Sonus Pharmaceuticals, Inc v Alliance Pharmaceutical Corp and Schering Aktiengesellschaft
[2001] APO 27
•1 June 2001
OFFICIAL NOTICE
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Application : No. 679428 in the name of Sonus Pharmaceuticals, Inc.
Title: Gaseous ultrasound contrast media and method for selecting gases for use as ultrasound contrast media
Action: Two oppositions to the grant of a patent by Alliance Pharmaceutical Corp and Schering Aktiengesellschaft
Decision: Issued
Abstract
The oppositions are successful.
The specification does not disclose microbubbles of gaseous perfluorohexane. There is an explicit disclosure of liquid perfluorohexane, but not gaseous perfluorohexane. The evidence of the declarants does not establish that gaseous perfluorohexane is implied. There is also no indication how to prepare microbubbles of gaseous perfluorohexane.
Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 discussed.
Consequently, there is a lack of fair basis, and a lack of full description.
CCOM Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260 and Patent Gesellschaft AG v Saudi Livestock Transport and Trading Co (1997) 37 IPR 523 applied.
Claims to perfluorohexane microbubbles lack novelty and inventive step as a consequence of deferred priority date.
PATENTS ACT 1990
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Re:Patent Application No. 679428 by Sonus Pharmaceuticals, Inc. and two oppositions to the grant of a patent by Alliance Pharmaceutical Corp and Schering Aktiengesellschaft
BACKGROUND
Patent application number 25503/92 was filed as an international application (number PCT/US92/07250) designating Australia on 2 September 1992 by Steven C. Quay. The applicant was changed to Sonus Pharmaceuticals, Inc (hereafter referred to as Sonus) during the international phase. The application claims priority from US 761311 (which was filed on 17 September 1991) and US 893657 (which was filed on 5 June 1992). The application was examined by the Commissioner, and advertised accepted under the serial number 679428 on 3 July 1997.
Alliance Pharmaceutical Corp (hereafter referred to as Alliance) filed a notice of opposition on 3 October 1997. A statement of grounds and particulars was served on 5 January 1998. The evidence stages (up to evidence in reply) were completed on 16 August 2000.
Schering Aktiengesellschaft (hereafter referred to Schering) filed a notice of opposition on 3 October 1997. A statement of grounds and particulars was served on 2 January 1998. The evidence stages (up to evidence in reply) were completed on 28 September 2000.
Molecular Biosystems, Inc filed a notice of opposition on 3 October 1997. This opposition was withdrawn following the service of evidence in reply.
On 31 January 2001 Sonus requested leave to serve further evidence in both of the oppositions. The requests were refused (decision reported as [2001] APO 13).
The present matter was heard in Canberra on 26 and 27 March 2001. Sonus was represented by Mr B.Hess of counsel assisted by Dr S.Boyer of Griffith Hack. Alliance was represented by Dr A.Bennett of counsel assisted by Mr I.Rajkovic of Baldwin Shelston Waters. Schering was represented by Dr P.Stearne and Dr R.Heisey of Davies Collison Cave. Professor MacFarlane and Dr Worah were also present.
GROUNDS OF OPPOSITION
The grounds of the Alliance opposition were:
* manner of manufacture
* novelty
* inventive step
* fully describe the invention
* fair basis
All grounds were argued at the hearing.
The grounds of the Schering opposition were:
* manner of manufacture
* novelty
* inventive step
* fully describe the invention
* defining the invention
* clarity
* fair basis
At the hearing the grounds were restricted to fair basis and fully describing the invention.
EVIDENCE
The evidence in support of the Alliance opposition consists of declarations by Dr Thomas Fritzsch and Rosemary Hay. The evidence in answer consists of declarations by Professor Douglas MacFarlane, Dr James Pratt, Mr Johnny Lai, Mr Dean Kessler, Dr Pamela Hilpert and Dr Vivien Santer. The evidence in reply consists of declarations by Professor Franz Grieser and Dr Volkmar Uhlendorf.
The evidence in support of the Schering opposition consists of declarations by Professor Russell Howe, Dr George Kossoff and Ms Ruth Clarkson. Evidence in answer consists of declarations by Professor Douglas MacFarlane, Dr James Pratt, Mr Johnny Lai, Mr Dean Kessler, Dr Pamela Hilpert and Dr Vivien Santer. The evidence in reply consists of declarations by Professor Russell Howe, Dr Leo Trevino, Dr Alexey Kabalnov, Dr David Klein and Dr Franz Grieser.
At the hearing there was debate about the weight to be accorded to the evidence of some of the declarants. For example, Dr Fritzsch and Dr Uhlendorf work in Germany. Dr Kossoff's background appears to lie more in the engineering side of ultrasound, rather than the chemistry of contrast agents. I believe that I should have regard to all of the evidence, but if any part of the evidence is critical to my decision I may have regard to the background of the particular declarant.
THE NATURE OF THE INVENTION
The issues in the present case require a careful analysis of the specification. The specification before me was amended after acceptance of the application. There is a further request to amend that has not been finalised (the request was advertised on 26 April 2001). The latest amendment alters the claims by narrowing the scope of claim 1, introducing a new appended claim, and renumbers some of the claims. The claims and subject matter that are the focus of this opposition are not affected by this amendment. The hearing was conducted on the basis of the specification as proposed to be amended.
The specification relates to ultrasound contrast compositions. Ultrasound images are created by detecting the reflection of ultrasound signals by organs and structures of the body. Unfortunately, ultrasound images can have a poor resolution, leading to the use of contrast enhancing agents to improve the quality and resolution of images. Additionally, detection of the movement of contrast enhancing agents can give information on blood flow patterns in cardiovascular patients.
