Alkermes Controlled Therapeutics Inc. Ii v Southern Research Institute
[2001] APO 41
•28 August 2001
OFFICIAL NOTICE
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Application : No 684324 in the name of ALKERMES CONTROLLED THERAPEUTICS INC. II
Title: Preparation of biodegradable microparticles containing a biologically active agent
Action: Opposition under Section 59 of the Patents Act 1990 by SOUTHERN RESEARCH INSTITUTE
Decision: Issued .
Abstract
Opposition fails on all grounds. Grounds of novelty, inventive step, manner of new manufacture and Section 40 not established.
The claimed invention differed from the closest prior art because it used a static mixer rather than a dynamic mixer, such as a mechanical stirrer in the mixing step. The use of the static mixer in the process of the claimed invention was found not to be obvious to try.
PATENTS ACT 1990
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Re:Patent Application No. 684324 by Alkermes Controlled Theraputics Inc. II and opposition under S.59 by Southern Research Institute
BACKGROUND
Patent application 684324 in the name of Alkermes Controlled Theraputics Inc. II (Alkermes) was filed on 18 November 1994 with a priority date of 19 November 1993. The application was advertised as accepted on 11 December 1997.
Southern Research Institute (SRI) filed a notice of opposition to the grant of this patent on 11 March 1998 followed by a statement of grounds and particulars on 11 June 1998. Each of the evidentiary stages were subject to a number of extensions while expert evidence was being obtained. Evidence in reply was deferred until after the allowance of S.104 amendments. The evidentiary stages were finally completed on 25 October 2000. The hearing on 684324 was held in Canberra on 15 & 16 February 2001. The opponent was represented by Mr Barry Hess as Counsel, instructed by Dr Stuart Boyer patent attorney for Griffith Hack, Melbourne. The applicant was represented by Ms Julia Baird of Counsel instructed by Peter Maxwell, patent attorney of Peter Maxwell and Associates, Sydney.
THE SPECIFICATION
The application relates to a method of encapsulating active agents to form controlled release microparticles using a static mixer.
Microparticles are solid particles containing an active agent such as a drug or protein dispersed or dissolved within a biodegradable polymer that serves as the matrix of the particle. The active agent may additionally or alternatively be encapsulated within a polymeric wall forming material to provide sustained or delayed release of drugs or other active agents.
The production of microparticles involves a step where the active agent and the polymer are dispersed as microdroplets, generally in an aqueous phase. Commonly the dispersion is an emulsion.
The organic solvent is then removed from the droplets and microparticles are formed.
In the prior art the dispersion step was said to be carried out using vibrators, stirrers or other dynamic mixing techniques. In the Alkermes application this step is done using a static mixer.
Static or motionless mixers are described as consisting of a conduit or tube in which is received a number of static mixing elements. Mixing occurs when the material is pumped through this conduit. Static mixers are said to provide uniform mixing in a relatively short length of conduit and in a relatively short period of time.
The method of the invention is said to have the following advantages:
Scaling from laboratory batch sizes to commercial batch sizes is reliable and accurate, while achieving a narrow and well defined size distribution of microparticles containing active agents.
The same equipment can be used to form microparticles of a well defined size distribution for varying batch sizes.
High quality microparticles having a high concentration of active agent can be obtained using a single step to remove the solvent, or through a phase separation technique.
Claim 1, defines:
A method of preparing microparticles comprising:
preparing a first phase, said first phase containing an active agent and a polymer
preparing a second phase;
preparing a quench liquid; and
pumping said first phase and said second phase though a static mixer into said quench liquid thereby forming microparticles containing said active agent.
Claim 22, defines:
A method for preparing microparticles substantially as hereinbefore described with reference to the examples and the drawings
Experts and their evidence
Appearing for the applicant:
Dr Raper is the Dean of the faculty of Engineering at the University of Sydney. She has taught aspects of particle and mixing technology for about 15 years. Since 1983 she has taught short courses to chemists and chemical engineers on particle characterization and the solution of problems associated with this in industry. Since 1984 she has published extensively on particle analysis.
Dr O'Neill is a chemical engineer who is a Senior Lecturer in Adelaide University, Australia. For the past 10 years he has been program manager in the tissue growth and repair cooperative research centre ("CRC"). Within this capacity he has spent 10 years supervising and conducting research into the process of homogenization and its use in biotechnology. He has published papers since early 1993 on the disruption of E.coli using a high pressure homogenizer. In the past he has used static mixers. He has also acted as a consultant on mixing.
Appearing for the opponent:
Mr DeLattre is a chemical engineer. He completed a BSc.BE(Hon) in 1992 and was employed by Sulzer Australia as a sales, process and design engineer in 1993. Sulzer is a manufacturer of static mixers.
Dr Godfrey is senior lecturer in chemical engineering at Bradford University in England.
Dr Godfrey worked for CSIRO in Victoria between 1962 and 1969 as an experimental officer, working on rheology and mixing of viscous liquids. At some time after 1970 he moved overseas.
From 1974-1979 he worked on several industry sponsored projects on static mixers.
Since 1985 he has written chapters on both static mixers and mixing in stirred tanks in several editions of the book; Mixing in the Process Industries. In the chapter on static mixers (referred to as Godfrey(a) in the exhibits listed below) he cites an article of his on static mixers published in 1965, while he was in Australia.
Dr Leng is a chemical engineer now working as a technical consultant for Leng Associates in Michigan, USA. Prior to 1996 he worked for 25 years for the Dow Chemical Company in Michigan, USA. During this time and prior to 1993, his work included scaling up of chemical reactors to improve yield and quality. He developed a commercialised emulsion based process for plastics and a continuous stirred tank reactor for a high-pressure process. Prior to the priority date he has published papers on scaling up mixing processes and drop dispersion in polymerization.
