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Merck & Co. Inc. v Arrow Pharmaceuticals (NZ) Limited [2006] NZIPOPAT 3 (31 January 2006)

Last Updated: 16 October 2008

P3/2006

IN THE INTELLECTUAL

PROPERTY OFFICE OF
NEW ZEALAND

IN THE MATTER of the Patents Act 1953

AND

IN THE MATTER of an application for Letters Patent No 501807 in the name of MERCK & CO INC

Applicant

AND

IN THE MATTER of opposition to said application under section 21 by ARROW PHARMACEUTICALS (NZ) LIMITED

Opponent

Hearing: 13 December 2005

B Brown QC and G Arthur assisted by K McHaffie for the Applicant

Decision

BACKGROUND

Patent application no. 501807 was filed on 17 July 1998, claiming priority from four foreign applications dated 20 August 1997, 22 August 1997, 22 July 1997 and 23 July 1997.

Notice of acceptance issued on 23 January 2003, acceptance being published in Patent Office Journal 1484 of 28 February 2003.

Notice of opposition was filed on 27 June 2003.

Amended notice of opposition and statement of case were filed on 24 October 2003. Grounds (b), (e) - first limb, (f) and (g) of section 21(1) were pleaded by the opponent.

A counterstatement was filed on 27 February 2004. The grounds pleaded by the opponent were denied.

A second amended notice of opposition and amended statement of case were filed on 16 April 2004. The same grounds were pleaded.

A third amended notice of opposition and second amended statement of case were filed on 29 June 2004. The same grounds were pleaded.

By way of letter dated 9 September 2004 the opponent withdrew, the opponent advising that the parties had agreed that there is to be no issue as to costs.

An amended counterstatement, together with unconditionally proposed amendment proposals, was filed on 20 September 2004. The grounds pleaded were again denied.

A patent advisor of the Intellectual Property Office of New Zealand (the office) advised that the amendment proposals were allowable as meeting the requirements of section 40(1).

Evidence was filed by both parties and a decision needs to be made in the public interest. The applicant requested, and attended, a hearing to make submissions in support of the application.

LOCUS STANDI

The applicant admitted that the opponent has locus standi. I accept that the opponent has locus standi.

PRIORITY DATES

All the cited documents were available before the earliest priority date to which the claims could be entitled. Therefore, nothing turns on the priority date of the claims and the priority date is not an issue.

EVIDENCE

Filed in support of the opposition were statutory declarations of:

James Steven ROWE, Pharmaceutical Consultant and Scientific Director of Technical Consultancy Services Pty Limited, of Blakehurst, New South Wales, Australia;

David John WILLIS, Managing Director of Arrow Pharmaceuticals NZ Limited, of Auckland, New Zealand;

Peter Henry Robert PERSICANER, Research and Development Manager for Arrow Laboratories, of Melbourne, Australia;

Timothy Frank CUNDY, Associate Professor in the Department of Medicine in the Faculty of Medical and Health Sciences at the University of Auckland, of Auckland, New Zealand (Cundy 1);

Lindsay Dudley PLANK, Senior Research Fellow at the Department of Surgery, University of Auckland, New Zealand;

Sharon June MIMILO, Legal Secretary employed by Baldwin Shelston Waters, the attorneys for the opponent in this matter, of Auckland,

New Zealand;

second statutory declaration of Timothy Frank CUNDY (Cundy 2); and

third statutory declaration of Timothy Frank CUNDY.

Also filed in support of the opposition were affirmations of:

Richard Bruce MAZESS, Emeritus Professor of Medical Physics at the University of Wisconsin, Madison, and Founder and Former Chairman of Bone Care International, Inc, of Madison, Wisconsin, United States of America (Mazess); and

David Allan WEISSBURG, Independent Business Consultant, of Monona, Wisconsin, United States of America.

Filed in support of the application were affidavits of:

Socrates E PAPAPOULOS, Professor of Medicine, Consultant Physician and Director of Bone Research at the Department of Endocrinology and Metabolic Diseases of the Leiden University Medical Centre, the Netherlands, of The Hague, the Netherlands (Papapoulos 1);

Michael Brian FENNERTY, Physician, and Professor of Medicine and the Section Chief of Gastroenterology at the Department of Internal Medicine, Section of Gastroenterology at Oregon Health & Science University (OHSU) in Portland, of Portland, Oregon, United States of America (Fennerty);

Peter Robert EBELING, Deputy Director of the Department of Diabetes and Endocrinology at the Royal Melbourne Hospital and Principal Fellow and Associate Professor in the Department of Medicine, University of Melbourne, Royal Melbourne Hospital, of Port Melbourne, Australia (Ebeling);

Alister BROWN, Managing Director of Merck Sharp & Dohme (New Zealand) Limited, of Auckland, New Zealand; and

supplementary affidavit of Socrates E PAPAPOULOS (Papapoulos 2).

AMENDMENT PROPOSALS

Section 40(1) relates to amendment of a specification after acceptance:

After the acceptance of a complete specification, no amendment thereof shall be effected except by way of disclaimer, correction, or explanation, and no amendment thereof shall be allowed, except for the purpose of correcting an obvious mistake, the effect of which would be that the specification as amended would claim or describe matter not in substance disclosed in the specification before the amendment, or that any claim of the specification as amended would not fall wholly within the scope of a claim of the specification before the amendment.

