Download Accord v Medac Approved Judgment

Neutral Citation Number: [2016] EWHC 24 (Pat)
Case No: HP-2014-000011
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Royal Courts of Justice
Strand, London, WC2A 2LL
Date: 13/01/2016
Before:
THE HON. MR JUSTICE BIRSS
--------------------Between:
ACCORD HEALTHCARE LIMITED
- and MEDAC GESELLSCHAFT FÜR KLINISCHE
SPEZIALPRÄPARATE MBH
Claimant
Defendant
----------------------------------------Adrian Speck QC and Lindsay Lane (instructed by Taylor Wessing) for the Claimant
Charlotte May QC and Mark Chacksfield (instructed by Bristows) for the Defendant
Hearing dates: 23rd, 24th, 26th November 2015
---------------------
Approved Judgment
I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this
Judgment and that copies of this version as handed down may be treated as authentic.
.............................
MR JUSTICE BIRSS
MR JUSTICE BIRSS
Approved Judgment
Accord v Medac
Mr Justice Birss:
Introduction
1.
This is a case concerning patent EP (UK) 2 046 332, entitled “Concentrated
Methotrexate Solutions”. The patent claims the use of a formulation of methotrexate
with a concentration of about 50 mg/ml for the treatment of individuals with
inflammatory autoimmune diseases by subcutaneous injection. The point of the
invention is that known concentrations of methotrexate used for this indication were
at a lower level (no more than 25 mg/ml) and so by using a higher concentration of
the drug, the injection volume can be reduced and so the injection will be less painful.
2.
The patent has a priority date of 21st July 2006. The patent was originally filed and
granted in the German language. The English translation is agreed.
3.
The proprietor of the patent is the defendant, medac. The company writes its name
with a lower case “m”. In this judgment I will use the lower case form of the name
unless the word appears at the start of a sentence. Medac is a privately owned
German company which promotes the development and marketing of therapeutics in
malignant diseases, particularly therapeutics for use in treating cancer and
autoimmune diseases. This patent protects medac’s Metoject® syringe and pen
products. These were launched in the UK in 2008 and are now widely used in the
treatment of rheumatoid arthritis (RA) and related inflammatory conditions.
4.
The claimant in this action is Accord, a generic company. It is seeking to clear the
way in order to launch its own 50 mg/ml injectable product. Accord claims that the
patent is invalid; medac contends that the patent is valid.
The issues
5.
Claims 1, 13, 15 and 27 have been asserted as independently valid by medac. They
are as follows:
Claim 1: Use of methotrexate for the production of a
medicament to be administered subcutaneously for the
treatment of inflammatory autoimmune diseases, wherein the
methotrexate is present in a pharmaceutically acceptable
solvent at a concentration of about 50 mg/ml.
Claim 13: Use according to claim 7, wherein the ready-made
syringe contains a dosage of 5 to 40 mg, in particular 5.0, 7.5,
10.0, 12.5, 15.0, 17.5, 20.0, 22.5, 25.0, 27.5, 30.0, 32.5, 35.0,
37.5 or 40.0 mg, of methotrexate.
Claim 15: Methotrexate for use in the treatment of
inflammatory autoimmune diseases, wherein the methotrexate
is to be administered subcutaneously and the methotrexate is
present in a pharmaceutically acceptable solvent at a
concentration of about 50 mg/ml.
Accord v Medac
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Claim 27: Methotrexate for use according to claim 21, wherein
the ready-made syringe contains a dosage of 5 to 40 mg, in
particular 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0, 22.5, 25.0, 27.5,
30.0, 32.5, 35.0, 37.5, or 40.0 mg, of methotrexate.
6.
Claims 13 and 27 are dependent on intermediate claims (7 and 21) between claims 1
to 13 and 15 to 27 respectively. Those intermediate claims provide that the
concentrated methotrexate solution is contained in a ready-made syringe.
7.
Claims 1 and 13 are Swiss form claims, claims 15 and 27 are purpose limited product
claims (EPC 2000). Nothing turns on this and no issues of claim construction arise in
this case.
8.
The issues are:
i)
ii)
Obviousness in the light of:
a)
The common general knowledge alone;
b)
A paper “Methotrexaat buiten de kliniek” by Jansen et al. (1999)
Pharmaceutisch Weekblad, Volume 134, No 46, p1592 (Jansen). The
original language of the paper is Dutch. There is an agreed translation;
c)
A letter “Tolerance of parenteral, higher dose methotrexate in children
with juvenile chronic arthritis” by Russo and Katsicas (2000) Clinical
and Experimental Rheumatology, Volume 18, No 3, p425, (Russo);
d)
The fact that the patent encompasses embodiments which make no
technical contribution. This is directed to claims 1 and 15 which
provide no limitation on volume. Accord argues that some of the
products within the claim offer no pain reduction advantage over the
prior art and therefore the claim encompasses embodiments which
make no technical contribution.
Insufficiency. The argument is that the patent does not render it plausible that
the claimed concentration could be safely administered to patients. This is a
squeeze on inventive step.
The witnesses
9.
Accord called two experts: a clinician and a formulator. Medac called an expert
clinician only.
10.
Accord called Dr Andrew Östör as its expert clinician. Dr Östör is a Consultant
Rheumatologist and Director of the Clinical Research Unit at Addenbrooke’s Hospital
in Cambridge. He is an Associate Lecturer in the Faculty of Clinical Medicine at the
University of Cambridge. He is also a Fellow of the Royal College of Physicians in
London and Edinburgh respectively.
11.
Accord called Dr Peter Rue as its expert formulator. Dr Rue is a Visiting Professorial
Fellow to the Department of Pharmacy of the University of Aston in Birmingham. He
also currently acts as a commercial pharmaceutical consultant. He has many years of
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experience working in formulation and development in industry. His experience
includes having worked as Head of the Pharmaceutical Development Department at
Glaxo Research and Development from 1990 to 1995.
12.
Medac called Professor Ulf Müller-Ladner as its expert. Prof Müller-Ladner is
currently Director of the Department of Rheumatology and Clinical Immunology at
the Kerckhoff Clinic in Bad Nauheim. He is also Professor of Internal Medicine and
Rheumatology at the Justus Liebig University Giessen and President of the German
Society of Rheumatology for the year 2015-2016. Prof Müller-Ladner has previously
worked with medac in a number of capacities, including as a consultant and as a
member of its research advisory board. He has also acted as an expert witness for
medac in a US action in respect of a related patent to EP 2 046 332 (US Patent No.8
664 231). Prof Müller-Ladner is a native German speaker but gave his evidence in
English.
13.
Each witness gave their oral evidence fairly, aiming to assist the court. The parties
made detailed submissions about aspects of each witness’s evidence but they are best
dealt with in context.
The person skilled in the art
14.
One of the important disputes in this case concerns the identity of the person skilled in
the art. Accord submitted that the skilled person is a team consisting of a clinician,
specialising in the field of inflammatory autoimmune diseases such as RA, and a
formulator. The team may also include a nurse and a pharmacist although these latter
two are not the focus of the controversy. Medac submitted that the skilled person is
the clinician alone. The identity of the clinician following medac’s approach is the
same as Accord’s. The major issue is about the position of the formulator. Accord
submits it is plain from the patent itself that it is directed to a team consisting of a
clinician and a formulator. So the skilled person is such a team.
15.
Looking ahead to medac’s case on obviousness, it makes the following submissions.
Medac argues that the formulator would only be brought into a team at the instigation
of the clinician, that it would not be obvious to the clinician to think there was any
need to produce a new formulation of subcutaneous methotrexate and so the clinician
would not approach a formulator at all. Therefore it is unfair to define the team as a
team consisting of a clinician and a formulator from the outset. To do so is to fall into
the trap identified by the Court of Appeal in Schlumberger v EMGS [2010] EWCA
Civ 819 in that it may involve hindsight to postulate a team consisting of two distinct
disciplines which had not been put together in reality before the priority date. The
fact that, given the patent, one would put the two disciplines together into a team in
order to implement the teaching does not mean that that team is the correct person
skilled in the art for the purposes of obviousness. Medac also contends that the way
in which Accord put its case in evidence was on the basis that impetus came from the
clinician and so it is not legitimate to allow Accord to change its case in closing after
the evidence had been heard.
16.
Starting with the general law: a patent is directed to those persons likely to have a
practical interest in the subject matter (see e.g. Medimmune v Novartis [2012] EWCA
Civ 1234 at paragraphs 72 and 76). In appropriate cases the skilled person can be a
team.
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Accord v Medac
17.
Schlumberger shows that the skilled person in the context of obviousness is not
necessarily the same as the skilled person from the point of view of reading and
implementing the patent. In paragraphs 55 and 63 of his judgment in Schlumberger
Jacob LJ (with whom Sullivan and Waller LJ agreed) explained that while it was
generally true that the same person/team would be considered for both purposes, it
was not necessarily so as a matter of law.
