed in respect of the Application (subsection 40(3)).
e.The claims of the Application do not define the invention (paragraph 40(2)(b)).
Evidence in support was completed on 4 January 2021 and consisted of a declaration from Simone Vink (Vink), together with exhibits SV-1 to SV-13.
A request to amend the application was filed on 9 March 2021, and allowance of the amendments was published on 15 July 2021.
Evidence in answer was completed on 6 April 2021, and consisted of declarations by Trevor Hambley (Hambley), together with exhibits TH-1 to TH-8, and Richard Peppard (Peppard), together with exhibits RP-1 to RP-13.
The opponent did not file evidence in response. Furthermore, they did not appear at the hearing, and have not provided written submissions. While this suggests that the opponent has no further interest in pursuing the opposition, they did not withdraw the opposition.
I therefore have only the opponent’s statement of grounds and particulars and the evidence in support from Dr Vink on which to make my determination. This makes my task less efficient since I do not have the benefit of responding evidence and submissions refining and focussing the proceeding on the key issues, including the extent to which the original particulars apply to the claims following the amendment of 9 March 2021. Nevertheless, I have attempted to consider all of the grounds raised by the opponent in their statement of grounds and particulars. However, I have dealt with matters more summarily where the material provided clearly does not meet the standard required.
The standard of proof
The application was filed on 21 August 2015, and a request for examination was filed on 13 April 2018. Accordingly, the substantive amendments to the Patents Act (the Act) brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 apply. The standard of proof in opposition proceedings under s 59 of the Patents Act is the balance of probabilities. Specifically, if I am satisfied, on the balance of probabilities, that a ground of opposition to grant of the standard patent exists, then I may refuse the application.
The experts
Dr Vink is a patent attorney with Davies Collison Cave. Dr Vink has a PhD in Biochemistry from the University of Queensland and has previously worked as a Research Officer at Protagonist Therapeutics, Inc.
10. Professor Hambley is an Emeritus Professor at the University of Sydney, where he was Professor in the School of Chemistry since 2002 and Dean of Science from 2010 to 2018. Dr Peppard is a consultant neurologist at St Vincent’s Private Hospital, specialises in diagnosis and management disorders and teaches at the St Vincent’s Clinical School.
11. The applicant noted that Dr Vink is a registered patent attorney and submitted that there was no evidence based on their CV or publication record that they had any practical experience in medicinal chemistry or the treatment of neurodegenerative disorders. In contrast, they submitted, Professor Hambley has practical experience in medicinal chemistry, including coordination chemistry, and Dr Peppard is a practising physician with expertise in the field of neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. They also noted that Dr Peppard’s and Professor Hambley’s evidence was prepared in stages to avoid hindsight biasing their views, while there was no indication of a similar approach being taken in Dr Vink’s evidence, which appeared to mirror the attorney submissions to the European Patent Office in the corresponding opposition proceedings on European Patent Application EP 3174526.
12. I share the concerns of the applicant. Dr Vink is a patent attorney with the firm representing the opponent. While it is not mandatory that evidence in proceedings before the Commissioner comply with the Federal Court’s Expert Evidence Practice Note, there is no indication in the declaration of the instructions that were given to Dr Vink, nor of the nature of the evidence. For example, Dr Vink does not provide any evidence in relation to the common general knowledge in the field of the invention. Much of the declaration appears to be an opinion in the capacity of a patent attorney and submissions on behalf of the opponent, rather than the evidence of an expert in the field. I therefore consider that I can give Dr Vink’s declaration little evidentiary weight in my determination on many of the grounds raised in the opposition. Nevertheless, the declaration serves to outline the opponent’s case and in the absence of any other submissions I will have regard to it in my determination.
The Specification and Claims
13. The invention is said to relate to a composition containing apomorphine ((6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol), and a divalent metal cation, a process for its preparation and its use as a medicament, in particular in diagnosing, preventing and treating Parkinson’s disease.[1] Apomorphine is administered by infusions or subcutaneous injection for the treatment of Parkinson’s disease. A commercially available product, APO-go®, apparently has a pH of 3 to 4.[2]
[1] Specification at page 1, paragraph 1.
[2] Specification at page 1, paragraph 2.
14. Apomorphine contains a fused benzene ring having ortho-dihydroxy substitution. In this decision I will refer to the individual groups as phenol or hydroxy groups, and to the fused dihydroxybenzene structure as a catechol group based on the “parent” structure 1,2-dihydroxybenzene, which is otherwise known as catechol.
15. The specification states that coagulative necrosis (cell death at the injection site) is a problem with existing treatments.[3] The invention is said to avoid or alleviate this problem by providing a formulation of apomorphine and a divalent cation in a molar ratio of 2 or less.[4] These formulations are said to have the further advantage of having a relatively high stability compared to apomorphine.[5]
[3] Specification at page 1, paragraph 3, see also Peppard at [11] and [18].
[4] Specification at page 1, paragraph 5.
[5] Specification at page 1, paragraph 6.
16. The specification goes on to describe various preferred embodiments of the invention. The molar ratio of apomorphine is said to preferably range between 2.0 to 0.2, preferably from 1.25 to 0.5, and more preferably from 1.25 to 0.83.[6] I understand this to mean, for example, that a molar ratio range of between 2.0 to 0.2 corresponds to a range of apomorphine to divalent metal ratios of 2:1 to 0.2:1.
[6] Specification at the paragraph bridging pages 1 and 2.
17. The specification states that the divalent metal ion can be any metal cation having two positive charges, which are pharmaceutically acceptable and do not cause any harm in the human body.[7] I understand this to mean that the divalent metal cation is non-toxic and does not cause any other significant deleterious effects in the amounts used in the invention. The divalent metal cation is preferably selected from one or more of Ca2+, Mg2+ and Zn2+, which are said to be particularly useful for avoiding or ameliorating coagulative necrosis.[8] A preferred composition comprises both Ca2+ and Mg2+ in a ratio of 1.37:1 to 1.72:1.[9] I understand this to be a molar ratio.
[7] Specification at page 2, paragraph 3.
[8] Specification at page 4, paragraph 2.
[9] Specification at page 4, last paragraph.
18. A significant issue in the present opposition related to the nature of the interaction of apomorphine with the divalent metal cation. The specification states that the formulations of the invention preferably contain a chelate comprising apomorphine as the ligand and the divalent cation as the central atom.[10] Chelation occurs through at least one, and preferably both, of the phenolic groups. This can apparently be achieved by adjusting the pH of the mixture, either before or after apomorphine and the divalent metal cation have been mixed.[11] Such compositions are said to be distinguishable from compositions in which no chelate is formed and apomorphine and the divalent metal cation are separate of each other.[12] It is preferred that at least 50%, and more preferably at least 90% of the apomorphine of the composition is present in the chelated form.[13]
[10] Specification at page 2, paragraph 4.
[11] Specification at page 3, first paragraph.
[12] Specification at page 3, paragraph 3.
[13] Specification at page 3, last paragraph.
