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England and Wales High Court (Patents Court) Decisions
You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Hospira UK Ltd & Anor v Novartis AG  EWHC 516 (Pat) (15 March 2013)
Cite as:  EWHC 516 (Pat)
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Fetter Lane, London, EC4A 1NL
B e f o r e :
| HOSPIRA UK LIMITED
GENERICS (U.K.) LIMITED trading as MYLAN
|- and -
Michael Tappin QC (instructed by Bird & Bird LLP) for Mylan
Andrew Waugh QC and Miles Copeland (instructed by Bristows) for Novartis
Hearing dates: 20-22, 25-26 February 2013
Crown Copyright ©
MR JUSTICE ARNOLD :
|Age and bone mass||21|
|Metabolic bone disorders||22-30|
|Bone mineral density||31-32|
|Treatments for osteoporosis||37|
|Modes of administration of bisphosphonates||50-51|
|The skilled team||81-82|
|Common general knowledge||83-118|
|Extrapolation between different bone disorders||85|
|Extrapolation between different bisphosphonates||86-88|
|Failures of bisphosphonates||89-94|
|Duration of action of bisphosphonates||95-98|
|Dosage of regimens exceeding three months||99-111|
|The significance of biomarker data||112-116|
|The skilled team and the common general knowledge||155|
|The inventive concept||156|
|Was the step obvious?||159-181|
|The context in which Boutsen is taken to be read||160|
|Would the skilled team obtain the poster?||161|
|Would the skilled team put Boutsen on one side?||162|
|What would the skilled team take from Boutsen?||163-168|
|Would the skilled team regard Boutsen's teaching as applicable to zoledronate?||169|
|What dose of zoledronate would the skilled team contemplate using in a Phase 2 trial?||170-172|
|The motive to find a solution to the problem||173|
|Other awareness of research||174-175|
|The effort required||176|
|The prospects of success||177|
|Summary of conclusions||187|
Age and bone mass
Metabolic bone disorders
Bone mineral density
a) Urinary hydroxyproline. Hydroxyproline is found mainly in collagen. It is not tissue-specific, and therefore by 2000 other bone resorption markers were seen as more informative and reliable.
b) Urinary (collagen type I cross-linked) N-telopeptide (NTX). NTX fluctuates in a sensitive manner in line with bone resorption patterns. It is often measured together with creatinine levels and expressed as a ratio of NTX/creatinine.
c) Urinary or serum C-telopeptide (CTX). C-terminal telopeptide (also known as carboxy-terminal collagen crosslinks) was regarded in 2000 as a very reliable biomarker for measuring the rate of bone resorption. The CTX test measures the concentration of a crosslink peptide sequence of type I collagen found in bone (and other tissues). This specific peptide sequence relates to bone turnover because it is the portion that is cleaved by osteoclasts during bone resorption, and its serum levels are therefore proportional to osteoclastic activity at the time the blood sample is drawn. The test used to detect CTX in serum is called the Serum CrossLaps test.
a) Bone specific alkaline phosphatase (BSAP)/Serum alkaline phosphatase (SAP). Alkaline phosphatase is an enzyme produced by osteoblasts, although its precise role in bone mineralisation was not fully understood. Alkaline phosphatase is also produced by the liver and the placenta. SAP has been used for many decades to diagnose Paget's disease. SAP cannot be used to differentiate between alkaline phosphatase produced by osteoblasts and by the liver, but the high level of osteoblastic activity in Paget's disease patients means that the alkaline phosphatase produced by the osteoblasts far outweighs that produced by the liver. For osteoporosis patients, where there is much less osteoblastic activity, and SAP may not be elevated out of the normal range, BSAP is a much more useful marker.
b) Serum osteocalcin (OC). This protein is secreted by osteoblasts and was widely accepted as a marker for osteoblastic activity and hence bone formation although its precise function remained unknown. However, OC is released into the circulation during resorption so the serum level at any one time has a component of both bone formation and resorption.