Declaratory Evidence
Evidence In Support
| Leng(1) | Declaration of Douglas E Leng made 28 August 1998 |
| Godfrey(1) | Declaration of James C Godfrey made 3 September 1998 |
| DeLattre(1) | Declaration of Pierre A DeLattre made 30 March 1999 |
| Santer | Declaration of Vivien B Santer (patent attorney) made 6 May 1999 |
Evidence In Answer
| Raper | Declaration of Dr Judy Raper made 17 December 1999 |
| O'Neill | Declaration of Dr Brian O'Neill made 23 December 1999 |
Evidence In Reply
| Leng(2) | Declaration of Douglas E Leng made 10 October 2000 |
| Godfrey(2) | Declaration of James C Godfrey made 24 October 2000 |
| DeLattre(2) | Declaration of Pierre A DeLattre made 29 September 2000 |
Exhibited Literature
Only those references cited in this decision are set out below:
| Edwards | MF Edwards, "A review of liquid mixing equipment" Chapter 7 of Mixing in the Process Industries (1985) |
| Godfrey(a) | JC Godfrey, "Static Mixers", Chapter 13 of Mixing in the Process Industries (1985) |
| Haas | Haas PA. "Turbulent dispersion of aqueous drops in organic liquids" AlChE Journal, (1987) |
| McDonough (i) | RJ McDonough "Shear Controlled Mixing Applications", Chapter 3 of Mixing for the Process Industries (1992) |
| McDonough(ii) | RJ McDonough, "Static Inline Mixing", Chapter 5 of Mixing for the Process Industries (1992) |
| Streiff | Streiff F, "In-line dispersion and mass transfer using static mixing equipment", Sulzer Technical Review (1977) |
| Sulzer(1) | Application of Sulzer Mixers for Gas/Liquid contacting in chemical and other industries (1983-1984) |
| Sulzer(2) | Sulzer Chemtech Design Manual; Section 10.4, p7 Table 10.1: "Range of drop sizes" (July 1978) |
| WO 90/13361 | Southern Research Institute, published 15 November 1990 |
| US 4574110 | Asona et al, published 4 March 1986 |
| US 5061410 | Sakamoto et al, published 29 October 1991 |
DECISION
Issues with the evidence
The opponent drew my attention to the many striking similarities that existed in the declarations of Dr O'Neill and Dr Raper. In each case the applicant's declarants only acknowledged having read the evidence of the opponent. There is a very substantial similarity between the two declarations and I consider that an explanation should have been provided for this. In these circumstances I think it is appropriate to give the declarations of Dr Raper and Dr O'Neill a weighting lower than that of two independent declarations where their wording is very similar but full weighting where they differ significantly.
Novelty
Counsel for the opponent argued that the claimed invention was anticipated by WO 90/13361.
WO 90/13361 was published 15 November 1990. This document teaches a method of producing microparticles such as microspheres or microcapsules where the active agent and wall forming agent/excipient is (typically) dissolved/suspended in an organic liquid and dispersed in an aqueous phase to form an emulsion.
In contrast with the admitted prior art, but in common with the Alkermes application, the microparticles are formed by quickly transferring the emulsion to an extraction medium (or quench phase) which removes the outer (usually organic) liquid phase of the emulsion resulting in the formation of microparticles.
This quick, single step removal of the organic phase overcame the prior art problem of poor encapsulation efficiency as it prevented the active agent being lost as the microparticles were being formed:
"By adding the emulsion to the processing medium all at once and thereby removing most of the polymer solvent very rapidly (within 3 minutes) agents highly soluble in the processing medium can be encapsulated as well as less soluble agents"
It is common ground between the parties that WO 90/13361 discloses a microcapsule production method with the following features of claim 1:
Preparing a first phase, this first phase comprising an active agent and a polymer
Preparing a second phase
Preparing a quench liquid
Forming microparticles containing an active agent in a quench liquid
In dispute is whether this citation discloses the remaining feature of:
pumping the first and second phases through a static mixer into the quench liquid.
In Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228 at 235, Aickin J described the test for novelty in the following terms:
"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."
In the case of a paper anticipation the hypothetical infringement arises not because of its publication but because someone hypothetically does, or makes, what the published document describes or suggests. Thus a prior publication, if it is to destroy novelty, must also give a direction or make a recommendation or suggestion that will result, if the skilled reader follows it, in the claimed invention.
This requirement is stated in the following well known passages of the decision of the Court of Appeal in The General Tire & Rubber Co v The Firestone Tyre and Rubber Co Ltd [1972] RPC 457, at 485:
"If the earlier publication ... discloses the same device as the device which the patentee by his claim, so construed, asserts that he has invented, the patentee's claim has been anticipated, but not otherwise. In such circumstances the patentee is not the true and first inventor of the device and his claimed invention is not new ...
... If the prior inventor's publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee's claim if carried out after the grant of the patentee's patent, the patentee's claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated."
and at 486:
"If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented ... . 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."
Before considering whether WO 90/13361 provides clear directions to perform, or merely a signpost towards the Alkermes invention, I need to identify the hypothetical skilled reader:
"The earlier publication and the patentee's claim must each be construed as they would be at the respective relevant dates by a reader skilled in the art to which they relate having regard to the state of knowledge in such art at the relevant date. The construction of these documents is a function of the court, being a matter of law, but, since documents of this nature are almost certain to contain technical material, the court must, by evidence, be put in the position of a person of the kind to whom the document is addressed, that is to say, a person skilled in the relevant art at the relevant date." (General Tire & Rubber Company v Firestone Tyre & Rubber Company Ltd [1972] RPC 457 at 485)
Counsel for the applicant argued, on the basis of evidence from Dr Raper and Dr O'Neill, that both the opposed patent and the alleged anticipation are directed at a chemist or scientist. This point is important because evidence was also provided that chemists and scientists, in contrast to engineers, had little knowledge of mixers.
Dr O'Neill stated that the early stage of process development would involve chemists or scientists rather than engineers:
"In my opinion both WO 90/13361 and the opposed specification relate to process development or work done by scientists and not to full scale commercial production which is the work of engineers."
Dr Raper stated:
"In my opinion both the Opposed Specification and WO90/13361 relate to process development. I base this on the kind of drawings in WO90/13361, the quantity of materials used in each of the examples and the quantity of materials produced in each of the examples. Therefore I would expect ordinary workers in Australia in the field to which these documents relate to have one or more science degrees, but no formal training, or formal qualifications or day to day experience in engineering or mixing technology"
I accept the applicant's evidence that the disclosed methods of making microparticles described in WO 90/13361 use small scale processes. However, I do not conclude from this that the patent applications are only of direct relevance to chemists and scientists.
A patent is a document used to protect a product or process that is thought to have commercial significance, and which has the potential for commercial production. Both Dr O'Neill and Dr Raper consider that engineers would be involved in scaling up a process developed by industrial chemists to a pilot plant process or to commercial production. For these reasons I conclude that the skilled addressee for both patent applications would be an engineer, as well as a process chemist.
I accept the evidence of Dr Raper and Dr O'Neill that industrial chemists might have only a modest knowledge of mixers and mixing, but I also accept the evidence of Dr Raper that:
"Chemical or mechanical engineers, within my experience as of 19 November 1993 had a high level and sophisticated knowledge and skill in engineering and mixing technology."
WO 90/13361 refers to mixers briefly, while providing a general description of the invention:
"The process medium is then mechanically agitated with devices such as homogenizers, propellers, or the like as the agent/wall material solvent mixture is added to the process medium. During this step of the process, no solvent is evaporated or removed from the microdroplets….The time required to form an emulsion is quite short. Generally, emulsions can be formed within 30 seconds to 5 minutes, depending on the surfactant used and method of agitation of the process medium. As soon as an emulsion forms, all the process medium containing the organic microdroplets is transferred, as quickly as possible, to an extraction medium."
The examples which illustrate embodiments of the invention, use impellers to stir the emulsions and in a prior step, homogenizers to disperse the active agent in a solvent.
