- This
case is concerned with the validity of a patent for a very simple, or apparently
simple, invention. It involves the production on an industrial scale of a substance
known as aspartame, a low calorie sweetener. The patent is European Patent EP
0 091 787 ("the patent") and the proprietor is the defendant, Ajinomoto
Co. Inc. ("Ajinomoto"). Its priority date is 12 April 1982. The claimant,
Daesang Corporation ("Daesang"), seeks revocation on the grounds of
anticipation, obviousness and insufficiency. Anticipation and obviousness are
alleged over a single piece of prior art, Japanese Laid-open Patent Specification
167267 ("JP ‘267"). There is no counterclaim for infringement because
the question of infringement in this country is being considered by the courts
in the Netherlands in conjunction with the issue of infringement of the Dutch
equivalent of the patent.
- At
the heart of the patent is a process of purification which involves crystallising
aspartame from a concentrated solution. The patent claims that the product is
easy to recover in high yields and high purity. Before considering the various
issues in the case, some understanding of crystallisation will be useful.
An
overview of crystallisation
- Crystallisation
is an important step in the production of many industrial chemicals. It is a way
of separating a product in substantially pure form from an impure solution. It
also has the advantage of delivering the product in solid form. Solids are generally
concentrated and easy to package and transport.
- A
common experiment used to demonstrate the growth of crystals to school children,
is as follows. Copper sulphate is dissolved in water. A hot strong solution is
made. It is poured into a beaker. A single crystal of copper sulphate is then
suspended in the solution. The beaker is left undisturbed on a shelf or in a cupboard
and the solution is allowed to cool and evaporate a bit. After a few days it will
be found that a larger crystal is now suspended in the solution. This demonstrates
the growth of a crystal in a static solution.
- There
is a limit to the amount of a substance which can be dissolved in a solvent. For
example if one takes ordinary cooking salt (sodium chloride) and stirs it into
a pot of water, a point will come at which no more will dissolve. The solution
is said to be saturated. Normally, it is possible to dissolve more by increasing
the temperature of the solvent (i.e. the water). So, a litre of water at 30oC
will dissolve less than at, say, 70oC. Figure 8 of the patent, which
is reproduced as Illustration 1 below, illustrates the solubility characteristics
of aspartame in water. It is a fairly conventional solubility curve. It shows
that at about 70oC, it is possible to make a solution which contains
about 5.5% by weight of aspartame. At 20oC, the solution can only contain
about 0.6% by weight of aspartame. If you take a saturated solution at 70oC
and cool it to 20oC, the amount of aspartame in solution must drop.
The cooling solution which has "too much" aspartame in it is said to
be supersaturated. The excess aspartame will come out as crystals. On the other
hand, if additional crystals are put in a 1% solution at 20oC, they
will not dissolve because the solution is already saturated. But if they are put
into a 1% solution at, say, 70oC, it is far from being saturated and
the added crystals will dissolve. At 70oC an aqueous solution can contain
nearly 56 gms of aspartame per litre, at 60oC it can contain about
40 gms per litre and at 10oC it can contain about 10 gms per litre.
It follows that if a saturated solution of aspartame at 70oC is cooled
to 60oC, about 16 gms of aspartame must come out of solution (i.e.
56 gms – 40 gms). If it were cooled from 70oC to 10oC, 46
gms would come out of solution leaving behind a saturated solution containing
only 10 gms per litre of aspartame. At 10oC, just under 20% of the
original aspartame is left in the liquor. It would be wasteful and therefore expensive
to throw this away. An efficient system would try to recover this valuable chemical
from the liquor.
Illustration
1:
- Basic
concepts in the field of crystallisation are set out in the expert reports of
Professor Garside, for Daesang, and Professor Hounslow, for Ajinomoto. Just before
the trial each considered the other’s reports and indicated which paragraphs he
agreed with. I suspect that there would have been even greater agreement had they
been given more time to carry out this task. Nevertheless much was agreed. The
following section of this overview is based on those agreed passages.
- In
any crystallisation process, two things happen. First the crystals must be born.
Second they must grow. The first of these is called nucleation. It is the process
of producing new centres of crystallisation ("nuclei") upon which new
crystalline material is deposited to form crystals. The more nuclei there are
in a solution the more crystals there will be but these crystals will tend to
be smaller than those formed in a similar solution but having a smaller number
of nuclei. In the latter case, the amount of solid coming out of solution is spread
amongst a smaller number of crystals. The growth rate is the rate at which the
crystals increase in size. The kinetics leading to the processes of nucleation
and growth are very different from each other and in developing a system to produce
large crystals the expert is balancing the nucleation process with the growth
process.
- Nucleation
can be split into two types, primary and secondary nucleation. Primary nucleation
is the spontaneous formation of crystals unmediated by the presence of other crystals.
Secondary nucleation is the process of formation of new crystals mediated by the
presence of other crystals. In the latter process, small "seed" crystals
are added to a system to form a foundation on which larger crystals can grow.
This is what is happening in the child’s example set out above.
- The
driving force for both nucleation and growth is supersaturation. The solubility
curve set out in paragraph 5 above, partitions the figure into two regions. Solutions
having a composition and temperature above the curve are said to be supersaturated.
Those below the curve are undersaturated. The further a system is away from the
curve in the top left part of the figure the more supersaturated it is. The higher
the degree of supersaturation, the higher the impetus for crystal growth and for
nucleation. The difference between the amount of solute (e.g. aspartame) in a
solution at a particular temperature and the amount it should have at that temperature
if the solution is saturated is sometimes referred to as its D C.
The larger the D C
the greater the drive to crystallise. The higher the D C,
the greater the impetus to crystal growth and the higher the rate of primary nucleation.
The product will include a large population of small crystals. These crystals
are often so small that the end result is termed a slime. This is what happens
if one starts with a saturated solution and rapidly decreases its temperature.
One ends up with a high degree of supersaturation (i.e. a high D C).
As Professor Garside explained, if a saturated solution is crash cooled (cooled
as fast as possible) then a very large number of nuclei form. On the other hand,
if the saturated solution is cooled slowly, the rate of nucleation is much lower
and this encourages the growth of existing crystals rather than the formation
of new nuclei. A smaller number of big crystals is produced. Once again the school
example set out above illustrates the effect of slow cooling.
- Supersaturation
not only affects the rate of growth but also the quality of the crystals produced.
Conditions of high supersaturation (i.e. high D C)
often produce crystals of a less desirable shape, for example with rough surfaces,
holes, etc. These crystals are undesirable because they adsorb more solvent making
solid/liquid separation more difficult.
- Nucleation
is extremely sensitive to the local environment over small distances. If a saturated
solution is subjected to uneven cooling, different parts will be at different
temperatures. In this state the solution is said not to be isothermal. Therefore
different parts of the solution, even though they are close to each other, will
experience different levels of supersaturation, and the rate of primary nucleation
and crystal growth in different parts of the solution will be different. In those
areas where solution has cooled a lot, the degree of supersaturation will be high
and this will tend to produce a very large number of small crystals; the slime
referred to above. On the other hand immediately adjacent to that part of the
system may be a volume of solution which has only cooled a little bit. Here the
degree of supersaturation will be small. This will tend to produce a small number
of large, well-formed crystals. Overall, the system will contain a mixture of
all the crystals produced in the various locations within it. This can result
in crystals of poor quality - many small and some relatively large. In this case
it is said that the crystals have a wide size distribution. This is to be contrasted
with a well-controlled process which would produce crystals having a relatively
narrow distribution of sizes, still showing some relatively smaller and some relatively
larger crystals, but nothing like to the same degree as is found with poor control.
The effect of uneven cooling of a solute can be illustrated by reference the same
Figure 8 in the patent. It is set out below showing three different D
Cs produced
if there is uneven cooling of a solution which is supersaturated at 70oC.