18.
What are the legal principles which govern the question ofwhether the skilled person
or skilled team are the same for both purposes or not? The court in Schlumberger
identified the following aspects as relevant. First, if an invention brought together
two disparate fields and was therefore “art changing”, then the identities of the
person/team from the two different perspectives may be different (Jacob LJ
paragraphs 55 and 64). Second, (paragraph 65) the court explained that a key
question is generally – what problem was the patentee trying to solve? That leads one
to consider the art in which the problem lay. It is the notional team in that art which is
relevant. Third, you cannot assume that a person in one field would know what was
known by a person in another field, proof is required (paragraph 70). Fourth, and
importantly in my judgment, the skills (and mind sets) of real persons or teams in the
art are what matter when one is constructing the notional skilled person/team to whom
the invention must be obvious if the patent is to be found invalid (paragraph 42).
19.
The evidence of both Dr Östör and Dr Rue was that the skilled person was a team
consisting of a clinician and a formulator. Prof Müller-Ladner’s evidence was that the
patent was addressed primarily to a clinician and that they would be able to call on the
expertise of other people such as formulators and pharmacologists.
20.
On the question of the person to whom the patent is addressed, in my judgment
Accord is correct and I prefer the evidence of Dr Östör and Dr Rue on the issue. The
document itself is not directed to a clinician alone who may or may not choose to
involve a formulator. It is directed to a team in which the clinician and the formulator
are working together. Formulation is at the heart of the matter. The invention is the
use of a new dosage form of a known drug (methotrexate) to treat diseases it is
already indicated for (RA and other diseases) using a known mode of administration
(subcutaneous). The new dosage form is a formulation of the drug in a solvent at a
particular concentration (about 50 mg/ml). The patent is plainly addressed to such a
team in a pharmaceutical manufacturer. After all that is where formulators work and
that is where these new dosage forms come from. Prof Müller-Ladner accepted in
cross-examination that the patent is directed to industry. It is common ground that the
clinician will be someone with experience of treating patients, but for the purposes of
considering this patent, they will work with the formulator.
21.
Turning to the question of the skilled person/team for the purposes of obviousness, I
will address the factors mentioned in Schlumberger. I am satisfied that such teams
existed in reality irrespective of the patent. Prof Müller-Ladner accepted that there
were companies which might wish to make methotrexate products to compete with
those already on the market and accepted that a skilled team working in industry
would typically include a formulator and a clinician. Therefore the existence of such
a team is not an assumption, it is based on the evidence. Moreover this is not a case
in which the invention is “art changing” or has brought together two disparate fields.
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Accord v Medac
22.
Consideration of the problem(s) which the invention aims to solve raises a number of
issues. The patent is directed to the problem of pain. The problem to be solved
described in the document is pain on subcutaneous injection caused by a relatively
large volume of drug being injected. The solution is a higher concentration of
methotrexate which therefore permits a lower volume to be used for a given dose.
Another aspect of the problem advanced by the patentee at trial (albeit not mentioned
in the patent) is a concern about possible side effects due to the higher concentration
deterring the skilled person from going forwards or at least meaning that there was not
a sufficient expectation of success in the testing which would be required to make the
invention obvious. Finally another aspect of the patentee’s case is that the skilled
person would not think there was a problem to solve at all. Taking these issues into
account does not mean that the skilled person/team should be considered as a clinician
alone rather than a team.
23.
Of course it is true that clinicians treating patients did not do that in a team with a
formulator and so another real skilled person/team would be a clinician on their own
(or in a team with a nurse). If the invention is obvious to that skilled person/team then
the patent will be invalid. However I conclude that it is also legitimate to consider the
issues of inventive step from the point of view of a skilled team comprising a clinician
and a formulator. It is not an exercise in hindsight to look at the matter that way. For
the patent to be valid, the invention must not be obvious to such a team.
24.
Standing back, there is really nothing surprising about this conclusion. Since such
real teams existed, it would be wrong in principle if a patent was upheld when the
invention was obvious to such a team. Real persons skilled in the art are entitled to
make obvious developments without fear of infringing patents.
25.
I reject the submission that it was not open to Accord to put its case about the skilled
team in the manner it did. Both Accord’s witnesses gave evidence based on the same
skilled team comprising a clinician and a formulator, and both gave evidence on the
basis that the initial impetus comes from the clinician. That position has not changed.
I would agree that a case based on the formulator deciding to do something without an
impetus coming from the clinician in the team would be a change but, whether or not
Accord made such a submission, it is not the argument I am considering.
26.
The clinician in the team would be a consultant level rheumatologist. They would
have been at medical school for six years with four years general medical training and
three to six years specialist training at registrar level. They would have significant
experience in treating patients.
27.
The characteristics of the skilled formulator were not addressed in detail. The focus of
Dr Rue’s experience with formulation was on tablets but he also had experience of
injectable formulations. His experience formulating injectable dosage forms was
much less than his experience with tablets but, given that tablets are by far the most
common dosage form, this is not surprising. I am satisfied he is in a position to help
the court in relation to the thinking of a skilled formulator asked to make an injectable
formulation. In my judgment the skilled formulator would be someone with
experience in developing injectable formulations (including subcutaneous) albeit in
the context of developing dosage forms in general.
MR JUSTICE BIRSS
Approved Judgment
28.
Accord v Medac
The point about a nurse in the team arises in this way. At the priority date, in both the
UK and Germany, the doctor would prescribe subcutaneous methotrexate to a patient
and a pharmacy would dispense it. However there was a difference between the two
countries in how the drug was administered. In Germany it was (and is today) the
doctor who administered subcutaneous methotrexate whereas in the UK this task was
and is carried out by nurses, sometimes specialist nurses. There was also selfadministration by patients in both Germany and the UK. Thus Prof Müller-Ladner
had extensive experience with the administration of subcutaneous methotrexate
whereas Dr Östör did not. Moreover while Prof Müller-Ladner therefore was directly
familiar with the injectable methotrexate products available on the market in 2006, Dr
Östör did not know what the pharmacists would dispense to fulfil a prescription he
would have written for subcutaneous methotrexate. Consistently with this, Dr Östör
did not know what concentrations of methotrexate were being administered to patients
at that time. So although I do not believe anything actually turns on it, it seems to me
that if one is considering a skilled team in the UK which is concerned with
administration it will include a nurse whereas a similar team in Germany will not.
Common general knowledge
29.
Rheumatoid arthritis is a systemic inflammatory autoimmune disease that
predominantly affects the organs of the locomotor system that provide form, support,
stability and movement to the body – although it can also affect a number of other
organs including the lungs, heart, eyes, skin and blood vessels. Whilst the symptoms
of RA vary widely with regard to type, severity and rate of progression, its clinical
diagnosis requires at least four of the following to be satisfied (the American College
of Rheumatology criteria):
i)
Morning stiffness;
ii)
Arthritis (soft tissue swelling or fluid) of at least three joints;
iii)
Arthritis of hand joints;
iv)
Symmetrical arthritis;
v)
Rheumatoid nodules;
vi)
Abnormal amounts of serum rheumatoid factor; and
vii)
Radiographic changes in the joint.
30.
Established RA is characterised by abnormally shaped wrists, fingers and toes caused
by inflammation of the synovial membrane of the relevant joints and secondary
damage to the joint cartilage and underlying bone. The causes of the condition are
unknown, but one of the theories (amongst several others) is that an infectious agent
triggers the generation of antibodies against the synovial membrane, resulting in
inflammation, pain, stiffness and potentially damage to the cartilage and bone
associated with the affected joints. In the UK, RA affects around 690,000 patients.
31.
At the priority date a number of options were available for the treatment of RA and
other rheumatic diseases. Of the conventional disease modifying anti-rheumatic
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drugs (referred to as ‘DMARDs’), methotrexate was the most common first choice
treatment, usually in combination with non-steroidal anti-inflammatory drugs
(‘NSAIDs’). At the beginning of treatment low-dose steroids may also have been
used.
32.
If methotrexate was found not to be effective, or not to be tolerated, then the
physician would usually attempt to treat the patient with one or more of the other
major DMARDs (e.g. sulfasalazine, hydroxychloroquine or leflunomide) alone or in
combination.
33.
If none of the DMARDs was found to be effective and tolerable then the physician
would use one of the then newer biological disease modifying anti-rheumatic agents
(‘biologics’), such as rituximab, adalimumab, infliximab (antibody products),
abatacept or etanercept (fusion protein products). These were second line therapies
due to their higher cost, and were used where the first line therapies (such as
methotrexate) proved ineffective or not tolerated.
34.
Methotrexate is a potent cytotoxic drug that was developed in the 1950s for cancer
chemotherapy. It was soon discovered, however, that it had a beneficial effect in the
treatment of psoriasis and RA at much lower doses, probably owing to its antiinflammatory and immunomodulatory properties.
35.