The amendments to claim 1 are (deletions shown italicised, additions shown underlined):

Use of alendronic acid or a pharmaceutically acceptable salt thereof, or a mixture thereof, for the manufacture of a medicament for inhibiting bone resorption in a human wherein said medicament is adapted for oral administration, in a unit dosage form which comprises from about 8.75 mg to about 140 mg 70 mg of alendronic acid or a pharmaceutically acceptable salt thereof, on an alendronic acid active weight basis, according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days wherein said schedule has a dosing interval of once-weekly.

The amendments to claim 1 are clearly disclaiming amendments and the scope of the invention claimed is very much reduced. The remaining amendments to the claims are consequential on the amendments proposed for claim 1 and are hence part of the disclaimer. The amendments are allowable and are to be made.

NATURE OF THE INVENTION

The title of the specification is:

Method for inhibiting bone resorption

The field of the invention is described in the specification as follows:

The present invention relates to oral methods for inhibiting bone resorption in a mammal while minimizing the occurrence of or potential for adverse gastrointestinal effects. These methods comprise orally administering to a mammal in need thereof of a pharmaceutically effective amount of a bisphosphonate as a unit dosage according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice weekly dosing, biweekly dosing, and twice monthly dosing. The present invention also relates to pharmaceutical compositions and kits useful for carrying out these methods.

Opening paragraphs describe the background of the invention as follows:

A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, Paget’s disease, periprosthetic bone loss or osteolysis, and hypercalcemia of malignancy. The most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture. Because osteoporosis, as well as other disorders associated with bone loss, are chronic conditions, it is believed that appropriate therapy will generally require chronic treatment.

Multinucleated cells called osteoclasts are responsible for causing bone loss through a process known as bone resorption. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of a variety of generalized or localized bone disorders caused by or associated with abnormal bone resorption. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 2nd Edition, Parthenon Publishing (1995), which is incorporated by reference herein in its entirety.

At present, a great amount of preclinical and clinical data exists for the potent bisphosphonate compound alendronate. Evidence suggests that other bisphosphonates such as risedronate, tiludronate, ibandronate and zolendronate, have many properties in common with alendronate, including high potency as inhibitors of osteoclastic bone resorption. An older bisphosphonate compound, etidronate, also inhibits bone resorption. However, unlike the more potent bisphosphonates, etidronate impairs mineralization at doses used clinically, and may give rise to osteomalacia, a condition resulting in an undesirable decrease in bone mineralization. See Boyce, B. F., Fogelman, I., Ralston, S. et al. (1984) Lancet 1 (8381), pp. 821-824 (1984), and Gibbs, C. J., Aaron, J. E.; Peacock, M. (1986) Br. Med. J. 292, pp. 1227-1229 (1986), both of which are incorporated by reference herein in their entirety.

Despite their therapeutic benefits, bisphosphonates are poorly absorbed from the gastrointestinal tract. See B. J. Gertz et al., Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int., Suppl. 3: S13-16 (1993) and B. J. Gertz et al., Studies of the oral bioavailability of alendronate, Clinical Pharmacology & Therapeutics, vol. 58, number 3, pp. 288-298 (September 1995), which are incorporated by reference herein in their entirety. Intravenous administration has been used to overcome this bioavailability problem. However, intravenous administration is costly and inconvenient, especially when the patient must be given an intravenous infusion lasting several hours on repeated occasions.

If oral administration of the bisphosphonate is desired, relatively high doses must be administered to compensate for the low bioavailability from the gastrointestinal tract. To offset this low bioavailability, it is generally recommended that the patient take the bisphosphonate on an empty stomach and fast for at least 30 minutes afterwards. However, many patients find the need for such fasting on a daily basis to be inconvenient. Moreover, oral administration has been associated with adverse gastrointestinal effects, especially those relating to the esophagus. See Fleisch, Id. These effects appear to be related to the irritant potential of the bisphosphonate in the esophagus, a problem which is exacerbated by the presence of refluxed gastric acid. For example, the bisphosphonate, pamidronate has been associated with esophageal ulcers. See E. G. Lufkin et al., Pamidronate : An Unrecognized Problem in Gastrointestinal Tolerability, Osteoporosis International, 4: 320-322 (1994), which is incorporated by reference herein in its entirety. Although not as common, the use of alendronate has been associated with esophagitis and/or esophageal ulcers. See P. C. De Groen, et al., Esophagitis Associated With The Use Of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1016-1021 (1996), D. O. Castell, Pill Esophagitis--The Case of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1058-1059 (1996), and U. A. Liberman et al., Esophagitis and Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1069-1070 (1996), which are incorporated by reference herein in their entirety. The degree of adverse gastrointestinal effects of bisphosphonates has been shown to increase with increasing dose. See C. H. Chestnut et al., Alendronate Treatment of the Postmenopausal Osteoporotic Woman : Effect of Multiple Dosages on Bone Mass and Bone Remodeling, The American Journal of Medicine, vol. 99, pp. 144-152, (August 1995), which is incorporated by reference herein in its entirety. Also, these adverse esophageal effects appear to be more prevalent in patients who do not take the bisphosphonate with an adequate amount of liquid or who lie down shortly after dosing, thereby increasing the chance for esophageal reflux.

Current oral bisphosphonate therapies generally fall into two categories: (1) those therapies utilizing continuous daily treatment, and (2) those therapies utilizing a cyclic regimen of treatment and rest periods.

The continuous daily treatment regimens normally involve the chronic administration of relatively low doses of the bisphosphonate compound, with the objective of delivering the desired cumulative therapeutic dose over the course of the treatment period. However, continuous daily dosing has the potential disadvantage of causing adverse gastrointestinal effects due to the repetitive, continuous, and additive irritation to the gastrointestinal tract. Also, because bisphosphonates should be taken on an empty stomach followed by fasting and maintenance of an upright posture for at least 30 minutes, many patients find daily dosing to be burdensome. These factors can therefore interfere with patient compliance, and in severe cases even require cessation of treatment.

