“(a) There was widespread interest in the clinical use of bisphosphonates to treat medical disorders of excess bone destruction. (b) The oral administration of etidronate was approved for use for the treatment of Paget’s disease in the UK and elsewhere. (c) The oral administration of etidronate, clodronate and pamidronate had been shown to be clinically effective in treating several medical disorders of excess bone destruction. (d) The 3 bisphosphonates which had been shown to be clinically effective in treating medical disorders of excess bone destruction had different efficacies and in particular, that etidronate had a relatively narrow therapeutic window. (f) The existing non-bisphosphonate treatments for medical disorders of excess bone destruction did not satisfy all clinical needs and there was room for a better therapy. (g) There were established tests which could be used for assessing the potential of a new therapeutic agent for use in the treatment of medical disorders of excess bone destruction.”
“1. A pharmaceutical composition which contains as the active ingredient at least one [of alendronate or anondronate] or a salt thereof with an alkali metal or an organic base or a basic amino acid, together with a pharmaceutically acceptable carrier or diluent. 2. A pharmaceutical composition according claim 1 in a form for oral administration 7. A pharmaceutical composition according to any one of the preceding claims which contains as an active ingredient [alendronate].”
“32. [The respondents] submit that this could not be clearer: Blum is specifically proposing the use of all three compounds for the production of pharmaceutical preparations. That must mean use as an active ingredient in such a preparation. 33. I think that must be right. A skilled man, aware as he would be of the C 3 compound (pamidronate) would naturally read this as a proposal to use the C 4-C 6 compounds as the active ingredient in a pharmaceutical. The point is straightforward and incapable of elaboration.”
“(i) his conclusion is not supported by the wording of the passage – there is simply no express or implicit disclosure in Blum of the use of the compounds as the active agent in pharmaceutical compositions i.e. compositions which comprise an active agent together with diluents and carriers etc. In other words, there are no clear and unambiguous directions in Blum to do something that would infringe claim 1 (and a fortiori claims 2 and 7) of the 042 Patent. (ii) he ignored the reference to “cosmetic preparations” in the relevant passage, concentrating solely on the word “pharmaceutical”; (iii) he considered what a skilled person may have thought on reading Blum, rather than what Blum actually disclosed to such a person.”
“I have no doubt that the reference [in Blum] to pharmaceutical preparations would be taken by the notional skilled person as a reference to the potential use of these compounds for clinical applications to treat medical disorders of excess bone destruction.”
“I disagree. By 1982, bisphosphonates were known to be inhibitors of bone resorption by everyone interested in the field of medical disorders of excess bone destruction. If such a person had been presented with [C 4] in 1982 I have no doubt that, for the reasons I explained in my first report, he would have expected it to have had a biological and potential therapeutic effect. Although its potency and toxicity profile would need to have been considered, this could readily have been done with further studies.”
“I think if we go back to what we have already established was known in 1982, we had pamidronate [C 3] with a quite extensive clinical experience. We already had the amino hexane [C 6] coming on the scene. Both of these compounds are active. I think if you took a vote among 100 people as to whether the two compounds in between would, first of all, work and secondly, be quite potent, you would get the majority saying that they would be...They would not be inactive; they would probably be active. They may be more or less active than the compounds either side in that series.”
“(1) Alendronate had come onto the market in 1995, approved in two oral dosage forms: 10mg daily for osteoporosis and 40mg daily for Paget’s disease. (2) The Paget’s treatment was only for six months, whereas the osteoporosis treatment was effectively for life. (3) There was a side effect problem – that alendronate could affect the gastrointestinal (GI) tract. The initial recommendations for administration were stringent: that it should be taken at least 30 minutes before the first food or drink of the day with a full glass of water and that the patient should not lie down for 30 minutes after administration. (4) Compliance with the conditions had some problems –not only would some elderly patients find them inherently difficult but also the very strict rules of the regime would not always be obeyed. (5) Marketing approval for the use of alendronate for osteoporosis was based on a number of clinical trials which would have been well known to bone disease clinicians. From these clinicians would have known that alendronate was a potent resorption inhibitor and had good anti-fracture efficacy. (6) Post-marketing surveillance showed that in rare cases only there were severe upper GI adverse events. Most of these were due to non-compliance – as Merck’s Dr Yates testified. It was not known whether poor compliance was the sole cause of the problem. (7) Although Paget’s disease is much rarer than osteoporosis, a substantial number of patients had taken alendronate in the 40mg daily dose for the 6-month period required for that disease. There was no evidence that associated GI problems were any greater with that dose as compared with the 10mg dose for osteoporosis. (8) In early 1996, because of the compliance problem, Merck made the instructions for administration more explicit – contraindicating for patients unable to comply with the 30-minute rule and those with certain oesophageal abnormalities. (9) This was expected (and did in the event) improve matters, but (as was also expected) there would continue to be a compliance problem. (10) Bisphosphonates had low oral bioavailabilty – which was reduced further if taken with food (hence the regime) (11) However once absorbed they had a long duration of action. (12) The size of their effect mainly depended on the total amount administered over time, not on the frequency of administration. Daily treatment was not critical to their effect on bone.”
“[0108] Tablets containing about 35mg of alendronate, on an alendronic acid active basis, are prepared using the following relative weights of ingredients [table referred to] [0109] The resulting tablets are useful for administration in accordance with the methods of the present invention for inhibiting bone resorption. [0110] Similarly, tablets comprising other relative weights of alendronate, on an alendronic acid basis are prepared: eg about 8.75, 17.5, 70 and 140 mg per tablet.”
“69.....it is necessary to construe the claim. In particular is it in substance merely to a 70mg dosage form, for example an oral dose containing about 70mg of alendronate? 70. I think the answer to this is clearly that the claim is wider. The patent does not teach that a particular dosage unit is new. It teaches that a particular dosing regime is new. How that regime is achieved is not material to the inventive concept of the claim. You can take 7 10mg pills or two 35mg pills or a liquid dose measured out from a bottle. Very likely the claim covers taking two of the known and available 40mg pills too - for on a purposive construction the claim cannot be limited to a mathematically precise 70mg dose. At one point I thought the claim might be to a method of preparation of a single dose of 70mg – single pills or separately prepared liquid doses (e.g. in sachets). But this cannot be so – the patent specifically contemplates 35mg tablets which are said to be useful for administration in accordance with the invention.”