The applicant argued in the general description of the process, the directions given had to be read in the context that the process medium was "mechanically agitated". The applicant argued (citing evidence from Dr Raper and Dr O'Neill) that as static mixers have a different mixing mechanism and do not agitate mechanically they are excluded from consideration. In contrast the opponent argued that an engineer would not read the import of these words so restrictively. Instead an engineer would focus on the fact that the passage refers to low shear mixers (propellers) and high shear mixers (homogenizers) and would read "like" mixers to also include medium shear mixers (such as static mixers).
There is additional evidence before me that supports the applicant's argument that the concept of mechanical agitation is not associated in the industry with static mixers:
(i) In McDonough(ii)
"Static mixers have been in use for over 25 years as an alternative to mechanically stirred agitators."
(ii) In Godfrey(a)
"The static mixer presents an alternative to the more traditional agitated vessel."
(iii) In Godfrey(2), Dr Godfrey states:
"With respect to Dr O'Neills' comments in paragraph 17, I again do not assert that static mixers agitate mechanically. Nevertheless, static mixers are and before the priority date were routinely considered as an alternative to mechanical agitation, as discussed above."
Overall, the evidence before me suggests that the words "mechanical agitation" would not normally be interpreted by an engineer (or a process chemist) as referring to a static mixer.
In Godfrey(1), Dr Godfrey has argued that a stronger direction is provided by the reference to "homogenizers, propellers, or the like", which would indicate to the person skilled in the art that a range of mixing devices of different energy intensities can be used. Dr Raper however argues that as well as energy intensity, factors such as efficiency, particle size and distribution, process time, quenching requirements, cost and other factors, must be considered. Subsequently, in Godfrey(2) Dr Godfrey stated that he was not proposing "that merely considering the energy requirements will lead to the selection of mixer type". Even allowing that energy requirements were an important factor, it appears that other factors would be considered.
Mr DeLattre refers to the fact that WO 90/13361 makes a reference to the option of producing microcapules using continuous processes. Mr DeLattre argues that static mixers were the only way that continuous mixing processes could be performed. However this does not seem to be supported by the publications of Edwards, or Streiff which indicates that impellers and homogenizers were also used for this purpose. In addition WO 90/13361 only briefly indicates that the process could be made into a continuous process, the overall teaching is to run the process as a batch process.
On balance, the evidence before me does not suggest that because the specification refers to both propellers and homogenizer that this would necessarily direct an engineer to use a static mixer in the cited process.
The opponent also argued, citing Dr Godfrey and Dr Leng, that the term "homogenizer" is a general term for any mixer that has a homogenizing action, including static mixers. For this reason static mixers were intentionally included by this reference. The applicant referred me to Raper, and paragraph 19 of Godfrey(1) which provided narrower definitions for homogenizer that does not include static mixers. An even smaller group of equipment (valve homogenizers and ultrasonic homogenizers) are described as homogenizers in the Edwards article. The Edwards article describes a number of types of propeller-like stirrers as well, and it is possible that the "like" equipment referred to in WO 90/13361 was intended to be include common variations of propellers and homogenizers. A further consideration is that if homogenizers were being used as inclusively as the opponent suggested, I see little reason for this passage to mention propellers as well. The examples in WO 90/13361 refer to particular commercial homogenizers, which accord with the equipment Edward describes as homogenizers. In the context of WO 90/13361, I consider a definition of homogenizers that does not include static mixers is the definition most likely to be applied by the skilled addressee.
Having considered the arguments of the opponent and the evidence before me, I find that WO 90/13361 does not provide a clear and unmistakable direction to use static mixers as part of their process to produce microparticles.
For these reasons I find that the claimed invention is novel.
Inventive step
Subsections 7(2) and 7(3) of the Patents Act 1990 when read in the light of the definition of "prior art base" provided in schedule 1 of the Act, relevantly indicate that a claimed invention will lack an inventive step when compared with the prior art base, if it is obvious in the light of:
(a) common general knowledge existing in the art before the priority date considered alone; or
(b) common general knowledge when considered with information in a single document, provided that document could be reasonably be expected to have been found, understood and regarded as relevant to work in the relevant art in the patent area before the priority date by the person skilled in the art.
The problems addressed by the opposed specification, from my reading of the specification as a whole, relate generally to overcoming problems in existing methods of producing microparticles.
The problems are:
Control of particle size and particle size distribution between batches or during scaling up. I understand, from my reading of the Alkermes application, that at least one aspect of the need for particle size control is the requirement that the particle size needs to be preferably 1-500 microns, more preferably 25-180 microns to allow administration to a patient with a standard gauge needle.
Production of high quality microparticles with a high concentration of active agent. Quality issues mentioned in the specification include avoidance of cracks in the shells of the particles, spherical shape, active agent release rates, low solvent residuals.
Developing a microparticle production method that can be scaled up easily while still producing microparticles with a narrow particle size distribution.
The specification also mentions that a problem of the prior art is the use of halogenated hydrocarbon solvents. The specification indicates that the applicant has spent some time optimizing a solvent system that does not use halogenated solvents, but describes the use of non-halogenated solvents as preferable rather than required. Claim 1 does not define processes or products free of halogenated hydrocarbon solvents. I therefore consider the devising of a method to produce microparticles using non-halogenated solvent is not a problem that claim 1 is required to solve.
From the evidence of Dr O'Neill and Dr Raper the person skilled in the art dealing with a problem of process development would be a process chemist, while scaling up processes would be dealt with an engineer. I think that as the problems I have identified involve aspects of both development and scaling up, the person skilled in the art would be a team or group that includes both chemists and engineers.
Common General Knowledge
The common general knowledge relevant to the question of obviousness was described by Aickin J. in Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Limited (1980) 144 CLR 253 at page 292 as:
"The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge."
None of the experts who have provided evidence for this hearing claim to have any experience concerning the production of microparticles or analogous pharmaceutical products. However I consider the evidence of declarants who are chemical engineers or process chemists to be of assistance in establishing some elementary common general knowledge that all teams containing chemical engineers and process chemists would possess.
Dr Raper, Dr O'Neill and Mr DeLattre are all engineers based in Australia. The applicant pointed out that it is unclear when in 1993 Mr DeLattre commenced work with Sulzer, Australia and gained his industrial experience on static mixers and mixing problems. I am prepared to accept that Mr DeLattre is qualified to provide evidence on the state of the art at the priority date. In addition some of his evidence is in the form of documents that appear to be of a much earlier date than the priority date in question.
Dr Leng and Dr Godfrey are based overseas, and the applicant argued that they could not establish common general knowledge in Australia. Dr Godfrey's direct experience in the Australian workforce ended some twenty years before the priority date of the Alkermes application.