The specification admits that the use of microbubbles of gas as an ultrasound contrast agent is known. It is recognised that gas bubbles are a highly effective contrast agent (page 3). However, there are problems with gas bubbles: the gas bubbles rapidly dissolve in solutions such as blood, giving a short lifetime to such contrast agents; and the gas bubbles must be sufficiently small that they do not carry the risk of embolism to the organism. Additionally, for imaging the cardiovascular system gas bubbles must be sufficiently small that they can pass through the lungs and reach the left heart, which means that the bubbles must be less than 8 microns.
The invention relates to improved microbubbles. The claims as proposed to be amended are directed to microbubbles containing one of four substances: octafluoropropane, decafluorobutane, dodecafluoropentane and perfluorohexane. These compounds are the perfluoro derivatives of the hydrocarbons propane, butane, pentane and hexane. Claim 1 is directed to microbubbles of decafluorobutane, dodecafluoropentane and octafluoropropane. Claim 20 is directed to microbubbles of perfluorohexane. The opposition centred on the substance perfluorohexane, and the question of whether the invention as described includes perfluorohexane. If perfluorohexane is described as part of the invention, then claims to perfluorohexane are fairly based. It is thus claim 20 (and claim 21 in so far as it is appended to claim 20), and not claim 1, that is the focus of the opposition. [Claims 1, 20 and 21 are reproduced in the Annex.] There is also the question of whether perfluorohexane is sufficiently described. With these questions in mind, I will now examine the specification in detail.
WHAT IS THE MATTER DESCRIBED IN THE SPECIFICATION?
The body of the description
The specification discusses a property called the Q coefficient. The Q coefficient for any gas can be calculated using an equation disclosed in the specification. The Q coefficient is a property that is first disclosed in the present application. The large Q coefficient is an indication that a substance is likely to be a useful ultrasound contrast agent when used in a microbubble. A microbubble is a small bubble of a gas within a continuous medium (in this case, an aqueous medium).
The key question to be answered is what is the nature of the gas that is encapsulated by the microbubble. The specification addresses this question in numerous places, and generally uses the term "gas" without any qualification or explanation. There are two other notable uses (the emphasis is mine):
"the ultrasound contrast-enhancing media described herein comprises microbubbles, composed of the biocompatible gases whose selection is also provided by this invention" (page 4 line 34 to page 5 line 2)
"microbubbles produced using a biocompatible gas or combination of gases selected by the physical and chemical parameters disclosed herein" (page 5, lines 24-26)
It is clear that the gas must be biocompatible (a term that is defined in the specification). The gas within the microbubble can also be a combination of biocompatible gases (as specified in the last quote). A biocompatible gas is defined in the text bridging pages 5 and 6:
"By using the term 'biocompatible gas' I mean a chemical entity which is capable of performing its functions within or upon a living organism in an acceptable manner, without undue toxicity or physiological or pharmacological effects, and which is, at the temperature of the living organism, in a state of matter distinguished from the solid or liquid states by very low density and viscosity, relatively great expansion and contraction with changes in pressure and temperature, and the spontaneous tendency to become distributed uniformly throughout any container."
The last portion of this extract is essentially the scientific definition of a gas. Thus the substance must not be harmful to the subject, and must be a gas at body temperature.
The opponents put forward the view that the gas is a single component substance, i.e it is a pure sample of a single compound. The applicant put forward the view that the gas can be a mixture of compounds. I concluded above that the microbubble can contain a mixture of biocompatible gases, so it cannot be correct to say that the specification excluded the possibility of microbubbles containing a gas that is itself a mixture. What is essential is that the gas mixture must satisfy the requirement of biocompatibility.
The Q coefficient of a number of gases is calculated and listed in Table II. It appears that these values relate to pure samples of the various gases. The specification then describes an alternative means for estimating the Q coefficient using only the molecular weight of the gas. By this means the Q coefficient for a much larger number of gases is calculated and listed in Table IV. It appears that these values relate to a pure sample of the various gases, except in the case of air (which is well known to be a mixture, predominately made up of nitrogen, oxygen and carbon dioxide). It must be noted that perfluorohexane is not one of the substances that has a listed Q coefficient in either Table II or Table IV.
The examples
The substances that are used to prepare microbubbles in the worked examples are perfluorobutane (in examples 1 to 3) and perfluoropentane (example 5). Example 6 is a comparison of perfluoropentane and perfluorohexane, and is the only reference to perfluorohexane in the description. I will return to example 6 later.
The examples 1 to 5 do not specify whether the microbubbles contain pure perfluoroalkane, or a mixture of perfluoroalkane and air. The clear implication is that the gas is pure, and the methods used would be expected to give essentially pure material, only contaminated by air dissolved in the aqueous medium.
Example 6
Example 6 is the key part of the disclosure. It reads as follows:
The relationship of the state of matter of a given chemical entity with a high Q-coefficient and its utility as an ultrasound contrast agent was tested by comparing the efficiency of perfluoropentane and perfluorohexane to act as an ultrasound contrast agent. Perfluoropentane (dodecafluoropentane) has a calculated Q-coefficient of 207,437 and a boiling point under standard pressure conditions of 29.5 degrees Centigrade. Perfluorohexane (PCR, Inc., Gainsville, FL) has a calculated Q-coefficient of 1,659,496 and a boiling point under standard pressure conditions of 59-60 degrees C. Therefore, at 37 degrees C, the body temperature of man, perfluoropentane is a gas while perfluorohexane is a liquid.
Aqueous dispersions of perfluoropentane and perfluorohexane (2% w/v) were formed at 4 degrees C by vigorous homogenization. A plastic beaker, containing approximately 1000 mL of water at 37 degrees C, was prepared to simulate human blood and was ultrasonically-scanned, as indicated in Example 5 above, before and after the addition of samples of each of the above dispersions.
Less than 1.0 mL of the perfluoropentane dispersion, when mixed with the simulated blood, produced an extremely bright ultrasound signal which persisted for at least 30 minutes. A 1:10,000 dilution was still detectable.