Cyclic treatment regimens were developed because some bisphosphonates, such as etidronate, when given daily for more than several days, have the disadvantage of actually causing a decline in bone mineralization, i. e. osteomalacia. U. S. Patent No. 4,761,406, to Flora et al, issued August 2,1988, which is incorporated by reference herein in its entirety, describes a cyclic regimen developed in an attempt to minimize the decline in bone mineralization while still providing a therapeutic anti-resorptive effect. Generally, cyclic regimens are characterized as being intermittent, as opposed to continuous treatment regimens, and have both treatment periods during which the bisphosphonate is administered and nontreatment periods to permit the systemic level of the bisphosphonate to return to baseline. However, the cyclic regimens, relative to continuous dosing, appear to result in a decreased therapeutic antiresorptive efficacy. Data on risedronate suggests that cyclic dosing is actually less effective than continuous daily dosing for maximizing antiresorptive bone effects. See L. Mortensen, et al., Prevention Of Early Postmenopausal Bone Loss By Risedronate, Journal of Bone and Mineral Research, vol. 10, supp. 1, p. s140 (1995), which is incorporated by reference herein in its entirety. Furthermore, these cyclic regimens do not eliminate or minimize adverse gastrointestinal effects, because such regimens typically utilize periods of multiple daily dosing. Also, the cyclic regimens are cumbersome to administer and have the disadvantage of low patient compliance, and consequently compromised therapeutic efficacy. U. S. Patent No. 5, 366,965, to Strein, issued November 22,1994, which is incorpoated by reference herein in its entirety, attempts to address the problem of adverse gastrointestinal effects by administering a polyphosphonate compound, either orally, subcutaneously, or intravenously, according to an intermittent dosing schedule having both a bone resorption inhibition period and a no-treatment rest period. However, the regimen has the disadvantage of not being continuous and regular, and requires nontreatment periods ranging from 20 to 120 days. PCT Application No. WO 95/30421, to Goodship et al, published November 16, 1995, which is incorporated by reference herein in its entirety, discloses methods for preventing prosthetic loosening and migration using various bisphosphonate compounds. Administration of a once weekly partial dose of the bisphosphonate is disclosed. However, the reference specifically fails to address the issue of adverse gastrointestinal effects or to disclose administration of larger or multiple dosages.

It is seen from current teachings that both daily and cyclic treatment regimens have shortcomings, and that there is a need for development of a dosing regimen to overcome these shortcomings.

In the present invention, it is found that the adverse gastrointestinal effects that can be associated with daily or cyclic dosing regimens can be minimized by administering the bisphosphonate at a relatively high unit dosage according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing. In other words, it is found that the administration of a bisphosphonate at a high relative dosage at a low relative dosing frequency causes less adverse gastrointestinal effects, particularly esophageal effects, compared to the administration of a low relative dosage at a high relative dosing frequency. This result is surprising in view of the teachings suggesting that adverse gastrointestinal effects would be expected to increase as a function of increasing bisphosphonate dosage. Such administration methods of the present invention would be especially beneficial in treating patients that have been identified as suffering from or are susceptible to upper gastrointestinal disorders, e. g. gastrointestinal reflux disease (i. e."GERD"), esophagitis, dyspepsia (i. e. heatburn), ulcers, and other related disorders. In such patients conventional bisphosphonate therapy could potentially exacerbate or induce such upper gastrointestinal disorders.

From a patient lifestyle standpoint, the methods of the present invention would also be more convenient than daily or cyclic dosing regimens. Patients would be subjected less frequently to the inconvenience of having to take the drug on an empty stomach and having to fast for at least 30 minutes after dosing. Also, patients would not need to keep track of a complex dosing regimen. The methods of the present invention are likely to have the advantage of promoting better patient compliance, which in turn can translate into better therapeutic efficacy.

It is an object of the present invention to provide methods for inhibiting bone resorption and the conditions associated therewith.

It is another object of the present invention to provide methods for treating abnormal bone resorption and the conditions associated therewith.

It is another object of the present invention to provide methods for preventing abnormal bone resorption and the conditions associated therewith.

It is another object of the present invention to provide methods which are oral methods.

It is another object of the present invention to provide such methods in humans.

It is another object of the present invention to provide such methods in patients that have been identified as suffering from or are susceptible to upper gastrointestinal disorders, e. g. gastrointestinal reflux disease (i. e."GERD"), esophagitis, dyspepsia (i. e. heatburn), ulcers, and other related disorders.

It is another object of the present invention to provide such methods while minimizing the occurrence of or potential for adverse gastronintestinal effects.

It is another object of the present invention to provide such methods comprising a continuous dosing schedule having a dosing interval selected from the group consisting of weekly dosing, twice- weekly dosing, biweekly dosing, and twice-monthly dosing.

It is another object of the present invention to provide such methods comprising a continuous dosing schedule having a dosing periodicity ranging from about once every 3 days to about once every 16 days.

It is another object of the present invention to provide such methods wherein the continuous dosing schedule is maintained until the desired therapeutic effect is achieved.

It is another object of the present invention to treat or prevent abnormal bone resorption in an osteoporotic mammal, preferably an osteoporotic human.

It is another object of the present invention to provide pharmaceutical compositions and kits useful in the methods herein.

The main claim is amended claim 1, above. The remaining claims 2-11 depend from this claim.