Illustration
2:
- The
crystals produced in those parts of the system where the D C
is 10oC will be large but comparatively few in number. The crystals
produced in those parts of the system where the D C
is 60oC will be very small but large in number.
- The
design of a crystallisation process usually involves attempting to make the initial
temperature and concentration as high as possible (subject to constraints such
as thermal stability of the molecules), and making the final temperature as low
as possible (subject to operating constraints, such as the temperature of the
available cooling medium and the freezing temperature of the solution). In this
way the maximum change in concentration, and so the maximum amount of precipitation
is assured. Therefore the maximum amount of desired product is recovered as crystals
and the least amount of it is left in the cool solution. On the other hand one
also wants to have crystals of good quality and of narrow size distribution. Therefore,
although the temperatures at the start and finish of the crystallisation process
can be far apart, the process will need to be controlled so as to obtain crystals
of suitable size, shape and quality.
- Finally,
crystals in a supersaturated solution sometimes do not grow, or grow as large,
as expected. The reason for this usually relates to the type and amount of impurities
in the solution and/or crystals. It was well known in 1982 that the rate at which
crystals grow can be strongly dependent on the presence of trace levels of impurity.
- All
of the above would have been known to the skilled worker in the field at the priority
date of the patent.
The
Patent
- The
patent is concerned with the purification of aspartame (which it refers to as
"APM") by using a static system to produce large crystals. It explains
that
"In
industrial production, the crystallization step for isolating APM from a reaction
solution is necessary for obtaining a final product, in the processes described
above. This crystallizing step is usually conducted, for example, by re-dissolving
a crude product in water, organic solvent or aqueous organic solvent, by cooling
the solution by heat exchange with a refrigeration medium (forced cyclization
type indirect cooling system) or evaporating part of the solvent under reduced
pressure (self-evaporating system) using a crystallizer equipped with a stirring
means, and by dewatering and filtering out the thus precipitated crystals by means
of a centrifugal separator or the like." (p 2 lines 13 to 18)
- It
goes on to report that such agitated crystallisation produces a product which
is unsatisfactory. It says that it consists of
"fine
needle-like crystals, and therefore have extremely bad solid-liquid separability
in the filtration and dewatering procedure." (p 2 lines 19 to 21)
- Some
of the difficulties in trying to recover these crystals are described. The solution
to these problems and the heart of the alleged invention consists of making use
of static crystallisation. In essence, the invention consists of taking a supersaturated
solution of aspartame and cooling it without agitation so that crystals are produced
which are easier to filter. If this process is used, a most unusual change takes
place. If one considers a supersaturated solution of aspartame at, say, 70oC
and one cools it to, say, 40oC, it will be seen from Illustration 1
above that the amount of aspartame in solution falls from 5.5% by weight to 2%
by weight. That means that about 3.5% by weight turns into crystals. The solution
which is left contains 98% by weight of water. Notwithstanding the fact that most
of the system is still liquid, it sets into what the inventors call a "pseudo-solid".
This is described in the consistory clause and the immediately following passage
in the patent:
"According
to the present invention there is provided a process for crystallizing APM on
an industrial scale from its aqueous solution by cooling in an industrial crystallizer,
which comprises adjusting the initial concentration of the ester so that the amount
of precipitated solid phase formed after cooling is about 10 g or more per litre
of solvent, cooling the solution by conductive heat transfer to form an apparently
sherbet-like pseudo-solid phase without effecting forced flow (that is to say
without mechanical stirring or the like), and, if necessary, further cooling the
system after formation of the pseudo-solid phase, converting said pseudo-solid
phase to a slurry, subjecting the slurry to a solid-liquid separation, and drying
the crystals of APM; wherein said sherbet-like pseudo-solid phase comprises bundle-like
crystal aggregates of APM and the solvent, has no fluidity, and may be converted
into a slurry by stirring.
As
a result of intensive investigations to improve the workability of the aforesaid
step in the production of APM by examining various conditions, the inventors have
found the following novel facts. Thus, surprisingly, it has been found that, in
crystallizing APM from its solution of a certain concentration or above by cooling
without stirring, the APM crystals take up the solvent into the space formed among
them, and the whole solution thus appears apparently solidified, and that the
crystals obtained in this state have extremely good properties in a subsequent
solid-liquid separation procedure. Observation of the crystals under a scanning
type electromicroscope has revealed that several needle-like crystals are bundled
together to form apparently one crystal (to be described hereinafter)." (p
2 line 50 to p 3 line 7).
- The
patent sets out one other feature of the process which, it claims, is unexpected.
When operating on an industrial scale, one objective is to obtain the desired
product as quickly as possible. For this and other reasons, there is forced cooling
of the supersaturated solution. This involves the use of cooling surfaces supplied
with coolant to reduce the temperature of the solution. Even though the contents
of the crystalliser solidify, they do not stick to the cooling surfaces. Furthermore
the pseudo-solid exhibits a property which Professor Hounslow described as astonishing,
namely that when agitated, for example with a spatula, it turns back into a liquid.
These characteristics are referred to in the patent:
"More
surprisingly, even under such crystallizing conditions that, with ordinary substances,
crystals adhere onto a heat-transferring surface to result in the formation of
scale which is difficult to remove, the precipitation of APM crystals in accordance
with the present invention is found to enable one to completely remove the crystal
layer from the cooling surface." (p 3 lines 11 to 14)
and
"The
thus obtained sherbet-like pseudo-solid phase comprising APM crystals, and the
solvent does not itself have any fluidity, but has extremely good separating properties
from the cooling surface, thus causing no difficulty upon discharge from the crystallizer.
It can be easily converted into a slurry, for example, by stirring and can be
transported through pumps or the like." (p 5 lines 2 to 5)
- The
patent describes various types of equipment which can be used to put the process
into effect. It also contains two examples to illustrate how the invention can
be put into operation.
- There
is one other passage in the description which deserves mentioning in the light
of one of the arguments advanced in this case. The patent includes what it describes
as a "comparative example". This involves running an aspartame purification
process but using agitated crystallisation. The supersaturated solution is stirred
while it is cooled from 25oC to 10oC. The product of this
example is then compared with the products obtained by the patented static crystallisation
process. Unsurprisingly, the purpose and effect of this example is to illustrate
how the key step of static crystallisation is essential to secure the desired
product.
The
Claims
- Ajinomoto
asserts independent validity for claims 1, 4, 5 and 6. Claim 1 reads as follows:
"A
process for crystallising [aspartame] on an industrial scale from its aqueous
solution by cooling in an industrial crystalliser, which comprises adjusting the
initial concentration of the ester so that the amount of precipitated solid phase
formed after cooling is about 10g or more per litre of solvent, cooling the solution
by conductive heat transfer to form an apparently sherbet-like pseudo-solid phase
without effecting forced flow (that is to say without mechanical stirring or the
like), and, if necessary, further cooling the system after formation of the pseudo-solid
phase, converting said pseudo-solid phase to a slurry, subjecting the slurry to
a solid-liquid separation, and drying the crystals of [aspartame], wherein said
sherbet-like pseudo-solid phase comprises bundle-like crystal aggregates of [aspartame]
and the solvent, has no fluidity, and may be converted into a slurry by stirring."
- Mr
Kitchin QC, who appears for Daesang, argues that some of the wording in this claim
is open to criticism. In particular he says that the expressions "industrial
scale"/"industrial crystalliser", "sherbet-like pseudo-solid
phase", "without effecting forced flow" and "bundle-like crystal
aggregates" are all ambiguous. However he accepts that, in the current state
of the law, he cannot rely on ambiguity as a ground for invalidity. Nevertheless
he wishes to keep the point open for consideration at a higher level. In addition,
he says that these expressions, and in particular the reference to "bundle-like
crystal aggregates" gives rise to an insufficiency attack. He does not put
this at the forefront of his arguments but rather advances it as a squeeze against
a too narrow construction of the prior art.