In the treatment of cancer, at the priority date methotrexate was frequently used in
doses of up to several grams, diluted in saline and given by intravenous (IV) infusion.
Such doses constituted an aggressive, short term therapy, which could not be
sustained long term. In oncology treatment, chemotherapy is usually given over a
relatively short period (of around 6 months) in cycles typically with 3 – 4 week gaps
between treatments to enable the body to recover from the side effects. The skilled
clinician concerned with RA would have known that methotrexate was used as a
cytotoxic drug in much higher doses than for the treatment of RA. I doubt they would
have known the exact dosage or precise details of a typical treatment regime, but
nothing turns on that.
36.
The treatment of RA is usually a life-long treatment. One common approach was to
start a patient on an initial dose of 7.5 mg or 10 mg weekly and then titrate the dose
upwards to a maximum of 25 mg/week. This was the highest dose typically regarded
as safe. A higher 30 mg/week dose was used occasionally but was very rare. Another
approach, more common in Germany, was to start treatment more aggressively using
a higher dose of 15 to 20 mg weekly. Following either approach, if the patient could
not tolerate the higher doses, the dose would be reduced to the lowest tolerable
effective dose. For most patients on long-term therapy, once the disease had been
brought under control, again the dose was reduced to the lowest possible dose that
remained effective; normally in the range of about 15 to 20 mg/week.
37.
In the UK by 2006 methotrexate was generally administered for the treatment of RA
(and other inflammatory autoimmune diseases) in oral tablet form, as it had been in
the past. Tablets are cheap, convenient and simple to manufacture, transport and
store. The use of parenteral administration, particularly subcutaneous, was growing
but subcutaneous administration of methotrexate was not authorised in the UK at the
time. It was prescribed off-label. Dr Östör estimated that about 5% of British RA
patients received subcutaneous methotrexate at the priority date. In evidence was a
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detailed 2004 guideline document from the Royal College of Nursing concerning
administering subcutaneous methotrexate for RA and JCA (as to JCA see below).
The 2004 guideline demonstrates that subcutaneous administration was undertaken
and also shows that methotrexate had to be handled appropriately and with real care
given its cytotoxic nature.
38.
In Germany in 2006 there were two subcutaneous methotrexate products with
marketing authorisations for RA and Prof Müller-Ladner estimated that about one
third of his patients received methotrexate in that form.
39.
In practice by 2006 the main approach to parenteral methotrexate administration was
subcutaneous. One reason for using parenteral administration of a drug instead of oral
tablets is because parenteral administration bypasses the first pass metabolism and
usually results in a higher bioavailability of a drug. With methotrexate in particular
parenteral administration reduced the variability within and between patients due to
variable absorption of methotrexate in the intestine. Another reason for parenteral
administration of methotrexate was gastric intolerance experienced by some patients
taking the tablets. Amongst parenteral routes, subcutaneous injections have a number
of advantages. They are less invasive than the intravenous route and cause less pain
than intramuscular injections. Patients can also self-administer subcutaneous
injections (a well known example is the insulin taken by insulin dependent diabetics).
40.
The mechanism of action of methotrexate in the treatment of RA was not understood
at the priority date (indeed, it is still not understood today), although several
mechanisms had been proposed. The skilled team would not have known the details
of all the various theories, but would have been aware that the mechanism of action
was unknown and the subject of ongoing research.
41.
As a drug, methotrexate, in common with other anti-proliferatives, was known to be
associated with a wide range of potentially serious side effects. Methotrexate was
known to be a very toxic compound, intended to kill tumour cells in the body. It was
known to be capable of inducing severe side effects including mucositis
(inflammation and ulceration of the mucous membranes in the mouth and
gastrointestinal tract), nausea and vomiting, diarrhoea, tissue necrosis, bone marrow
suppression, alopecia, anaemia, problems with blood clotting and teratogenicity (the
disruption of the development of an embryo or foetus, often leading to death or
deformation).
42.
However there are important differences in the thinking of the skilled person about
the side effects depending on whether one is concerned with cancer treatment or RA.
Cancer can represent an immediate threat to the life of the patient. RA cannot be
cured and requires regular treatment throughout a patient’s lifetime. It may shorten
the lifespan of the patient but RA is not terminal in the sense that cancer can be.
Therefore whereas physicians and patients dealing with cancer are prepared to deal
with the risk and occurrence of what can be significant side effects, RA physicians
were less willing to put their patients at risk of significant side effects.
43.
On the other hand, and importantly, the significant side effects mentioned above are
most severe when methotrexate is used in the very high chemotherapy doses. The
doses are orders of magnitude larger than the doses used in RA. RA patients
receiving methotrexate can still experience serious side effects and the skilled team
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would have been aware that there were reported instances of patients having died
from low dose methotrexate treatments due to the weekly dose being given on a daily
basis as a result of tragic mistakes by staff. Well known side effects of methotrexate
for RA included dizziness, nausea, hair loss, mucositis and dermatological side effects
but listing them in this way and focussing on the patient deaths is capable of giving
the wrong impression. Dr Östör characterised the drug in the context of RA as “pretty
benign”. Dr Östör’s evidence was not that methotrexate was at all risk free but he
used this expression to explain why he did not accept the manner in which medac’s
case was put, placing such emphasis on side effects. Prof Müller-Ladner did not
agree with that characterisation but (for reasons which are given below) I preferred Dr
Östör’s evidence on this to that of Prof Müller-Ladner.
44.
Another important feature of side effects is whether they are systemic or local in
nature. If an effect has a systemic cause then in general it will not matter how the
drug is delivered (orally by tablets or parenterally). What matters is the overall dose.
Whereas if a side effect is local, then the site at which the drug is delivered and the
mode of delivery matters. Dr Östör explained that methotrexate does not cause an
injection site reaction, erythema, inflammation or redness and overall was well suited
for subcutaneous therapy.
45.
The fact that a side effect is skin related does not mean it has a local cause. Some of
the dermatological side effects associated with methotrexate are systemic. Moreover
the deaths caused by the tragic mistakes in administering methotrexate daily instead
of weekly were systemic in nature.
46.
The side effects were generally dose dependent in a given patient but between patients
the dose response was unpredictable and that is why it was common practice to start
patients on a low dose and then titrate upwards in stages to the maximum level that
could be tolerated, subsequently reducing the dose again once the disease was under
control.
47.
Dr Östör gave evidence that at the priority date around one third of patients
discontinued treatment within a year due to intolerance but this was based on a
retrospective survey conducted years afterwards and he accepted he could not say it
was known at the relevant time. I find that, in general, in 2006 patient compliance
with methotrexate treatment in RA was regarded as good. So long as the side effects
remained modest, patients would generally tolerate these provided that they also
experienced improvement in their symptoms. Where patients experienced more
severe side effects, then they could be switched to a different treatment or to a lower
dose of methotrexate (providing that efficacy was maintained).
48.
There was a dispute about the common general knowledge relating to pain associated
with methotrexate injections. There is no doubt that in general injections hurt and
there is no doubt that injection pain in general can be due to a number of different
factors, including the size and shape of the needle, the injection technique, the
injection volume and its formulation. The specific issues relating to pain with
subcutaneous methotrexate administration are best addressed in context below.
49.
At the priority date there were a number of oral tablet formulations available for
methotrexate. There were also subcutaneous injectable methotrexate formulations
available in both the UK and Germany. This included prefilled methotrexate
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syringes. They were not licensed for the treatment of RA in the UK but in Germany
there were subcutaneous formulations licensed for RA.
50.
RA is an inflammatory autoimmune disease and the claims are not limited to RA.
The other inflammatory autoimmune disease which plays a role in this case is juvenile
chronic arthritis (JCA), also known as juvenile idiopathic arthritis (JIA). This disease
has similar symptoms to RA but is a different disease. It is treated the same way.
Notably children are able to tolerate somewhat higher doses of methotrexate that
adults, probably due to their faster metabolism. Weekly doses of 25 mg and even 30
mg of methotrexate are more common in children with JCA/JIA than in adults with
RA.
51.
Issues relating to the common general knowledge of the skilled formulator in the team
are best dealt with in context.
The patent
52.
At paragraph 1, the patent states that the present invention relates to the “use of
methotrexate in the production of a subcutaneously administered medicament for the
treatment of inflammatory autoimmune diseases, wherein the methotrexate is present
in a pharmaceutically acceptable solvent at a concentration of about 50 mg/ml.”
Paragraph 2 identifies methotrexate as a folic acid antagonist. Paragraph 3 notes that
methotrexate has previously been used to treat breast cancer and leukaemia in
children as a result of its effectiveness as a cytostatic agent and has also been used to
treat psoriasis, which can accompany RA. Paragraph 5 notes that disease-modifying
anti-rheumatic drugs (DMARDs), such as methotrexate, have a disease modifying
effect in RA.
53.