In contrast, a 1.0 mL sample of the perfluorohexane dispersion was undetectable by ultrasound scanning under the same conditions, as was even a 10 mL sample (1:100 dilution).
The conclusion to be drawn is that both a high Q-coefficient and a gaseous state at the body temperature of the organism being scanned is necessary for a substance to be effective as an ultrasound contrast agent according to the method that is the subject matter of this invention.
In this example microdroplet dispersions of perfluoropentane and perfluorohexane are formed. At body temperature (approximately 37 degrees) the perfluoropentane evaporates, giving microbubbles of perfluoropentane gas. It is clear that the microbubbles of perfluoropentane gas are an effective ultrasound reflector. Perfluorohexane remains as a liquid at body temperature, and the microdroplets of perfluorohexane do not effectively reflect ultrasound. This example strongly supports the conclusion that the microbubbles must contain a gas in order to be a useful contrast agent.
Alliance and Schering contended that example 6 further demonstrates that perfluorohexane is not useful in microbubble contrast agents. This follows from the fact that perfluorohexane is not a gas at body temperature. Sonus contended that example 6 shows that perfluorohexane is not useful in microbubble contrast agents when it is present as a liquid. However, they suggest that example 6 says nothing about the usefulness of perfluorohexane when used as a gas.
In essence, Sonus argue that if perfluorohexane were incorporated into a microbubble in its gas form, then it should be highly effective as a contrast agent due to its extremely high Q coefficient. The construction that Sonus advances is not apparent from the description. There is no suggestion of preparing microbubbles containing liquids in the gas form. While I accept that such microbubbles are not precluded by the description, it is entirely clear that they are not explicitly referred to in the description.
Does the specification imply the use of perfluorohexane in gaseous form?
A specification also discloses those things that a skilled reader would understand are implied. The implied disclosure takes me to the declarations in the evidence.
At this point it should be noted that Sonus' argument appeared to proceed on two fronts. First, it was suggested that the specification discloses that gaseous perfluorohexane should be used, rather than liquid perfluorohexane. Gaseous perfluorohexane is perfluorohexane that is present as a gas, rather than as a liquid. Second, it was stated that since perfluorohexane is not a gas at body temperature, the gaseous perfluorohexane is necessarily a mixture of perfluorohexane vapour in air.
The declarations in support are uniformly silent on whether example 6 implies anything about the possibility of using perfluorohexane as a gas. Rather, the declarants in support are consistent in stating that perfluorohexane will not form microbubbles of gas at body temperature. It is Professor MacFarlane who introduces the idea of gaseous perfluorohexane in his declarations in answer.
The MacFarlane declaration in the Alliance opposition deals with his interpretation of example 6 at paragraph 12. An equivalent passage appears in the evidence in relation to the Schering opposition (paragraph 43), which refers to the Fritzsch declaration rather than the Howe declaration. It is fair to say that Professor MacFarlane comes to the conclusion that the specification includes a disclosure of the use of gaseous perfluorohexane. This conclusion appears to arise from:
. the specification refers to the use of gases as contrast media
. example 6 did not utilise gaseous perfluorohexane
. example 6 does not refer to gaseous perfluorohexane as unsuitable
. claim 20 refers explicitly to perfluorohexane as a component of the gaseous microbubble
. perfluorohexane has a high vapor pressure
I will now quote the relevant paragraph from Professor MacFarlane's declaration in the Alliance opposition in full. The passage is very long, so I will quote it in sections, and discuss each section in turn.
The opposed specification clearly demonstrates that perfluorohexane has a larger Q value than perfluoropentane (opposed specification p 40, line 9), and therefore that in its gaseous microbubble form it would be a useful ultrasound contrast agent. Example 6 of the opposed specification shows, in addition that when perfluorohexane is not in its gaseous form (that is, below its boiling point of 59°C), it is NOT a useful contrast agent because it is in a liquid form. However, as is commonly known to one skilled in this art, any liquid will have a certain vapor pressure and produce a certain quantity of vapor at temperatures below the boiling point. In fact, by definition, the boiling point is the temperature where the vapor pressure equals the atmospheric pressure. Therefore while Example 6 emphasizes that there is a need for the substance used as a contrast agent to be in gaseous form, it does not say that the vapor from a high Q chemical would not be useful as a contrast agent. Thus it is clear to me that Claim 25 (claim 19 in the amended specification) [which is claim 20 in the specification that I am considering] relates to the use of perfluorohexane vapor at a temperature below the boiling point of perfluorohexane. Alternatively, that it relates to the use of perfluorohexane at a temperature above the boiling point of perfluorohexane, or under reduced pressure conditions, wherein its boiling point was reduced. It appears from the Howe declaration that clinical applications involving the use of gaseous perfluorohexane vapors, which are included in the claimed applications, have been overlooked.
Professor MacFarlane begins by noting that gaseous perfluorohexane is not excluded. Professor MacFarlane appears to rely on claim 20 as the source of a positive indication to regard gaseous perfluorohexane as part of the invention. Use of the claims to aid construction of the description is a complex issue. It is well established that the specification is to be read as a whole (for instance, see Rosedale Associated Manufacturers Ltd v Carlton Tyre Saving Co Ltd [1960] RPC 59 at 69). This principle is normally applied as an aid to the construction of claims (for instance, in Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461 at 479 it was stated that the body of the description could be used to help resolve an ambiguity in a claim, and in International Business Machines Corp v Commissioner of Patents (1991) 22 IPR 417 at 422 it was stated that the description provides a context for the claims). However, the converse is also appropriate. The description includes the claims and any drawings (see AMP Incorporated v Utilux Pty Ltd (1971) 45 ALJR 123 at 127; reversed on other grounds on appeal, see (1974) 48 ALJR 17), and it is appropriate to have regard to the claims as an aid to understanding the body of the description (see Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 at [16]):
"it does not follow that the description is to be gleaned solely from one part (the body) and that it is forbidden to obtain any assistance by regard to the remainder (the claims) of the complete specification. Rather, the text indicates that the specification must be read as a whole and that reference to the claims may dispel ambiguity or uncertainty from the body of the specification concerning the description of the invention."