- Although
it will be necessary to consider the meaning of "industrial scale" below,
it is convenient to say at this stage that there is nothing in the allegation
of ambiguity. It is true that each of the expressions complained about is imprecise
but there is no suggestion that anyone in the art would have any difficulty in
understanding them, the specification or the claims. Daesang’s central argument
is that, if one crystallises aspartame from a static aqueous solution, inevitably
one will see the solution turn into a sorbet-like solid and that is because, inevitably,
it contains crystals which the patentee describes as bundle-like aggregates. The
end point is so clear that there can be no doubt if you reach it. In context,
the limits of the claim are also clear.
- There
is also nothing in the insufficiency attack. The method for obtaining the pseudo-solid,
which inevitably means obtaining the correct type of crystals, is simple in the
extreme. Mr Kitchin says it amounts to nothing more than crystallisation without
forced flow, that is to say static crystallisation. He says that if the system
is static, the inevitable cooling must be by conduction. One will inevitably obtain
the pseudo-solid. It must and can be broken up into a slurry for filtering and,
as the patent states and is not in dispute, this is easy to do. Inevitably one
has thereby obtained the type of crystals with which the patent is concerned.
There is nothing in the drying step. I do not think any of this was in dispute.
Implementing the process covered by the claim is, therefore, extremely simple
and insufficiency is unarguable.
- Furthermore,
this analysis also throws light on the inventive concept in the claim. Most of
the integers in it consist of no more than a description of the inevitable result
of carrying out the crystallisation. Even the requirement that the precipitated
solid phase formed after cooling is about 10g or more per litre of solvent adds
nothing. It sets a limit on recovery from the crystallisation process which is
so low as to be virtually meaningless. In the result I think that Mr Kitchin is
right to say that the inventive concept in this claim amounts to no more than
crystallizing aspartame from an aqueous solution without forced flow (i.e. statically)
on an industrial scale. It is very simple.
The
witnesses and the approach to the prior art
- Before
turning to consider the issues of substance, namely anticipation and obviousness,
it is convenient to consider the witnesses and the correct approach to the prior
art. Only a small number of witnesses were cross examined. None of them struck
me as being other than truthful. Mr Kitchin criticised Dr Kishimoto, a senior
Ajinomoto employee, as being an advocate for his employer’s case. I think that
is an unduly harsh criticism. He had been employed by Ajinomoto for a long time
and, inevitably, he recounted the history of its discovery and exploitation of
the patented process from the perspective of someone on the inside. I accept the
accuracy of his evidence. Its relevance is another matter.
- The
major witnesses were the experts. Daesang called Professor John Garside. He is
Principal and Vice Chancellor of the University of Manchester Institute of Science
and Technology ("UMIST"). Prior to this he was Professor of Chemical
Engineering at UMIST. He has had a long and distinguished academic career but
he has also had commercial experience, more recently as a consultant, as well.
Ajinomoto called Professor Michael J Hounslow, the Head of the Department of Chemical
and Process Engineering at the University of Sheffield. He is younger than Professor
Garside but also has had a distinguished academic career and has had considerable
commercial experience as well. Both the expert witnesses were clearly honest and
knowledgeable. If there is any criticism of them it is that they both were much
more able and knowledgeable than the notional skilled addressee of the patent
and prior art. The areas of dispute between them represented bona fide differences
of opinion. Professor Hounslow was the more exuberant of the two. He appeared
to enjoy the intellectual stimulus of being cross-examined and, at times, seemed
concerned to work out the underlying purpose of Mr Kitchin’s questions. I think
a little time would have been saved had he concentrated exclusively on answering
the questions put to him rather than speculate on what was likely to come next.
Mr Kitchin said he was lacking in objectivity. I do not agree. He is probably
a good lecturer who can deliver his message with some dash. His evidence was given
in this style. However I do not think it was in any respect untruthful or unfair.
When he expressed disagreement with Mr Kitchin or Professor Garside, he did so
courteously but quite forcefully. Professor Garside was quieter, but no less firm
in his views. Both of them were well able to explain to me the technology which
would have been known to the skilled addressee and both expressed views as to
how that addressee might have understood the prior art. I did not feel that in
giving evidence either of them stepped outside areas of technology familiar to
them.
- One
of the major areas of dispute between the parties is as to the meaning of the
only piece of prior art relied on, JP ‘267. In the end the meaning of that document
is for the court. However the differences in interpretation voiced by the Professors
reflects the submissions of the parties and, perhaps, throws light on its clarity
or otherwise.
- In
relation to obviousness, courts have frequently warned against the dangers of
hindsight. Once an invention has been made and understood it can be easy to arrive
at it from the prior art by a series of logical and apparently obvious steps.
The smaller the invention, the easier it is to analyse, explain and discredit
it. However the misleading effect of hindsight is not limited to the issue of
obviousness. When trying to understand the disclosure of a piece of prior art
it is just as essential to view it through the eyes of the skilled addressee at
the time without knowledge of the invention. After-acquired knowledge may result
in the reader getting more out of a document than he would have had he read it
at its date of publication or at the priority date of the patent.
The
Prior Art - JP ‘267
- Daesang
alleges both anticipation and obviousness in the light of JP ‘267. In this judgment
references to JP ‘267 are to the translation of it used at the trial. Daesang
also pleads obviousness over common general knowledge. In opening, Mr Kitchin
did not argue that case although he did not expressly abandon it. In reply, I
understood him to put rather more emphasis upon this attack. As indicated above,
it is necessary to determine what that prior art teaches without regard to the
existence of Ajinomoto’s patent. For ease of reference, and because there are
no line numbers on the pages of the translation, each of the extracts set out
below will be numbered.
- The
area of technology at which JP ‘267 is directed is indicated by the opening paragraph
of the section entitled "Detailed Description of the Invention". It
reads as follows:
Extract
1:
“This
invention relates to a method of purifying α-L-aspartyl-L-phyenylalanine
lower alkyl ester (hereinafter α-APE), more particularly to a method for
purifying crude α-APE by a combination of an ion-exchange method using an
anion-exchange resin, and a crystallization method."
α-APE
is aspartame.
- The
specification then refers to known methods of making aspartame and notes that
during production certain groups of chemicals are always made and appear as impurities.
It refers to certain known methods for removing these impurities but says that
they are not satisfactory for various reasons. The objective of the patent is
then stated:
Extract
2:
"The
purpose of this invention is to provide an industrial method whereby purified
α-APE can be isolated easily from crude α-APE.”
- I
should mention, in passing, that none of the witnesses suggested that they had
any difficulty in understanding what was meant by this statement and, in particular,
the reference in it to "an industrial method". The authors then describe
briefly their investigations:
Extract
3:
“The
inventors have investigated a process in which a solution containing crude α-APE
is put in contact with an anion-exchange resin, the resin is separated out, and
the α-APE is recovered by such methods as cooling crystallization. To improve
the recovery rate, the mother liquor is concentrated and recycled, and is once
again put into contact with an anion-exchange resin and a fresh solution containing
crude α-APE.
However,
the inventors found that repeated circulation of concentrated mother liquor significantly
reduces the crystallization yield for cooling crystallization, and that the resulting
crystals are small, which causes problems in an industrial operation. Also, the
α-APE produced by this type of method was not of satisfactory purity.
To
solve these problems the inventors attempted a process in which a portion of the
mother liquor was withdrawn and the remainder was concentrated and recycled. However,
it was necessary to withdraw a considerable amount, and it became clear that it
was difficult to achieve an α-APE recovery yield that was industrially acceptable.”
- Extract
3 is significant. It concentrates on trying to use the anion-exchange resin to
reduce the impurity level. It says nothing about the method of crystallization
used. Indeed, its reference to crystallization appears to be deliberately vague,
hence the use of the words "such methods as cooling crystallization"
in the first paragraph. The results were unsatisfactory.