19. The compositions are preferably aqueous solutions, which is said to make the invention suitable to be used as a medicament, for example for injection or as an infusion. For such applications, the solution is sterile and does not contain any ingredients that are not pharmaceutically acceptable. The solution can also be adapted to be used as an injection solution or as a concentrate for an infusion, or directly itself as an infusion.[14] The compositions are said to avoid or ameliorate coagulative necrosis, have a good tissue protective effect, bioavailability and storage stability.[15]
[14] Specification at page 4, first paragraph.
[15] Specification at paragraph bridging pages 10 and 11.
20. The compositions can contain other pharmaceutical additives and excipients, including antioxidants,[16] cosolvents, surfactants, pH adjusters, tonicifier and inert gas.[17] The pH of the solution is preferably 3 to 10, which provides optimum stability, and is preferably adjusted to override the solubility barrier of pH 6.2 and close to the physiological pH of 7.4.[18] The compositions have an apomorphine concentration of 0.1 mg/ml to 50 mg/ml, and most preferably 3-10 mg/ml.[19] Table 1 illustrates the invention with a number of specific ingredients together with their function and purpose in the formulations.[20] Notably the table names three specific divalent metal ions, Ca2+, Mg2+ and Zn2+, which are preferably added as the chloride salt, and indicates that their function is as a “central atom in the chelate”. Table 2 provides some more specific preferred compositions.[21]
[16] Specification at page 5, first paragraph.
[17] Specification at paragraph bridging pages 5 and 6.
[18] Specification at page 6, last line.
[19] Specification at page 7, paragraph 2.
[20] Specifications at pages 8 and 9.
[21] Specification at page 10.
21. The specification also describes processes for preparing the formulations of the invention, wherein apomorphine, the divalent cation and other optional ingredients are mixed in solution.[22] The order of addition does not appear to be essential, but preferably the divalent metal ion is added to an aqueous solution of apomorphine together with the optional ingredients. If necessary, the pH of the solution can subsequently be adjusted.[23]
[22] Specification at page 11, paragraph 2.
[23] Specification at page 12, paragraph 2.
22. The examples provide two specific formulations of the invention. These are shown in the following table. APO HCl corresponds to the hydrochloride salt of apomorphine. As shown in the table, the molar ratio of apomorphine to divalent metal ion is approximately 1:1. The molar ratio of Ca2+ to Mg2+ is about 1.54:1.
| Ingredient | Example 1 | Example 2 |
| APO HCl | 5.0 mg/ml (16.46 mmol/l) | 10 mg/ml (32.92 mmol/l) |
| MgCl2 | 1.32 mg/ml (6.5 mmol/l) | 2.64 mg/ml (13 mmol/l) |
| CaCl2 | 1.47 mg/ml (10 mmol/l) | 2.94 mg/ml (20 mmol/l) |
23. A comparison is made between these formulations and the commercially available APO-go® having an APO HCl concentration of 5 mg/ml (Comparative Example 1) and 10 mg/ml (Comparative Example 2). As an aside I note the commercial product has a pH of 3 to 4, while the pH of Examples 1 and 2 is not given. There is no indication that the pH of Examples 1 and 2 is adjusted following mixture of the ingredients, so it would appear that the pH of the solution is that which is obtained by mixing the named ingredients. Examples 1 and 2 are said to reduce the level of coagulative necrosis in comparison to the comparative examples.
24. The specification also provides a summary of stability tests for the formulation of Example 1 at various pH, and with different antioxidants. I understand Example 1 to be most stable at lower pH, and with the addition of antioxidants. Formulations at pH 7 appear to be less stable than formulations at lower pH, even with the addition of antioxidants.
25. The specification ends with 20 claims. The meaning of the terminology used in the claim is otherwise consistent with the discussion provided above in relation to the description. Claim 1 is representative of the invention:
Composition comprising apomorphine and at least one divalent cation in a molar ratio of 2 or less, wherein the composition is a pharmaceutical solution or suspension.
26. Claims 1 to 16 define compositions comprising apomorphine and one or more divalent metal cations. I note that while the problem solved by the invention relates to coagulative necrosis at injection and infusion sites, the claim is not limited to injectable pharmaceutical solutions or suspensions.
27. Claims 17 and 18 define processes for preparing the compositions of Claims 1 to 16. Claims 19 and 20 define compositions comprising apomorphine and one or more divalent metal cations when used for treating Parkinson’s disease. The latter claims are interpreted as being equivalent in scope to methods of treatment. The claims are given in full in the Attachment.
28. The opponent’s statement of grounds and particulars and evidence in support repeated several arguments under each of the grounds of utility, clarity, support and sufficiency. Some of these submissions impact on my determination under novelty. I will therefore consider these grounds before I turn to the grounds of novelty and inventive step.
Utility
29. Section 18(1)(c) requires that an invention be useful. A useful summary of relevant principles was provided by the Full Court of the Federal Court in Artcraft Urban Group v Streetworx (citations omitted):[24]
119. It is “no objection” to the validity of an innovation patent granted under the Act that it is “commercially impracticable”. The utility of the patent depends upon whether, by following the teaching of the specification, the result claimed is produced…
120. The “basic principle” of inutility is that if an invention “does what it is intended by the patentee to do, and the end attained is itself useful, the invention is a useful invention”… What the invention is “intended” to do is a matter to be gathered from the “title and the whole of the specification”.
121. Put another way, the two questions are: first, what is the promise of the invention derived from the whole of the specification?; second, by following the teaching of the specification, does the invention, as claimed in the patent, attain the result promised for it by the patentee?... Further, “everything” that is within the scope of a claim must be useful, that is, attain the result promised for the invention by the patentee.
[24] Artcraft Urban Group Pty Ltd v Streetworx Pty Ltd [2016] FCAFC 29 at [118] – [121].
30. The gist of the opponent’s case was that it is a promise of the invention that the compositions avoid coagulative necrosis. However, the claims fail to meet this promise since:
There is no evidence that the compositions avoid coagulative necrosis. The opponent argued that the only evidence in support of the alleged invention avoiding coagulative necrosis is provided in the examples which state that “less coagulative necrosis was caused in the test persons receiving the compositions of Example 1 and 2 compared to the administration of composition of Comparative Examples 1 and 2”. The opponent submitted that causing less coagulative necrosis does not equate to avoiding coagulative necrosis.[25]
There is no experimental data or further explanation of the experiments in the way of the solvent or carrier used in the compositions of the examples and comparative examples, the pH of the compositions, the volume that was administered to each test person, the number of test persons, the inclusion and exclusion criteria for the selection of test persons, the duration of treatment, the length of the observational period, the route of administration, the scoring system for assessing coagulative necrosis, the extent of the alleged difference in coagulative necrosis and the statistical evaluation.[26] The validity of the statement that “less coagulative necrosis” was caused would be questioned by the person skilled in the art, who the opponent claimed would question the plausibility of the invention, particularly since no scientific justification has been advanced which would support the ability of the composition to cause “less” coagulative necrosis, let alone avoid coagulative necrosis.[27]
The definition of compositions having apomorphine in combination with a divalent metal cation in a molar ratio of 2 or less encompasses very low molar ratios. The specification only exemplifies compositions in which the molar ratio is about 1, and even the ability of these to avoid coagulative necrosis is disputed.[28]
Page 4, paragraph 4 states that the occurrence of coagulative necrosis can be avoided “very efficiently” using a composition comprising Ca2+ and Mg2+ in a ratio of 1.37:1 to 1.72:1. There is no evidence that this is the case since the examples compare the activity of such compositions with a composition comprising only apomorphine and does not include a comparison with compositions comprising other metal cations.[29]
[25] Statement of grounds and particulars at 3.1. See also similar comments by Vink at [34] – [35].