Treatments for osteoporosis
|Etidronate*||OH||CH3||Osteoporosis, Paget's disease|
|Pamidronate*||OH||CH2CH2NH2||Hypercalcaemia, myeloma, Paget's disease|
|Alendronate*||OH||(CH2)3NH2||Osteoporosis and other indications|
|Risedronate*||OH||CH2-3-pyridine||Registration pending for osteoporosis|
|Ibandronate*||OH||CH2CH2N(CH3)(pentyl)||In development, osteoporosis and other diseases|
|Zoledronate||OH||CH2-imidazole||In development, several diseases|
Modes of administration of bisphosphonates
"This invention relates to bisphosphonates, in particular to the pharmaceutical use of bisphosphonates in the treatment of conditions of abnormally increased bone turnover, such as osteoporosis."
"The mechanisms by which bisphosphonates inhibit bone resorption are still poorly understood and seem to vary according to the bisphosphonates studied."
"Surprisingly we have now found that bisphosphonates, in particular recent potent bisphosphonates, can be used for prolonged inhibition of bone resorption in conditions of abnormally increased bone turnover by intermittent administration, wherein the periods between bisphosphonate administrations are longer than was previously considered appropriate to achieve satisfactory treatment. In particular and contrary to expectation we have found that satisfactory treatment results can be obtained even when the dosing intervals greatly exceed the natural bone remodelling cycle.
Accordingly the present invention provides a method for the treatment of conditions of abnormally increased bone turnover in a patient in need of such treatment which comprises intermittently administering an effective amount of a bisphosphonate to the patient, wherein the period between administrations of bisphosphonate is at least about 6 months.
The invention further provides use of a bisphosphonate in the preparation of a medicament for the treatment of conditions of abnormally increased bone turnover in which the bisphosphonate is administered intermittently and in which the period between administrations is at least about 6 months."
"In particularly preferred embodiments the invention may be used for the prophylactic treatment of osteoporosis and similar diseases. Thus for example bisphosphonate may be administered to individuals at risk of developing osteoporosis on a regular basis at dosing intervals of at least about 6 months e.g. bisphosphonate may be administered routinely to postmenopausal women at dosing intervals of once every 6 months or less frequently."
"In accordance with the present invention the bisphosphonate dosing interval is at least about 6 months, e.g. once every 180 days, or less frequently, conveniently once a year, or any interval in between, e.g. one every 7, 8, 9, 10, or 11 months. Dosing intervals of greater than once per year may be used, e.g. about once every 18 months or about once every 2 years, or even less frequently, e.g. a frequency of up to about once every 3 years or less often."
"The pharmaceutical compositions may be, for example, compositions for enteral, such as oral, rectal, aerosol inhalation or nasal administration, compositions for parenteral, such as intravenous or subcutaneous administration, or compositions for transdermal administration (e.g. passive or iontophoretic).
Preferably, the pharmaceutical compositions are adapted to oral or parenteral (especially intravenous, intra arterial or transdermal) administration. Intra-arterial and oral, first and foremost intra-arterial, administration is considered to be of particular importance. …"
"The particular mode of administration and the dosage may be selected by the attending physician taking into account the particulars of the patient, especially age, weight, life style, activity level, hormonal status (e.g. post-menopausal) and bone mineral density as appropriate.
The dosage of the Agents of the Invention may depend on various factors, such as effectiveness and duration of the active ingredient, e.g. including the relative potency of the bisphosphonate used, mode of administration, …. sex, age, weight and condition of the warm-blooded animal.
Normally the dosage is such that a single dose of the bisphosphonate active ingredient from 0.005-20 mg/kg, especially 0.01-10 mg/kg, is administered …
The dose mentioned above is typically administered intermittently with a period of at least 6 months between doses. The period between bisphosphonate administrations may be longer, e.g. conveniently once per year, once per 18 months or once every 2 years, or even longer, or any period in between.