- The
passage also explains the relationship between the quality of the crystals produced
and the recovery rate. As explained at paragraph 5 above, even if one crystallises
from a very hot saturated solution by cooling to a low temperature, a considerable
amount of the aspartame remains in the cool liquor at the end of the crystallisation
process. Jettisoning that would be wasteful. The first paragraph in Extract 3
is directed to increasing the "recovery rate", that is to say reducing
the amount of aspartame wasted by the process. The suggestion in that paragraph
is that the aspartame-containing liquor left after the crystallisation is concentrated
and recycled. No doubt the impurities in the liquor will also be concentrated
and recycled as well. Because of that, as the second paragraph explains, the yield
and quality of the recovered crystals of aspartame falls. The third paragraph
describes an attempt to minimise this problem, in other words to avoid excessive
wastage of aspartame but, at the same time, not to cause too great a deterioration
of the quality of the crystals recovered. This proposal involved only recycling
part of the liquor. As the authors point out, to make this work, that is to say
to maintain the quality of the crystals, it was necessary to jettison a "considerable
amount" of the liquor and this pushed down the rate of recovery of aspartame
to levels which were not industrially acceptable.
- The
solution to these difficulties is set out in the next paragraph as follows:
Extract
4:
"The
inventors have arrived at the current invention as a result of intensive investigation
of an industrial method for purifying crude α-APE. They have found that the
following procedure produces large crystals of purified α-APE without a decrease
in crystallization yield: α-APE is recovered by crystallization after an
aqueous solution of crude α-APE has been put in contact with an anion-exchange
resin; the mother liquid is concentrated, and α-APE is crystallized by such
methods as cooling; the resulting crystals are again dissolved in an aqueous solution
and this solution, together with a new batch of α-APE in aqueous solution,
is put in contact with an anion-exchange resin; continuing in like manner the
α-APE is crystallized, and the process is continuously repeated.”
- What
the authors are doing is replacing the simple recycling of the liquor which was
described in Extract 3 by a process which involves recovering the aspartame in
it in a more purified form for recycling. This recovery procedure involves concentrating
the liquor and crystallising out the aspartame (which should then be more pure
than the liquor itself) followed by redissolving this aspartame and recycling
it so that it is passed through the anion-exchange resin. It is apparent that
the main purpose of this procedure is to try to leave most of the impurities behind,
rather than recycling them.
- It
should be noticed that in this Extract, once again, no details are given of the
crystallization process. On the contrary, essentially the same general words "crystallized
by such methods as cooling" are used as in Extract 3. What is identified
as being the reason for turning failure into success and which was only discovered
after the claimed intensive investigation is the modified recycling procedure.
There is nothing to suggest that the method of crystallisation was investigated,
let alone identified as a significant factor. This passage is immediately followed
by the consistory clause:
Extract
5:
“Accordingly,
this invention provides a method for purifying α-APE, especially α-APE
containing AP and DKP as its main impurities. The method comprises: (A) A process
whereby impure α-APE in aqueous solution is put in contact with anion-exchange
resin in salt form. The impurities are adsorbed by the anion-exchange resin, and
are separated and removed, together with the anion-exchange resin. (B) A process
whereby purified α-APE is crystallized out of the aqueous solution that has
been separated from the anion-exchange resin, and the crystals are separated form
(sic) the mother liquor and recovered. (C) A process whereby the mother liquor
obtained in (B) is concentrated, α-APE is crystallized out of it and recovered.
(D) A process whereby the α-APE obtained in (C) is put into aqueous solution
and cycled back to process (A) so as to be put in contact with the anion-exchange
resin in salt form."
- Once
again, in this passage there is no suggestion that any particular type of crystallisation
has been or has to be used. The difference between the purification system described
in Extract 3 which is said not to work and the one in accordance with the consistory
clause (Extract 5) which it is claimed does work can be represented in the form
of the flow diagrams set out below in which the non-working system is on the left.
The flow diagram on the right has been marked to show each of the four steps (A)
to (D) referred to in Extract 5.
The
flow diagram on the right indicates that the recovered crystals, that is to say
the final product, is produced at stage (B).
- The
specification then states that the invention will be explained "in detail"
process by process. The description of step (A) takes up almost all of page 4
of the translation. The types of solvent which can be used are discussed as are
the suitable anion-exchange resins. Ways of feeding the solution past the resin
are also described, together with acceptable temperature ranges for that part
of the process. This passage also considers the concentration of the α-APE
solution, the amount of resin to be used and the residence time of the solution
within the resin.
In relation to the amount of resin to be used, the authors state that it must
be enough to adsorb the impurities in the α-APE and, in relation to residence
time, they say that it is to be sufficient to complete adsorption. The teaching
of this part appears to concentrate on ensuring that the impurities in the solution
are reduced to a minimum.
- The
description of process (B), that is to say the crystallisation stage, is very
short. It reads, in its entirety, as follows:
Extract
6:
"Process
(B)
Means
such as cooling are used to induce crystallization in aqueous solution that has
been treated with anion-exchange resin of process (A). Alternatively, crystallization
can take place after concentration. The purified α-APE that has been deposited
is then separated from the mother liquor and recovered.
When
process (A) is carried out with heating, α-APE is crystallized by cooling.
When the concentration of the aqueous solution is low, it is also possible first
to concentrate it and then cool it to recover α-APE. However, if the solution
is to be concentrated, it is desirable to do this at the lowest possible temperature,
or about 15 – 60oC, so as to avoid decomposition of the α-APE.”
- There
are also descriptions of stages (C) and (D) but they are not relevant to any of
the issues in this case. The authors describe the benefits of their process as
follows:
Extract
7:
“By
practicing the above invention, a highly purified α-APE can be obtained from
a crude α-APE. Also, large crystals of α-APE can be obtained without
decreasing the crystallization yield. Accordingly, α-APE can be purified
profitably by industry.”
- The
document ends with two worked examples in which the process of the patent is compared
with the unsuccessful recycling process described in Extract 3. These examples
only involve the collection of a few tens of grams of α-APE. They are laboratory
scale experiments, not industrial scale. They are about a thousandth of the scale
of the examples in the patent in suit. Example 1 of JP ‘267 is the process which
is said to produce the beneficial results. For present purposes it is only necessary
to set out the description, again brief, of stage (B). It reads as follows:
Extract
8:
"Process
(B)
The
passed-through liquid and the washing water were combined and kept at 5oC
overnight. The crystals precipitated were collected by filtration and washed with
36 ml of water to obtain 19.6g of purified α-APE.”
- The
authors operated the cycle 5 times. They give results which show that the purity
and yield of the α-APE recovered was as high at the beginning of those cycles
as it was at the end. The crystallization yield was stated to be about 80%. As
for purity, this was said to be 100% which, the authors explain, means that compounds
other than α-APE were below the detection limit or could not be detected
by high-speed liquid chromatography and thin-film chromatography. It also states:
Extract
9:
“The
crystals were 200 - 400μ in size in each repetition.”
- The
example of the non-working system, called the "Comparative Example"
in the translation, is described on pages 6 and 7 of the specification. It is
stated that stages (A) and (B) were carried out in the same way as in example
1. However, in this case the second purification stage was not used (see the flow
diagram at paragraph 37 above). On the first run through, the crystallisation
yield was 79.5%. The specification does not say anything about the size of the
crystals at this point. 75% of the aspartame-containing liquor which is left after
the extraction of the crystals is mixed with new aspartame-containing liquor and
introduced to the anion-exchange resin. As explained in relation to Extract 4
above, this presumably is an attempt to reduce the quantity of impurities which
are returned to the top of the anion-exchange resin. This recycling procedure
is done five times. By the fifth cycle, the crystallization yield had dropped
to 58%, the size of the purified α-APE crystals was 80 μm or less and
impurities were detected by thin-film chromatography.
The
teaching of JP ‘267 with regard to crystallisation.
- There
is no dispute that the general teaching in JP ‘267 tells the reader nothing about
how crystallisation is carried out. Daesang argues that the most relevant disclosure
on this issue is Extract 8 above relating to the examples. This is said to disclose,
at least by inference, that static crystallisation was used in that experiment.