Dr Godfrey 's work on mixing in Australia for CSIRO included work for a paper on static mixers and Dr Godfrey claims to have followed the research activities of colleagues in Australia and other countries. Dr Godfrey asserts that the base of industrial knowledge in the field of mixing and fluid dynamics is generally consistent among industrial nations. This is not contested by either Dr Raper or by Dr O'Neill, and I will accept this as being fact. However the base level of knowledge was only claimed to be "generally consistent". Where the evidence of Dr Leng and Dr Godfrey is consistent with evidence from suitably qualified expert(s) based in Australia, it can be used to support a finding of common general knowledge in Australia. When there is conflict in the evidence provided by the experts, I will consider the evidence of the overseas declarants but give their evidence a lower weighting than the evidence of Dr Raper, Dr O'Neill or Mr DeLattre. In addition to a role in establishing common general knowledge, Dr Leng and Dr Godfrey's evidence is of value in assisting my understanding of technical issues, as both experts are clearly very knowledgeable on many aspects of mixing and mixers.
From the evidence of the experts, I think it is reasonable to conclude the following was common general knowledge among chemical/process engineers in Australia at the priority date.
Knowledge of a range of mixers including; static mixers, homogenizers, and agitated tanks systems and of the existence of theoretical calculations/models covering the predicted behaviour of different mixers.
Mechanical agitators were in common use to form emulsions in all major industry segments.
Static mixers were considered inexpensive and to offer long life as industrial mixers
Static mixers are generally used in continuous mixing systems.
Each type of mixer has its own characteristics, advantages and disadvantages relative to other mixers.
Surfactants and shear rates can be used to control emulsion drop size during mixing.
The opponent asserted that some of the exhibited technical articles were common general knowledge in the art. None of the exhibited articles were shown to have been widely read and relied upon by the person skilled in the art, by Dr O'Neill, Dr Raper or Mr DeLattre. The evidence before me is insufficient to allow me to conclude that any of the technical articles are common general knowledge in Australia at the relevant date.
The opponent also relies on WO 90/13361 being found to be common general knowledge by virtue of being mentioned in the opposed specification. The basis in law given for this argument was the following passage in the Federal Court decision of Bristol-Myers Squibb Co v F H Faulding & Co Ltd [2000] FCA 316 (22 March 2000)
"If a patent application, lodged in Australia, refers to information derived from a number of prior publications referred to in the specification or, generally, to matters which are known, in our view the Court - or the Commissioner - would ordinarily proceed upon the basis that the knowledge thus described is, in the language of s 7(2) of the 1990 Act, part of "the common general knowledge as it existed in the patent area". In other words, what is disclosed in such terms may be taken as an admission to that effect. In substance, we think, that is what happened, both in Microcell and in Philips. "
Whether cited patent art is common general knowledge was recently considered in Centaur Nickel Pty Ltd v QNI Ltd [2000] APO 65 (31 October 2000). The delegate found that in the absence of any other evidence, the cited patent documents did not form part of the common general knowledge in the art in Australia.
It seems logical that references to prior documents detailed in a patent specification must have to meet the same requirements as other prior documents put forward as disclosing common general knowledge. In Bristol-Myers (supra) some general requirements for a document (not referred in a patent) to be common general knowledge under inventive step can be identified from the review of the findings of the primary judge on whether a particular editorial was common general knowledge:
"His Honour's finding about that editorial must be read with an earlier finding, at 471, to which senior counsel for the respondent referred us also:
"The field of cancer medicine is a global one. A number of eminent Australian specialists gave evidence in this case. It is apparent from their evidence that they travel regularly to attend overseas conferences and have access to overseas journals."
It should be noted also that his Honour referred specifically to certain passages in the evidence, including oral evidence, in support of the proposition that the editorial would, at the relevant time, have been known to the hypothetical skilled addressee.
Senior counsel for the appellant submitted that the findings to which we have referred do not "go so far as to show that it is being held by his Honour to be part of the common general knowledge in the sense that it's known to persons working in the art and is treated by them as part of their basic common general knowledge". In our view, however, it is difficult to read his Honour's findings in any other way. If Australians working in the field customarily read major overseas literature (and it would be very surprising if they did not) and if, before the priority date, they read the editorial (as his Honour held that they would have) and believed it to be reliable (as, again, his Honour held that they would have) it is not easy to see what element is lacking without which it would not be right to describe the information in the editorial as being, from early 1992, part of the relevant common general knowledge. "
I consider that Bristol-Myers (supra) indicates that for a document to be found to be common general knowledge under inventive step the requirements include at least the following:
The document belongs to a group or type of documents that would be customarily read by the person skilled in the art in Australia.
The document would have been read by the person skilled in the art before the priority date.
The information in the document would be believed to be reliable.
This accords with the views on common general knowledge expressed by Laddie J in RayChem Corp.'s Patent (1988) RPC 31 at p40:
"The common general knowledge is the technical background of the notional man in the art against which the prior art must be considered. This is not limited to material he has memorised and has at the front of his mind. In (sic) includes all the material in the field he is working in which he knows exists, which he would refer to as a matter of course if he cannot remember it and which he understands is generally regarded as sufficiently reliable to use as a foundation for further work or to help understand the pleaded art."
As there is a requirement in many jurisdictions (although not Australia) for a patent application to acknowledge the existing prior art, a reference to a patent in an application that originates from overseas may exist for this reason alone. In the present case the specification does not make a clear acknowledgement that the teaching of WO 90/13361 is sufficiently widely known and relied upon. I cannot determine with certainty the reason this document is mentioned. There are some examples in the Alkermes application that use a dynamic mixer, these examples may be comparative examples using the method of WO 90/13361, but they do not acknowledge such origins. In the absence of any other evidence on this matter, I find that WO 90/13361 is not common general knowledge.
Although I have not found WO 90/13361 to be common general knowledge it may still be relevant for inventive step as a document that the person skilled in the art would find, understand and consider relevant.
Would WO 90/13361 be found by the person skilled in the art and considered relevant?
To reiterate, in general terms the problems faced by the person skilled in the art were:
Control of particle size and particle size distribution between batches or during scaling up of processes. The specification states that particle size should preferably be 1-500 microns, more preferably 25-180 microns to allow administration to a patient with a standard gauge needle.
Production of high quality microparticles having a high concentration of active agent. Quality issues mentioned in the specification include avoidance of cracks, spherical shape, controlled release of active agents, low solvent residuals.
Developing a microparticle production method that can be scaled up easily while maintaining particle size control.
Faced with these problems, I consider it is likely that the person skilled in the art would search the patent literature, which forms much of the admitted prior art information on microparticle production. WO 90/13361 is likely to be found and understood as it clearly teaches a method of producing microparticles containing biologically active agents. With regard to the problem of producing microparticles of suitable size and size distribution, I would expect that the person skilled in the art would notice that WO 90/13361 taught microparticles that have a size distribution of 0-250 microns with one product in the range 45-150 microns. The particles are thus a suitable size range for injection.
