Monday, December 15, 2014

Obviousness, common general knowledge and expectations of success: Leo gets a mauling

Obviousness and common general knowledge are features of patent law
that are of very limited application, if any at all, in most other
areas of intellectual property.  For this reason it all too often
happens that Katposts on these issues are skipped by readers who
consider patent law too hard, abstruse or arcane to deserve their
attention.  The decision of Mr Justice Birss in the case reviewed below
is however so interesting that this Kat hopes that some of the good folk
who habitually skip the patent stuff will give it a read. The author is
occasional and much-appreciated guest contributor Suleman Ali (Holly IP), who writes as follows:

Teva UK Limited &
Teva Pharmaceuticals Limited v Leo Pharma A/S & Leo Laboratories Limited
[2014] EWHC 3096 (Pat) is a decision by Mr Justice Birss in the Patents Court, England and Wales. This
case is about treatment of psoriasis with a combination medicinal formulation
comprising two substances known to treat psoriasis (a corticosteroid and a
vitamin D analogue) and a particular solvent that is able to stabilise the
combination formulation. The invention lies in the putting together of the two therapeutic
substances in the same formulation and the choice of the solvent. The decision
mostly concerns whether this was inventive. Since the invention could be seen as an ‘incremental’
one which concerns optimising use of known drugs, rather than the discovery of
new drugs, this decision provides insights as to how such incremental inventions
will fare for inventive step in the Courts of England and Wales. More broadly the decision adds
to the case law of how inventive step is assessed in a complex pharmaceutical
setting. 

Other recent
pharmaceutical cases concerning inventive step 

There have been several cases in recent times where inventive
step been determined in the context of a pharmaceutical invention. In Novartis AG v Generics (UK) Limited (t/a Mylan) [2012] EWCA Civ1623, discussed by the IPKat  the Court of Appeal had to review the decision of Floyd  J  in assessing inventive step where the compound
went through several steps during research and development. Whether or not the
compound would have passed each test would have been difficult to predict, and
yet the compound was found to be obvious. 


In Hospira UK Ltd v Genentech Inc
[2014] EWHC 1094 (Pat), noted by the IPKat here, Birss J had to deal with inventive step of an ‘incremental’
invention, and he found the inventive concept, which related to a dosage
regimen, to be obvious. 


In Glenmark
Generics (Europe) Limited & others v The Wellcome Foundation Limited &
Glaxo Group Ltd, [2013] EWHC 148 (Pat), reported by the IPKat here, Arnold J decided that a
combination product for treating malaria was obvious. 


From these cases we can see how inventive step
is being assessed by these courts where the invention concerns a
multi-step R&D process. In addition it seems clear that incremental inventions
in the pharmaceutical field are being found invalid for inventive step. 

The present invention 

In this case Leo was defending two patents, EP 1178808 and
its divisional EP 2455083. The claims of EP 1178808 relate to a pharmaceutical
composition comprising vitamin D or an analogue of it, a corticosteroid and a specific
solvent. EP 2455083 relates to a more specific embodiment where the vitamin D
analogue is calcipotriol and the corticosteroid is betamethasone. These therapeutic
substances were known for treating psoriasis, and the solvent, polyoxypropylene
15 stearyl ether, was disclosed in a prior art publication ‘Turi’, US patent
4,083,974. There are several aspects to the contribution being made by the
invention. One lies in realising that providing the two therapeutic substances
in a single formulation would increase patient compliance in comparison to
asking patients to take two separate products. However, given that the two
substances are stable at different pHs, they cannot simply be added to each
other in an aqueous formulation. A second aspect of the contribution is making
a non-aqueous formulation choosing to use polyoxypropylene 15 stearyl ether as
a solvent. 

The expert witnesses
and the ‘team’ for inventive step 

The expert witnesses gave evidence on treatment of psoriasis
with the two substances, whether they would consider combining them in a single
formulation an whether the co-formulation would be stable. Under
cross-examination it became clear that the expert reports contained ‘sweeping
generalisations’ and in their testimonies they were guilty of ‘overstatement’.
However Birss J was appreciative of the contribution of all the experts which
allowed him to determine the common general knowledge in the art and on the
skilled person being a team that included a skilled clinician and a skilled
formulator of pharmaceutical compositions. 

Common general knowledge 

Birss J held that, from the common general knowledge, it was
known that patient compliance was important in psoriasis and that using a
single combination formulation would increase compliance over
prescribing two different
ones. However he did not accept Leo’s argument that the common general
knowledge of the skilled clinician would assume that combining the two
substances in a single composition was not possible. Birss J built up a
complex
picture of the common general knowledge of a skilled formulator and how
such a person would tackle the making of non-aqueous solutions
containing substances
sensitive to pH. A key point was that the skilled formulator is an
empiricist who
would proceed to test solvents that might have worked. 



Birss J noted that there are some cases where inventive step can
be decided on common general knowledge alone, and commented that Teva’s inventive
step attack was slightly unusual in that it started from the common general
knowledge (knowing that a single combination product would increase compliance)
and involved adding a prior art reference, Turi, which disclosed the solvent.
This was not a situation where inventive step was assessed by identifying the
differences between the invention and primary prior art reference. 