… Single dose unit forms such as ampoules of infusion solution or sold for preparation of infusion solution doses, capsules, tablets or dragees contain e.g. from about 0.5 mg to about 500 mg of the active ingredient. It will be appreciated that the actual unit dose will depend upon the potency of the bisphosphonate and the dosing interval among other things. Thus the size of the unit dose is typically lower for more potent bisphosphonates and greater the longer of the dosing interval. For example, for more potent, recent bisphosphonates such as zoledronic acid a unit dose of from about 1 up to about 10 mg may be used. For example, also for such recent, more potent bisphosphonates a unit does of from about 1 to about 5 mg may be used for dosing once every 6 months; whereas a dose of from about 2 up to about 10 mg may be used for once a year dosing
Unit doses may be administered as a single or divided dose… In accordance with the invention, the time interval between administration of the last part of the divided dose and administration of the first part of the next, following divided dose is at least 6 months or longer, e.g. about 1 year."
"Parenteral formulations are especially injectable fluids that are effective in various manners, such as intravenously, intramuscularly, intraperitoneally, intranasally, intradermally, subcutaneously or preferably intra-arterially."
"The 12 month results showed that all treatment arms demonstrated a percent change from baseline in BMD significantly (p<0.001) greater than placebo and not dissimilar one from another."
"Suppression of biochemical markers of bone formation and bone resorption confirmed and supported the BMD results, demonstrating suppression of bone turnover to the pre-menopausal level throughout the 6 and 12 month dosing intervals."
"The BMD data indicate that zoledronic acid dose administration as infrequent as every 6 or 12 months can safely result in a statistically significant and medically relevant bone mass increase. It is believed that these data further indicate that a continued preservation of new bone beyond one year, without additional dose administration, is likely or that further bone mass increase is possible. It is also believed that re-treatment in additional cycles of every 6-month, 12-month, or less frequent dose administration will lead to further BMD increase. A reduction of risk of osteoporotic fracture is expected to accompany the bone mass increase."
"Bisphosphonates, in particular recent more potent bisphosphonates such as zoledronic acid and derivatives, can be used with satisfactory results for the prolonged inhibition of bone resorbtion in conditions of abnormally increased bone turnover, eg osteoporosis, by intermittent administration, wherein the periods between bisphosphonate administrations are longer than was previously considered appropriate, e.g. a dosing interval of at least about 6 months or less frequently."
"For example, for
more recent, potent bisphosphonates such aszoledronic acid a unit dose of from about 1 up to about 10 mg may be used for parenteral, e.g. intravenous, administration. For example, also for such recent, more potent bisphosphonates aA unit dose of from about 1 to about 5 mg may be used parenterally for dosing once every 6 months; whereas a dose of from about 2 up to about 10 mg may be used for once a year parenteral dosing."
"1. Use of [zoledronic acid] or a pharmaceutically acceptable salt thereof or any hydrate thereof in the preparation of a medicament for the treatment of osteoporosis in which the [zoledronic acid] or a pharmaceutically acceptable salt thereof or any hydrate thereof is administered intravenously and intermittently, and in which the period between administrations is at least about 6 months.
2. Use according to claim 1, wherein the period between administrations is at least about once a year.
5. Use of [zoledronic acid] or a pharmaceutically acceptable salt thereof or any hydrate thereof for the preparation of a medicament for the treatment of osteoporosis wherein said medicament is adapted for intravenous administration in a unit dosage form which comprises from about 1 up to about 10mg of [zoledronic acid] or a pharmaceutically acceptable salt thereof or any hydrate thereof, wherein the period between administrations of bisphosphonate is at least about 6 months.
6. Use according to claim 5, wherein the unit dosage form comprises from about 1 up to about 5 mg and the period between administrations is about once every six months.
7. Use according to claim 5, wherein the unit dosage form comprises from about 2 up to about 10 mg and the period between administrations is about once a year."
"1. Zoledronic acid or a pharmaceutically acceptable salt thereof or any hydrate thereof for use in a method of treating osteoporosis in which the zoledronic acid or the pharmaceutically acceptable salt therefore or the hydrate thereof is administered intravenously and intermittently and in which the period between administrations is at least about 6 months.
2. Zoledronic acid or a pharmaceutically acceptable salt thereof or any hydrate thereof for use according to claim 1 wherein the osteoporosis is postmenopausal osteoporosis.
6. Zoledronic acid or a pharmaceutically acceptable salt thereof or any hydrate thereof for use according claim 1 wherein the period between administrations is at least about a year.