I think that the person skilled in the art would also note the teaching on reducing loss of active agent by rapidly transferring the microdroplets into a quench phase. This teaching is clearly relevant to the problem of achieving microparticles with a high loading of active agent. The teaching on using a quench step may also be considered relevant to someone seeking to develop a production method for microcapsules less subject to the problems of loss or deactivation. This is because the use of a quench step in WO 90/13361 means a shorter period of exposure to solvents than some prior art methods referred to in the opposed application.
I think therefore that the person skilled in the art would find, understand and consider as relevant to their problems the prior art document WO 90/13361. Of course this still leaves the question of whether the person skilled in the art would consider it obvious to vary the method disclosed in the citation so as to use a static mixer rather than a mixer that provides mechanical agitation. The opponent submitted that a static mixer was obvious to try.
Obvious to try?
In Beecham Group Limited's (Amoxycillin) Application (1980) RPC 261 at pp.290-291 Buckley LJ, with whom Browne LJ agreed, spoke of the notion of "obvious to try"
"It is clearly established that, for a particular step or process to be obvious for the purpose of either section, it is not necessary to establish that its success is clearly predictable (Johns-Manville Corporation's Patent (1967) R.P.C. 479 at 494 line 10). It will suffice if it is shown that it would appear to anyone skilled in the art but lacking in inventive capacity that to try the step or process would be worthwhile (Technograph Printed Circuits Ltd. v. Mills & Rockley (Electronics) Ltd. (1972) RPC 346, per Lord Reid at 355 line 37 and 356 line 3; Johns Manville, supra, per Diplock L.J. at 493 and 494; Tetra Molectric Ltd. v. Japan Imports Ltd. (1976) RPC 547 at 581 line 41, 583 line 37, 584, line 2). Worthwhile to what end? It must, in my opinion, be shown to be worth trying in order to solve some recognised problem or meet some recognised need. The uninventive expert (see (1972) R.P.C. page 355, line 5) should not be supposed to be attempting to discover something new, that is, to be striving for inventiveness. Having been shown what was disclosed by the prior art, he must be supposed to be attempting to solve some problem or fulfill some need which has not been resolved or satisfied by the prior art but which appears to his uninventive mind to be possibly capable of solution or satisfaction by taking the step or doing the thing under consideration. This, it seems to me, must involve the uninventive but skilled man having a particular problem or need in mind. If on carrying out his test he finds that the new step has the sort of consequence he had hoped but in an unexpectedly high degree, this would or might not mean that the new step was inventive or other than obvious; it might merely mean that a new and obvious step has solved the problem or met the need unexpectedly well. The question would, I think, be one of degree. If, on the other hand, the new step produces some unexpected result productive of an improvement or benefit of an unexpected kind it may well be held to be inventive, the association of the new step with its result not having been obvious."
In the "obvious to try" test provided in Beecham (supra), the person skilled in the art having become aware of WO 90/13361, would first assess whether this document provided a complete solution to their problems. I must therefore assess whether the solution given in WO 90/13361 leaves any residual problems.
WO 90/13361 appears to solve, at least to some extent, the problem of control of particle size for small scale production as it demonstrates production of microparticles within the required range of 1-500 microns, with one microparticle type in the preferred range of 25-150 microns.
WO 90/13361 does not disclose or discuss scaling up production of microparticle in this size range or producing such microparticles on a large scale and so these parts of the problem are not satisfied by WO 90/13361.
Then there is the problem of producing of high quality microparticles having a high concentration of active agent. It appears to me that WO 90/13361 discloses some information of relevance to these issues. On the issue of quality WO 90/13361 discloses that the microparticles produced in accordance with the method are free flowing powders of spherical particles. Porosity governs the rate of release of active agent and can be controlled by such factors as the selection of suitable solvents, the concentration of wall material, as well as by choosing suitable loadings of the active agents in the microparticles. Microparticles with high concentrations of active agent (up to 80% of total weight) are envisaged.
All this information suggests that microparticles of good quality and high loadings of active agent can be produced using the method of WO 90/13361, at least when the scale of production is small.
On a larger scale it is possible that the issue of long exposure to solvents causing inactivation of active agent may still exist despite the use of a quench step. The Alkermes application mentions that the length of time to produce an emulsion in a large agitated tank can cause inactivation of active agent. However the Alkermes application does not indicate whether this problem is solved by their claimed invention and so I will not have further regard to it.
WO 90/13361 provides no teaching relevant to the problem of achieving easier optimization of mixer settings and processing parameters at each change of scale.
The problems that do not appear to be solved by WO 90/13361 are:
Controlling microparticle size and particle size distributions while scaling up production of microparticle compositions of injectable size or when producing these injectable compositions on a large scale.
More efficient optimization of the process when scaling up.
In the light of these problems I need to consider whether the person skilled in the art would consider changing the mixer, and whether they would consider a static mixer worth trying.
The Alkermes specification provides some background relevant to these problems which suggests that one action that the person skilled in the art would consider worthwhile would be to change the mixer.
It appears that the problem of broad particle size distribution arises from a lack of uniform mixing:
"Tests were conducted in an attempt to scale-up a laboratory emulsion formation process from small stirred reactors to production equipment for microparticles containing estradiol benzoate. The shear created by the mixer blades determined the particle size of the emulsion; the higher the shear, the smaller the particles. Due to the low viscosity of the oil (organic) phase in the estradiol benzoate process, low shear is required to produce the large emulsion particles which were desired. In large reactors it is difficult to maintain low shear and still provide uniform mixing. The speed at which the agitator must turn to provide a uniform tank composition produces a small particle size with a broad distribution of sizes. Larger mixing blade diameters and multiple mixing blades along the shaft helped to provide better mixing at low shear but still produced a very broad distribution of sizes. Particle size control becomes less reliable as batch size was increased."
I interpret this passage in the Alkermes application to mean that it is disclosing that the problem of providing uniform mixing to achieve a narrow drop size distribution while maintaining a low shear is a known one. Similar difficulties in achieving narrow drop size distributions while scaling up tanks using mechanical agitators are disclosed in McDonough(i):
"The range of fluid shear rates in a large tank is considerably greater than in a small tank. Therefore the emulsion characteristics can change for each scale. This variation in fluid shear rate with scale is critical in designing emulsion polymerisation mixing systems. In this application emulsion droplet size must be achieved within a narrow distribution band to achieve acceptable process results. The mixing fluid shear rate, consistent with achieving this droplet size, must be the same at all scales to optimize process results"
The Alkermes application mentions that their initial attempt at a solution was to change the mixing blade. A person skilled in the art, wanting to improve uniformity of mixing in a large emulsion tank would be likely to consider making changes to the mixer. Mixing is also involved in the problem of optimizing stir speeds and scaling up. While changing the mixer may not be the only option the person skilled in the art would consider, I think it would at least be one avenue that they could be expected to pursue when faced with these problems.