This is explained by Professor Garside as follows:
"Example
1 describes the purification and crystallisation of a solution initially containing
3.73% by weight of aspartame. In step (B) the liquid having previously been passed
through an anion exchange resin was crystallised overnight at 5°C (presumably
left in the fridge overnight). I would assume from the text that the vessel was
neither stirred nor agitated. If stirring had been used I would have expected
this to be stated and information to be given as to the type of stirrer used and
the stirring speed (see for example the comparative example in the patent in suit)."
(Expert Report paragraph 54)
-
Based on this he says:
"If
I had read JP'267 I would certainly have considered the process described worth
investigating. I would have noted that the crystallisation was carried out using
a purification step and that the solution was crystallised in a static manner.
I would have expected the static aspect to be wholly or partially responsible
for production of large crystals." (Expert Report paragraph 57)
- Professor
Garside’s view that the document discloses static crystallisation is the opposite
of the conclusion of Professor Hounslow. Among other things, the latter said:
"71. My
overall perception of JP’267 is that it teaches that crystallisation on its own
does not work - that impurity reduction by some means other than simple crystallisation
is needed. The comparative example teaches that one-stage crystallisation alone
is likely to give poor yields and small crystals.
72. It
does not give any information in relation to whether the crystallisation vessel
should be stirred, or indeed any conditions that are to be used in the laboratory
crystallisation vessel. No information is given on how the crystallisation reported
in the Examples were conducted. …
"75. …
[JP ‘267] does not teach me anything about the recommended method of crystallisation
on an laboratory scale, let alone on an industrial scale, nor the method actually
used in Example 1. It says nothing about heat transfer, formation of a pseudo-solid,
or agitation. Nor does it lead me to believe that such pseudo-solid could be easily
converted to a slurry for solid-liquid separation and drying." (First Expert
Report)
- Furthermore
he said that, whatever may have been the process conditions employed for the examples,
there is nothing to suggest that static crystallisation should be used if the
purification system was to be applied on an industrial scale. This is not only
referred to in paragraph 75 of his First Report which is quoted above, but in
other passages as well:
"73. JP’267
is silent on which, if any, of the [crystallisation] conditions described above
are to be used [in the example].
74. Even
less does it give any information about the conditions to be used in an industrial
scale crystallisation vessel."
And
“82. …
The document does not teach me anything about the industrial-scale crystallisation
of α-APE.”
- The
question of what JP ‘267 teaches can be split into two parts (i) what does it
teach about the method of crystallisation used in the examples and (ii) what does
it teach about the method of crystallisation which should be used in any industrial
application?
(i)
what does JP ‘267 teach about the method of crystallisation used in its examples?
- The
description of the examples in JP ‘267 must be read in the context of the document
as a whole. There is nothing in the general teaching before the section dealing
with the examples which suggests that the authors had any interest in different
types of crystallisation. The references in the text to "crystallized by
such methods as cooling" reinforces the point. From the evidence given before
me, it appears that Professor Garside was not convinced that the authors knew
much about crystallisation. Furthermore, the patent claim at the beginning of
the document places no emphasis on the type of crystallisation employed. If the
particular method of crystallisation had been important to securing the alleged
better quality product of JP ‘267, it would be expected that the authors would
have demonstrated that by running examples of the process with and without the
relevant crystallisation method. This would have shown how failure to use the
particular method resulted in a poor product. One of the notable features of the
patent is that the authors do include comparative examples to highlight the factor
which they assert changes failure into success. But that factor is not the type
of crystallisation used. It is whether or not impurity-containing liquor from
the output of the filter should be recycled to the input of the anion-exchange
resin, as in the unsuccessful process, or cleaned of impurities by steps (C) and
(D) in the successful process. As noted above, the crystallisation step at stage
(B) – which is the relevant one for present purposes – is identical in
the two examples.
- In
my view, the authors are concentrating on a new way of reducing impurities in
order to obtain a better crystallised product at high yield. This is consistent
with the common general knowledge referred to at paragraph 14 above that impurities
can adversely effect crystallisation.
- This
is the context in which the teaching relating to the examples should be construed.
The same indifference to the method of crystallisation is shown as in the rest
of the teaching. One is left in the dark as to the precise method used. As Professor
Hounslow explained, the authors could have been referring to one of a number of
ways of carrying out the crystallisation. Professor Garside appears to have read
the absence of reference to agitation or any other more sophisticated method of
crystallisation as meaning that a simple static system was used. But the better
view is that the description of the method of crystallisation is short, not because
the method was simple, but because the authors were not interested in describing
in detail a step in the process which was of little interest to them. I do not
think that the skilled addressee who knew nothing of Ajinomoto’s patent, would
have read this document as Professor Garside does.
- The
lack of teaching of the use of static crystallisation manifests itself in another
way. For reasons set out below, even now it is impossible to be certain that the
authors actually used static crystallisation. If they did not use it, it is hardly
surprising they did not describe it.
- The
authors of JP ‘267 were aiming to make a pure product by isolating pure crystalline
aspartame from an impurity-containing liquor. The crystals have to be recovered,
for example by filtration. This can be seen in the flow diagram in paragraph 40
above. They say that small crystals do not work as well. They were seeking large
crystals with low impurity levels. It is not in dispute that, if the authors had
carried out the static crystallisation, they would have obtained the pseudo-solid
described in the Ajinomoto patent. The filtration step described in relation to
example 1 (see Extract 8 above) therefore would have involved filtering a solid
mass or the liquifaction of that mass before filtration. None of this is described.
- There
was no dispute between the Professors that the creation of a pseudo-solid would
have been a strange and unexpected event. In his First Report, Professor Hounslow
said, in a passage agreed with by Professor Garside:
"There
are a few known examples of pseudo-solids today. In order for this type of phase
to form, interaction between crystals is needed. The amount of interaction depends
on the number, mass, and length of crystals, but a volume fraction of at least
30 to 40% of crystals is usually required before the degree of interaction is
sufficient to form a pseudo-solid. I was not aware of such pseudo-solid phases
in 1982, and I do not believe they would have been well known. Certainly even
today I am not aware of any other systems in which a pseudo-solid phase forms
at a solids volume fraction of less than about 30%." (paragraph 40)
- Professor
Hounslow expanded upon this under cross-examination. He said that the pseudo-solid
would have appeared very unusual to the skilled team in 1982. In a passage in
his cross examination when he was responding to a suggestion that scaling up would
not have required any special techniques he said:
"Q
It does not require any special technique to enable it to be done? A. I don't
altogether agree with that because of the novelty of treating a product like this
statically, unprecedented. It forms a pseudo-solid which, as far as I know at
that time, was unprecedented. You can turn it into something which flows easily
mechanically which again is unprecedented and was not obvious to me from the laboratory,
so the suggestion that this might be, to use a word that has come up often, routine
does not seem to me to capture what is necessary." (Transcript Day 3 page
51)
- Later
he said:
"Q
Opening the valves at the bottom? A. Ah, that is a very different situation because
at this point everything has got to get through that valve. So we have to have
a terrifically convergent flow. Now, what I have discovered on the plant, in the
lab, of what we can understand is that it can fall down as a plug; but that it
can fall down as a plug and break up and go out through that valve, I have to
say continues to astonish me. I am not sure. I should tell you why I am astonished.
I saw [the] patent [used] on the plant and I was agog. I am looking down at a
large vessel with a vast amount of solid, and then three seconds later it is all
gone. Down through the bottom. So, I move well beyond speculation. I know what
happens, but confronted with this evidence, would I build a device in which everything
had to go through a small opening at the bottom? Certainly not.