7. Zoledronic acid or a pharmaceutically acceptable salt thereof or any hydrate thereof for use according to any one of the preceding claims wherein the period between administrations is one year."
The skilled team
Common general knowledge
Extrapolation between different bone disorders
Extrapolation between different bisphosphonates
"Each bisphosphonate has its own physicochemical and biological characteristics. This variability in effect makes it impossible to extrapolate with certainty from data for one compound to others, so that each compound has to be considered on its own, with respect to both its use and its toxicology."
Accordingly, Prof Compston accepted that one could not extrapolate from one bisphosphonate to another for efficacy or safety without actually doing the experiment.
Failures of bisphosphonates
"… in a large multicentre study on osteoporotic women, either 50 or 200 mg given orally for 7 days each month, were effective neither on bone mineral density nor on the fracture rate."
Duration of action of bisphosphonates
"There are not many studies examining the consequences of discontinuing bisphosphonate administration. It appears that the results depend on the bisphosphonate administered, the dose, and the length of treatment. In general, bone turnover increases again within 3 months and reaches pre-treatment levels within a year.
After discontinuation of treatment bone turnover returns to pre-treatment values within months and bone loss appears to resume again, although later."
Dosage regimens exceeding three months
"Q. But if they felt that there was a ceiling of three months, they would never have said 2-4?
A. I am not sure they would never have said, because even the best of us can be inconsistent in what we sometimes say. I do really think that this remodelling cycle, three month, is a really important concept because if you imagine what happens when you give a bisphosphonate, you have osteoclast [a]round, the bisphosphonate inactivates them. You know, for a period of time, the bisphosphonate has virtually disappeared and sooner or later osteoclasts are going to come back. By the end of a three month, all those remodelling cycles which have been busy filling in their space, you know, will have done that and there will be a whole new, what, 5 million units of remodelling coming back into play. So I really think that this is an important part of it. And we see it, you know, so often stated. I think there are more people who refer to the osteoclast lifecycle and the remodelling cycle as influencing their thinking than those who do not care about that. Let us put it that way."
"The most interesting observation that we observed was that biochemical evidence for the inhibition of bone resorption persisted for at least 6 months after a 4 day exposure to alendronate. Our observations suggest that treatment with alendronate does induce effects on bone turnover in osteoporosis in much the same manner as observed in Paget's disease. This finding is in contrast to the results reported by Adami et al using a lower dose (5 mg) and a single infusion of alendronate in which the effect wore off within weeks of stopping treatment. This may be due to the lower dose given (5 vs 30 mg)."
"Although the lack of a control group limits the conclusions on the duration of the therapeutic response, the significant changes observed in the biochemical indices were greater than the long-term coefficient of variation for each variable. Exposure to a short course of alendronate in high doses thus appears to induce a prolonged effect on bone resorption, which remained significantly below pre-treatment values for at least 1 year and probably 2 years following treatment. The effects on BMD would support this view. … The effects of oral treatment on bone resorption are similar, suggesting that the pharmacodynamic response over the first year may depend on the total dose given rather than the duration of exposure."
"Little is known yet about the best mode of administration of these compounds. Is there any advantage in discontinuous versus continuous administration? One study in rats showed no difference when tiludronate was given over a period of 16 weeks at the same total dose for five days every four weeks or five days a week (Ammann et al., 1993). If discontinuous treatment was used, what would be the best regimen? There is no proof that the regimen prescribed for etidronate is optimal. Indeed, the ADFR theory, if it is applicable at all, may well be inapplicable to a drug with a long-term action. A single administration of pamidronate every three months actively increased bone mineral density in various sites (Thiébaud et al., 1994). Recently it was shown that 10 mg of alendronate infused over five days was effective on bone turnover for 720 days in Paget's disease, 120 days in metastatic bone disease, 124 ± 82 days in postmenopausal osteoporosis, 28 ± 32 days in primary hyperparathyroidism and only 12 ± 9 days in humoral hypercalcemia of malignancy (Adami et al., 1992). This might raise the possibility of a biannual treatment in osteoporosis and, since the duration probably depends on the dose, a less frequent treatment may even be envisaged. However, since the total dose is most probably the relevant one, the less frequent the administration, the higher the individual dose, which might present drawbacks, the continuous administration having the advantage of lower peak blood levels.