[26] Ibid.
[27] Statement of grounds and particulars at 3.1. See also similar comments by Vink at [36] – [37].
[28] Statement of grounds and particulars at 3.2. See also similar comments by Vink at [38].
[29] Statement of grounds and particulars at 3.2. See also similar comments by Vink at [39].
31. The opponent also stated that the specification states that “a further advantage of the composition is that it shows a relatively high stability with respect to apomorphine”. The only stability data provided was in the example on page 14, which assesses the discoloration of compositions containing apomorphine hydrochloride, MgCl2 and CaCl2 in the presence and absence of varying amounts of antioxidant. They noted that the solvent was not specified, nor was any comparison made between the compositions of the invention and apomorphine alone. They argued that the example demonstrates a lack of stability in the absence of an antioxidant, and even in the presence of an antioxidant at certain pH values, and the claimed invention therefore does not meet the advantages and/or objectives of the application.
32. Finally, the opponent noted that the passage bridging pages 10 and 11 states that the compositions do not cause coagulative necrosis, has a good tissue protective effect, has good bioavailability and is a good tolerable apomorphine solution for injection/concentrate for continuous infusion (in particular for the treatment of Parkinson’s), and has enhanced storage stability.
33. As an initial observation, the opponent’s case appears to be predicated on a need for detailed “experimental evidence” in support of any promise, or any purported advantages, of the invention. For example, Dr Vink questioned the validity of the statement that “less coagulative necrosis” was caused and the plausibility of the alleged invention, no evidence was adduced in support of these submissions. Indeed, the opponent’s statements in the second dot point above suggests that a full clinical trial would be required in order to establish that the promise of the invention has been met. I see no basis in patent law for such a high standard of experimental detail being required of a patent application, and no basis for these being required on the facts of the present case.
34. The opponent has also identified specific combinations of featured defined in the claims that they claim would not work. No evidence was adduced that would support the argument that small molar ratios would have no effect, but in any case, this opponent’s approach appears inconsistent with the principle that the skilled person is approaching the invention with the aim of making the invention work, and not with the intention of finding failure. As noted in Apotex v AstraZeneca (No 4) (citations omitted):[30]
“Section 18(1)(c) requires that an invention be “useful”. This will be the case if the claimed invention does what it is intended by the patentee to do, in the sense of meeting the object or promise in the specification, and the end result obtained is itself useful… For this purpose, the claims must be construed from the perspective of a skilled person in a commonsense way, and not in a way that any such addressee would appreciate would lead to an unworkable result…
It is not necessary for the description in the specification to spell out matters which the skilled person could supply without the exercise of any inventive faculty in order to achieve the promise of the invention. The patentee is entitled to assume that the reader has a reasonably competent knowledge of what was known before and reasonably competent skill in the practical mode of doing what was then known. A purposeful adoption of an embodiment that would obviously lead to an unworkable or inferior result is not an appropriate way of testing utility. It is also relevant to pay attention to the nature of the alleged “promise” in the specification… Ultimately, an asserted lack of utility must be established by appropriate evidence, not by mere speculation that the invention will not work or meet the promise set out in the specification.” [emphasis added].
[30] Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162, see [352].
35. Turning to the issue of whether the term “avoid” requires absolute absence of symptoms following treatment, I note that amendments have been made to the specification that result in the references to avoiding coagulative necrosis now reading avoiding or ameliorating coagulative necrosis. This would appear to have addressed the issue raised in the opponent’s submissions. However, even if such amendments had not been made, I am not satisfied that the promise of the invention lies in complete or absolute avoidance of coagulative necrosis. The opponent has isolated specific words or phrases in the specification and given them a strictly literal interpretation. This is not consistent with a common-sense approach to construing the specification to determine the meaning that the person skilled in the art would give to the terms used.[31]
[31] Eli Lilly and Co Ltd v Apotex Pty Ltd [2013] FCA 214; 100 IPR 451 at 482.
36. In this regard, Dr Peppard stated in relation to the specification prior to the amendment:[32]
“In my view, the Opposed Application describes a means of reducing coagulative necrosis caused by subcutaneous apomorphine administration by improving the stability of apomorphine in solution.”
[32] Peppard at [18].
37. Professor Hambley stated that:
“The Opposed Application is focused on producing an apomorphine metal complex that has an improved stability and greater tolerability over the apomorphine molecule per se… In terms of the object of the invention, it is my view that the invention sets out to provide a pharmaceutical formulation that is more tolerable in terms of the known side effects associated with apomorphine injection or infusion.”
38. On balance I prefer the evidence of the applicant on this point. As noted previously, I consider that little evidentiary weight can be given to the statements by Dr Vink, and the opponent has provided no evidence from a relevant person skilled in the art in support of their assertions. Absent such relevant evidence there is no basis on which I could conclude that the compositions of the invention do not meet the promise of the invention as set out in the specification as a whole. To the contrary, the evidence of Dr Peppard and Professor Hambley establishes that a person skilled in the art would not understand the specification to mean that the invention absolutely avoids coagulative necrosis, but rather that it provides a reduction in this side effect. The amendments made by the applicant, in my view, act to further clarify this point.
39. The opposition fails on this ground.
Clarity
40. Subsection 40(3) requires that the claims must be clear. A claim will lack clarity if a third party would be unable to ascertain whether an act would fall within the scope of the claim.[33] The opponent made several submissions in relation to the clarity of the claims, some of which were addressed in the amendments of 9 March 2021:
The absence of a lower limit in the definition of a molar ratio of 2 or less is unclear as to how the invention would work at the “extremely low” molar ratios of apomorphine to divalent metal cation. I note that this is essentially the same submission that was made in relation to utility, and I have dealt with it under that ground. There is nothing that would lead me to consider the argument to be successful under the ground of clarity.
Claim 4 lacks clarity because Dr Vink considered that the definition “one or more separate coordinate bonds are formed between apomorphine and the divalent metal cation”, was unclear as to how a chelate between apomorphine and a divalent metal cation can contain only one, or more than two coordinate bonds between apomorphine and the divalent metal cation. I prefer the evidence of Professor Hambley on this point, who stated that in order for chelation to occur, one of the hydroxy groups of the catechol moiety would be deprotonated in order to react with a corresponding calcium or magnesium ion.[34] This would provide a single chelate bond. To the extent that Dr Vink appears to be reading the claim to include multiple chelate bonds that would appear to contradict the laws of chemistry, the evidence of Professor Hambley indicates that a skilled inorganic chemist would read the reference to “one or more” as the maximum number of chelate bonds being determined consistent with the properties of the divalent metal ion and the stoichiometry used.[35] The opponent’s arguments on this point fail.