THE LAW

The applicant referred to the high onus of proof which applies in opposition proceedings, the relevant points being gathered in Astra Aktiebolag v Cipla Ltd (Decisions of the Commissioner, P28/2005, 25 October 2005), pages 12-13.

It is accepted law that opposition proceedings should only succeed in clear cases. In Saxpack Foods v Watties Canneries, unreported, 11 July 1988, Ongley J stated:

I approach the proceedings upon the basis that the purpose of opposition proceedings is to clear the register of patents which are manifestly untenable. It is not to provide a method of disposing of truly contentious cases...

As stated in T A Blanco-White, ‘Patents for Inventions’, Fourth Edition, at pages 236 to 237:

The value of this right of opposition is limited. The benefit of any doubt must be given to the applicant for a patent or patentee: for an unsuccessful opponent has another chance to make out his case, in proceedings before the High Court after grant [pursuant to section 41], whilst an unsuccessful applicant has no second chance. The question to be decided is, in effect, whether the specification opposed “must necessarily be invalid.” Thus it is a difficult matter to secure refusal of grant (or revocation), if the opposition is contested, and whilst most oppositions secure at least amendment of the specification to meet the attacks made by the opponent most such amendments strengthen and not weaken the patent. Even the insertion of a specific reference, normally regarded as a defeat for the applicant, is a defeat only in relations to prestige: such references also tend to strengthen and not weaken the patent in whose specification they occur...

The benefit of the doubt has to be given to the patentee in opposition proceedings, particularly where there appears to be conflict of fact or credible expert opinion. This was discussed in Beecham Group Limited v Bristol Myers Company (No2) [1979] NZLR 629 at 632-634, which includes, at 634, a quote from Lord Diplock in General Electric Company’s Application [1964] RPC 413 at 453:

The right principle is that if on the face of the written evidence filed there appears to be a bona fide conflict of fact or credible expert opinion upon a question on the answer to which the existence or non-existence of the ground for refusal specified ..... depends, the [Commissioner] should not exercise his jurisdiction to refuse the grant unless, after cross-examination of the witness if he thinks fit to order it, the conflict is clearly resolved in favour of the party opposing the grant.

The onus in these proceedings is clearly on the opponent. The onus is high. I need to be satisfied beyond doubt if I am to refuse the application. The high threshold that an opponent must reach in opposition proceedings was also referred to in Sealed Air New Zealand Ltd v Machinery Developments Ltd (unreported, HC WN CIV-2003-485-2274, 25 August 2004, MacKenzie J), paragraph 10, and Jones v Attorney-General [2004] 1 NZLR 433 at 440 (PC).

PRIOR PUBLICATION – section 21(1)(b)

Section 21(1)(b) states:

That the invention, so far as claimed in any claim of the complete specification, has been published in New Zealand before the priority date of the claim —

(i) In any specification filed in pursuance of an application for a patent made in New Zealand and dated within 50 years next before the date of filing of the applicant’s complete specification:

(ii) In any other document (not being a document of any class described in subsection (1) of section 59 of this Act)

The usual test for prior publication is that set forth in the judgment of the English Court of Appeal by Sachs LJ in The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited and Others [1972] RPC 457 at 485 to 486:

If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor’s publication will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.

If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee’s claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented ... A signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.

The applicant pointed out that it is the ‘the invention’ which is to be prior published. This point was underpinned by the alternative approach to prior publication favoured by the Court of Appeal in Beecham Group Ltd v Bristol-Myers Company [1981] 1 NZLR 600 at 606:

It is true that the OMP patent does not expressly tell the reader to prepare the epimer separately by firstly resolving the starting acid, but merely describes the making of the DL mixture with racemic acid. We are not to be taken as ruling that counsel for Beecham is wrong in his argument that this point is decisive. But we find the liberalism of that test unattractive and prefer in relation to semi-synthetic chemical compounds a more direct approach to whether the invention claimed has been “published” in New Zealand previously. If such a compound has not been made before, its properties often cannot be predicted with any confidence; and where that is the case we do not consider that the invention claimed can fairly or accurately be described as “published”, even if a skilled chemist would realise that to make the compound by routine means would be practicable. A making of the compound and a discovery of its properties is necessary before the “invention” has occurred and can be “published”.

Since the claims under consideration are in the form of Swiss-type claims the basis for the claimed invention lies in the discovery of a new method of use to which the known medicament is to be put. In the present case a citation has to disclose a medicament containing about 70 mg of alendronic acid or a pharmaceutically acceptable salt thereof, on an alendronic acid active weight basis, and this dose of alendronic acid or salt has to be described as being for once-weekly oral administration for inhibiting bone resorption in a human.

Lunar News, April 1996, page 31

This article was said in the second amended statement of case to have been distributed and available in New Zealand in or about April to May 1996 and to have been available, inter alia, from the Department of Medicine, University of Auckland; the Department of Surgery, University of Auckland, and the University of Otago Medical School since 1996. The applicant, as far as I can see, has not challenged the availability data.

The second amended statement of case stated that the article discloses the feasibility, potential advantages and lack of disadvantages of a once a week treatment regimen using oral alendronate for treatment of osteoporosis and treatment with high doses (40 mg per day) in Paget’s Disease. Osteoporosis sufferers were usually taking about 10 mg/day at the time of the article and at the priority date of the present application.