…
Yes,
because it transpires this material has this astonishing property that it can
liquidize." (Transcript Day 3 page 58)
- No
doubt Professor Hounslow’s language is more colourful than would be used by Professor
Garside but I did not understand the underlying message to be in contention. The
creation of a pseudo-solid would have been a surprise. Indeed it is apparent from
the evidence in the trial that, on the small scale being used in the example in
JP ‘267, the flask containing the aspartame would not just have turned solid,
the contents would not fall out if you turned it upside down. The ease with which
it could be returned to a liquid was unprecedented. None of this is referred to
by the authors of JP ‘267.
- The
failure to report this is particularly noticeable in relation to the comparative
examples. There the differences between the patented and non-patented process
were being highlighted. The authors were paying particular attention to the structure
of the recovered aspartame, hence the disclosure of the size of the crystals.
This means that those crystals must have been subject to examination under a microscope.
If Daesang is right and the authors of JP ‘267 used static crystallisation, the
difference between the product of the two processes would have been impossible
to miss. Furthermore, on this hypothesis, when the authors of the document refer
to the second stage of the patented process and report that "the crystals
precipitated were collected by filtration", they ignored the fact that to
do that they needed to liquefy a pseudo-solid.
- Furthermore
the way in which the authors describe the non-patented comparative example is
particularly surprising. It will be recalled that the first run of that example
produced gave a 79.5% crystallisation yield and, because for that run there was
no inclusion of recycled, impurity-containing liquor, it would have produced good
quality crystals. The purpose of the experiment is to demonstrate that continued
recycling of the aspartame containing liquid which is left after the crystallisation
stage – something which is necessary to avoid wastage of aspartame – causes the
build up of impurities which affect crystal size. Therefore the purpose of the
experiment is, amongst other things, to demonstrate the difference between the
type of crystals obtained on the first run through with a clean new aspartame-containing
solution and the type of crystals obtained once there had been repeated recycling
of the liquor after filtration. Once again, if Daesang is correct and static crystallisation
was used, the product of the first run must have been a pseudo-solid which would
have needed to be liquefied in order to extract not only the crystals but to release
back the aspartame-containing liquor for recycling. By comparison, the later runs
which contained the increased levels of impurities would not have produced the
pseudo-solid. This difference would have been unmissable. It is not referred to
by the authors.
- In
my view it is by no means clear that the authors of JP ‘267 obtained a pseudo-solid
in any of their experiments. Had they done so, the likelihood is that they would
have reported that fact. Since Daesang’s case is that use of static crystallisation
would inevitably have produced a pseudo-solid, and it ran experiments to prove
as much, it must follow that it is not possible to be confident that the authors
of JP ‘267 used static crystallisation. If they did not use it, it is hardly surprising
that they did not describe it.
(ii) what does JP ‘267 teach about the method of crystallisation which should
be used in any industrial application?
- Even
if, contrary to the above conclusions, JP ‘267 does describe laboratory scale
experiments which included static crystallisation, does it describe or teach the
use of that type of crystallisation on an industrial scale? It does not. On the
contrary, as pointed out above, the general description and the claims in the
patent pay no attention to the particular type of crystallisation method used.
There is no suggestion that any particular type of crystallisation should be used
if an attempt were to be made to carry out the recycling process on an industrial
scale.
Anticipation
- There
is no dispute as to the law. Daesang must prove that JP ‘267 contains clear and
unmistakable directions to carry out a process falling within the claims of Ajinomoto’s
patent. The examples in JP ‘267 do not describe such a process, not least because
it is carried out on a laboratory scale. Furthermore, for the reasons set out
above, it does not contain clear and unmistakable directions to carry out the
examples using static crystallisation. For the reasons set out in the last preceding
paragraph, there is also no teaching of using such crystallisation in an industrial
scale process. The allegation of anticipation fails accordingly.
-
This leaves the question of obviousness. There are two topics which should be
considered first, namely the meaning of "on an industrial scale" and
the relevant common general knowledge which the skilled person in the art would
have had in 1982 as to the use and application of static and agitated crystallisation.
Industrial
Scale
- Mr
Kitchin argues that this expression is imprecise, which it clearly is. He says
that it is ambiguous but concedes that, on the law as it stands at the moment,
that is not a basis for attacking the validity of the claims. In any event, the
evidence does not support the suggestion that this term is ambiguous in the sense
that the reader does not know what it means. On the contrary, although the exact
boundary between industrial and non-industrial scale is unclear, none of the witnesses
appeared to have any difficulty in understanding the term. For example Professor
Garside refers throughout his report to "industrial scale" and "industrial".
He states that his own areas of expertise include teaching, speaking at conferences
and writing articles about industrial crystallisation issues. His comment on this
expression in the patent is as follows:
"Industrial
Scale
The
claims in the patent in suit refer to crystallisation on an " industrial scale".
This is not an exact term. Any process producing a product in industrial quantities
is on an "industrial scale". The specific size/scale depends very much on what
is being made. The crystalliser which is in fact used in the example of the patent
- 380 litres capacity - is at the small end of the industrial scale and in fact
is described by Mr Kishimoto as a pilot plant. This size of crystalliser is of
course what one would expect in a process for crystallisation of chemicals for
the food or pharmaceutical industries where production quantities are relatively
small." (Expert Report paragraph 27)
- Neither
he nor any other witness criticised the use of this expression. The use of the
expression "industrial scale" serves to distinguish commercial production
from the sort of activity which is carried on in a laboratory. Within reason,
the scientist carrying out a laboratory experiment does not care how expensive
the experiment is nor how long it takes to run it. His primary concern is to get
the product he is after. Running a process on an industrial scale is quite different.
Someone wishing to run a process on such a scale will want it to produce large
quantities of product, speedily, at reduced unit cost and with uniform and predictable
quality. No doubt each of these qualities is imprecise in the sense that they
involve relative values such as "large", "reduced" and so
on. A weight of product which would be called large if the product were an ingredient
for a pharmaceutical would, no doubt, be insignificant if it were steel ingots.
This is why Professor Garside pointed out that 380 litres was on the industrial
scale where the food or pharmaceuticals industries were concerned. For any particular
product, those in the art would have little difficulty recognising an industrial
scale. The borders of "industrial scale" may be imprecise, but that
is all. In the end I did not understand Mr Kitchin to disagree with this analysis.
"Industrial scale" incorporates at least those requirements of bulk
production, speed, reduced costs and uniform and predictable quality. Someone
wishing to turn a laboratory scale process into an industrial one must address,
or be hopeful that he will be able to address, all of those requirements.
Common
General Knowledge concerning the utility of static and agitated crystallisation
in industrial processes.
- Although
there was a great deal of evidence given in relation to the state of knowledge
of agitated and static crystallisation and as to what the skilled team’s approach
to selecting a suitable crystallisation process for the industrial production
of aspartame would have been in 1982, in the end there was much common ground.
- As
mentioned above, someone designing a plant for the industrial production of any
chemical, including aspartame, would be attempting to recover the final product
at speed, in bulk, at reduced cost and at uniform and predictable quality. The
crystallisation process chosen would be designed to meet those requirements.
- As
mentioned above, at a late stage before the commencement of the trial, the two
Professors read each other’s reports and marked up those passages with which they
agreed. Some of those agreed passages are of particular importance to this issue.
They include the following:
- From
Professor Garside’s Report:
"AGITATION
19. Another
cause of high nucleation was known to be a high rate of agitation. Agitation tends
to increase the number of nuclei although the processes involved are not completely
understood.
20. If
the system is not agitated then there may be a tendency towards lack of uniformity
of concentration and temperature within the system. The simplest way to keep the
system uniform is to use some form of agitation. Too much agitation however can
sometimes also lead to significant physical breakage of crystals which can give
rise to new centres for crystallisation ("pseudo nuclei") or to encourage
the production of so called secondary nuclei which arise in some way from the
pre-existence of crystals in the solution. Therefore, agitation can, by increasing
the number of pseudo or secondary nuclei, lead to a larger number of smaller crystals.
Secondary nucleation can also result in a change in the size distribution.