Claim 7 (as originally accepted) is unclear as the definition of “the composition contains apomorphine and Ca2+ and Mg2+ which are present in a ratio of 1.37:1 to 1.72:1”. Dr Vink stated that it was not clear whether these ratios referred to the ration of apomorphine to (Ca2+ and Mg2+), or Ca2+ to Mg2+. I consider the normal grammatical meaning would be the latter. I see no reason to depart from that interpretation.
[33] Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59.
[34] Hambley at [13].
[35] Ibid.
41. In summary, the opposition fails on the ground of clarity.
Clear enough and complete enough disclosure
42. Subsection 40(2)(a) of the Act requires that a complete specification disclose the invention in a manner that is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art.
43. The opponent made submissions on several points:
The specification at page 2 paragraph 5 to page 3, last paragraph indicates that chelate formation is important to the working of the invention, and Dr Vink considered it is unclear how the invention would work if a chelate was not present.[36] Claims 1 to 3 and 5 to 14 (as accepted) do not require chelate formation.
At page 3 paragraph 2, the specification states that it is preferable that one or both of the hydroxyl groups of apomorphine are in the deprotonated form which can be achieved by suitably adjusting the pH of the composition. Dr Vink noted that the only mention of a suitable pH in the specification relates to the addition of a pH adjuster to bring the pH into a range of 3 – 10 (page 6), and that the specific adjusters (HCl and NaOH) were intended to bring the pH into the range of 3 – 6.2 (table 1). It was not clear to Dr Vink whether any of these pH ranges would be suitable for chelate formation, and that further experiments would be required to determine such pH.[37]
The claims define solutions and suspensions, but the only solvent provided in the specification was water. Dr Vink considered there would be an undue burden for the skilled person to determine suitable solvents that would avoid coagulative necrosis.[38]
Claim 1 defines a composition which is suitable for use as a pharmaceutical solution or suspension and comprises any divalent metal ion. The specification provides no directions as to how all divalent metal cations and amounts thereof, including those associated with toxicity, may be suitable for use in a pharmaceutical composition, let alone avoid coagulative necrosis. Only two compositions are exemplified, these containing specific combinations of calcium and magnesium. An undue burden would be required to determine and test all divalent cations and combinations to determine which would avoid coagulative necrosis.[39]
Claim 14 (as accepted) defines that the composition is used in the diagnosis prevention and treatment of Parkinson’s, but no details are given as to how the composition is used (amount to be administered, frequency of administration etc.).
[36] Vink at [43].
[37] Vink at [44].
[38] Vink at [47].
[39] Vink at
44. The opponent also repeated the previous submissions made under clarity and utility in relation to the number of coordinate bonds between apomorphine and the divalent metal cation and the molar ratio of apomorphine to divalent metal cation having no defined lower limit. I do not consider that these submissions would lead to a different outcome under the ground of sufficiency, and therefore will not consider them further.
45. In CSR[40] the delegate adopted a three-step test for determining whether the specification provided a clear enough and complete enough disclosure of the claimed invention as follows:
What is the scope of the invention as claimed?
What does the specification disclose to the skilled person?
Does the specification provide an enabling disclosure of all the things that fall within the scope of the claims?
[40] CSR Building Products Ltd v United States Gypsum Company [2015] APO 72.
46. An expanded approach was taken in Evolva.[41] The third consideration of enablement set out in CSR was assessed according to the following criteria:
Is it plausible that the invention can be worked across the full scope of the invention?
Can the invention be performed across the full scope of the claims without undue burden?
[41] Evolva SA [2017] APO 57.
47. The approach taken in CSR and Evolva, and in particular their conformity with the laws of the UK and Europe, have received approval by Burley J in Cytec v Nalco,[42] and more recently by Rofe J in Jusand v Rattlejack.[43] I will apply this approach in the present consideration.
[42] Cytec Industries Inc. v Nalco Company [2021] FCA 970 at [145]-[147].
[43] Jusand Nominees Pty Ltd v Rattlejack Innovations Pty Ltd [2022] FCA 540 at [352]-[369].
48. The key issue in the opponent’s evidence relates to the broad definition of a divalent metal cation, and whether the specification provides a clear and complete enough disclosure across the full scope of the claims. In this regard an invention may be defined in general terms and be considered sufficient provided the specification discloses a principle of general application. As stated in Biogen v Medeva:[44]
“If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them.
Thus if the patent has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect... On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.”
[44] Biogen Inc. v Medeva plc [1996] UKHL 18; [1997] RPC 1 at 48-49.
49. In the present case, I do not consider that the specification provides a single principle of general application that is common to substantially all of the claimed matter (being the broad class of divalent metal cations), but instead provides enablement for a narrower class of divalent cations, namely magnesium, calcium and zinc.
50. In this regard, Dr Peppard stated that:[45]
“it is my understanding that the apomorphine is stabilised in solution by virtue of the apomorphine molecule reacting with a divalent metal cation. The apomorphine molecule has a catechol moiety which is capable of forming a chelate ring with the divalent metal ion, which I understand to be more stable than simply forming a single bond with the metal centre…
The Opposed Application describes a way of improving the stability of apomorphine in a pharmaceutical solution by forming a complex between apomorphine and a divalent metal cation.”
[45] Peppard at [18].
51. Similarly, Professor Hambley stated that:[46]
“it is my view that the invention sets out to provide a pharmaceutical formulation that is more tolerable in terms of the known side effects associated with apomorphine injection or infusion. This may be achieved by increasing the stability of the apomorphine. Indeed, from a stability perspective, while I am unclear on the mode of decomposition of the apomorphine molecule, it is logical to me based on the information provided by the Opposed Application that coordination, and more particularly, chelation would be an appropriate means by which to reduce the likelihood of decomposition and other reactions occurring…”
[46] Hambley at [20].
52. However, Professor Hambley went on to state that:[47]
“Previously when the attorneys acting from Britannia Pharmaceuticals Limited asked me to comment on what metal cations I would consider to be appropriate for chelation with the apomorphine molecule for use in treating Parkinson’s Disease, I made the suggestion that cobalt ions may prove to be suitable for ‘chaperoning’ the apomorphine in vivo. Having now viewed the Opposed Application, it is clear to me that cobalt ions would be more relevant for the purpose of achieving an apomorphine-metal complex that is more stable in the bloodstream over the ‘long-term’ rather than one that is merely required for the ‘short-term’ transportation of the apomorphine molecule safely into the bloodstream.
Based on my reading of the Opposed Application, there is a clear rationale to using divalent metal ions such as the Ca2+, Mg2+ and Zn2+ divalent metal ions disclosed on page 4, line 16 for coordination with the apomorphine molecule to stabilise the molecule in vivo for the ‘short term’ transportation of the apomorphine molecule safely into the bloodstream.”
[47] Ibid.