Paragraph 6 explains that, when used to treat RA as opposed to treating cancer,
methotrexate is administered in significantly lower doses, which can be up to 1,000
times lower than doses used in chemotherapy. In Germany a dosage range of 5.0 to
30.0 mg per week is identified as common, while doses of up to 40.0 mg per week are
apparently routinely administered in other European countries. Paragraph 6 then
emphasises that “It is extremely important that methotrexate only be administered
once a week.”
54.
Paragraph 7 identifies that methotrexate can be administered orally and parenterally.
Parenteral administration is said to be more commonly used because methotrexate,
when orally ingested in tablet form, can be absorbed by the patient in an unreliable
way. This is undesirable in a dosage-dependent therapy, where a sufficient degree of
accuracy needs to be guaranteed. The remainder of paragraph 7 together with
paragraph 8 emphasises the desirability of ready-made syringes for parenteral
administration of methotrexate because of the difficulties and restrictions around
handling and preparing medicaments containing cytostatics. Paragraph 9 notes that
there are two products known from the prior art which are ready-made syringes for
parenteral administration containing methotrexate solution at a concentration of up to
25 mg/ml. These are Lantarel® produced by Wyeth and Metex® produced by medac.
The Lantarel® product with the concentration 25 mg/ml is said not to be approved for
subcutaneous application. Paragraph 10 goes on to say that the subcutaneous
administration of methotrexate for the treatment of RA has been described in a
number of publications, including Jansen.
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55.
Paragraphs 11 and 12 set out the problem that the patent is trying to solve, namely the
need for “pharmaceutical formulations of methotrexate which can be administered to
the patient, including children, as easily and pain-free as possible, while providing
good bioavailability, over a long period of time at regular intervals, in particular
weekly, which therefore leads to a high degree of patient compliance”. In addition,
the medicament should allow for self-administration by the patient. Paragraphs 13
and 14 explain that the disadvantages of the prior art can be overcome by using the
claimed invention. Paragraph 15 states that the first embodiment of the invention
relates to the use of methotrexate which is present in a pharmaceutically acceptable
solvent at a concentration of “about 50 mg/ml” for subcutaneous administration for
the treatment of inflammatory autoimmune diseases. Further embodiments of the
invention are set out between paragraphs 16 to 34.
56.
Within these further embodiments, paragraphs 24 and 25 are worth noting. Paragraph
24 explains that, although the provision of methotrexate solutions in ready-made
syringes has had a positive impact on patient compliance, the existing products
approved for subcutaneous application have the disadvantage that potentially large
amounts of liquid have to be injected under the patient’s skin. This could be as much
as 3 ml, if the patient uses the existing 10 mg/ml formulation and requires a weekly
dose of 30 mg. The requirement that the patient be subjected to such large volume
injections is described as being “often hard to convey to the patient, in particular
children, which leads to a reduced patient compliance.” The patent states at paragraph
25 that this problem is solved by highly concentrated formulations of methotrexate,
where a concentration of 50 mg/ml would only require 0.6 ml of liquid in order to
administer a 30 mg weekly dose.
57.
There are two examples in the patent, at paragraphs 35 to 41, which set out methods
of preparing formulations of a methotrexate solution with a concentration of 50
mg/ml.
58.
The patent consists of 28 claims in total. As noted above, only claims 1, 13, 15 and 27
are said to be independently valid. There are no arguments about claim construction.
Obviousness
59.
Section 3 of the Patents Act 1977 (based on Art 56 EPC) provides:
“An invention shall be taken to involve an inventive step if it is
not obvious to a person skilled in the art, having regard to any
matter which formed part of the state of the art…”
60.
It is convenient to assess inventive step using the structured approach set out by the
Court of Appeal in Pozzoli SpA v BDMO SA [2007] EWCA Civ 588. The key,
statutory step is the fourth one, that is: viewed without any knowledge of the alleged
invention as claimed, do the differences between the prior art and the claimed
invention constitute steps which would have been obvious to the person skilled in the
art or do they require any degree of invention?
61.
The analysis is a multifactorial one, having regard to all of the relevant circumstances,
as Kitchin J (as he was then) put it in the much cited passage from Generics v
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Lundbeck [2007] RPC 32 at paragraph 72, approved in Conor v Angiotech [2008]
UKHL 49.
62.
In Medimmune Kitchin LJ explained that in cases involving a question of whether
something is “obvious to try”, that is only one of the considerations which it may be
appropriate to take into account (paragraph 92). When considering “obvious to try”
the Court of Appeal in Teva v Leo [2015] EWCA 779 emphasised the expectations of
the skilled person. For example, the fact that something might work is not enough
and nor would be performing a test simply on the basis of a hope that it will succeed
(see also Conor). The Court of Appeal in Teva v Leo also emphasised the importance
of assessing the question of obviousness by reference to what real-life skilled people
would think and do.
63.
In the end however the task of the court is to evaluate the evidence against a single
statutory test expressed in simple terms whose meaning is not necessarily made much
clearer by elaborate judicial exposition (Medimmune, paragraph 95).
64.
Medac referred to the point addressed by Floyd J (as he then was) in Dr Reddy’s
Laboratories v Eli Lilly [2008] EWHC 2345 (Pat) at paragraph 170. There the judge
observed that there can be a risk in focussing too much on the disclosure of any
particular document and losing sight of the whole common general knowledge.
Medac submitted that while the law requires that the pleaded prior art be notionally
read with interest by the skilled person, that person does not approach it on the
assumption that that particular document (out of all the others directed to the same
problem) in fact contains pointers towards the solution, and an unnatural focus on it
may lead to an unbalanced analysis and hindsight. I agree with that submission. The
key issue is that the skilled person does not approach a document on the assumption
described. To do so would indeed involve hindsight.
65.
Finally I will mention secondary evidence. An important part of medac’s argument
was to ask the rhetorical question – if it was obvious, why was it not done before? It
was common ground that while this is a form of secondary evidence, as compared to
the primary evidence being the reasons given by the experts for their opinions, such
secondary evidence has its place and in a proper case can be powerful.
66.
In arguing their case relating to obviousness each side put a different starting point
first. Accord started with its case over common general knowledge alone, then
referred to Jansen and Russo. Medac started with its case over Jansen and then
focussed on Russo and common general knowledge alone. I will start with Russo.
Obviousness over Russo
67.
Russo is a letter published in the journal Clinical and Experimental Rheumatology in
2000. The letter reports the results of a small study concerning the tolerance of
parenteral higher dose methotrexate in children with JCA. Higher dose parenteral
methotrexate is compared to lower dose oral methotrexate. The study compares 20
children given the higher parenteral dose and 124 on the oral dose. The mean age of
the children treated with the parenteral dose was about 10 ½ years old and the mean
duration of their disease was about 3 ½ years. The mean higher dose was 23.25
mg/m2 per week. They had all been on low dose oral methotrexate for a year on
average beforehand.
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68.
The letter reports positive results. The letter recognises that the observations are
based on a retrospective study but explains that nevertheless the data shows that
higher dose parenteral methotrexate is safe and is not associated with more frequent
side effects that lower dose oral administration, at least in the first year of treatment.
Further prospective studies will be undertaken.
69.
Russo only refers to “parenteral” administration and does not specify whether that
relates to intramuscular and/or subcutaneous administration. In my judgment the
skilled team reading Russo at the priority date would see the reference to “parenteral”
as covering either mode (they would not think it meant intravenous or intrathecal). It
would be entirely obvious to any skilled reader to consider what is disclosed by Russo
as applicable to subcutaneous or intramuscular administration or both. If the skilled
team thought about it in any more detail they might consider that the work actually
reported most likely involved some intramuscular administration (the title of reference
1 in the letter refers to intramuscular methotrexate and following up the references
bears that out) but this does not alter the fact that subcutaneous administration is
obvious over Russo.
70.
A relevant aspect of Russo is what is said about side effects and in particular, given
the issues in this case, what is said about pain. The results table reports the various
side effects experienced by both groups. “Pain at injection site” is reported in four out
of the twenty children on the higher parenteral dose (i.e. 20%). In the text the paper
mentions the various side effects, including the fact that four patients reported pain
and states that “No patient needed to permanently discontinue the drug due to side
effects”. The text also mentions that the parenteral methotrexate group experienced a
much lower occurrence of complaints related to the gastro-intestinal (GI) system
whereas for the oral methotrexate, 19 (15%) of patients had to permanently
discontinue the treatment due to side effects, of whom 17 experienced side effects
related to GI intolerance.
71.
The skilled team and the common general knowledge have been identified above.
The difference between Russo and claim 1 is that while Russo does describe the use
of a methotrexate medicament to be administered parenterally for the treatment of an
inflammatory autoimmune disease (JCA/JIA), it does not disclose a concentration of
the parenteral methotrexate and does not single out subcutaneous administration.
72.