Thus it is clearly proper to use the claims to resolve ambiguity or uncertainty in the description. However, there is a limit to the legitimate use of the claims: if a claim can supply a feature missing from the description that would make a mockery of the third leg of the Mond Nickel test (see Mond Nickel Co Ltd's Application [1956] RPC 189).
It follows that the use of claim 20 to interpret the description is appropriate in limited circumstances. Professor MacFarlane did not suggest that the description was ambiguous about whether it extended to the use of gaseous forms of liquids. Instead of an ambiguity, the description is silent on the matter, and does not explicitly exclude the possibility. It seems more likely than not that Professor MacFarlane did not find the description ambiguous on this point.
Referring to the rest of this passage, it seems that it was significant that Professor MacFarlane was readily able to identify ways to produce a microbubble containing perfluorohexane as a gas. The first two methods involve raising the temperature above the boiling point of perfluorohexane or reducing the pressure so that the boiling point of perfluorohexane is reduced to below body temperature. Neither of these suggestions are practical given that the microbubbles are intended to be administered to a living patient. In fact, these suggestions indicate that the use of microbubbles of perfluorohexane as a gas would not have been considered as taught by the description, since the conditions are clearly not biologically compatible.
Indeed, a careful reading of Example 6 indicates that it does not show an attempt to conduct ultrasound imaging with gaseous perfluorohexane. The perfluorohexane in this example was used in the form of a liquid rather than a gas. At the end of the example, the text states that both a high Q coefficient and a gaseous state at the body temperature of the organism being scanned are necessary for a substance to be effective as an ultrasound contrast agent according to the method of this invention.
This is a statement of the construction of example 6 that is advocated by Sonus. It is significant that Professor MacFarlane stresses what the example does not show, because this is what Sonus argues is disclosed by the description.
One skilled in the art would recognize that from the extremely high Q coefficient (calculated as on 1,659,496 in the Example) perfluorohexane would be quite suitable as a gaseous ultrasound contrast agent. Certainly, the opposed specification teaches that linear perfluorocarbons are one of the preferred classes, and it teaches, in Example 6, the Q value of perfluorohexane (the highest Q value mentioned in the specification). While perfluorohexane boils at 59-60°C under standard conditions, that is, above normal body temperature, it has a relatively high vapor pressure at ambient temperature. Literature indicates a vapor pressure of 44 mm Hg at 25°C, and the vapor pressure would be even higher at the body temperature of 37°C. From this information, one skilled in the art could well expect that though the boiling point of perfluorohexane is above human body temperature, a sufficient amount of this gas would be available in the body to function as an ultrasound contrast agent according to the invention, due to its vapor pressure.
Professor MacFarlane's view as to why gaseous perfluorohexane would be likely to be useful as a contrast agent are logical, since it has an extremely high Q coefficient. However, this is not relevant to the question of whether the specification is disclosing gaseous perfluorohexane as the invention. While it is true that the description does not say that gaseous perfluorohexane is unsuitable as a contrast agent, this is a consequence of the general silence of the specification with regard to this compound.
Referring to the rest of this passage, Professor MacFarlane goes on to suggest other methods for preparing gaseous microbubbles of perfluorohexane. The first is that there should be sufficient vapour pressure at body temperature to produce an ultrasound signal. Vapor pressure is the pressure of the vapour of a substance that forms when the substance is allowed to stand. Thus, a liquid in an enclosed space will form a defined amount of vapour, dependent only on the nature of the substance and the temperature. By referring to the fact that perfluorohexane has a high vapour pressure at body temperature, Professor MacFarlane appears to be saying that a liquid sample of perfluorohexane would be accompanied by a significant amount of perfluorohexane vapour. I interpret this as a suggestion that microdroplets of liquid perfluorohexane at body temperature should contain some perfluorohexane vapor, and this vapor would be able to act as an ultrasound contrast agent. This is exactly the experiment that was carried out in example 6, and whatever vapour pressure of perfluorohexane was present, it was not sufficient to give an ultrasound signal. This view seems to be in conflict with the evidence of the specification.
This fact, combined with the extremely high Q coefficient of this substance would clearly indicate its usefulness as a gaseous ultrasound contrast agent notwithstanding the fact that in the particular experiment described in Example 6 of the opposed specification the sample was not detectable by ultrasound scanning. This lack of detection would have been a result of the fact that in this Example the perfluorohexane was utilized as a liquid rather than as a gas. Indeed, a careful reading of Example 6 indicates that it does not show an attempt to conduct ultrasound imaging with gaseous perfluorohexane. For instance, I note that no attempt is described to convert the perfluorohexane from the liquid to the vapor form and it would be clear to one skilled in the art from the description of the work in this Example that perfluorohexane vapor did not form. There is, for example, no introduction of a blanket of vapor into the beaker, or of any indication of agitation, sonication or other treatment that could cause the formation of gaseous microbubbles of the perfluorohexane at the temperature of the measurement.
Here Professor MacFarlane goes on to suggest other methods for preparing gaseous microbubbles of perfluorohexane. He refers to the use of a blanket of vapour, agitation or sonication. This is surprising, since example 6 involves the use of "vigorous homogenization". To my mind, this sounds like agitation. And it is clear that the example 6 sample, when heated to body temperature, did not give an ultrasound signal.
I note that Mr Lai provided a declaration in answer in which he reports preparing microbubbles of gaseous perfluorohexane. His method is not one of those described by Professor MacFarlane. I will return to Mr Lai's evidence later.