53. This suggests that the solution provided by the invention does not simply lie in the ability of the divalent metal cation to form a chelate, but rather its ability to form a chelate with a particular characteristic (the ability to provide “short-term” as opposed to “long-term” transportation). Moreover, even though the declarants were of the common view that the invention lies in stabilisation of the catechol moiety by chelation, the specification states that chelation is preferable. Thus, the invention requires more than selecting a divalent metal ion, but rather requires the selection of a divalent metal cation having specific properties.
54. The claims encompass products including chelated forms (which are further distinguished by the specific properties of chelates, and their suitability for pharmaceutical use), as well as unchelated mixtures (also further distinguished by the suitability of any particular divalent metal cation or salt for pharmaceutical use). In my opinion, the specification provides little guidance on the selection of divalent metal ions that would be suitable for pharmaceutical use and possess the properties required to provide the desired reduction in coagulative necrosis, including instructions on how to proceed in case of failure.
55. In particular, no guidance is otherwise provided as to the properties of the divalent metal ion that would provide the features required to achieve the outcomes of the invention, or alternatively how such an assessment can be made. For example, in response to the opponent’s evidence in relation to the toxicity of mercury and boron, the applicant submitted that these clearly would not meet the criteria for selection as a pharmaceutical due to that toxicity. However, I note that Professor Hambley also stated that copper and iron, while naturally present in vivo, are prone to promote redox reactions in cells that can potentially lead to cell death.[48] But, while not determinative, the applicant did not appear to dispute the opponent’s arguments that copper-containing formulations would be suitable as pharmaceuticals on the basis of toxicity. This arguably highlights the lack of guidance provided by the specification in relation to toxicity (or not causing “harm”), let alone the further property of avoiding coagulative necrosis.
[48] Hambley at [11].
56. On balance I consider it would require an undue burden of experimentation to work the invention substantially across the full scope in relation to the choice of the divalent metal ion. The specification therefore does not disclose the invention in a manner that is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art in relation to the definition of divalent metal cations.
57. On the other hand, I consider the specific choice of Ca2+, Mg2+ and Zn2+ is sufficiently enabled by the specification. Prima facie, the examples use a mixture of the free divalent metal salts and apomorphine, as there is no apparent synthetic step or conditions that would result in chelation. This conclusion is also supported by Professor Hambley who stated that the specification does not provide definitive confirmation that chelates are formed in the compositions of the invention.[49] The compositions of the examples comprising these apparently unchelated divalent metal cations are said to provide a reduction in the level of coagulative necrosis when these formulations are administered to patients.
[49] Hambley at [20].
58. Furthermore, the evidence of Professor Hambley and Dr Peppard indicates that it is plausible that chelation further stabilises the catechol moieties of apomorphine and reduces undesirable decomposition that results in toxic metabolites.[50] Professor Hambley also provided a plausible synthetic route to such species which prima facie would not require any prolonged research, enquiry or experiment.[51] I am therefore satisfied that the specification is clear enough and complete enough in relation to formulations comprising Ca2+, Mg2+ and Zn2+, whether in chelated or unchelated form. No evidence was adduced by the opponent that would establish otherwise.
[50] Peppard at [18].
[51] Novartis AG v Johnson Medical Ltd [2009] EWHC 1671 (Pat).
59. Finally, in relation to the opponent’s comments in relation to the selection of solvents, and the lack of specific dosage schedules and the like, the applicant submitted that the person skilled in the art would be familiar with the range of solvents that will be useful for subcutaneous injection,[52] and that the clinical framework of using apomorphine to treat Parkinson’s disease was known.[53] I agree with these submissions. No evidence has been adduced from a person working in the relevant field that would lead me to consider there to be an undue burden of experimentation in this regard.
[52] Applicant’s written submissions for hearing at [233].
[53] Applicant’s written submissions for hearing at [238].
60. In summary I consider the specification does not disclose the invention in a manner that is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art in relation to the broad class of divalent metal cations but is sufficient in relation to the use of Ca2+, Mg2+ and Zn2+.
Support
61. Section 40(3) requires that a specification must be supported by matter disclosed in the specification. In CSR, the delegate stated that this required that the claims should correspond to the technical contribution to the art.[54] This approach has been given judicial approval in MSD v Wyeth.[55]
[54] Supra at [109].
[55] Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) [2020] FCA 1477 at [546].
62. The opponent made similar comments on support to those made under the other grounds discussed above. I see no need to reiterate these. At hearing the applicant submitted that the technical contribution lay in the provision of pharmaceutical solutions or suspensions comprising apomorphine and at least one divalent metal cation in a molar ratio of 2 or less.
63. As noted in CSR, an important consideration when considering support is whether the technical contribution is a general principle or the specific examples in the specification.[56] For similar reasons to those discussed above in relation to sufficiency, I consider that the description does not disclose a principle of general application in the use of divalent metal cations, but rather relates to the use of the specific divalent metal cations Ca2+, Mg2+ and Zn2+.
[56] Supra at [110].
64. It follows that Claims 1 to 7 and 11 to 20 lack support.
Best method
65. Section 40(2)(aa) sets out the requirement that a specification disclose the best method known to the applicant of performing the invention. In Kineta, the Deputy Commissioner stated that:
“it is necessary to determine what method is disclosed in the specification, and then ask whether there is any evidence that the applicant was aware of a better method of performing the invention.”
66. Again, the comments in the statement of grounds and particulars and evidence in support made by the opponent on this ground were similar to those made under other the grounds of utility, support, sufficiency and clarity. The gist of the arguments was that certain features were indicated as being essential or important to the invention – pH, chelation, the identity of the solvent, details of the route of administration, frequency of administration etc. I have dealt with those issues under the other grounds above. The applicant noted that the opponent had provided no evidence to show that the Applicant was aware of any better method than that disclosed in the application, nor that, on the face of the specification, a better method exists. They submitted that the opponent’s attack fails at the first hurdle.[57]
[57] Applicant’s written submissions for hearing at [241].
67. I agree with the submissions made by the applicant. The specification has set out various methods of preparing and using compositions containing apomorphine and some divalent metal ions, including a description of various alternatives (inclusion of antioxidants, adjusting pH etc). The applicant also noted that the skilled person would have regard to the established methods of administering APO-goTM to determine dosage amounts, frequency and the like.[58] I agree with these submissions. Moreover, as noted by the applicant, the opponent has provided no evidence that the applicant was aware of a better method of performing the invention than those given in the specification. The opposition fails on this ground.
[58] Applicant submissions for hearing at [245]- [248].
Novelty
68. For the purposes of subsection 7(1) of the Patents Act, an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the prior art information. It is well established that the general test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aickin J in Meyers Taylor v Vicarr Industries:
“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.”[59]
[59] Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19 at [20]; [1977] HCA 19; 137 CLR 228 at [235].
69. This test is satisfied if the alleged anticipation discloses all of the essential features of the invention as claimed.[60] To meet this requirement, the prior art must contain “clear and unmistakable directions to do what the patentee claims to have invented”.[61] As noted in General Tire v Firestone:
“A signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee”.[62]
[60] Nicaro Holdings Pty Ltd v Martin Engineering Co [1990] FCA 40 at [19]; [1990] FCA 40; 16 IPR 545 at [549].
[61] The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at [486].