The optimal dose will have to be determined for each bisphosphonate. It should be chosen such that bone turnover is not decreased excessively, but bone loss is still inhibited adequately, or better yet, bone is gained.
Many other questions remain. For example, do differences exist between various bisphosphonates? Will it be of advantage to administer the bisphosphonates together with a compound which increases bone formation, such as fluoride? Should these compounds be used both for treatment and for prevention of disease?"
"The bisphosphonates represent an important development in the field of treatment of bone diseases, and it is probably that we are only at the beginning of a new era of therapy.
Many issues are still unresolved. For example, we do not yet know whether we have found the optimal regimen for the various compounds available. This is especially the case in treatment of osteoporosis. How can the intravenous versus the oral therapy be compared? Is there an advantage to the use of an intermittent therapy? Are the newly proposed regimens of a weekly tablet, or of a 3-monthly injection, just the first step in a new evolution? Could one use longer intervals, possibly even once yearly treatment? Which are in the different cases the optimal regimens for the various bisphosphonates? Will there be an advantage in the future to combine bisphosphonates, or bisphosphonates with another inhibitor of resorption, such as estrogens in hormone replacement therapy, as is already done by some clinicians, SERMS, or with stimulator of bone formation?
Since the long persistence of bisphosphonates in the body is a concern for some, it may be possible in the future to devise drugs that are similar to the bisphosphonates, have similar effects, but are metabolically broken down.
Lastly, it could be that with a still better knowledge of the mode of action of these compounds at the cellular level, new insight will be gained into the physiological and pathophysiological function of bone, opening up new approaches to therapy."
The significance of biomarker data
"The patent claims must clearly define the subject-matter for which protection is sought under Art. 84 EPC. In T 94/82 (OJ 1984, 75) it was held that this requirement was fulfilled in a claim to a product when the characteristics of the product were specified by parameters relating to the physical structure of the product, provided that those parameters could be clearly and reliably determined by objective procedures which were usual in the art. In such a product claim, it sufficed to state the physical properties of the product in terms of parameters, since it was not mandatory to give instructions in the claim itself as to how the product was to be obtained. The description, however, had to fulfil the requirements of Art. 83 EPC 1973 and thus enable the person skilled in the art to obtain the claimed product described in it (see also T 487/89, T 297/90, T 541/97). Nor should this be understood as also referring to those variants falling under the literal wording of the claim but which the skilled person would immediately exclude as being clearly outside the scope of practical application of the claimed subject matter, for example, claims including an open ended range for a parameter where it was clear for a skilled person that the open-ended range was limited in practice. Values of the parameter not obtainable in practice would not be regarded by the skilled person as being covered by the claims and thus could not justify an objection of insufficiency of disclosure (T 1018/05)."
"The requirement for claiming priority of 'the same invention', referred to in Article 87(1) EPC, means that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the skilled person can derive the subject-matter of the claim directly and unambiguously, using common general knowledge, from the previous application as a whole."
"The approach is not formulaic: priority is a question about technical disclosure, explicit or implicit. Is there enough in the priority document to give the skilled man essentially the same information as forms the subject-matter of the claim and enables him to work the invention in accordance with that claim?"
"So the important thing is not the consistory clause or the claims of the priority document but whether the disclosure as a whole is enabling and effectively gives the skilled person what is in the claim whose priority is in question. I would add that it must 'give' it directly and unambiguously. It is not sufficient that it may be an obvious development of what is disclosed."
(b) for the treatment of osteoporosis;
(c) administered intravenously;
(d) at least about six months between administrations.
(b) for the treatment of osteoporosis;
(c) administered intravenously;
(d) in a unit dosage form of about 1-10 mg;
(e) at least about six months between administrations.