The article describes one of the difficulties with alendronate, its low oral bioavailability. When taken with water in a fasting state only about 0.8% of the oral dose is bioavailable. Even coffee or juice is said to reduce this by 60%, and a meal reduces it by >85%. Alendronate must be taken after an overnight fast, 30 to 60 minutes before breakfast. The patient should remain seated or standing. A small group of patients have reported some upper gastrointestinal (GI) distress if this is not done. This regimen may be difficult to maintain for any length of time, especially for the elderly. The article suggests that an intermittent treatment program (for example, once per week, or for one week every three months) with higher oral dosing needs to be tested, presumably to make the administration regimen easier, and hence easier to adhere to. The article also states that a sustained response has been demonstrated to intravenous administration of high-dose alendronate, although no further details are given.

The article does not disclose a medicament containing about 70 mg of alendronic acid or a pharmaceutically acceptable salt thereof, on an alendronic acid active weight basis. It further does not disclose a 70 mg alendronate dose for once-weekly oral administration in a continuous schedule of administration for inhibiting bone resorption in a human. The article therefore does not give clear and unmistakable directions to do what the applicant claims to have invented.

The article does not prior publish the applicant’s invention as it is proposed to be claimed.

Lunar News, July 1996, page 23

This article was said in the second amended statement of case to have been distributed in New Zealand in or about July to August 1996 and to have been received by, and to have been available from, inter alia, the Department of Medicine, University of Auckland; the Department of Surgery, University of Auckland, and the Christchurch Radiology Group, Christchurch. The applicant, as far as I can see, has not challenged the availability data.

The second amended statement of case stated that the article discloses the feasibility, potential advantages, and lack of disadvantages, of the administration of oral alendronate in a 40 or 80 mg dose once a week for the treatment of osteoporosis.

The article relates to the treatment of osteoporosis. The article states that approval of the use of alendronate outside the United States (US) lags behind that in the US, however some US physicians are reluctant to treat osteoporosis sufferers with alendronate because of: side effects; difficulty of dosing; and high costs. The article states that Merck sent a letter to physicians warning of oesophagitis. Some 5 to 15% of patients are said to experience gastric and/or oesophageal distress but the majority of patients have not experienced such side effects. Serious side-effects of ulceration and stricture are said, in the article, to appear to be rare. Some patients stop using alendronate because of the dosing difficulties. Because of the cost of alendronate, some patients are recommended to use lower cost cyclical etidronate.

The article suggests that difficulties with oral bisphosphonates may favour their episodic (once/week) or cyclical (one week each month) administration. Even oral alendronate, it is said, could potentially be given in a 40 or 80 mg dose once/week to avoid dosing problems and reduce costs. Intravenous administration is said to be possible too. Ibandronate is identified as the most likely candidate since it can be given as a simple injection every 3 months rather than as an infusion.

The article does not disclose a medicament containing about 70 mg of alendronic acid or a pharmaceutically acceptable salt thereof, on an alendronic acid active weight basis, for once-weekly oral administration in a continuous schedule of administration, for inhibiting bone resorption in a human. The article does not give clear and unmistakable directions to do what the applicant claims to have invented.

The article does not prior publish the applicant’s invention as it is proposed to be claimed.

I find that the ground of prior publication is not made out.

OBVIOUSNESS - section 21(1)(e)

Section 21(1)(e) reads:

That the invention, so far as claimed in any claim of the complete specification is obvious and clearly does not involve any inventive step having regard to matter published as mentioned in paragraph (b) of this subsection, or having regard to what was used in New Zealand before the priority date of the applicant’s claim

The usual test for obviousness is that set out by Oliver J in Windsurfing International Inc v Tabur Marine (Great Britain) Ltd [1985] RPC 59 at 73, and followed in New Zealand by Gault J in Ancare v Cyanamid [2000] 3 NZLR 299 at 309 (paragraph 45)

There are, we think, four steps, which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as being “known or used” and the alleged invention. Finally the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention.

The approach was summarised by the applicant as:

1. identify the inventive concept,
   
2. assume the mantle of the normally skilled but unimaginative addressee at the priority date and impute to him what was the common general knowledge in the art in question,
   
3. identify what if any differences exist between the matter as being “known or used” and the alleged invention, and
   
4. viewed without any knowledge of the alleged invention, do any of those differences constitute steps which would have been obvious to the skilled addressee or do they require a degree of invention?
   

As stated by the Court of Appeal in Ancare, at 309 (paragraph 43) per Gault J:

... the test [for obviousness] is well established. It postulates a person (or, where appropriate, a team), skilled in the field but not inventive, invested with the common general knowledge available in the field at the priority date, presented with the prior knowledge or prior use relied upon. Prior documents may be looked at together if that is what the skilled person or team would do. It asks whether to that person or team the alleged inventive step would be obvious and would be recognised, without bringing to bear any inventiveness, as something that could be done or is at least worth trying. That is a question of fact. If any embodiment within the scope of the claim is obvious the claim is invalid. These propositions are helpfully expanded upon in the recent English cases which are still applicable though under the 1977 Act; see the Windsurfing International case, Hallen Co v Brabantia (UK) Ltd [1991] RPC 195 at p 211, and Molnlycke AB v Procter & Gamble Ltd [1994] RPC 49 at p 112.

The applicant drew on Tompkins J in Smale v North Sails Ltd [1991] 3 NZLR 19 at 42-44 where the Windsurfer test was adopted; the notional addressee was said to be well informed in the art in question and to possess all the relevant skills, but was incapable of even a scintilla of invention; and the cases were said to be replete with warnings against being wise after the event as the result of ex post facto analysis.