Accord submits that the invention would be obvious to a skilled team over Russo. It
would be obvious for the team to create a subcutaneous methotrexate formulation in
the light of Russo. A subcutaneous formulation of 50 mg/ml methotrexate would be
nothing more than the product of routine optimisation by the skilled team and so
claim 1 is obvious. If claim 1 is obvious so too are the other claims. The limitation to
ready made syringes and to the doses listed in claim 13 adds nothing. Claims 15 and
27 fall for the same reasons.
73.
Medac does not agree. It submits that claim 1 would not be obvious. Its arguments
are as follows. The clinician would not be motivated to ask the formulator to do
anything at all. If the clinician wanted a methotrexate formulation for subcutaneous
administration then there were already such products available on the market and no
need to create another. If the formulator was asked to prepare methotrexate for
subcutaneous administration, it was not obvious to arrive at a 50 mg/ml concentration.
Injection volumes in the range from about 0.5 ml to 1 ml, 1.5 ml or even 2 ml were
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Accord v Medac
standard for subcutaneous administration. Two key steps in Accord’s case are
incorrect. First that it was obvious that reducing the injection volume below 1 ml
would reduce pain and second that the skilled formulator would target a volume of 0.5
ml. The first proposition is now known to be true as a fact today and is the reason
why the invention has been very successful but Accord failed to establish it was
known or obvious at the priority date. The second proposition was based on a
personal preference of Dr Rue and was not established to represent the thinking of the
ordinary and uninventive skilled formulator. Even if a 50 mg/ml subcutaneous
methotrexate formulation was contemplated, the skilled person would be put off by a
concern about side effects caused by the increase in concentration over what were
then the highest known subcutaneous concentrations of methotrexate, at 25 mg/ml.
At most the formulation would have to be tested but there would be no basis for a fair
or reasonable expectation of success. Moreover secondary factors matter. Russo was
published in a well read and respected journal six years before the priority date. If
there was ever a case in which to ask the question – if the invention was obvious why
was it not done before? – this is such a case. Medac submits there is no satisfactory
answer to that question from Accord.
74.
In addition to engaging with medac on the facts, Accord submits that the point on side
effects is not open to medac or, if accepted, leads to insufficiency because the patent
says nothing at all about side effects. Not only is there no data showing that 50 mg/ml
subcutaneous methotrexate is safe, there is no discussion of the point at all. So if that
is an aspect of the problem to be solved for the purposes of inventive step, the patent
does not render the claimed solution plausible.
75.
Turning to the evidence, I will address Dr Östör, Dr Rue and Prof Müller-Ladner in
sequence.
76.
In his written report Dr Östör’s evidence was that it would be obvious for a clinician
reading Russo to prompt the team to embark on creating a parenteral formulation of
methotrexate not just for JCA but for inflammatory autoimmune diseases generally
(in particular including RA). Subcutaneous administration would be obvious. The
clinician would understand Russo to teach that, at the doses described, parenteral
methotrexate does not have more frequent side effects and appears better tolerated
than low doses of oral methotrexate. They would ask the formulator to prepare a
suitable methotrexate formulation for subcutaneous use. The mention of 20% of
patients experiencing pain would lead the clinician to ask the formulator to see if a
subcutaneous dosage form could be prepared that minimises pain.
77.
In cross-examination Dr Östör accepted that he did not know what volumes and
concentrations were in use (off-label) in the UK at the priority date and that it did not
occur to him at the time that the approach to subcutaneous administration of
methotrexate for RA in the UK which existed at that time (2006) was not the optimal
solution from the point of view of pain or discomfort, and accepted that this would be
a fair reflection of the position of the skilled clinician at the priority date. This
acceptance was a key aspect of medac’s submission that the skilled clinician would
not be motivated to ask the formulator to optimise a formulation. Medac submits it
would have been thought to be already optimal.
78.
As to the level of pain reported in Russo, medac put to Dr Östör that it was low, his
answer was that it was “lowish”. There was a debate about the duration of the study
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in Russo in the context of the significance of the pain reported but I was not
convinced anything significant turned on the duration point. Dr Östör accepted, as
Russo states in terms, that the pain was not bad enough for those patients to stop
treatment in the context of the study.
79.
In terms of patient compliance and any problem due to pain, as I have mentioned
already Dr Östör accepted that his evidence about what the position was in 2006 had
been based on a later published study looking back in time.
80.
As to concern about side effects, Dr Östör’s evidence about a 50 mg/ml formulation
of methotrexate was that concern about side effects would not deter the skilled team.
He maintained that evidence in cross-examination. He maintained that an important
distinction was between systemic and local side effects. So, for example, 2.5 ml of 10
mg/ml drug and 1 ml of 25 mg/ml drug provide the same dose and have the same risk
of systemic side effects.
81.
Dr Östör explained that given an increase in concentration, the side effects which
might be relevant would be local side effects but that the skilled clinician would have
no specific concerns about local side effects of subcutaneous methotrexate. He
thought the risk of local side effects described in Prof Müller-Ladner’s expert’s report
was a purely academic and theoretical possibility. Dr Östör said that given the
experience at lower concentrations, in all likelihood 50 mg/ml would be safe.
82.
Medac submitted that Dr Östör’s evidence about the likely safety of 50 mg/ml
subcutaneous methotrexate was based on knowledge of a point of detail within an
SmPC for a form of methotrexate called Abitrexate. That SmPC in particular bears
writing in Hebrew and medac submitted it was not established to be part of the
common general knowledge in the UK at the relevant time. I agree the Abitrexate
SmPC was not part of the common general knowledge and knowledge of its content
cannot be relied on. But the main reason for Dr Östör’s view was his experience that
the subcutaneous methotrexate he prescribed was administered safely. I have
considered whether the fact that Dr Östör did not know at the time what the
concentrations administered actually were has any impact on this. In my judgment it
does not. It is clear that the concentrations used in the UK will in all likelihood have
been in the 7.5-25 mg/ml range. A clinician who wanted to know at the time would
simply have asked the pharmacist or nurse.
83.
Dr Rue’s evidence was from the perspective of a formulator asked to prepare a
subcutaneous methotrexate formulation. He thought the formulator would do so and
would proceed as follows. The formulator would readily identify methotrexate
products on the market in 2006. One of the pieces of information a formulator would
wish to know was the solubility limit of methotrexate. The information from the
products on the UK market would show that injectable methotrexate solutions were
available in solutions including the following: 2.5 mg/ml, 7.5 mg/ml, 25 mg/ml and
100 mg/ml (Hospira and Wockhardt UK Ltd). As I have said, in the UK the
parenteral products were indicated for cancer and psoriasis. They were not indicated
for RA or any other disease within the claims.
84.
Dr Rue’s evidence was that part of the formulator’s common general knowledge was
that a smaller injection volume caused less pain. The formulator would optimise the
injection volume on that basis and it was obvious to prepare the smallest injection
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Accord v Medac
volume possible that was still practical. Dr Rue would target a volume of 0.5 ml. The
average parenteral dose described in Russo is 23.25 mg/m2. That equates to a dose of
about 26 mg (based on the appropriate average body surface area). To deliver 26 mg
in 0.5 ml one would use a concentration of 52 mg/ml. The claim is to about 50
mg/ml. Therefore the claim is obvious.
85.
Dr Rue also exhibited a paper by Jorgensen published in 1996 (Jorgensen et al Pain
Assessment of Subcutaneous Injections The Annals of Pharmacotherapy 1996
July/August, Vol 30 p729). This paper was not said to be common general
knowledge but it bore out Dr Rue’s view that as a matter of fact increasing injection
volume from 0.5 ml to 1 ml increases pain significantly.
86.
It was pointed out to Dr Rue in cross-examination that while the standard formulation
text books he exhibited supported his view that subcutaneous injection volumes were
usually in the range between about 0.5 ml to 2 ml, they did not contain any statement
that reducing the volume within that range reduced pain nor did they refer to a target
of 0.5 ml. Dr Rue accepted that the textbooks did not contain those statements.
However he maintained his opinion on those issues as representative of the views of
the skilled formulator.
87.
Medac submitted that Dr Rue did not have any relevant experience about
subcutaneous administration and that what emerged in cross-examination was that the
basis for his opinion about injection volumes generally and a 0.5 ml target in
particular was work done at another department in Glaxo while he was there. I am
satisfied that Dr Rue’s actual experience was sufficient to put him in a position to give
cogent evidence about injection volumes. Moreover he was entitled to have regard to
what he was aware of about what happened at the other Glaxo department as support
for his opinion. It was clearly Dr Rue’s honestly held opinion that pain is reduced by
smaller volumes and that a target of 0.5 ml was representative of the thinking of a
skilled formulator concerned with a subcutaneous formulation. He expressed that
view well aware that the particular point he was making was not set out in the general
text books he cited.
88.