As further evidence that gaseous perfluorohexane is useful as an ultrasound contrast agent in the invention of this application I submit the following text, which is contained in a later filed Australian Patent Application, No 61624/94, as Example 18. A copy of Example 18 from 61624/94 is now shown to me marked Exhibit DRM-9. It shows the testing of eight materials as ultrasound contrast agents, including decafluorobutane (gaseous at room temperature), dodecafluoropentane (liquid at room temperature but gaseous at body temperature) and perfluorohexane (liquid at room temperature and at body temperature but having a vapor pressure above 20 Torr). The perfluorohexane was shown to have an enhancement (in percent-minutes x 1000) of 178, making it suitable for use as an ultrasound contrast agent.
In this passage Professor MacFarlane seems to be confirming that gaseous perfluorohexane is useful as a contrast agent, based on his knowledge of later published information. This is a very concerning part of the evidence. It raises the question of the extent to which Professor MacFarlane's knowledge of the usefulness of perfluorohexane derived from a later published document has influenced his reading of the present specification. I have no positive evidence of the use of hindsight by Professor MacFarlane, so I will accept his evidence at face value.
On its face, this passage says nothing more than that perfluorohexane gas has been shown to be a useful ultrasound contrast agent. It says nothing about whether a person would have understood that the present specification discloses such an invention. I note that the patent application 61624/94 appears to use perfluorohexane in liquid form, and states that it provided "some contrast", but goes on to say that "the mechanism for enhancement by these materials is not fully understood and is not considered practically useful relative to those materials which boil at about 40°C or below". I can find nothing relevant to gaseous perfluorohexane. This document does not support Professor MacFarlane's views.
When Professor MacFarlane refers to gaseous perfluorohexane he does not explicitly refer to a mixture of perfluorohexane vapour and air. It seems that the distinction that is drawn is between perfluorohexane as a liquid and as a gas. I would characterise Professor MacFarlane's evidence as relating to pure gaseous perfluorohexane. Professor MacFarlane is careful not to say that when he read the specification it said to him that gaseous perfluorohexane (either pure or as a mixture) was described as part of the invention. Rather, I characterise Professor MacFarlane's evidence as suggesting that the specification implies that gaseous perfluorohexane would be a fruitful subject of further investigation.
At the hearing Mr Hess suggested that the gas that is used in the case of perfluorohexane would be a mixture of perfluorohexane vapour and air, since pure perfluorohexane at body temperature is a liquid. As already noted, it does not seem that Professor MacFarlane read the specification as implying perfluorohexane/air mixtures. I can find no reference to such mixtures in his declarations in answer. The other declarants do not suggest that they read the specification as disclosing air mixtures. I conclude that there is no evidence to support the view that the specification discloses microbubbles containing perfluorohexane/air mixtures.
I conclude that the specification does not describe microbubbles of gaseous perfluorohexane, either pure or as a mixture with air. I will also briefly discuss whether the specification describes the preparation of microbubbles containing gaseous perfluorohexane.
Mr Lai prepared microbubbles containing gaseous perfluorohexane. Tests on these microbubbles are recorded in Table 2 of his declarations. The declarations do not specify exactly how the microbubbles were prepared: the general method merely refers to using 1 ml of the gas. However, perfluorohexane is not a gas. In the case of perfluoropentane, which is also not a gas at room temperature, Mr Lai explains how he prepared a sample of the gas by placing a 15 ml sample in a 100 ml vial, evacuating the headspace, heating the vial to boiling point, and removing a sample from the headspace. Mr Lai notes that "constant gas flow was difficult to achieve for perfluoropentane" (common sense suggests that this difficulty arises from the gas condensing to its liquid form). No such information is given for perfluorohexane, so it is unknown how Mr Lai prepared his gas filled microbubbles. I can only assume that Mr Lai used a method analogous to that used for perfluoropentane, and thus prepared microbubbles of pure gaseous perfluorohexane. It is interesting that the gaseous perfluorohexane apparently did not condense into perfluorohexane liquid at body temperature. However, since the perfluorohexane microbubbles were not tested in vivo (in contrast to the shorter chain perfluoroalkanes; see the declarations of Mr Kessler) it is left as an interesting question whether the microbubbles remained effective as ultrasound contrast agents when equilibrated to body temperature. Dr Trevino noted similar concerns with Mr Lai's evidence (in his declaration in reply in the Alliance opposition). However, given Mr Hess' view at the hearing that the specification is really disclosing gaseous perfluorohexane mixed with air, it is not surprising that there is no teaching of preparing pure gaseous perfluorohexane.
Turning to the possibility of using perfluorohexane/air mixtures, there is no disclosure of how to prepare microbubbles containing the mixture. I am aware that there are declarations by Professor MacFarlane in the rejected further evidence in which he says that the method of example 1 "could" have produced microbubbles of perfluorohexane/air by using a sample of gas drawn from the headspace of a liquid sample of perfluorohexane (since this gas would contain perfluorohexane vapour). Mr Hess made the same assertion (but suggesting it would work) during the course of the hearing. Given the qualified nature of Professor MacFarlane's evidence, it would not have advanced Sonus' case.
The use of a perfluorohexane/air mixture to form microbubbles seems to be very similar to the method actually used in the later filed patent application AU 74782/94 in the name of Alliance (which is a novelty citation in the present case). It appears from AU 74782/94 that it is essential to stabilise the microbubbles with a membrane (such as a surfactant) because the air is rapidly lost to the aqueous medium. The fact that this method is the subject of a later filed application suggests (but is not proof) that this method would not have been implied to a reader of the present application at its date of filing.
Mr Hess suggested other methods that could have been used to prepare microbubbles containing gaseous perfluorohexane/ air: specifically, the methods of examples 1 and 5 of the specification used with perfluorohexane liquid would give gaseous microbubbles. I am unable to confirm from the evidence on file that a reader other than Mr Hess would have understood this from the specification.