[62] Ibid.
70. The opponent relied on the following documents in their opposition:
D1 Cardioprotective and antioxidant effects of apomorphine, I. Khaliulin et al., Free Radical Research, 37(7), (2003), 721-30.
D2 Ion-exchange and iontophoresis-controlled delivery of apomorphine, K. Malinovskaja et al., European Journal of Pharmaceutics and Biopharmaceutics, 83, (2013), 477-484.
D3 Iron chelating, antioxidant and cytoprotective properties of dopamine receptor agonist: apomorphine, M. B. H. Youdim et al., Journal of Neural Transmission, 58, (2000) [Suppl], 83-96.
71. Notably, the claims require that the composition is a pharmaceutical solution or suspension. This was a key issue in the opposition. A plain meaning of the term “pharmaceutical solution” is a liquid in which a therapeutic agent is dissolved. The opponent’s evidence on novelty presupposes that prior art compositions need only be suitable for use as a pharmaceutical and does not require that the composition be used in therapy to anticipate a claim to a pharmaceutical composition per se.
72. I consider that the plain meaning of a pharmaceutical solution would require that the solution be for pharmaceutical use. However, I agree with the opponent’s arguments in that it may be sufficient to anticipate the present claim that the ingredients and the quantities used in a prior art composition would be suitable for pharmaceutical use. For example, the prior art composition may contain materials that are known pharmaceutical excipients, or the active ingredient may be in a form, a quantity or a concentration that is consistent with pharmaceutical use of that active. However, evidence may be required in support of such submissions.
73. D1 describes a study on the effect of apomorphine on myocardial ischemic reperfusion injury in isolated rat hearts.[63] The opponent identified several disclosures in D1 that they considered anticipated the present claims.
[63] Perfusion is the passage of a liquid through the circulatory or lymphatic system to an organ or tissue. Reperfusion injury is the damage caused to tissue when blood supply returns following a blockage.
74. Isolated heart perfusion was maintained using a modified Krebs-Henseleit (KH) solution. The solution contained 118 mM NaCl, 4.9 mM KCl, 1.2 mM MgSO4, 1.2 mM KH2PO4, 25 mM NaHCO3, 11.1 mM glucose and 2.5 mM CaCl2. The KH solution was aerated with a mixture of 95% oxygen and 5% carbon dioxide. Perfusion was maintained at 37℃. Apomorphine was dissolved in saline and perfused through a side arm directly into the aortic cannula by a syringe pump at a concentration of 40 µM to provide a final concentration in the perfusion medium of 2 µM.
75. Dr Vink stated that the dissolution of apomorphine in the KH solution provided an aqueous solution that is suitable for use as a pharmaceutical solution or suspension and has a molar ratio of apomorphine to divalent metal ions (Ca2+ and Mg2+) of 2:3700 (or 5.4 x 10-4).[64] Dr Vink also referred to similar experiments in D1 using apomorphine concentrations of 1, 5 and 25 µM which corresponded to molar ratios to calcium in the final KH solution of 2.7 x 10-4, 0.0014, and 0.0068.
[64] Vink at [13].
76. The applicant submitted that the solution described in this procedure was not prepared as an “autonomous” formulation, but was formed in situ during the experiment. To this end, neither Dr Peppard nor Professor Hambley considered that D1 disclosed a pharmaceutical solution or suspension as defined in the claims.[65] Dr Peppard stated that:
“…the KH solution was not mixed with the apomorphine saline solution. Rather the modified Krebs-Henseleit (KH) solution was merely used to mimic the extracellular fluid associated with the heart during the aortic perfusion of rats.”[66]
[65] Hambley at [25], Peppard at [20].
[66] Peppard at [20].
77. I find the applicant’s submissions on this point to be persuasive. As noted by Dr Peppard, the KH perfusion and apomorphine-saline solutions are mixed in situ. While the opponent noted that the molar ratio of apomorphine was within the levels required by the claims, the claims further require that the composition is a pharmaceutical solution or suspension. This is therefore an essential feature of the invention that must be disclosed by the prior art document, either explicitly or inherently, in order for the claim to be anticipated.
78. Given my interpretation of the experiment described in D1, I consider the mixture would be unsuitable for use as a pharmaceutical solution. The reperfusion fluid is in contact with isolated rat hearts and the conditions described in the reperfusion experiment fundamentally change the content of the reperfusion fluid. D1 states that perfusion with the KH solution releases proteins which are a marker of reperfusion damage.[67] The authors also postulate that apomorphine binds to transition metal ions which are released during ischemia-reperfusion and suggest that up to 97% of the perfused apomorphine is bound to iron (III).[68] The presence of such extraneous materials would appear to make the resulting perfusion solution wholly unsuitable for pharmaceutical use.
[67] D1 at page 722, “Ischemic/reperfusion Damage”, Figure 2.
[68] D1 at page 728, first paragraph.
79. Furthermore, I also note the apomorphine is used at a concentration of 2 µM in the final reperfusion solution. The opponent provided no calculation of the specific quantity of active ingredient disclosed in the reperfusion study, but my understanding is that 2 µM corresponds to about 0.0005 mg/mL. This compares with the preferred dosage amounts defined by the claims (which are consistent with known therapeutic dosages of apomorphine) of 0.1 to 40 mg/mL. Prima facie, treatment using a 2 µM solution would require significant quantities of solution to achieve a therapeutic dosage amount. For example, the lowest preferred dosage concentration of 0.1 mg/mL is 200 times greater than the concentration of the reperfusion solution. Even if I were to accept the opponent’s submissions in relation to the excipients in the final reperfusion solution being suitable for pharmaceutical use, there is no evidence before me that would establish that such a low concentration of apomorphine would be considered suitable for pharmaceutical use.
80. I therefore do not consider that the present claims are anticipated by the reperfusion studies described in D1.
81. D1 describes two other studies that the opponent considered relevant as they used solutions that fell within the defined ratio of divalent metal ion to apomorphine and would be suitable for use as pharmaceuticals.
82. The first of these studies describes the effect of apomorphine on ascorbate oxidation in which apomorphine (50 µM) was preincubated with sodium ascorbate (5 mM), copper sulfate (50 µM) and HEPES buffer (5 mM, pH 7) at 37℃ under aerobic conditions.[69] The applicant submitted that due to the relatively high temperature and aerobic conditions used during the experiments the formulations disclosed in D1 cannot be regarded as a pharmaceutical formulation in the sense of Claim 1.[70] I agree with the applicant on this point. The experiment involves subjecting the reaction mixture to oxidising conditions that result in the formation of oxidised ascorbate and show the presence of redox-active metals. While the paper suggests that apomorphine binds to copper in solution, the aerobic conditions used in the experiments would prima facie result in some formation of oxidised products. The paper does not disclose the specific composition of the reaction mixture, nor did the opponent provide any evidence on this point and the extent to which such products, if present, would be pharmaceutically acceptable.
[69] D1 at page 723, column 1.
[70] Applicant submissions for hearing at [113].