The evidence of Dr Godfrey and Dr Raper, persuades me that the most popular type of a mixer for preparing emulsions is an impeller driven mixer. There seems to a wide variety of types; McDonough(i) mentions impellers for emulsions as including anchor agitators, flat bladed or variable pitch turbines, hydrofoils, flat bladed or curved paddles and hybrid impellers. There are thus many variations in impellers that could be tried. Apart from impellers, other mixers that could be used for this purpose include homogenizers and jet mixers. Static mixers are mentioned in a few references in the exhibited technical literature and Sulzer exhibits for use in making emulsions. Even though a static mixer is a less popular choice for the job, a lack of inventive step may still be found if it can be shown that the static mixer would be one of the candidate mixers that would be routinely tried in order to overcome the problem faced by the person skilled in the art.
In the Alkermes application the initial attempt at large scale production used a batch method for production. Batch methods were also used in WO 90/13361, although the possibility of continuous production methods was mentioned.
Mr DeLattre provided evidence that static mixers may be used in a semi-batch procedure where the mixed material is recycled back into the tank until the desired level of homogenization is reached. Mr DeLattre does not discuss whether this method was in common use in Australia before the priority date. McDonough(i) describes equipment for producing emulsions and in a table of suitable equipment is listed "recirculation with in-line static mixers" as one typical type of high shear mixer for the production of microemulsions. Microemulsions are a type of dispersion which has a droplet size of 0.5-1.5 microns. McDonough(i) has not been shown to be common general knowledge nor does this reference indicate whether larger droplet sizes could be generated using this technique and what the particle size distribution would be. I do not consider this evidence is sufficient to establish that the use of a static mixer in a semi-batch procedure to make emulsions is well known in Australia, or would be considered a worthwhile option by the person skilled in the art in Australia when faced with the Alkermes problem.
The evidence before me indicates that static mixers are generally used for large scale continuous applications. Mr DeLattre asserts that it would only involve routine trial and error to adapt a batch process using a mechanical stirrer to a continuous process using a static mixer. I accept that this may be so. The issue again, is would a continuous mixing system employing a static mixer be considered? Dr Godfrey who appears to have had the most experience out of all the experts in using static mixers to solve mixing problems appears to suggest that the person skilled in the art would be uncertain whether static mixers can produce emulsions in the size range required:
"I would have to consider whether the static mixer could prepare an emulsion having a small enough drop size. Drop size is affected principally by (1) energy intensity, and (2) surface tension in the emulsion droplets. Because WO 90/13361 states that surface active agents can be used in the emulsion (p. 9, lines 33-35) a static mixer could most likely form sufficiently small emulsion droplets."
Dr Godfrey supports a decision to select static mixers with several literature references including Haas, which Dr Godfrey considers is a closely analogous system. Haas describes a comparative study of three dispersion devices using a liquid gel material. One of the devices was a static mixer, another was a simple tube and the other was a Couette flow disperser. The gel droplets produced by the static mixer in this study were in the range of 40-640 microns. The qualitative conclusion was that static mixers provide the best uniformity of droplet size out of the three devices. This study does suggest that static mixers may be a suitable for generating fine dispersions, but I have insufficient evidence to consider that engineers in Australia would be aware of this document and consider it’s finding reliable to apply on a commercial scale.
Dr Raper suggests that if they were considered, static mixers would be viewed as an attractive option for creating emulsions:
"If the inventive chemists of WO 90/13361 had contemplated static mixers, I believe it would have been thought of as a very attractive method for creating the emulsion and would have at least been mentioned. It would be immediately attractive because static mixers are inexpensive, quick, easy to replace and offer long life."
However Dr Raper also states; "I note, however that in my direct experience, static mixers were unknown to chemists in the pharmaceutical industry before 19 November 1993.
On what engineers would know about static mixers, Dr Raper makes a number of relevant comments. Dr Raper admits to having heard of static mixers being used to form emulsions, although only in isolated very high volume production applications. Dr Raper does not elaborate further on the nature of these applications. Dr Raper states that she has not heard of static mixers being used in a pharmaceutical context and that the difficulty in cleaning static mixers would mitigate against them being used in a drug manufacturing environment. Dr Raper also disagrees with the assessment of Dr Leng that:
"..emulsion and dispersion phenomena in static mixers are well documented, and the calculations associated with scale-up and design are …widely known”
Mr DeLattre, as well as Dr Godfrey and Dr Leng refer to several prior patents that briefly suggest static mixers as a mixer option in methods of making particular emulsions/microparticles as evidence of their known suitability for such purposes. No particular advantage associated with the use of a static mixer is mentioned in these patents. The mixer chosen for the examples to illustrate the inventive method of these patents is generally not a static mixer, this may be because the examples usually involve preparations on a small scale. There is no evidence to indicate that the person skilled in the art is familiar with these patents. As many patents disclose methods that never go into commercial use, such passing references to static mixers in a few foreign patents, does not constitute strong evidence that the use of static mixers to prepare emulsions or microparticles is generally well known in Australia. For all of these reasons I do not regard the evidence of these other prior art patents as particularly significant in determining whether the person skilled in the art would consider using a static mixer.
Mr DeLattre provided some detailed information on industrial applications Sulzer static mixers have been used for. Mr Delattre's evidence includes Sulzer(1) which appears to be an excerpt of a Sulzer in-house manual which briefly describes uses made of static mixers sold to customers around the world. This evidence is not appropriately witnessed or otherwise validated as being a copy of company material. However I will take this evidence on its face value as a copy of a Sulzer company document. There is in the order of 100 sales recorded, and these indicate that prior to the priority date static mixers have been used for many applications including; dispersing gases in liquids, mixing plastics, and homogenizing, foaming and blending food products. The records include a sale of equipment in Australia for the purpose of dispersing vegetable oil in raw milk.
There is no indication of the drop size or the range of drop sizes obtained in the Sulzer records of applications involving liquid/liquid dispersions. Without more evidence on the exemplified uses, I consider the records show little more than that the person skilled in the art may be aware that static mixers are used in the preparation of some types of dispersions. No specific examples have been shown to be commercial applications of a static mixer to prepare emulsions.
From the evidence before me static mixers do not appear well known to the person skilled in the art in Australia for the preparation of emulsions or fine dispersions.
Mr DeLattre's evidence lists one sale where a static mixer was used to make cough syrup in Brazil, a product that can be considered a pharmaceutical. Various exhibited brochures of Sulzer static mixers (of uncertain publication date) describe a variety of uses of static mixers, but if they contain any references to pharmaceuticals, the references are not prominent. The closest product mentioned was food. Mr DeLattre refers to McDonough(ii) where there it is mentioned that static mixers can be sanitary in design for applications in the food and pharmaceutical industries. As well as not being common general knowledge, I am not convinced that this brief reference covers the issue of ease of cleaning raised by Dr Raper. It is also possible that the person skilled in the art might be more concerned about such issues in the injectable products of Alkermes in comparison to oral medicines and foods.