I conclude that it has not been demonstrated that a reader would have understood how to prepare a microbubble of perfluorohexane/air had the specification suggested that such microbubbles were the invention.
Consequently, the specification does not disclose, explicitly or implicitly, that the invention includes microbubbles containing gaseous perfluorohexane, or how to prepare microbubbles containing gaseous perfluorohexane.
CONSTRUCTION OF THE CLAIMS
The next question is the construction of claims 20 and 21 with regard to the nature of the gas in the microbubbles. Claims 20 and 21 read:
20. A biocompatible contrast medium for ultrasound image-enhancement, comprising gaseous microbubbles of perfluorohexane.
21. A biocompatible contrast medium according to any one of claims 1 to 20, wherein said microbubbles of gas are free gas microbubbles.
In claim 20 the microbubbles are gaseous, which means that they contain a gas at body temperature. The question is whether the gas is purely perfluorohexane, or whether it can be a mixture of perfluorohexane and air. This is the kind of ambiguity that permits reference to the description (see Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461). However, the description does not clearly resolve this matter. The definition of "biocompatible gas" on page 5 to 6 is broad enough to include mixtures. The specific detail in pages 16 to 41 seem to imply the use of pure gases. However, the comparison gas is air, which is itself a mixture. I conclude that I should construe the term broadly as including both pure gases and mixtures.
Claim 21 adds the limitation that the microbubbles are "free gas microbubbles". There is no evidence on this matter, but I take the term "free" to apply to the microbubbles, and not the gas. I assume that the microbubbles are free in the solution, rather than trapped or constrained in some way.
SECTION 40 MATTERS
Turning now to the matters at the heart of this opposition, it can be seen that the specification does not comply with section 40.
Fairly based
Fair basis is assessed using the "real and reasonably clear disclosure" approach (for example, see CCOM Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260 at 278). In the context of the present opposition, it is significant to note that "there cannot be a real and reasonably clear disclosure if there is no disclosure" (CCOM v Jiejing, supra at 284).
The matter described does not include microbubbles of gaseous perfluorohexane. The absence of a disclosure means there is a lack of fair basis for claims 20 and 21.
It was also argued that there is a lack of fair basis due to the disconformity between the description and the claims, as described in Mullard Radio Valve Co Ltd v Philco Radio and Televison Corporation of Great Britain Ltd (1936) 53 RPC 323 at 347. The use of perfluorohexane in gaseous form is beyond the inventive concept as disclosed, so this argument is also correct.
Describe the invention fully
There are two aspects of the requirement to describe the invention fully. First, the specification must make it clear what the invention is, and second there must be sufficient detail to enable the reader to carry out the invention.
"The specification contains a full description if it makes the nature of the invention plain to persons having reasonably competent knowledge of the subject and also makes it plain, to persons having reasonable skill, how to perform the invention"
[Patent Gesellschaft AG v Saudi Livestock Transport and Trading Co (1997) 37 IPR 523 at 530]
In deciding whether the invention is fully described, the invention is the embodiment which is described, and around which the claims are drawn (see Kimberly-Clark v Arico, supra at [18-21]). With reference to the aspect of the invention claimed in claim 20, the specification does not make the gaseous perfluorohexane aspect of the invention plain. There is no explicit description of such an invention, and a description cannot be reasonably inferred. Next, there is no description of how to prepare such microbubbles. As a consequence, the specification does not fully describe the invention as claimed in claim 20.
NOVELTY AND SELECTION
Only Alliance argued lack of novelty. The argument was based on ten documents that are listed in the statement of grounds and particulars, and was directed to claims 20 and 21 only.
The law of novelty
The test for novelty is the reverse infringement test. The classic formulation of this test is that given by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228 at 235:
"The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement."
A more recent summary of the law on novelty is in Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 at 517:
"It is well accepted that the prior art must disclose all features of the invention embodied in the patent in suit and must do so in clear, unequivocal and unmistakable terms. The prior art must enable the notionally skilled addressee at once to perceive and understand and be able practically to apply the discovery without the necessity of making further experiments. Whatever is essential to the invention must be read out of or gleaned from the prior publications"
Consequently, the alleged anticipation must disclose all of the essential features of the invention as claimed.
Priority date of the present application
The priority date of a claim is determined according to sections 43 and 114, and regulations 3.12, 3.13 and 3.14. The basic principle derived from these provisions is that the priority date of a claim is the date that the subject matter of the claim was first disclosed, either by filing the priority document, by filing the patent specification or by filing amendments to the specification.
The present case is very similar to that in Emory University v Biochem Pharma Inc [1999] APO 50. In that decision, claims were found to be not fairly based, so took the date of their own filing as their priority date. In the present case, the subject matter of claim 20 (and claim 21 so far as it is dependent on claim 20) has not been disclosed in the specification, so they should take the date of first filing of a claim equivalent to claim 20. On 9 April 1997 an amendment inserting claim 25 relating to gaseous perfluorohexane was filed. I regard this as the priority date of the present claim 20.
The citations
Swanson, D P et al "Enhancement Agents for Ultrasound: Fundamentals" in Pharmaceuticals in Medical Imaging, Macmillan Publishing Co Inc, 1990, pp 682 to 687
This document is a review article relating to ultrasound contrast agents. There is a specific disclosure of Fluosol-DA (which is an emulsion of perfluorodecalin and perfluorotripropylamine that can be used as an oxygen carrier). Dr Kossoff declared in relation to this document (at paragraph 19):
"Insofar as this document does not specifically describe the use as perfluorocarbons of decafluorobutane, dodecafluoropentane, … octafluoropropane … those of skill in the art before 16 September 1991 would have, if posed with the problem of bubble stability, on reading this document been directed to try each of these"
Dr Kossoff is Alliance's declarant, and he does not believe that the Swanson article discloses the use of the relevant perfluoroalkanes. I agree with Dr Kossoff.