SIZE
DISTRIBUTION
21. Generally
a narrow size distribution (in other words uniform size of crystals) will permit
more efficient solid-liquid separation. …"
- From
Professor Hounslow’s First Report:
"55. A
widely adopted rule of thumb in crystallisation theory is that better crystals
can be obtained using programmed cooling. This involves controlling the rate of
cooling over time. In order to achieve this the whole vessel has to be reasonably
isothermal, which necessitates agitation. By controlling the rate of cooling,
one can control the driving force of the crystallisation process. If the driving
force is too high, high rates of nucleation ensue. As mentioned above, this results
in many small crystals, and perhaps some large crystals, and/or crystals with
undesirable shapes. Such mixtures of crystals are harder to separate from the
liquid phase."
- Together
these passages indicate that, subject to avoiding excessive agitation, an agitated
crystallisation gives better crystals and greater uniformity of product. The reason
for this can be explained by reference to the discussion of supersaturation set
out towards the beginning of this judgment. Assume that one has decided to use
cooling crystallisation to produce pure crystals and that the starting material
is a saturated solution of a substance, such as aspartame, at 70oC.
Also assume that the objective is to get as high a yield of crystals as possible
in as short a time as possible, while still getting a uniform product. The objective
of high yield means that one will want to cool to as low a temperature as possible
so that most of the target chemical comes out of solution. The objective of high
speed will mean that the cooling has to be done as quickly as possible. Assume
that, to meet these requirements an attempt is made to use static crystallisation.
The solution is put in a crystalliser which is fitted with cooling surfaces maintained
at, say, 10oC. Because there is no agitation, the temperature of the
charge in the crystalliser will vary from place to place. Those parts of the charge
which are immediately in contact with the cooling surfaces will be rapidly cooled
to 10oC or a temperature close to it. Those parts which are furthest
from such surfaces will be at a much higher temperature, up to 70oC.
Their cooling will be slower. The temperature of the charge will vary from location
to location. The charge is not isothermal. As explained in paragraph 11 above,
the result will be that there will be a wide distribution of crystal sizes because
the rates of nucleation and crystal growth will vary from location to location
within the charge. In an agitated system, variations in temperature of the charge
are minimised. It is for this reason that Professor Hounslow said, and Professor
Garside agreed, that the normal approach is to use programmed cooling so that
the whole crystalliser will be reasonably isothermal, and that that "necessitates"
agitation. It is also why Professor Garside said, and Professor Hounslow agreed,
that the simplest way to keep the system uniform is to use agitation. The resulting
product will have a narrow size distribution and, as Professor Garside said, this
permits more efficient solid-liquid separation.
- This
explains why, on an industrial scale, a better quality crystalline product is
obtained by using an agitated crystalliser. That this was, at the priority date,
the thinking of those skilled in the art can hardly be denied. Reference can be
made, for example, to a standard textbook; The Chemical Engineer's Handbook,
Fifth 5th Edition, edited by Perry and Chilton, McGraw Hill, 1973 ("Perry").
Professor Hounslow described this as the chemical engineer’s Bible. Professor
Garside agreed that it was often referred to in that way. He said that it would
perhaps be the first book that a chemical engineer would look at if he was coming
new to a particular process. Perry contains a section dealing with static crystallisation:
"While
the equipment required for such a system is extremely inexpensive and simple,
there is nothing simple about its operation. Nucleation is difficult to control
or predict, and the cooling rate varies considerably in an open tank depending
on the humidity and air velocity. Because of the lack of agitation there is only
a slow circulation within the system caused by differences in density, and supersaturation
levels normally rise to very high values. The result is formation of dendritic
crystals and crystals containing considerable quantities of occlusions of mother
liquor. It is also common to observe the formation of very large singular crystals
as well as "slush" consisting of copious quantities of extreme fines.
Removal
of the crystals is generally time-consuming and expensive ...
Such
systems are now used only for certain specialized applications such as the production
of Glauber's salt for synthetic sponges, or for very small-scale operations, or
in primitive areas where the cost of labor is extremely low."
- Professor
Hounslow said in relation to these passages that the discussed difficulties inherent
in using un-agitated vessels accorded with his own experience. Such systems were
difficult to operate and produced a very irregular product. He confirmed that
the commercial production of aspartame is not cost-effective on a "very small
scale" nor would it be produced in "primitive areas by the application
of copious cheap labour". It therefore falls outside the group of specialized
applications in which Perry says static crystallisation might be used notwithstanding
its known disadvantages.
- These
passages were also put to Professor Garside in cross-examination. He said that
what Perry said about static crystallisers was broadly true. He agreed that there
are perceived to be a number of "serious disadvantages" with them and
they certainly would not be the first choice for crystallization processes. They
would not be the thing you would look at first. On the other hand he suggested
that they would be "one of a suite of possibilities". However the latter
suggestion should be viewed in the light of other evidence he gave under cross-examination.
For example he was asked how the practical engineer would view the options:
"Q
… Now, is this right? If a chemical engineer is called in to advise and to consult,
then he would have at the forefront of his mind always the idea that in real life
you nearly always use agitated crystallization and not static crystallization
as the method of choice? A. Yes." (Transcript Day 1 page 73)
And
"Q.
In general, we agree that the natural choice is the agitated crystallizer, and
one of the reasons that you have an agitator in such a vessel is to promote more
even cooling and to cool it more rapidly? A. Yes." (Transcript Day 1 page
75)
- Professor
Hounslow was firm on this subject. In his First Report he said that in relation
to solution crystallisation, that is to say the sort of crystallisation at issue
here, one would "invariably" choose an appropriate agitated design.
He went on to say this:
"54. An
agitated vessel can be cooled much faster and more uniformly than an unagitated
vessel of the same size. Less cooling surface area is required, and there is a
reduced need to place cooling surfaces inside the crystallisation vessel. The
overwhelming expectation is that any crystalliser that requires cooling by the
uses of cooled surfaces (for example cooled by cold water), would most certainly
require agitation or some other means of forcing flow of liquid past the cooling
surfaces. This would be true of any process, whether involving crystallisation
not, but is particularly important in crystallisation, as failure to provide flow
near cooling surfaces results in much colder regions near those surfaces and the
direct precipitation, or fouling, of material onto the surfaces, thus reducing
their effectiveness for heat transfer and necessitating complicated and expensive
cleaning" (emphasis added)
- Under
cross-examination he was equally firm:
A.
Okay. So different rates of cooling; most certainly. It is in all the text books.
I teach it. I've done it. it works very well. Whether or not to agitate; I will
say again that has never occurred to me. I have never seen an unagitated crystallizer.
I have never seen a design method. I have not read, I think anywhere, of a problem
which is solved by not agitating other than minimising capital cost. Different
agitation regimes; yes. That is a sensible thing to do. Possibility of seeding
would be investigated; now, I would add to that list, but with the exception of
whether or not to agitate, these are routine sensible things." (Transcript
Day 3 page 15)
- Professor
Garside did suggest that static crystallisation might be used in some processes.
However even here, the areas where such an application would be appropriate was
very limited:
Q
Is it not a fact that in 1982 the concept or the process of static crystallization
had a somewhat poor reputation in terms of the end result that people thought
was going to come out? A. Broadly, that is a true statement, that the cases
where there would have been static crystallization would often be those where
the totality of the form of the crystal that you produced might not have
been of overriding importance. (Day 1 page 56 – emphasis added)
- Needless
to say, this does not apply to aspartame where the form of the crystals to be
produced is of importance. Some idea of how wedded those in the art were
to the use of agitated crystallisation was given by Professor Garside when he
was challenged on how long a skilled worker would persist with trying agitated
systems:
"Q
What I am wondering is this, how long do you envisage someone starting off down
the road knowing nothing except what was conventional, how long do you envisage
they spend their time investigating stirred crystallization before they gave up
and tried a new tack? A. A very difficult to that. It would depend very much on
the commercial pressures that were on that organisation, the amount of resource,
the way they put it and all sorts of things. I do not think one can give a general
answer to what ----
Q
Can you imagine them spending two years doing it? A. Yes, you could imagine them
spending two years." (Transcript Day 1 page 80)
- On
the evidence it appears that over the wide field in which crystallisation has
been used in industrial processes, static crystallisation has virtually never
been used. It is not suggested that it has ever been used where a consistent product
with narrow size distribution of the crystals was required. The reader of JP ‘267
would not find any indication in it that static crystallisation should be used
if the examples or teaching were to be applied on an industrial scale. There is
nothing in what is written which would suggest that any benefit it promises could
not be achieved, and indeed achieved better, by employing agitated crystallisation.