The applicant submitted that the ‘at least worth trying’ consideration is quite narrow. I agree. That which is worth trying has to be obvious to the notional addressee. That a successful conclusion to the trial could not be predicted at the start of the trial did not make the trial any less obvious. As stated in Johns-Manville Corporation’s Patent [1967] RPC 479, at 494, certainty of success before actual testing is not necessary:

I think that “would be” puts it too high if it postulates prior certainty of success before actual testing ....; it is enough that the person versed in the art would assess the likelihood of success as sufficient to warrant actual trial.

In SmithKline Beecham plc v Apotex Europe Ltd [2004] EWCA Civ 1568; [2005] FSR 23 (CA) Jacob LJ commented on the matter of something being obviously worth trying. The judge posed the question why the skilled man in that case should have taken a particular step, in that case, why should he suppose that the slurry step had any effect on the crystals? He answered the question in paragraph 67:

The answer - essentially there is no harm in trying though there would seem no point, does not make trying obvious - a word whose Latin root [ob via] is worth remembering - “in the way”. And here it is again worth remembering that we are in the field of obviousness, not novelty. For the latter a blind following of an apparently pointless or even apparently deleterious step, as part of an unambiguous instruction, will count.

The applicant pointed out that an obvious line of research may culminate in an invention which is not obvious and does involve an inventive step if a sufficiently distinctive advantage is discovered, as in the Court of Appeal in Beecham Group Ltd v Bristol-Myers Company [1981] 1 NZLR 600, at 609:

But that does not dispose of the question of obviousness. The search for medical advance is to be encouraged. It can be long, expensive and fruitless. The pursuit of one of a number - perhaps many - obvious lines of research may produce a signal or particularly valuable discovery. In deciding on patentability it would seem to us regrettable, and not in accord with a primary purpose of patent law, to have to rule this out automatically in the name of obviousness. We think that the pursuit of an obvious line of research, in the synthesising and testing of a new chemical compound, may be held to culminate in an invention which is not obvious and does not involve an inventive step, if a sufficient distinctive advantage is discovered. It is a question of degree....

From Hoechst Celanese Corp v BP Chemicals Limited [1997] EWHC 370; [1997] FSR 547 at 566, the applicant pointed out two questions which need to be answered in assessing prior art asserted to render the invention obvious:

(i) what would the pleaded prior art document convey to the notionally skilled man - i.e. what does it mean and promise, and

(ii) what would be his reaction to it?

The notional addressee

The applicant submitted that the notional addressee would approximate to a clinician skilled in the treatment of bone resorption diseases (specifically osteoporosis) who is experienced in the practical difficulties associated with oral administration of bisphosphonates.

Fennerty, Papapoulos 1 and Ebeling described the skilled person as a practicing physician with experience in preventing and treating diseases using bisphosphonates. They described the practice and research into bone disease and the knowledge about disease treatment in New Zealand as being substantially the same as the practice and research in Europe and other Western countries.

It has never been held that the skilled addressee is the entire resources of a company. The Cundy 2 declaration defined the skilled addressee as the entire pharmaceutical company with knowledge of, and qualifications in, amongst other things, chemistry, biological sciences, toxicology, manufacturing of pharmaceutical, the law, regulations and codes of practice governing pharmaceutical production, packaging and marketing. The applicant submitted that this goes far beyond the skills needed to put the invention into practice and thus significantly devalues the opponent’s evidence on what constitutes common general knowledge or how the skilled addressee would respond to or assess the prior art.

Persicaner stated that the skilled addressee would be a team developing medications and that such a team would include people such as himself. Mr Persicaner is a Research and Development Manager. The applicant pointed out that researchers, and specifically Research Managers, are the antithesis of the skilled addressee as researchers have inventive capacity. Thus the applicant understood the opponent as misunderstanding the attributes of the skilled addressee.

To me the notional addressee would be a clinician skilled in the treatment of bone resorption diseases, specifically osteoporosis, who is experienced in the difficulties associated with oral administration of bisphosphonates, especially alendronate.

The common general knowledge

The applicant pointed out that common general knowledge is derived from a commonsense approach to the practical question of what would be known to the appropriately skilled addressee, the sort of man good at his job that could be found in real life, as in The General Tire & Rubber Company Limited and Others v The Firestone Tyre and Rubber Company Limited and Others [1972] RPC 457 beginning at 482:

On the other hand, common general knowledge is a different concept derived from a commonsense approach to the practical question of what would in fact be known to an appropriately skilled addressee - the sort of man, good at his job, that could be found in real life.

The applicant submitted that the skilled addressee is steeped in the folklore, perceptions and prejudices of the trade as in Haberman v Jackel International Limited [1999] FSR 683 at 699:

This analysis is compelling. Does it reflect what an ordinary man in the art, steeped in the folklore, perceptions and prejudices of the trade would have done?

The applicant noted the common general knowledge of the relevant skilled person has both positive and negative aspects (or perceptions and prejudices). The relevant common general knowledge includes all the attitudes and perceptions of the skilled addressee. A particular ‘mindset’ of those skilled in the field must be given due weight, as in Dyson Appliances Limited v Hoover Limited [2001] EWCA Civ 623; [2002] RPC 22 at 486:

The mantle of the skilled person is that of an actual skilled person. The purpose of assuming the mantle of the skilled person is to enable the decision as to what is obvious to be a decision based on actual facts. They include all the attitudes and perceptions of such a person.

The inventive concept

The inventive concept is the use of alendronic acid or a pharmaceutically acceptable salt thereof, or a mixture thereof, in the manufacture of a medicament with a relatively large dose (70 mg) of the alendronate for oral administration once-weekly.

The common general knowledge of the normally skilled at the priority date

Lunar News, April 1996, page 31 and Lunar News, July 1996, page 23

These articles were considered above under Prior Publication.