83. The second describes an in vitro study of the interaction of apomorphine and Cu2+ ions in Tris buffer. Apomorphine (0 – 0.2 mM) was mixed with decreasing concentrations of copper sulfate (0.1 – 0 mM) in Tris buffer (10 mM, pH 7.2).[71] Like their submissions on the reperfusion study described in D1, the opponent considered that the reagents used in these studies would be suitable for use as pharmaceutical solutions but provided no corroborative evidence in support of these assertions.[72] In response the applicant submitted that this assumed that apomorphine and copper formed a stable solution under the conditions used, and particularly at pH 7.2.
[71] D1 at paragraph bridging pages 722 and 733, and paragraph bridging pages 725 and 726.
[72] Vink at [18].
84. Here the concentration of apomorphine appears to be relatively close to the preferred ranges defined by the present claims. For example, my understanding is that a 0.2 mM solution of apomorphine corresponds to a formulation having about 0.055mg/mL. This compares with the preferred lower dosage given in the specification of 0.1 mg/mL. On balance the concentration of apomorphine used in these experiments is consistent with pharmaceutical solutions.
85. However, I consider there is a question as to suitability of the apomorphine copper complex as a pharmaceutical. No detail was provided by the opponent on why they considered that a copper chelate of apomorphine is suitable for use as a pharmaceutical. At hearing the applicant did not specifically address this point, but Professor Hambley stated that copper and iron, while naturally present in vivo, are prone to promote redox reactions in cells that can potentially lead to cell death.[73] It therefore appears unlikely based on this evidence that a copper chelate of apomorphine would be considered suitable as a pharmaceutical (noting that the present problem lies in alleviating a type of cell death). No evidence was provided by the opponent that would counter this conclusion. On balance I do not consider that the opponent has discharged the onus of establishing that the solutions disclosed in D1 would be considered suitable as pharmaceuticals.
[73] Hambley at [11].
86. On this point I acknowledge that the formulations defined by Claim 1 are not limited to any specific treatment or disease. Furthermore, the specification does not explicitly exclude any particular divalent metal ions from consideration. But the claims require that the formulation is a “pharmaceutical solution or suspension” and therefore they must be suitable for such a purpose. To this end, the specification does not provide any particular criteria for selection of a suitable metal cation or indeed any other excipient other than the general requirement that it does not cause any harm to the human body.[74] However, this goes to the grounds of sufficiency and support which I have dealt with above. Nevertheless, I am satisfied that the evidence, on balance, indicates that an apomorphine copper chelate would not be suitable for pharmaceutical use, and therefore would not fall within the scope of the claims.
[74] Specification at page 2, paragraph 3.
87. I therefore consider that the opponent has not made out the ground of novelty in relation to citation D1.
88. D2 discloses a study of a potential transdermal drug delivery system. Apomorphine is loaded onto cation exchange fibres (Smopex®-101 and Smopex®-102), which are then immersed in an electrolyte extracting solution of NaCl2 or CaCl2. The opponent’s submissions on novelty were directed at the electrolyte extracting solution following extraction of apomorphine from the cation exchange fibres. While concluding that the solution would be suitable for use as a pharmaceutical, as was the case with D1, Dr Vink provided no specific evidence as to the why the amount or concentration of apomorphine would make the solution suitable for pharmaceutical use.
89. Neither Dr Peppard nor Professor Hambley considered that D2 disclosed a pharmaceutical solution, but this appears to be on the basis of the use described in document and they did not address the issue of whether the solution and its components would inherently be suitable as a pharmaceutical.[75] At hearing the applicant submitted that the opponent’s submission on this point were mere speculation that was not supported by evidence. The applicant also submitted that D2 did not disclose a solution or suspension since it still contains and is in contact with the fibre bundle which is loaded with apomorphine.[76] I do not find this argument persuasive since the fibres are not an inextricable part of the apomorphine solution.
[75] Peppard at [21], Hambley at [28].
[76] Applicant’s written submissions for hearing at [119] – [120].
90. Dr Vink provided little detailed analysis of the disclosure beyond the relative molar ratio of apomorphine to CaCl2. I have attempted to determine the composition and properties of the solutions described but cannot definitively ascertain these properties since some details have not been provided in D2. This is further discussed below.
91. D2 discloses drug release studies which were performed on individual fibre bundles, with 3 fibre bundles being separately used to provide a mean value.[77] I understand these to have a weight of 100 mg each.[78] Apomorphine is loaded on the fibres at a quantity of between 0.16 and 0.827 mmol/gram for Smopex®-101, and 0.155 and 0.796 mmol/gram for Smopex®-102.[79] This is dependent on the conditions used, including the concentration of the apomorphine loading solution and the loading period (24 hours with a single loading solution, or 2x24 hours using two separate loading solutions). A study was also done of the effect of pre-treatment with NaCl or HCl.[80]
[77] D2, Part 2.3, first 2 lines, and Fig. 2 reference to “mean ± SEM, n=3”.
[78] D2, part 2.2, lines 1 to 3.
[79] D2, Table 2.
[80] D2, part 2.2, lines 9 to 18.
92. D2 goes on to describe the release of the apomorphine from the cation exchange fibres in a 15 mL extraction solution containing calcium ions in an equivalent ratio, a ten-fold excess, and a 100-fold excess, to apomorphine. A 100-fold excess achieved about 15% release of apomorphine from Smopex®-101, and about 30% release from Smopex®-102.[81] Dr Vink specifically referred to these results in evidence.
[81] D2, Fig. 2 (C and D).
93. I note that the final composition of the solutions following extraction is not specifically determined. The study is aimed at determining the release properties of the bundles and the extraction solution is merely the means by which those properties are determined under different conditions. D2 also does not specifically identify which apomorphine-loaded bundle is used in the release studies relied upon by the opponent. The results of the extraction are reported in relative rather than absolute quantities. This lack of detail was noted by the applicant at hearing.
94. If the apomorphine-loaded fibres used in the release studies correspond to one of the fibres set out in Table 2, then my understanding is that these would result in final concentrations close to, or within, the range defined in the present claims. These concentrations of apomorphine would appear to be suitable for pharmaceutical use. For example, Smopex®-102 can be loaded to a capacity of 0.796 mmol/gram fibre. If this fibre released 30% of the total apomorphine content, then it would appear that the resulting solution with have an apomorphine content of about 0.43 mg/mL.[82] At the lowest loading given in Table 2 for this fibre, the resulting solution will have an apomorphine content of about 0.08 mg/mL. These apomorphine concentrations are within or similar to the ranges defined in the present claims.
[82] Based on the use of a fibre bundle of 0.1g and loading of 0.796 mmol/g, a 30% release will result in 0.02388 mmol in 15 mL of solution, or 0.43 mg/mL (based on a molecular weight of 267.322 for apomorphine).
95. In the case of Smopex®-101, the corresponding apomorphine content would be about 0.42 mg/mL and 0.04 mg/mL at the highest and lowest loading shown in Table 2. Here, the apomorphine concentration at the lower loading level is less than half the lowest value in the therapeutic range defined in the claims.