AU 27891/92
This document describes ultrasound contrast agents capable of forming gaseous microbubbles. Dr Kossoff declared in relation to this document (at paragraph 20) that the relevant perfluoroalkanes are not specifically described. I agree with Dr Kossoff.
AU 40651/89
This document describes ultrasound contrast agents in the form of host/guest complexes. Upon dissolution of the host molecule, the guest is released. When the guest is a gas, gas microbubbles form. Dr Kossoff declared in relation to this document (at paragraph 22) that the relevant perfluoroalkanes are not specifically described. I agree with Dr Kossoff.
US 5,501,863
This document describes microparticles of biodegradable polymers that optionally contain gases. Dr Kossoff declared in relation to this document (at paragraph 23) that the relevant perfluoroalkanes are not specifically described. I agree with Dr Kossoff. Additionally, such microparticles are not microbubbles.
US 5,147,631
This document describes porous particles that may contain an entrapped gas. Dr Kossoff declared in relation to this document (at paragraph 24) that the relevant perfluoroalkanes are not specifically described. I agree with Dr Kossoff. Additionally, such particles are not microbubbles.
AU 14253/92
This document describes gas filled liposomes. Dr Kossoff declared in relation to this document (at paragraph 25) that the relevant perfluoroalkanes are not specifically described. I agree with Dr Kossoff.
EP 474 833
This document discloses gas filled microbubbles. Dr Kossoff declared in relation to this document (at paragraph 26) that the relevant perfluoroalkanes are not specifically described. I agree with Dr Kossoff.
AU 74782/94
This document was published on 9 February 1995, and has a priority date of 30 July 1993. Both of these dates are before the priority date of claim 20. The document relates to microbubble compositions for use as ultrasound contrast agents. I note that the examples include microbubbles of "perfluorohexane saturated air" (for example, in Example IX, amongst others). Dr Kossoff mentions the disclosure of perfluorohexane at paragraph 27 of his declaration. Claims 20 and 21 are clearly not novel in the light of this document.
US 5,605,673
This document was published on 25 February 1997. This is before the priority date of the claim 20. The document relates to microbubble compositions for use as ultrasound contrast agents. I note that the examples include microbubbles of "air saturated with perfluorohexane vapour" (prepared in Example 1). Claims 20 and 21 are clearly not novel in the light of this document.
US 4,276,885
This document discloses the use of microbubbles for ultrasonic image enhancement. Dr Kossoff declared in relation to this document (at paragraph 28) that it does not disclose the use of a fluorine-containing gas. I agree with Dr Kossoff.
Conclusion on novelty
It follows that the invention defined by claims 20 and 21is not novel in the light of the documents AU 74782/94 and US 5,605,673.
Selection
There was some discussion at the hearing of whether the invention is a selection, and of the consequences of such a categorisation. In American Home Products Corp.'s Application [1994] APO 58 I noted that a selection patent is anticipated if the prior art actually discloses the claimed matter. My conclusion above was that there is a specific disclosure of microbubbles of gaseous perfluorohexane in the prior art. It follows that claims 20 and 21 are anticipated even if they are a selection.
INVENTIVE STEP
The Alliance statement of grounds and particulars specified that the ten documents mentioned under the heading of novelty are also relevant to inventive step.
The law on inventive step
Section 7(2) provides a definition of inventive step for the purposes of the Patents Act.
"(2) For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with either of the kinds of information mentioned in subsection (3), each of which must be considered separately.
(3) For the purposes of subsection (2), the kinds of information are:(a)prior art information made publicly available in a single document or through doing a single act; and
(b)prior art information made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art in the patent area would treat them as a single source of that information;
being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area."
[The prior art base is defined in Schedule 1 of the Act.]
It is clear that inventive step is a matter that is presumed, unless it is demonstrated that the invention is obvious. The assessment of obviousness can be made against the common general knowledge alone, or the common general knowledge together with a document (or act) of the type covered by section 7(3). Section 7(3) documents must satisfy several requirements: the document must be publicly available inside or outside Australia (see the definition of "prior art base"); and the document could have reasonably been expected to have been ascertained, understood and regarded as relevant.
The normal approach to obviousness is the problem-solution approach: for instance, see Rhone-Poulenc Rorer S.A.'s Application [1995] APO 50. Once the problem has been formulated, and the common general knowledge or prior art base has been determined, the question of whether the claimed solution is obvious must be addressed. The test for obviousness is whether it would have been a matter of routine to proceed to the claimed invention.
"It is still correct to say that a valid patent may be obtained for something stumbled upon by accident, remembered from a dream or imported from abroad, if it otherwise satisfies the requirements of the legislation. What is important is that the patent itself should involve an inventive step, whether or not it was consciously taken by the patentee and whether or not it appeared obvious to the patentee himself. The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not."
[Wellcome Foundation Ltd v V.R. Laboratories (Aust.) Pty Ltd (1981) 148 CLR 262 at 286]
The question of what would be routine can be considered using the "obvious to try" approach. This approach is well explained in Beecham Group Ltd's (Amoxycillin) Application [1980] RPC 261 (which has been approved in Coopers Animal Health Australia Ltd v Western Stock Distributors Ltd (1986) 67 ALR 390 at 410 and W R Grace & Co v Asahi Kasei Kogyo Kabushiki Kaisha (1993) 25 IPR 481 at 492 - 494) at 290 - 291:
"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. 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. 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."
[citations omitted]
The problem
Mr Hess characterised the problem addressed by the claimed invention as the need to find an ultrasound contrast medium having good reflection characteristics, and prolonged persistence compared to air.