The applicant submitted that Lunar News is a free desk top marketing publication; that it is not a scientific publication; that it is a non-scientific publication which is not peer reviewed; and that it is not, according to the evidence, seen by all who work in the relevant field. Thus, this would appear to reduce the impact of any statements of Lunar News. The view of the opponent, said the applicant, appeared to be that because this non-scientific marketing publication proposed alternatives of episodic treatment (eg once per week) or cyclical (eg one week every three months) or intravenous administration, that the skilled addressee would react to that publication by deciding to put once per week with a large dose into practice. The reality, submitted the applicant, is that the reaction of the skilled addressee to the Lunar New articles would be to simply ignore them.

The first article suggests that an intermittent treatment program (for example, once per week, or one week every three months) with higher oral dosing needs to be tested. The intermittent treatment is a suggestion for trial. There is no further discussion of intermittent treatment programs, including for example why the examples were chosen and what would be the patient tolerability of, and side effects from, intermittent treatment programs.

The first article also states that a sustained response has been demonstrated to intravenous administration of high dose alendronate, although no further details are given.

The second article suggests that difficulties with oral bisphosphonates may favour their episodic (once/week) or cyclical (one week each month) administration. Even oral alendronate, it is said, could potentially be given in a 40 or 80 mg dose once/week to avoid dosing problems and reduce costs. The intermittent treatment is a suggestion. There is no further discussion of the alternative treatment programs, particularly with regard to any side effects they may present. The treatments are suggested as a way to avoid dosing problems and to reduce costs. Again, the suggested treatment schedules are quite different from each other.

The applicant submitted that, firstly, the Lunar News articles propose cyclical treatment as one option, yet such an option would already be known to the skilled addressee as having failed to show anti-fracture efficacy (Papapoulos 1, paragraphs 57-66, 114, 119). Secondly the articles talk about GI side effects but have nothing to suggest to the skilled addressee that increasing the dose would not have the expected result of increasing side effects. The Lunar News articles do not address safety/side effect concerns. Thirdly the April 1996 Lunar News article is silent on dose and the July 1996 article refers to 40 mg and 80 mg. 80 mg is not equivalent to about 70 mg (Papapoulos 1, paragraph 130; Brown). The applicant’s view was that the skilled addressee would not believe that there was anything worthy of trial; that the suggestions in the articles could be dismissed as uninformed speculation; and that the skilled addressee would know that cyclical dosing does not work and that increasing the dose will exacerbate the side effect problems.

Mazess deposed that he was advocating the idea in Lunar News that, rather than take the standard dose of 10 mg daily, osteoporosis patients should take one or two 40 mg tablets every week. His rationale included his understanding that they were safe to use and effective since they had been approved by the US Federal Drug Agency (FDA).

Mazess deposed that a once-weekly 40 mg dose was equivalent to 10 mg taken daily based on assumed absorption figures. At the same time as the Lunar News articles were appearing, he stated he was giving such advice in reports, in lectures, and to physicians and friends who were using alendronate, and he deposed that some of the more aggressive practitioners he spoke to were already prescribing 40 mg alendronate tablets in this way.

A ‘Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures’, D M Black et al, The Lancet, vol 348, 1535 (1996)

This article was said to have been available from the University of Auckland Green Lane Library, Auckland, since 27 December 1996.

Women in the study were treated orally with alendronate for three years. The initial daily dose of alendronate was 5 mg, which was increased to 10 mg at 24 months. The treatment significantly increased average bone mass and lowered the risk of fractures. Upper GI problems were experienced in about the same number of women receiving alendronate and those receiving the placebo, ie about 40%. The 10 mg daily dose was already in use to treat adult patients. The applicant submitted there is nothing in the paper to suggest that higher and less frequent doses of alendronate could be used effectively or safely.

B ‘The Bisphosphonate Alendronate (MK-217) Inhibits Bone Loss Due to Ovariectomy in Rats’, J G Seeds et al, Journal of Bone and Mineral Research, vol 6, 339 (1991)

This article was said to have been available from the Philson Library (Auckland Medical School), Auckland, since 10 April 1991.

The article discloses the treatment of ovariectomised rats given alendronate subcutaneously every two weeks, weekly or twice a week (ie two, four or eight injections per month). The study found that the total amount of drug the skeleton received was more important than the frequency or number of treatments to administer the dose. The applicant submitted that the delivery is subcutaneous in rats and hence does not teach possible adverse GI side effects as there are no such effects with subcutaneous dosing.

C ‘The Effects of a 2-year Treatment with the Aminobisphosphonate Alendronate on Bone Metabolism, Bone Histomorphometry, and Bone Strength in Ovariectomized Nonhuman Primates’, R Balena et al, The Journal of Clinical Investigation, 92, 2577 , ( 1993)

This article was said to have been available from the library of Adis International Limited Information Resource, Centre, Mairangi Bay, Auckland, since 20 December 1993.

The article discloses the treatment of oestrogen deficiency bone loss in baboons using alendronate at 0.05 or 0.25 mg/kg intravenously every two weeks for two years. The study found that bone turnover was normalised, bone loss was prevented, and vertebral bone strength was increased. Intravenous alendronate is effective in treating the effects of ovariectomy in baboons. The applicant submitted that the article does not teach the skilled person about treatment of humans with oral alendronate and does not teach possible adverse GI side effects as there are no such effects with intravenous dosing.