Prof Müller-Ladner’s written evidence was that the skilled clinician would have no
particular desire to change the existing concentrations of methotrexate. The professor
routinely used 10 mg/ml in 2006. Secondly even if the skilled person considered
injection pain to be a problem, there was no reason to focus on the volume of
methotrexate. Pain could be caused by a number of aspects (the size and shape of
needle itself, and injection technique). Third and importantly, if the skilled team did
think of an increased concentration of methotrexate, they would have serious concerns
about the risk of side effects due to the toxic nature of methotrexate. The skilled
person would be concerned that there was a threshold concentration of methotrexate
above which RA patients could not tolerate methotrexate subcutaneously but it could
not be predicted in advance what this “invisible barrier” or “red line” would be. So
even if a 50 mg/ml formulation was tested, it could not be predicted that it was safe.
This is particularly so given the limited blood supply to the subcutaneous layer
compared to other tissue such as the muscle targeted with intramuscular injections.
89.
In cross-examination Prof Müller-Ladner’s evidence was quite different. He agreed it
was obviously desirable to optimise an injection product like this one, which is going
to be given regularly to patients over an extended period of time, in effect for a
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lifetime. It was not necessarily the case that the injections always hurt but he agreed
that while some patients reported that it did not hurt, some patients given
subcutaneous methotrexate injections complained to him about the pain of the
injection. The pain depended on a number of factors but one of them was volume.
90.
Prof Müller-Ladner accepted that Russo showed that the number of patients reporting
pain was “significant”, by which I understood him not to refer to statistical
significance (nor to the level of pain itself) but to be an indication that the occurrence
of the side effect was regarded as noteworthy by the authors.
91.
Prof Müller-Ladner agreed that it was fair for a formulator to consider optimising for
pain and he also agreed that if the skilled team did optimise the volume, they would
produce a product at around 50 mg/ml. Accord placed particular emphasis on that
evidence.
92.
Prof Müller-Ladner said he would not disagree with Dr Rue’s evidence that 0.5 ml
would be considered to be good by the skilled formulator. That latter evidence arose
as follows. Counsel for Accord put to Prof Müller-Ladner that 0.5 ml would be
considered good from the point of view of pain. The professor agreed, nevertheless,
as medac emphasised, he said that it was not the only volume that was possible and
convenient. Medac submitted this was an important qualification and that it meant in
effect that the professor did not agree that it was obvious for a formulator to optimise
the volume to 0.5 ml bearing in mind pain. I do not accept that. Prof Müller-Ladner
fully understood the importance of the 0.5 ml volume in this case. In crossexamination the professor had fair opportunities to say if he thought targeting 0.5 ml
was not obvious but he did not. A fair summary of Prof Müller-Ladner’s view about
volumes was that 0.5 ml was one obvious volume but not the only one. Somewhat
higher volumes were also obvious.
93.
Medac also submitted that it was not put to Prof Müller-Ladner that starting from an
injection volume of 1 ml, it was common general knowledge or obvious that reducing
the volume down from there to 0.5 ml would reduce the pain experienced by the
patient. The distinction is between the idea that reducing a volume from (say) 3ml
down to something in the range 0.5 ml – 1.5 ml would be expected to reduce pain
(which was common ground) and the idea that reducing a volume already within the
range down to 0.5 ml would be expected to reduce pain. The latter is something
medac contends was not obvious and is what medac contends was not put. The point
applies whatever the upper bound of the range is, i.e. regardless of whether the range
is 0.5 - 1 ml; 0.5 - 1.5 ml; or 0.5 - 2 ml. The significance of the numerical difference
between 1 ml and 0.5 ml in the context of this dispute is that with the highest typical
dose of 25 mg, you do not need a 50 mg/ml concentration to produce a volume of 1
ml. 25 mg/ml will suffice. So if 1 ml was targeted instead of 0.5 ml medac says the
skilled person would not come up with a 50 mg/ml concentration. I do not accept
medac’s submission about what was put to Prof Müller-Ladner. It was clearly put to
the professor that it was obviously desirable to optimise the injection volume in order
to minimise pain and further that the clinician would want as low a millilitre quantity
as possible so that the product could be administered more easily. Prof Müller-Ladner
agreed with this.
94.
On the issue of side effects, the tenor of Prof Müller-Ladner’s evidence can be seen
on the issue of Lyell’s syndrome. Prof Müller-Ladner’s written reports placed
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significant emphasis on the risk of severe dermatological side effects, particularly a
life threatening condition known as toxic epidermal necrolysis or Lyell’s syndrome.
This is a very severe toxic skin necrosis which is often fatal. It has been associated
with methotrexate but it is very rare indeed and, importantly in the context of this
case, it has a systemic cause. Dr Östör explained that in his experience it was
“incredible – you know one in a million”. More generally Dr Östör explained there
was vast experience of using methotrexate for autoimmune inflammatory disease,
starting in 1985, with hundreds of thousands perhaps millions of patients. In his view
actual local reactions were very uncommon and completely distinct from systemic
potential side effects. I found this aspect of Dr Östör’s evidence credible and
convincing. In my judgment Prof Müller-Ladner’s written evidence, which placed
such emphasis on side effects such as skin necrosis being associated with
methotrexate, was exaggerated.
95.
On the general issue of local side effects, Dr Östör’s characterisation of methotrexate
as “pretty benign” was put to Prof Müller-Ladner in cross-examination. He was not
prepared to go that far and pointed out that “benign” is a relative term, but he did
agree that 25 mg/ml methotrexate was safe and had no major problems. When crossexamined about a concentration of 50 mg/ml, the professor maintained a number of
times that the skilled clinician would have a safety concern which would put them off
from trying it. Accord emphasised that when Prof Müller-Ladner was asked
specifically about how a concern about toxicity on the part of a skilled person seeking
to optimise injection volume would be taken into account, the professor said that he
would not be deterred, he would just be cautious and concerned, and accepted that he
would be aware that you needed to verify that the formulation was not toxic. Accord
submitted, rightly, that this evidence was much closer to Dr Östör’s opinion on the
topic than the professor’s written evidence. Medac submitted that those answers had
to be seen in the light of the other oral evidence the professor gave, which I have
mentioned already, that the skilled clinician would have a safety concern which would
put them off from trying 50 mg/ml. Medac’s counsel provided a list of references to
the relevant parts of the transcript.
96.
In considering the rival submissions about Prof Müller-Ladner’s evidence, I think an
important point is that the answers he gave on which Accord rely were clear and
involved no misunderstanding on his part. They were not a mistake. In my judgment
those answers reflected his truly held opinion. To the extent that they differ from the
other statements medac rely on, the answers qualify those other statements. In other
words the cross-examination as a whole revealed that Prof Müller-Ladner’s opinion
was not reflected by the words used in his report. He had a serious concern about risk
of local side effects with increasing concentration. A higher concentration such as 50
mg/ml needed to be tested before it was used but he did not positively expect 50
mg/ml to be unsafe and would not be deterred by this concern from optimising.
97.
A key part of the written report prepared by Prof Müller-Ladner for the US
proceedings was his view about the risk of local side effects caused by such a high
concentration of methotrexate. That US evidence is similar to his written evidence
here but in the US it is expressed even more strongly. His US evidence was that local
side effects would be expected (my emphasis) using concentrated methotrexate (which
means >30 mg/ml) and that the safety of concentrated methotrexate was unexpected.
In cross-examination Prof Müller-Ladner suggested that the difference between the
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US evidence and his evidence here was due to the use of a second language. I reject
that. Prof Müller-Ladner was an accomplished English speaker and the difference is
not only in the word “would” in his US report but in the whole tenor of the evidence
given. The difference between the way Prof Müller-Ladner expressed himself in
writing in his US report and his answers given in cross-examination here bears out
why cross-examination of experts is an important tool in patent disputes. Like his
written evidence here, Prof Müller-Ladner’s written evidence on side effects in the
US report was exaggerated.
98.
Overall, on the issue of the skilled person’s thinking about risks associated with side
effects, there was not so much between Dr Östör and Prof Müller-Ladner’s evidence
in cross-examination. Nevertheless, to the extent the two experts differed on side
effects, I preferred Dr Östör. In particular I do not accept that concern about a so
called “invisible barrier” represents the thinking of the skilled clinician.
Assessment
99.
I find that a skilled team reading Russo in 2006 would set about producing a
formulation of subcutaneous methotrexate for use as a treatment for inflammatory
autoimmune diseases such as JCA and RA. The clinician member of the team would
ask the formulator to do that. The impetus would come from the clinician reading
Russo as part of the team. The fact that formulations existed on the market already
would not deter the team from aiming to produce their own.
100.
It was obvious for the formulator to optimise such a putative formulation with respect
to pain. The express reference in Russo is in itself a sufficient impetus to the skilled
team to think about pain. Although there are other issues which can be addressed
overall when considering pain (such as the needle shape and injection technique),
from the point of view of the skilled formulator, it would be wholly obvious to
optimise injection volume with that in mind.
101.