The information in
the patents 

Leo’s patents make note of the fact that patient compliance could
be improved by using a single combination product. They also give the
results
of stability tests and provide evidence of a better therapeutic effect
than using
the substances separately. The patents also refer to ‘synergy’
occurring, but this
aspect was not pursued by Leo in the trial to show inventive step. Had
it been, it would have been a valuable addition to the case law in this
area. 

The appropriate inventive
step test 

Birss J recited the much-quoted statement from Generics v Lundbeck which opens:

‘The question of obviousness must be considered on the facts
of each case. The court must consider the weight attached to any particular
factor in the light of all the relevant circumstances.’ 


He considered this to mean that ‘obvious to try’ is simply
‘one of a variety of factors’ to be considered. He added:


‘Obvious to try cases usually involve consideration of the level
of expectation of success but one cannot lay down a general characterisation of
what the true level of expectation must be in every case beyond stating that it
must be a fair one. In that way the differences between different cases is
taken into account. It is wrong to ask whether something might achieve a particular
desired effect. It is correct to ask whether it was obvious that it would
achieve that effect.’

What does Birss J mean? Is
he saying one should not judge inventive step by asking whether the skilled
person would have predicted it would have worked but instead, once the
invention has been found to work, one should then ask ‘was it obvious that it
would have worked’? Is that the correct approach to ‘expectation of success’?
Readers' comments in this point would be most appreciated. 


 From Birss J’s comment it seems that ‘expectation of success’
is something complex and very fact-specific. I also wonder whether the learned judge should
have defined what ‘success’ would be in the present case. Was it simply
production of a stable combination composition or was it providing better therapeutic
results? 

Was the invention
obvious? 

Birss J started his inventive analysis from the position that
a combination formulation was desirable from the common general knowledge to
increase patient compliance. The skilled clinician would expect the combination
formulation to be more effective than using the therapeutic substances
separately. It was well known, for example, that the corticosteroid would
reduce the irritation caused by calcipotriol. 


Leo argued there would be ‘prejudice’ against use of corticosteroids
due to potential side effects over the long term. However Birss felt there
would not be prejudice against short term use or in the combination. 




Birss J then switched his analysis to the perspective of the
skilled formulator. It was obvious to use a non-aqueous solution to overcome
the issue of the substances being stable at different pH’s. The issue came down
to whether the solvent disclosed in Turi would be obvious to use in the
formulation. Turi disclosed a non-aqueous composition containing the solvent
and betamethasone (one of the therapeutic substances used in the present
invention) and based on this Birss J concluded that the skilled formulator would not
ignore it or dismiss it. 


Leo criticised the benefits described in Turi as ‘illusory’,
but Birss J felt this was an overstatement. Leo also put forward arguments based
on the fact that the solvent disclosed in Turi was not widely used and this
might would add potential cost, time and uncertainty, for example if a
regulator required extensive testing of the solvent. However, Birss J felt that
whilst factors such as this can be relevant they rarely outweigh technical
considerations. 


A crucial point for inventive step was the skilled person’s
perception of how difficult it would be to solve the pH problem. The expert
witnesses had disagreed on this issue, but Birss J felt that Teva’s case on this
was more persuasive. The skilled formulator presented with Turi would proceed
to test the solvent it disclosed and result would be positive. A clinical study
would then be carried out using the combination formulation and this would
confirm it was an effective treatment. This meant the invention was obvious. 

Inventive selections
and the Technograph test
 

Birss J went on, tantalisingly, to discuss the situation in which the
selection of the solvent would be inventive. If evidence had been provided that
a ‘vast range of obvious agents had not worked’ then this could have been ‘compelling
evidence of non-obviousness’. However Leo had not done this. 


Birss J also asked whether his analysis was an example of the
unfair step-by-step approach identified in Technograph Printed Circuits Ltd v
Mills and Rockley (Electronics)Ltd [1972] RPC 346. In that case Lord Diplock had
said:


"The cross-examination of the respondents' expert
followed with customary skill the familiar "step by step" course. I
do not find it persuasive. Once an invention has been made, it is generally
possible to postulate a combination of steps by which the inventor might have
arrived at the invention…if he had started from something that was already
known…"

Birss J felt he had not made this error since his analysis had
considered the normal steps in development of a pharmaceutical product and thus
could not have been influenced by hindsight. 

Unanswered Questions 

1. How should ‘expectation of success’ have been addressed
for this case? Should Birss J have analysed this based on ‘would the skilled
formulator have expected the solvent disclosed in Turi to have worked?’ instead
of ‘would the skilled formulator have tested the solvent disclosed in Turi?’.
Often in pharmaceutical cases there is little chance of success for any one
candidate, but the skilled person would have had reasons to test it. 


2. If the inventive step analysis follows the normal steps
in development of a pharmaceutical product, is there a danger of failing the
Technograph test? How can one determine one has not failed the Technograph
test? 


3. Are other incremental inventions also likely to be found
obvious? It seems that often for such inventions the contribution is modest and
there is a lot of relevant prior art. 


4. What does it take for a combination product to be
inventive? Does it need to have an element of inventive selection or a
demonstration of synergy?


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