There is no expert evidence from a representative of the pharmaceutical industry to explain why static mixers appear to have had little use in the pharmaceutical industry or the criteria for selecting a mixer to produce microparticles. In the absence of more persuasive evidence from the opponent, I will accept the evidence of Dr Raper, who has had some dealings with workers from the pharmaceutical industry, that the person skilled in the art would have had some reluctance to select a static mixer to prepare a pharmaceutical.
Another reason that a static mixer could be considered worth trying, is if the person skilled in the art believed static mixers are known to produce a narrow droplet size and maintain it when the process is scaled up.
Dr Leng briefly states in Leng(1) that:
"Static mixers can control the size of the emulsion droplets and, when implemented properly, give an emulsion having a narrow size distribution of emulsion droplets"
Dr Leng does not state whether his experience in mixing includes use of static mixers to create emulsions and so I am not certain where he derives this conclusion. In his declaration he subsequently refers to two US Patents; US 5061410 and US 4574110 that deal with emulsion polymerisation processes. These patents mention a number of mixers including a static mixer as suitable for producing emulsions. However the embodiments in these patents do not use a static mixer. While narrow particle size range is said to be achieved, this benefit is said to be obtained by altering reaction conditions such as temperature or the amount of components rather than by appropriate selection or adjustment of a mixer. In any case these patents have not been shown to be part of the common general knowledge.
Dr Godfrey considers that many people would select a static mixer for the job because of their known advantages. However he does not then elaborate on the nature of these "known" advantages. Dr Godfrey refers to the benefit of narrow drop size distribution in Godfrey(1), without suggesting that he considers that static mixers achieve it:
"One potential advantage of using a static mixer is the narrow drop size distribution that static mixers are believed to achieve. Most equipment suppliers claim that the drop size distribution is narrow compared to that produced by an agitated tank."
Dr Godfrey's own review on static mixers, Godfrey(a) does not list narrow drop size among the advantages possessed by static mixers. The review also refers to the untested nature of many claims made of the benefits of static mixers:
"The static mixer differs from most conventional agitated tank designs in being a continuous rather than a batch mixer and this generally means that the size of a static mixer and the space it requires is less than the corresponding agitated tank. Other advantages are also claimed for a static mixer - flexibility in that one installation could be designed to process a range of different fluids; predictable and repeatable mixing performance, low power requirements; a wide choice of materials of construction. Obviously a number of these points are not yet supported by more independent investigation and in some cases the apparent superiority of static mixers is more associated with a fresh approach to mixing problems rather than the inherent characteristics of the mixer itself."
Dr Godfrey's evidence tends to suggest that the person skilled in the art would have reservations about accepting the claims of a supplier of static mixers on the advantages of their products.
In this review Dr Godfrey also expressed uncertainty about the validity of theoretical predictions of drop size, that can be used to design and scale up mixer systems:
"It has always been difficult to have confidence in the prediction of drop size from correlations even though the situation is less complicated than in an agitated tank, this is also likely to be the case for static mixers."
The issue of ease of scale up is not much considered by the local experts, although several of the exhibited articles briefly indicate that scale up of static mixer processes present few problems. While I can conclude that scale up is feasible, I cannot conclude that it is well known that a static mixer is easier to scale up than a mechanical stirrer.
More recently McDonough(i) refers briefly to the difficulties in maintaining properties of emulsions, including drop size distribution, while scaling up a mechanical agitator system and in McDonough(ii) compares static mixers with mechanical agitators. Static mixers are not suggested as a solution for problems in scaling up and narrow drop size is not mentioned as a known advantage of static mixers.
The reviews of Godfrey(a) and McDonough(i) and (ii) do not support the view that that the advantages claimed for static mixers in the Alkermes application are advantages that the person skilled in the art was likely to accept that static mixers possessed at the priority date.
Mr DeLattre, Dr Raper and Dr O’Neil do not state that a narrow drop size distribution is one advantage expected from using a static mixer or indicate that this advantage could be expected to be retained during scaling up a mixing process. Dr Raper describes the quality of mixing obtained by a static mixer as unpredictable, and supports this with statements in Godfrey(a).
"I agree with Dr Godfrey's sentiment that it was not possible to estimate mixture quality at that time nor to state definitely or automatically for which application a static mixer is genuinely suited. I believe that this would have been equally true at the 19 November 1993 priority date."
On balance, I do not consider that there is sufficient evidence to show that the person skilled in the art in Australia would have expected static mixers to produce a narrower particle size distribution than an agitated tank, or to maintain a narrower particle size distribution when scaled up at the priority date of the Alkermes application.
Another issue discussed that is relevant to the choice of a mixer to prepare emulsions is mixer efficiency. Some of the exhibited evidence such as Sulzer(2) and McDonough(ii) suggests that static mixers are not particularly efficient at preparing dispersions or emulsions in comparison to a mechanical agitator. Dr Raper considers static mixers are less efficient, Dr Leng and Mr DeLattre disagree. Dr Godfrey considers that the relative efficiency depends on the specific application but does not suggest that static mixers were generally known to be efficient at preparing emulsions.
I found this evidence somewhat confusing, as the context of the term "efficiency" was often not given. In some cases the term appeared to be used in the context of the mixing obtained for a particular energy input and at other times in terms of the mechanism by which homogenization was obtained. It was not made clear to me that in each case what was being discussed was equivalent. For this reason and because the claims to efficiency were disputed, I do not make any conclusion as to whether the efficiency of a static mixer would be a positive or negative factor in determining whether a static mixer was worth trying.
It has not been shown that the static mixer had particular mixing properties that would have encouraged the person skilled in the art to try a static mixer in order to overcome the problems before them. Static mixers appear to have been seldom used on a commercial scale for production of emulsions and very rarely on a commercial scale to produce pharmaceutical products in any form. The perception of a difficulty in cleaning static mixers is a disincentive to try a static mixer in this case. Overall the evidence before me does not demonstrate that in this instance, the use of a static mixer would be a routine option that the person skilled in the art would think worthwhile to try. A static mixer was therefore not obvious to try.
For these reasons I conclude that the claimed invention has an inventive step.
Manner of New Manufacture
The opponent proposed that the use of a static mixer rather than a mechanical agitator is the use of a known apparatus in a known process. The known process was described either as the method of WO90/13361, or the use of a mixer with a quench step. The reference in the Alkermes patent to WO 90/13361 or the use of quench step in other methods in the prior art admitted them to be part of the common general knowledge against which the "quality of inventiveness" is to be considered according to Bristol-Myers (supra).
I have found that the disclosure in WO 90/13361 is not common general knowledge. The use of the quench step in making microparticles appears to have provided much of the subject matter for WO 90/13361. No evidence has been provided that the use of a quench step is common general knowledge and so the opponent's argument fails on this ground.