The fact that Russo also states that none of the side effects led to any patient
permanently discontinuing the drug does not make it any less obvious for the team to
consider pain. The skilled reader would think pain was significant enough for the
authors to draw attention to it. Moreover the skilled team would know that the
patients would be given subcutaneous methotrexate weekly for a very long time. The
fact that the pain reported by Russo was not sufficient to lead to a problem with
patient compliance in Russo would not lead the skilled team to leave pain to one side.
102.
I accept Dr Rue’s evidence about targeting small volumes like 0.5 ml. Medac did not
call an expert formulator to give evidence to contradict Dr Rue’s opinion and I am
satisfied his views represent those of the skilled person. I find that it was common
general knowledge that larger volumes cause more pain than smaller volumes both in
general and in the context of comparing the likely pain caused by 1 ml as opposed to
0.5 ml. It was obvious to target a small volume like 0.5 ml.
103.
The skilled team would find out what products were on the market. They include
products in which the injection volume would be greater than 2 ml. The ready to use
syringe of the Lantarel product for a 20 mg dose had an injection volume of 2.67 ml.
It was made using a 7.5 mg/ml concentration of drug. That volume is materially
larger than the widest range regarded as normal for subcutaneous injection and would
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be seen as such. A likely problem of pain with such an injection volume would also
be obvious.
104.
I am sure it would be obvious to the skilled clinician in the team given Russo to ask
the formulator to optimise with regard to pain. The significance of Dr Östör’s
evidence seems to me to be that without the prompt of reading something like Russo
or a prompt to find out what was actually being administered in the UK, a UK based
clinician acting on their own, and not part of the skilled team, would have no reason
to think of embarking on a project to optimise a formulation of methotrexate for pain.
105.
In the context of injection volumes, the higher doses of methotrexate obviously are
the ones to consider. One obvious one to consider would be 25 mg. The aim would
be to produce a solution of methotrexate at a sufficient concentration to provide a 25
mg dose (or 26 mg using the numbers in Russo precisely) with an injection volume of
0.5 ml. The formulator would know from publicly available information that with
those values there is no problem of solubility and would produce such a dosage form,
in a suitable isotonic form for injection, without difficulty. The concentration of
methotrexate produced would be about 50 mg/ml.
106.
I have addressed the common general knowledge of methotrexate as a cytotoxic agent
above. The skilled team would know that the drug is cytotoxic and therefore has to be
treated with real care. In doses orders of magnitude higher than the ones relevant to
this case it is a dangerous drug. When considering side effects of the optimised
formulation, systemic effects would not be a concern at all because the dose is
unchanged. The issue would be the possible risk of local toxicity. Although the
relative risk of local toxicity would be expected to increase as concentration increases,
the absolute magnitude of that risk would be very low. The correct way to
characterise the attitude of the skilled team to local toxicity is as follows. The
existence of a risk of local side effects is not frivolous. There is some evidence from
medac’s internal letters of doctors asking questions about it. The team would know
that methotrexate had been administered in a subcutaneous fashion without problems.
One known side effect of methotrexate is a rash.
107.
The concentrations actually used in the UK to administer off-label prescribed
subcutaneous methotrexate in 2006 will in all likelihood have been in the range 7.5
mg/ml to 25 mg/ml. If the skilled team in the UK were at all concerned about side
effects they would readily find out what was done in practice from a nurse or
pharmacy. Thus in the UK the team would find out that the drug had been
administered safely at these concentrations, up to 25 mg/ml.
As regards
administration in Germany (which a UK team would know did occur) the same
concentrations would be applicable. The team’s expectation would be that 50 mg/ml
would be safe but they would know the product would have to be tested. They would
have a high expectation of success. They would conduct simple tests (perhaps in a
small animal study) with a view to verifying that it was safe. “Verifying” is an
appropriate way to characterise the approach. The word verify was accepted by Prof
Müller-Ladner and also appears in a medac internal document in the same context.
108.
For these reasons there is a powerful case that claim 1 (and therefore all the other
claims) are obvious over Russo. It does not involve an undue focus on the document
(c.f. Dr Reddy’s). I turn to consider the “secondary” indications, starting with the
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question emphasised by medac: that if it really was obvious it would have been done
before; and then dealing with other matters.
109.
Medac’s main case is this: The 25 mg/ml formulation for methotrexate has been
available since 1995. Subcutaneous administration was well established by at least
2000. The years leading up to the priority date were a period of intense focus on RA
as a result of the new biologics. Yet the invention was not made until medac did the
work leading up to the patent. A 50 mg/ml solution of methotrexate can be readily
produced and so the absence of any such thing in intervening years is evidence that it
was not obvious to produce it. Moreover medac’s own 50 mg/ml product launched
after the priority date has been conspicuously successful and become popular. That
popularity is down to the lower pain of injection caused by the small volume.
Considering Russo itself, it was published in 2000, six years before the priority date in
a widely read journal. So many skilled clinicians will have read it, and yet, again, the
invention was not made.
110.
In evaluating this argument I start with the position in Germany. By 2006 there were
two suppliers of subcutaneous methotrexate formulations with licences for RA: medac
and Wyeth. Medac’s product had a 10 mg/ml concentration and Wyeth’s was 25
mg/ml. In Germany as in the UK the normal dose range was 10 mg to 25 mg. A 25
mg dose made up using the medac product would have a volume of 2.5 ml. It was
clear from Prof Müller-Ladner’s oral evidence and parts of his US written evidence
that this happened in practice. It is also clear in the evidence that pain caused by
injection volume of subcutaneous methotrexate was a recognised problem in
Germany. Prof Müller-Ladner knew about it and sometimes he would split the dose
into two injections in order to avoid the pain problem. His US evidence about the
existence of a long felt need is based on the same point. The thrust of this part of his
US report was that those working in the field had a long felt need for concentrated
(>30 mg/ml) methotrexate for RA because of the injection volume problem but
positively expected it to be locally toxic. That long felt need was met when a safe
concentrated subcutaneous methotrexate formulation was produced.
111.
In addition to the evidence of Prof Müller-Ladner, I refer to internal documents from
medac. There is an internal medac email dated 27th April 2005 and also a later
document dated 18th December 2007. Based on these documents I infer that clinicians
with whom medac was in contact, I presume in Germany, wanted methotrexate at
higher concentrations as a result of the pain caused by injection volume, particularly
in children.
112.
Therefore, whatever the reason why no 50 mg/ml product was produced in Germany
before 2006 actually was, it was not because thinking of a higher concentration/lower
injection volume was not obvious. Nor am I persuaded that it did not emerge due to a
fear of side effects. Probably the art was just more focussed on the new biologic
agents. Also important, in my judgment, is that despite the large size of the
methotrexate market by volume, it is still a generic medicine. Margins will be tight.
The evidence did not address the commercial factors either way and so one is left to
speculate, but I would not be at all surprised if it only became commercially attractive
to go to the time, trouble and cost of producing a 50 mg/ml product, verifying its
safety, and getting authorisation once subcutaneous administration became very well
established on a large scale, which was towards the priority date. However whatever
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the reason was, as I have said, it is not because the idea of a higher concentration
product was not obvious.
113.
Turning to the UK, the position here was that by 2006 the subcutaneous approach was
common general knowledge. Nevertheless by that time there was still no licensed
subcutaneous methotrexate product for RA. It represented only 5% of prescriptions
and was prescribed off label. So subcutaneous administration was much less popular
in the UK at the time than in Germany. Moreover I infer that the practicalities of
subcutaneous administration were not and had not been focussed on in as much detail
by clinicians in the UK as in Germany. As evidence of the position in the UK, Dr
Östör’s testimony shows that doctors were not aware of a problem of pain here, I infer
because they were not the ones administering the drug. Therefore whatever the
reason why no 50 mg/ml product was produced in the UK before 2006 actually was, it
was not because clinicians had the opportunity to see a problem in practice but missed
the obvious solution. They were not in a position to encounter the problem at all.
Neither side called a nurse, and I will draw no inference either way about their actual
knowledge.
114.
Thinking about Russo, it was in a well read journal and I infer it was read by some
skilled clinicians at the time but it is clear the art did develop somewhat between 2000
and 2006, although the extent of that development was not addressed in detail. No
evidence was called from anyone who actually did read the paper at the time. Neither
expert said they remembered actually reading it and as a document it was not
established to be common general knowledge. The fact that no-one apparently took it
forward in 2000 does not prove that the invention was not obvious in 2006.
115.
Separately medac submitted that one can infer Accord’s legal team conducted major
literature searches. We know that both Dr Östör and Dr Rue did so. Nevertheless
there were no papers in evidence stating that 25 mg/ml was not already optimal, none
suggesting pain was a significant issue (except Russo) or caused a problem with
compliance (Russo did not) and none suggesting the injection volumes were high.