96. However, as noted above D2 does not specify exactly which apomorphine-loaded bundles are used in the release studies, and the opponent did not address this point. As a consequence, I am unable to definitively determine the final concentrations of the extraction solutions, and whether these would be suitable for pharmaceutical use. Moreover, the extraction solutions contain up to a 100-fold molar excess of calcium ions, so apomorphine loadings that provide pharmaceutically suitable concentrations of apomorphine also include very large excesses of calcium chloride. No specific evidence was provided as to whether apomorphine solutions containing such large concentrations of calcium chloride would be suitable for pharmaceutical use. I do not consider the opponent has discharged the onus of establishing, on balance of probability, that the solutions disclosed in D2 anticipate the present claims, and in particular would be suitable as pharmaceutical solutions.
97. I therefore conclude that the claims are novel in view of D2 based on the evidence provided by the opponent.
98. D3 discloses a study of the neuroprotective effects of apomorphine on isolated rat brain mitochondria which are incubated with ascorbic acid and FeSO4.[83] As a review article, D3 provides little experimental detail. Nevertheless Dr Vink stated that D3 discloses compositions containing apomorphine and Fe2+, and that such compositions are suitable for use as pharmaceutical solutions.[84] Dr Vink interpreted the disclosure to disclose solutions which were formed by mixing the solvent, divalent metal cation and apomorphine.[85] In contrast, Professor Hambley stated that the isolated rat mitochondria were incubated with ascorbic acid and FeSO4 and then exposed to apomorphine – that is the divalent cation, ascorbic acid and apomorphine at no time exists as a discrete pharmaceutical solution, but rather as an assay solution comprising the components defined by the claims, but also the biological materials used in the assay.[86]
[83] D3 at page 87, first paragraph.
[84] Vink at [28].
[85] Vink at [29].
[86] Hambley at [29].
99. On balance I do not find the opponent’s submissions persuasive. There is clearly a difference in interpretation between the experts as to the way apomorphine is added, and particularly whether it is added simultaneously with the ascorbic acid and FeSO4 or whether it is added consecutively. I prefer Professor Hambley’s interpretation of the document. I do not understand the procedure to involve mixing of the three solutions prior to addition. Rather, the three reagents appear to be added as separate solutions to provide ascorbic acid 50 mM, FeSO4 1-10 mM and apomorphine 0.3 or 0.6 mM. There is no apparent disclosure of any discrete solution comprising all three components in any specific quantity.
I therefore consider that the claims are novel in view of D3.
In summary, the claims are novel in view of documents D1, D2 and D3. The opponent’s opposition fails on this ground.
Inventive step
The statement of grounds and particulars set out lack of inventive step as a ground of opposition and stated that the common general knowledge “will be established by the evidence of expert witness(es) and includes prior art cited in the Application”. A list of items was purported to constitute common general knowledge.[87]
[87] Statement of grounds and particulars at 2.2.
However, Dr Vink provided no evidence in relation to the common general knowledge in the art and merely “noted” the submissions made in the corresponding opposition on European Patent 3174526 without identifying any specific submission or providing any relevant evidence in relation to on those submissions. No details have otherwise been provided as to the specific combination(s) of common general knowledge, or of any specific item of common general knowledge in combination with any specific document, that the opponent is seeking to rely on in the present opposition. I am unable to glean any tangible case under Australian Law made by the opponent in support of this ground.
Under the circumstances I consider that I can deal with this ground in a summary manner. The opponent has failed to meet the standard of proof required to establish, on balance of probabilities, that the claims lack inventive step.
Conclusion
The opposition has been successful.
The specification does not disclose the invention in a manner that is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art in relation to the definition of divalent metal cations.
Claims 1 to 7 and 11 to 20 lack support for similar reasons.
I consider that these may be overcome by amendment. I give the applicant two (2) months from the date of this decision to propose amendments to attempt to overcome the identified deficiencies.
Costs
Costs generally follow the event. The opposition has been successful, albeit requiring me to glean arguments from the statement of grounds and particulars and (similar) evidence in support and drawing on the evidence provided by the applicant’s experts. The applicant also arguably conceded on some issues and made amendments to the opposed claims to address some of the issues raised by the opponent.
Nevertheless, the case run by the opponent would arguably have better suited a re-examination process, and their actions in not withdrawing their opposition (which would also have initiated a re-examination) has resulted in a less efficient and timely resolution of the issues.
I therefore make no award of costs.
Leslie F. McCaffery
Delegate of the Commissioner of Patents
Claims
Composition comprising apomorphine and at least one divalent metal cation in a molar ratio of 2 or less, wherein the composition is a pharmaceutical solution or suspension.
Composition according to claim 1, wherein the molar ratio of apomorphine and the at least one divalent metal cation is from 2 to 0.2.
Composition according to claim 1, wherein the molar ratio of apomorphine and the at least one divalent metal cation is from 1.25 to 0.5.
Composition according to claim 1, wherein the molar ratio of apomorphine and the at least one divalent metal cation is from 1.25 to 0.83.
Composition according to any one of the preceding claims, comprising apomorphine and the at least one divalent metal cation in a stoichiometric amount ± 10%.
Composition according to any one of the preceding claims, containing a chelate comprising apomorphine as a ligand and the at least one divalent metal cation as a central atom, wherein one or more separate coordinate bonds are formed between apomorphine and the at least one divalent metal cation.
Composition according to any one of the preceding claims, wherein water is present as a solvent for apomorphine and the at least one divalent metal cation.
Composition according to any one of the preceding claims, wherein the at least one divalent metal cation is selected from the group consisting of Ca2+, Mg2+ and Zn2+.
Composition according to any one of the preceding claims, wherein the composition contains apomorphine, Ca2+ and Mg2+, wherein the Ca2+ and Mg2+ are present in a ratio of 1.37:1 to 1.72:1.
10. Composition according to any one of claims 1 to 8, wherein the composition contains apomorphine, Ca2+ and Mg2+, wherein the Ca2+ and Mg2+ are present in a ratio of 1.545:1.
11. Composition according to any one of the preceding claims, further comprising an antioxidant.
12. Composition according to any one of the preceding claims, wherein the composition is a pharmaceutical solution for parenteral administration.
13. Composition according to any one of the preceding claims, having a concentration of apomorphine from 0.1 mg/ml to 40 mg/ml.
14. Composition according to any one of claims 1 to 12, having a concentration of apomorphine from 1 mg/ml to 15 mg/ml.
15. Composition according to any one of claims 1 to 12, having a concentration of apomorphine from 3 mg/ml to 10 mg/ml.
16. Composition according to any one of claims 1 to 12, having a pH of 3.0 to 6.2.
17. Process for preparing the composition as defined in any one of the preceding claims, the process comprising:
providing apomorphine, and the at least one divalent metal cation as components of a mixture; and
dissolving or suspending the mixture in a solvent to form the composition.
18. Process according to claim 17, wherein the mixture further comprises an antioxidant.
19. Composition comprising apomorphine and at least one divalent metal cation in a molar ratio of 2 or less, wherein the composition is a pharmaceutical solution or suspension, when used for treating Parkinson's disease.
20. Composition as defined in any one of claims 2 to 16 when used for treating Parkinson's disease.
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