However even if I am mistaken on the arguments of common general knowledge, I do not think that the opponent's arguments can prevail. Taking the process of making microcapsules using a mixer and a quench step as known, the opponent then relied on the following case-law:
British Celanese Ltd v. Courtaulds Ltd 52 RPC 171 at pages 193-194:
"It is accepted as sound law that a mere placing side by side of old integers so that each performs its own proper function independently of any of the others is not a patentable combination, but that where the old integers when placed together have some working inter-relation producing a new and improved result then there is patentable subject matter in the idea of the working inter-relation brought about by the collocation of the integers."
Or alternatively;
Gadd v. The Mayor of Manchester Corporation (1892) 9 RPC 516:
"A patent for the mere use of a known contrivance, without any additional ingenuity in overcoming fresh difficulties, is bad and cannot be supported. If the new use involves no difficulties but is in manner and purpose analogous to the old use, although not quite the same there is no invention."
As there is no evidence of fresh difficulties in using a static mixer, the opponent asserts there is therefore no invention.
The case of Gadd v. The Mayor of Manchester Corporation(supra) was raised and the use of old contrivances for a known or analogous purpose was considered in the High Court decision of Willman v Petersen 2 CLR 1. Griffith C J applied the following test:
"A combination of two or more known mechanical appliances the result of which is to effect a new purpose, or to effect an old purpose with greater efficiency and economy, may be the subject matter of a patent, if it involves some substantial exercise of the inventive faculty.
The use of a static mixer in the Alkermes application in combination with a quench step, is said to produce improvements such as controlling particle size distributions and efficiency in scaling up. It thus would appear to effect an old purpose with greater efficiency and so is suitable subject matter for a patent.
More recently the inventiveness of combinations was considered by Judge Aickin in Meyers Taylor v Vicarr Industries Ltd (1977) 137 CLR 228 at 248:
"It was further argued that in order that the claims could be regarded as claims for a true combination it had to be expressly included in the claim that it was in respect of a combination of the various features mentioned. In my opinion that submission is misconceived. It is enough if it appears from the specification and the claim that there are a number of features, whether old or new, which in fact operate in combination to produce a new or improved result."
The opponent has argued that the alleged benefits are only those which the art would expect from using a static mixer. I have already considered this argument under inventive step where I found that the use of a static mixer was not a routine choice and that there was insufficient evidence to accept that the persons skilled in the art in Australia would expect the use of the static mixer to achieve the disclosed benefits of a narrow particle size distribution or even of ease of scale up.
The opponent also characterises the use of a static mixer in the method of the claims as a mere collocation, but this argument also fails on the ground that the use of the static mixer in the method of the invention appears to produce benefits not expected of it.
For all these reasons I find that the claimed invention is a manner of new manufacture.
SECTION 40
No evidence was filed for this ground.
The opponent did not provide any detailed submissions at the hearing but referred me to issues raised in the statement of grounds and particulars. The issues raised there are fair basis, clarity and sufficiency. In the absence of expert evidence, the claimed invention would need to be manifestly insufficient or unclear before I could find in the opponent's favour on these grounds.
I do not consider the specification is defective to that degree.
One issue the opponent raised, that I will briefly consider under sufficiency is whether the description of the Alkermes application supports the advantages claimed for using a static mixer in the method of the invention.
Counsel for the opponent has argued that the Alkermes specification does not demonstrate that the invention achieves any improvement in particle size control or scalability that is attributable to the use of a static mixer. The opponent contends that the examples show little more than the operation of a static mixer to produce microparticles. The opponent also points to comparative examples in the Alkermes application which the opponent describes as refuting the claimed advantages on particle size distribution by demonstrating that the particle size distribution achieved by using the static mixer is no different from that achieved by a mechanical agitator.
The examples used to illustrate the Alkermes invention do not show production of microparticles on different scales or on a commercial scale. The description indicates that the invention can be scaled up using known relationships between shear rate, pressure drop, element number and drop size, and I take this to refer to the types of relationships described in McDonough(ii). As indicated earlier in this decision Dr Raper appeared to consider that such calculations were not widely known, but I would need more evidence than that to find that the patent was insufficient or not fairly based on that basis. There is no indication in the specification or evidence from the experts, to show that if the method was scaled up the claimed advantages of particle size control would not be achieved. In this regard the examples do not refute the promise of the invention.
As highlighted by the opponent, the examples do allow a limited comparison of particle size control on a laboratory scale achieved by a static mixer versus a mechanical agitator. Examples 1 and 16 produce microparticles containing the same active agent, using an emulsification method with the same non-halogenated solvent system and a quench step. In example 16 the different batches were subject to varied operating conditions, producing variations in yield and quality. It is true that both examples produce microparticles in the same size range, but when information from both examples is compared the results do not appear equivalent. I have collated some of the information in the following table.
| Norethindrone microparticle batch # | % Yield* 25-90 microns | % Loading of agent | Quality Indications |
| Static Mixer (Example 1) | |||
| 1 | 65 | 30 | nd |
| 2 | 63 | 33 | nd |
| 3 | 68.5 | 50 | nd |
| Mechanical stirrer (Example 16)** | |||
| 1 | 46 | 46.1 | Not round, very porous |
| 2 | 35 | 41.6 | Inconsistent, less porous |
| 3 | 32 | 45.6 | Inconsistent, rough |
| 4 | 29 | 44.5 | Round, more consistent |
| 5 | 7.6 | 42.2 | Round, less consistent |
| 6 | 49 | 43.1 | High levels of residual solvent |
| 7 | 39.2 | 42.1 | Round, smooth |
| 8 | 2.2 | 43.1 | Round, uneven |
| 9 | 24.8 | 42.7 | Round, uneven |
These examples indicate that mechanical stirrers may produce lower yields than static mixers in the desired range of particle sizes, at least when one solvent system is used. This suggests that the particle size range achieved by a static mixer may be narrower than that achieved by a mechanical stirrer. In addition when a mechanical stirrer was used quality appears to be low in many batches. Contrary to what the opponent has asserted, these results do not refute the applicant's claim that static mixers achieve a narrower particle size distribution size than a mechanical agitator. I conclude that the application is sufficient.
None of the fair basis issues raised in the statement of grounds and particulars would in my opinion lead to the claims being invalid if granted. I consider therefore that the claimed invention is fairly based.
Having considered these issues, I find that the Alkermes application complies with Section 40.
CONCLUSION
The opposition fails on all grounds.
Unless the Commissioner is served with a notice of appeal within 28 days of the date of this decision, I direct the application to proceed to sealing.
COSTS
The power of the Commissioner to award costs is discretionary, so I must take into account all relevant considerations. I have found that the opposition fails on all grounds. No other relevant considerations were brought to my attention. In this circumstances it is appropriate for costs to follow the event.
I award costs in accordance with Schedule 8 against Southern Research Institute.
Ross Osborne
Delegate of the Commissioner of Patents
Patent attorneys for the applicant : Peter Maxwell and Associates, Sydney
Patent attorneys for the opponent : Griffith Hack, Melbourne
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