Nor were there any textbooks or review articles suggesting that the common general
knowledge was that optimal injection size was 0.5 ml. These submissions about the
state of the documents are all correct. Nevertheless I have mentioned the evidence of
Prof Müller-Ladner and from medac’s documents about what doctors familiar with
actually injecting subcutaneous methotrexate did and thought in Germany. Also I
carefully considered Dr Rue’s evidence about 0.5 ml in its context above.
Obviousness over Russo – conclusion
116.
Medac’s submissions about secondary evidence are legitimate points which carry
weight overall. Calling them “secondary” might give the wrong impression since
arguments of this kind can be decisive in a proper case. I have considered them
carefully, and the weight to be attached to them. However in the end I conclude that
the invention is obvious over Russo. They are not strong enough to overcome what is
a powerful obviousness case over Russo. I conclude that all the claims lack inventive
step.
Obviousness over Jansen
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117.
There is no need to consider the case over Jansen in detail. The paper was published
in 1999. It provides a clear proposal to use subcutaneous administration of
methotrexate for RA. The differences between Jansen and Russo are these. Jansen
does not mention pain at all. In fact Jansen goes further and makes two important
statements. First it states that delivery in ready-made syringes is “comfortable and
safe”. Second it states that volumes to be administered are between 0.2 ml and 1.2 ml
(corresponding to doses of 5 mg to 30 mg) and that “these small quantities are very
well suited to subcutaneous and intramuscular administration”. Medac submits these
teach away from the invention. The other major difference between Jansen and Russo
is that the journal in which Jansen was published was in the Dutch language and not
widely read. Accord submits this means the secondary evidence arguments related to
Russo cannot apply to Jansen.
118.
In my judgment Accord’s case over Jansen is not as strong as its case over Russo and
so there is no point in considering it further. On the evidence as it came out before
me, if the invention is not obvious over Russo then it will not be obvious over Jansen.
Obviousness over common general knowledge alone
119.
I am not satisfied that the invention is obvious based on the common general
knowledge alone attack relied on by Accord. That is because the relevant common
general knowledge must be that in the UK (see Arnold J in Generics (UK) v Warner
Lambert [2015] EWHC 2548 (Pat) at paragraphs 123-124) and in the UK the skilled
clinician was unaware as a matter of common general knowledge what concentrations
were being administered subcutaneously to patients and was unaware, without
prompting, of any particular issue of pain arising from the subcutaneous
administration. There is therefore nothing to provide an impetus to the skilled team to
think about the issue at all.
120.
Before leaving the argument based on common general knowledge alone, I will
mention the words of Floyd J (as he then was) in ratiopharm v Napp [2008] EWHC
3070 (Pat) at paragraphs 155-159 and in particular the passage at paragraph 158
which warns that such attacks need to be scrutinised with care since they can be
favoured by parties because the starting point is not obviously encumbered by
inconvenient details of the kind found in documentary disclosures. I respectfully
agree with Floyd J. Since it seems to me that this case provides a good example of
the problems identified in ratiopharm I will add a few words of my own.
121.
Normally the person attacking validity will rely on a particular concrete document or
well defined prior use as a starting point. The fact that such a concrete item of prior
art may be part of the common general knowledge is not the point. That is different
from an attack based on common general knowledge alone.
122.
Many inventions involve a combination of known features. However a combination
of features, all of which individually were common general knowledge, can give rise
to a valid patent claim if that combination is new and non-obvious. Patent trials are
inevitably ex post facto and a key problem is to identify and avoid hindsight.
Combinations of features can pose a particularly acute hindsight problem. The thing
about concrete items of prior art, whether they are prior published documents or prior
used products or processes, is that whatever combination of features that concrete
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prior art consists of, is not one which was created with hindsight knowledge of the
invention.
123.
The problem with arguments over common general knowledge alone is that the
combination of features relied on is always and necessarily one created with hindsight
knowledge of the invention, and worse, is one which the person attacking validity has
not been able to find as a pre-existing combination in the concrete prior art. If they
had they would have relied on that concrete prior art. Either the combination has not
been made in the concrete prior art at all or it only appears with additional
inconvenient details. If an invention is not obvious over the concrete prior art which
is relied on, the court is entitled to be sceptical that an argument that it is nevertheless
obvious over common general knowledge alone is correct.
124.
The problem is illustrated in this case. Sometimes an invention belongs to a field
which is not well documented but in this case Accord did not lack possible starting
points. It has pleaded two documents and could easily have pleaded others, such as
the existing SmPCs for subcutaneous methotrexate. However the documents contain
what might have been thought of as “inconvenient” details. Russo does not mention
subcutaneous administration by name and is aimed at JCA rather than RA. Russo is
also a small study and was published six years before the priority date. Jansen does
mention subcutaneous and is for RA but it does not mention pain and contains the two
statements referred to above which medac relies on. That the “inconvenient” details
in Russo have not led to a finding of non-obviousness is not the point. To invent as a
starting point in the prior art an amalgam of the best bits of the two cited documents
while leaving out the inconvenient aspects, which is in effect what the argument was,
created a combination which did not hitherto exist.
Obviousness – no technical benefit
125.
Accord accepts that the no technical benefit argument would not invalidate the higher
doses in claim 13. I am not satisfied that if the claims had been otherwise valid, the
lack of technical benefit argument would justify revoking any claims. The argument
is about the lower doses covered by the claims. The argument depends on an issue of
fact, whether the painfulness of injections gets any less as the volume is reduced
below 0.5 ml, so that there comes a point somewhere in the range of doses at which a
concentration of 50 mg/ml does not make the injection any less painful than the
known injections for that dose. I am not satisfied that the factual premise for this
argument is made out. In other words on the evidence I find that it is more likely than
not that the reduction in pain caused by reducing injection volume continues to reduce
as volume reduces below 0.5 ml. No lower limit was established and so there is no
basis on which to find that the lower reaches of claim 13 do not confer a technical
benefit.
Insufficiency
126.
On my findings on obviousness the insufficiency argument does not arise. However I
do agree with Accord that if the argument about side effects had materially
contributed to a finding that the claims involve an inventive step then the claims
would have been insufficient because the patent does not make that invention
plausible.
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127.
For the law on plausibility relating to sufficiency I will refer to the Court of Appeal in
Regeneron v Genentech [2013] RPC 28 at paragraphs 95-103, Lilly v HGS [2011]
UKSC 51 and the recent judgment of Henry Carr J in Actavis v Lilly [2015] EWHC
3294 (Pat).
128.
The problem for medac is that the patent says nothing at all about side effects. Medac
referred to Actavis as authority for the proposition that the law does not require a
patent to contain experimental data in order for the plausibility test to be satisfied.
The judge so held and I respectfully agree. However Actavis can be distinguished
from this case because in Actavis although there was no experimental data the patent
did contain information and reasoning on the issue. It was that reasoning which the
judge held made it plausible that the drug would have utility as a treatment for the
disease (see paragraphs 178-181). The judge was not talking about a patent which
contained no reference to the issue at all. In the present case there is no experimental
data nor is there any reasoning or information at all addressed to side effects. There is
nothing on which a skilled reader could base a view about the credibility of whether
50 mg/ml subcutaneous methotrexate does or does not have a side effect problem.
129.
Prof Müller-Ladner explained in his evidence that he regarded the invention as
plausible because the holder of the patent, medac, was a well respected
pharmaceutical company. Medac relied on this evidence. It is not relevant. As a
matter of law, the identity of the inventor or patentee cannot have anything to do with
sufficiency in general and plausibility in particular. The issue is an objective legal
standard. It is based on the technical disclosure only. In that respect it may differ
from consideration of an item of prior art. In some (unusual) cases the identity of the
author of an item of prior art may be relevant to what the skilled person does with it.
130.
Both Dr Rue and Dr Östör were asked about plausibility. When asked about the
matter in an unqualified way they said it was plausible, but that was because they
thought the invention was obvious. When asked on the correct basis, essentially from
the point of view of a skilled person who was sufficiently concerned about side effects
that a test of 50 mg/ml was not obvious to try with the appropriate expectation of
success, the most Dr Östör said was that it could work. That is not enough.
131.
This case illustrates why in a proper case there can be a squeeze between plausibility
for insufficiency and obviousness. There is no squeeze concerning pain due to
injection volume. If it was not obvious to a skilled person to make a 25 mg dose
using a 50 mg/ml concentration in a 0.5 ml volume in order to reduce pain, such a
finding would not reveal a sufficiency problem not least because the patent explains
that the reduced volume reduces pain. However the position with side effects is
different. If it was not obvious to administer a 25 mg dose using a 50 mg/ml
concentration in a 0.5 ml volume subcutaneously because of a concern about the risk
of side effects, then the patent does not give such a skilled person any comfort at all
about that risk. If that skilled person would not administer the formulation to treat RA
due to the risk, they would still not do it after reading the patent, and the claim to the
use of that formulation would be insufficient.
Conclusion
132.
I find that patent EP 2 046 332 (UK) is invalid for obviousness over Russo. It will be
revoked.