Unless the reader of JP ‘267 was taught, or had reason to suspect, that an agitated
system would not work, for compelling technical reasons he would automatically
use such a system. In the light of these considerations, the teaching of JP ‘267
does not render claim 1 of the patent obvious. However that is not the end of
the story.
- In
his reply speech, Mr Kitchin approached the issue of obviousness from a different
angle. The argument can be summarised as follows. The sort of chemist who would
carry out simple laboratory scale experiments on aspartame would carry out a static
crystallisation. He is likely to leave a pot of solution unstirred for crystallisation,
for example in a cupboard or in a fridge. He would find and examine the pseudo-solid
phase. He would determine solubility curves. He would look at crystals under the
microscope. Laboratory scale crystallisation experiments would be carried out
to examine the effect of crystallisation conditions on crystal size, size distribution,
habit and the effect of seeds (that is to say artificially added nuclei) and the
effect of these crystal characteristics on filterability. Different rates of cooling,
whether or not to agitate and different agitation regimes would be investigated.
He would find that the pseudo-solid breaks up and does not leave a residue. If
an agitated system was tried, filterability problems would probably have been
found in the lab, and certainly on a pilot scale. He would end up using static
crystallisation for the industrial process. It is said that all of this would
be done in the course of routine investigations.
- This
approach can be applied to the teaching in JP ‘267. The routine investigations
referred to above would be applied as of course to the repetition of the examples
in the patent. The sequence of investigations would be followed and one would
end up using a static crystallisation process. It will be appreciated that, for
this argument, the detailed teaching (or lack of it) in JP ‘267 is irrelevant.
Daesang’s case is that these routine investigations would be carried out by any
team which is trying to purify aspartame. In reality, JP ‘267 is a distraction.
Any company trying to make aspartame would carry out these investigations. In
substance, Daesang argues that the invention is obvious in the light of common
general knowledge.
- At
the outset it must be said that this argument is not well served by history. Aspartame
was discovered some 16 years before the priority date. A number of large chemical
companies became involved in trying to find a commercial product to put on the
market. If Daesang’s argument is right, all of them should have stumbled on the
pseudo-solid at a very early stage and, from there, have arrived at the use of
a static crystallisation process. If that happened, no one seems to have published
the fact. Even the discovery of the pseudo-solid is not reported. The authors
of JP ‘267, who on this analysis, should have found the pseudo-solid and from
there worked out that it was static crystallisation which was the important step,
seem to have failed to do so.
- The
argument proceeds along a series of small logical steps which is very easy to
construct after the event. It is the kind of hindsight analysis which can be unfair
to patentees. As Mr Prescott argues, even if one found the pseudo-solid, there
is a significant prospect that it would be regarded as an irrelevance or worse.
Professor Hounslow suggested that the last thing one would want to try to scale
up would be something which set solid in the crystalliser. This would be a significant
deterrent to going down this route. That would be particularly so unless it was
known or reasonable to predict that the creation of the pseudo-solid would be
better than the product of a normal agitated system. If the products were likely
to be equivalent, there would be obvious technical reasons for not going down
the pseudo-solid route. Why create a pseudo-solid which might give problems of
encrustation and variability in product and which would need to be liquefied before
it could be filtered, when a liquid could be made directly by known agitation
processes? As far as the evidence goes, there was no reason to believe or suspect
that the pseudo-solid route would produce the better crystals. A static system
would be expected to produce just those differences in supersaturation which have
commonly led to unpredictable products with wide size distribution of crystals.
There is nothing to suggest that aspartame in a static system used on an industrial
scale would have been any different. The point can be put another way. Assume
that the skilled worker discovered that a satisfactory product could be obtained
on the small scale with static crystallisation, notwithstanding the fact that
it inevitably suffered from uneven temperature distribution and, therefore, uneven
levels of supersaturation. Even in those unpromising conditions, a promising filterable
product could be obtained. There is nothing to suggest that the skilled worker
would believe that the same or better results would not be obtained by using the
well known, more controllable and faster agitated system in which crystal size
distribution would confidently be expected to be narrower with the result that
filterability would be better.
- It
seems to me that the skilled worker’s experience would suggest to him that he
would obtain technically better results by using the agitated system. If that
was his view, he would not choose or contemplate a static system for commercial
production because it would fail to deliver those benefits of speed, predictability,
uniformity and cost saving required in such a process. If, on building a pilot
plant or going into full scale production he found there was a problem with separating
the crystals from the liquor, he would then have to try to find out what had caused
it. Perhaps after two years he would have given up trying to use agitated crystallisation.
Professor Hounslow gave a list of possible routes he would have examined to try
and solve the crystal/liquid separation problem. It is not necessary to set them
all out here. He said in re-examination that, after running through a number of
possible options he would "probably cast about rather wildly" looking
for something else to change.
- Professor
Hounslow expressed the view that the Ajinomoto process was counterintuitive and
far removed from the accepted wisdom of the day. I accept that evidence. Whether
one starts from JP ‘267 or common general knowledge, claim 1 is not obvious.
The
subsidiary claims
- Ajinomoto
only asserts independent validity in relation to claims 4 to 6. In view of the
findings above, all the subsidiary claims survive. However I can deal briefly
with each of claims 4 to 6 in case the finding of validity of claim 1 is overturned
on appeal. None of them was the subject of spirited defence by Mr Prescott.
- Claim
4 provides:
"A
process as claimed in claim 1, 2 or 3, wherein the temperature of the refrigeration
medium used in the process is from -5 º to 35 ºC."
- Professor
Garside said that this is a very broad range and determining the preferred coolant
temperature is merely a matter of carrying out straightforward trials on the equipment
and the cooling device used. I accept that evidence. If Claim 1 were invalid for
obviousness, this claim would be also.
- Claim
5 provides:
"A
process as claimed in any of claims 1 to 4, wherein the maximum distance between
the cooled solution and the cooling surface is 500 mm or less."
- Professor
Hounslow acknowledges that for liquids and simple suspensions, the choice of the
dimensions would be relatively straightforward. He says that it is not so straightforward
in the case of a pseudo-solid. Professor Garside says that the preferred design
of cooling arrangements is something that can be determined by straightforward
calculations and trials. I accept the latter evidence. I would only add that it
would be obvious in a non-stirred system where temperature differences could be
a problem, to ensure that the distance between all parts of the charge in the
crystalliser and cooling surfaces are kept to a minimum. That, in effect, is the
inventive concept of this claim.
- The
only other claim to consider is claim 6. This provides:
"A
process as claimed in any of claims 1 to 5, wherein desupersaturation is carried
out by cooling and/or by effecting forced flow, after the formation of the pseudo
solid phase."
- As
Mr Kitchin points out, Ajinomoto only attempts to support the validity of this
claim if the words "and/or" means "and". Mr Prescott does
not suggest otherwise nor did he argue the point of construction. In my view,
the words "and/or" mean what they say. They are not limited to cases
of "and". Professor Garside says that cooling alone would give supersaturation
and that that is a usual way of causing crystal precipitation. This evidence was
not challenged. If claim 1 were invalid for obviousness, this claim would be also.
- In
the result, Daesang’s claim fails. The patent is valid.