The citations
Mr Hess stated that there is no evidence that any of the citations were read before the priority date, or that they would have been ascertained, understood and regarded as relevant. It is not necessary to establish that the documents were known before the priority date, only that they were published. It is true that the declarants may not have been aware of all of the documents before being asked to comment on them for the purposes of the opposition. The question posed by section 7(3) is whether a skilled person "could" be reasonably expected to have ascertained, understood and regarded them as relevant. These are matters that I am prepared to presume without evidence if the circumstances are appropriate. I will return to this point below.
As a generalisation, the citations refer to the use of fluorinated compounds as contrast agents. Fluorohydrocarbons are specifically mentioned in some of the documents. I will deal with some general principles before looking at the individual citations.
I recognise that there are a wide range of fluorine containing compounds, including fluorides of uranium, sulfur and xenon. Fluorocarbons are only one of many members of the class of fluorine containing compounds, and without a more specific statement I do not believe that the disclosure of fluorine containing compounds would make it a matter of routine to try fluorocarbons, let alone perfluorohexane.
A reference to perfluorohydrocarbons is a reference to a much smaller class of compounds, and it is reasonable to see this as a suggestion to try readily available members of this class. Whether this suggestion would extend to gaseous perfluorohexane is problematic. It would be necessary to show two things: (1) it would have been obvious to try gaseous perfluorohexane in the light of the disclosure in the citation; and (2) it would have been a matter of routine to prepare microbubbles containing perfluorohexane in a gas form (either pure or as an air mixture). It is this second point that is critical in the present case.
As already discussed above, the present specification does not provide a full description of how to prepare gaseous microbubbles of perfluorohexane, and a skilled reader would not have appreciated how to prepare such microbubbles. It follows that the same person would not have regarded it as a matter of routine to prepare the same microbubbles when reading any of the citations (unless the citation explicitly states how this is done).
The only documents that explain how to prepare gaseous microbubbles of perfluorohexane are the novelty citations AU 74782/94 and US 5,605,673. As already discussed these documents relate to microbubble compositions for use as ultrasound contrast agents. These documents are of a type that would be expected to be ascertained, understood and regarded as relevant: this is an art where patenting is common (as evidenced by the number of patent documents served in evidence), so is it reasonable to consult patent documents; the documents relate to ultrasound imaging using microbubbles, making them straightforward to locate and clearly relevant; the technical complexity of the documents is similar to that of the present specification, suggesting they would be readily understood. Both documents state that the microbubbles have prolonged longevity. Consequently it is apparent from the face of the documents that they provide a solution to the problem, and one form of that solution is the use of microbubbles of gaseous perfluorohexane. Consequently these documents deprive claims 20 and 21 of inventive step.
Conclusion on inventive step
Claims 20 and 21 lack an inventive step in the light of AU 74782/94 and US 5,605,673.
MANNER OF MANUFACTURE
Alliance argued that the invention is a mere discovery of an inherent characteristic (i.e. the Q co-efficient). It is true that the Q co-efficient is a value that is determined by calculation, and it is not of itself a patentable piece of information. However, the application goes further and discloses how to use the Q co-efficient to identify substances that should be useful as ultrasound contrast agents. The specification goes on to demonstrate that certain high Q compounds are effective contrast agents. It is the microbubbles containing the relevant gases that are the invention as claimed, and not the Q co-efficient.
It is clear that microbubbles of gas are a normal subject matter of letters patent as they are repeatedly the subject of patents (as is evidenced by the documents raised under the ground of novelty). I see no reason to consider that microbubbles of gas are not a proper subject matter of letters patent.
The oppositions are unsuccessful on the ground of manner of manufacture.
CONCLUSION
The Alliance opposition succeeds on the grounds of section 40, novelty and inventive step with respect to claims 20 and 21.
The Schering opposition succeeds on the ground of section 40 in respect of claims 20 and 21.
As the opposition is successful only with respect to some of the claims it is appropriate to allow Sonus the opportunity to propose amendments to overcome the deficiencies that I have identified. I allow Sonus 4 weeks from the date of this decision in order to propose suitable amendments.
COSTS
The Alliance opposition is successful on the grounds of section 40, novelty and inventive step. I consider that Alliance should be regarded as completely successful, and thus entitled to an award of costs in their favour.
The Schering opposition is successful on the ground of section 40. Schering did not pursue the grounds of novelty and inventive step. Mr Hess suggested that Schering has only argued a limited part of the case foreshadowed by the statement of grounds and particulars, so they should not be entitled to full costs. Schering stated that the claims had been amended during the opposition, so their case had changed appropriately. I note that the claims as accepted included gases such as sulfur hexafluoride, which is explicitly mentioned in some of the citations. It seems a reasonable presumption that the claims were amended in the light of the evidence in the opposition, and the amendment to the claims necessitated a change in the cases of the opponents. I do not agree that Schering have improperly limited their case to section 40 matters. Normally section 40 is a minor part of an opponents case, and success on section 40 alone does not entitle an award of costs. In the present case, once the claims were narrowed post-acceptance, the section 40 matters are the heart of the matter. I consider that Schering is still entitled to an award of costs in their favour.
I award costs in accordance with Schedule 8 against Sonus Pharmaceuticals, Inc in both oppositions.
Dr S.D.Barker
Delegate of the Commissioner of Patents
Patent attorneys for the applicant : Griffith Hack, Melbourne
Patent attorneys for Alliance : Baldwin Shelston Waters, Sydney
Patent attorneys for Schering : Davies Collison Cave, Sydney
ANNEX
Claim 1: Biocompatible contrast medium for ultrasound image-enhancement, comprising a gas emulsion, in which the gas emulsion includes microbubbles of a gas selected from the group consisting of decafluorobutane, dodecafluoropentane and octafluoropropane.
Claim 20: A biocompatible contrast medium for ultrasound image-enhancement, comprising gaseous microbubbles of perfluorohexane.
Claim 21: A biocompatible contrast medium according to any one of Claims 1 to 20, wherein said microbubbles of gas are free gas microbubbles.
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