"The aim of this study was to compare the efficacy of two regimens of intravenous pamidronate as primary prevention of glucocorticoid-induced osteoporosis (GIOP). At the time of initiating steroid therapy, 10 patients (Group A) received a single intravenous infusion of pamidronate (Aredia®, Novartis, Basle, Switzerland), 90 mg in 500 ml NaCl 0.9% over 2 hours; 10 patients (Group B) received a first infusion of 90 mg pamidronate and, subsequently, a 30-mg dose, in 250 ml NaCl 0.9% over 30 minutes every three months. As with control patients (Group C), they were all put on a daily 800-mg elemental calcium suppplement given as calcium carbonate. Patients were matched taking into account starting steroid doses, sex, menopausal status and hormonal replacement therapy. Lumbar spine and hip (total and subregions) bone mineral densities (BMDs) were measured at the start and at 6-monthly intervals by dual-energy X-ray absorptiometry (QDR-2000 Hologic, Inc.). Serum type I collagen fragments were measured using a one step ELISA method (CrossLaps®, Osteometer Biotech A/S Denmark) kindly analyzed by Claus Christiansen's group. Statistics were performed by ANOVA with repeated measurements. One patient (Group B) no longer required glucocorticoids after 3 months so that only 27 matched patients remained available for final analysis. After 1 year, cumulative steroid dosages expressed as mg prednisolone were respectively 3993 (2787) (Group A), 4962 (3300) (Group B) and 3162 (1425). BMD measurements at one year are expressed as % of initial values [mean(SD)] in the table.
|Group A||Group B||Group C|
|L1-L4||101.6 ± 2.1||102.2 ± 3.4||95.4 ± 2.8|
|Femoral neck||101.2 ± 2.2||101.2 ± 2.3||96.8 ± 4.1|
|Total hip||101.0 ± 3.5||102.6 ± 3.1||97.7 ± 2.2|
No difference was observed between pamidronate regimens but a highly significant difference was observed between both pamidronate regimens and the control group; p<0.001 at the lumbar spine; p<0.01 at the femoral neck and p<0.05 at the total hip. Serum CrossLaps demonstrated a progressive decrease in all groups during the first six months, more marked after 3 months in groups A and B. A sustained decrease was only observed throughout in group B. As far as BMD evolution over one year is concerned, intravenous pamidronate given as a single infusion or on a three-monthly regimen effectively achieved primary prevention of glucocorticoid-induced osteoporosis."
"(1)(a) Identify the notional 'person skilled in the art';
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the 'state of the art' and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?"
"90. One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.
91. For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way. Lord Hoffmann summarised the position in this way in Conor at :
'In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent  RPC 479, by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case.'
92. Moreover, whether a route is obvious to try is only one of many considerations which it may be appropriate for the court to take into account. In Generics (UK) Ltd v H Lundbeck,  EWCA Civ 311,  RPC 19, at  and in Conor  UKHL 49,  RPC 28 at , Lord Hoffmann approved this statement of principle which I made at first instance in Lundbeck:
'The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.'
93. Ultimately the court has to evaluate all the relevant circumstances in order to answer a single and relatively simple question of fact: was it obvious to the skilled but unimaginative addressee to make a product or carry out a process falling within the claim…."
The skilled team and the common general knowledge
The inventive concept
a) Boutsen was concerned with pamidronate, not zoledronate.
b) Boutsen did not disclose intravenous administration at intervals of at least about six months.
c) Boutsen did not disclose that intravenous administration at intervals of at least about six months was effective in the treatment of osteoporosis.
Was the step obvious?
a) developing new bisphosphonate molecules;
b) developing prodrugs of existing bisphosphonates;
c) using existing bisphosphonates for alternative conditions;
d) investigating different formulations;
e) investigating combinations of existing drugs; and
f) investigating different routes of administration.
"The heart of the test is: 'Can the skilled person readily perform the invention over the whole area claimed without undue burden and without needing inventive skill?'"
On the facts, he agreed with counsel for Johnson & Johnson at  that the patent in suit "did no more than invite the reader to perform a research program where, if he succeeded, the patent claimed the fruits of his research".
Summary of conclusions
a) None of the claims is entitled to priority from PD2. It follows that both Patents are invalid.
b) None of the claims is obvious over Boutsen.
c) Claims 1, 2 and 5 of 689 and claims 1, 2, 6 and 7 of 122 are invalid for insufficiency.