D ‘Clinical Pharmacology of Alendronate’, B J Gertz et al, Osteoporosis International, Suppl. 3: S13-16 (1993)

This article was said to have been available from the Philson Library (Auckland Medical School), Auckland, since 31 May 1993.

This review article cites the low oral bioavailability of alendronate and its long-term presence in the skeleton. The applicant submitted that the studies were pharmokinetic studies as opposed to clinical studies on efficacy or safety; the studies were of short duration and involved a small number of patients; and the results are not clinically relevant for assessing the GI toxicity of alendronate.

E ‘Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis’, U A Liberman et al, The New England Journal of Medicine, vol 333, 1437 (1995)

This article was said to have been available from the AgResearch Information & Library Services, Ruakura Research Centre, Hamilton since 8 December 1995.

The article reports the treatment of menopausal women with alendronate, receiving 5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year. The treatment led to significant increase in bone density and reduced incidence of new vertebral fractures. The 5 mg dose regime was less effective than the 10 mg regime. The 10 and 20/5 mg regimes showed no significant difference in efficacy. The study found similar rates of adverse upper GI effects between all groups. The article notes at page 1441 that dose-dependent upper GI irritation is the primary side effect associated with several other bisphosphonates which are administered at higher doses.

F ‘Oral Alendronate Induces Progressive Increases in Bone Mass of the Spine, Hip and Total Body Over 3 Years in Postmenopausal Women with Osteoporosis’, J P Devogelaer et al, Bone, vol 18, 141-140 (1996)

This article was said to have been available from the University of Otago Medical Library, Dunedin, since 2 April 1996.

The article discloses continuous daily administration of 10 mg of alendronate for the treatment of osteoporosis. The applicant submitted that the article confirms what was already known.

G ‘Esophagitis and Alendronate’, U A Liberman et al, The New England Journal of Medicine, vol 335, 1069 (1996)

This article was said to have been available from the AgResearch Information & Library Services, Ruakura Research Centre, Hamilton since 11 October 1996.

This is a letter reporting in detail adverse oesophageal effects of the study reported in article E above and was sent in response to article K below. It proposes reasons for not detecting an increase in severe adverse oesophageal effects similar to those reported by de Groen et al in article K below. The applicant submitted that this article (ie G) is a key publication that heightened the awareness and concern about using alendronate even with a 10 mg dose (Fennerty, paragraph 91). The authors reported serious and severe GI effects in a proportion of the study population, also reported in article K below. The letter recommended strict adherence to the dosing instructions.

H ‘Pill Esophagitis - The Case of Alendronate’, D O Castell, The New England Journal of Medicine, vol 335, 1058 (1996)

This article was said to have been available from the AgResearch Information & Library Services, Ruakura Research Centre, Hamilton since 11 October 1996.

This is an editorial discussing severe or serious oesophageal effects in patients taking alendronate for postmenopausal osteoporosis. The author concludes that the incidence appears to be low, but advises careful instructions to patients taking alendronate. He noted the low incidence of severe and serious effects in the Liberman trial (article E above) and noted an important factor was the regular follow-up visits and reminders to patients to follow administration instructions. The applicant noted that such follow-ups are not necessarily possible with ‘real life’ patients.

This was said, in evidence of the applicant, to be a key publication that heightened the awareness and concerns with using orally administered alendronate, even at the 10 mg dose (Fennerty, paragraph 52 and 91).
I ‘Bisphosphonates; Mechanism of Action and Clinical Use in Osteoporosis - An Update’, H Fleisch, Hormone and Metabolic Research, vol 29 145 (1997)

This article was said to have been available from the Massey University Library, Palmerston North, since 30 June 1997.

Fleisch reviews the knowledge of the mechanism of action and use of bisphosphonates in treating osteoporosis. He refers to doses between 5 and 40 mg daily over two years. He concludes that 10 mg appears to be the most favourable dose.

J ‘Studies of the oral bioavailability of alendronate’, B J Gertz et al, Clinical Pharmacology & Therapeutics, vol 58, 288 (1995)

This article was said to have been available from the Adis International Limited Information Resource Centre, Auckland, since 30 October 1995.

The article reports a bioavailability study, not a clinical study, of the factors that affect single oral (up to 80 mg) and intravenous doses of alendronate and their absorption. The article suggests a dosing strategy of taking the dose 30 minutes before the first food of the day (ie after fasting overnight) with water, to maximise absorption of the drug.

K ‘Esophagitis Associated with the Use of Alendronate’, P C de Groen et al, The New England Journal of Medicine, vol 335, 1016-1021 (1996)

This article was said to have been available from the AgResearch Information & Library Services, Ruakura Research Centre, Hamilton since 11 October 1996.

This article discusses three patients who developed severe oesophagitis after starting to take alendronate and also analyses adverse oesophageal effects reported to Merck. de Groen concluded that alendronate can cause chemical oesophagitis including severe ulceration in some patients. The applicant submitted that this is another article that highlights the difference between the clinical study environment and ‘real life’ environment in considering the adverse effects of alendronate. Evidence in support of the application stated that this was a seminal paper that heightened awareness and concern about using alendronate (Papapoulos 1, paragraphs 72, 88-90, 144; Fennerty, paragraphs 45-50, 91).

L ‘Biochemical and Radiological Improvement in Paget’s Disease of Bone Treatment with Alendronate: A Randomized, Placebo-Controlled Trial’, I R Reid et al, The American Journal of Medicine, vol 101, 341-8 (1996)

This article was said to have been available from the Adis International Limited Library, Auckland, since 24 October 1996.

The article reports the effectiveness of 40 mg per day of alendronate on Paget’s disease sufferers. The report concluded that oral alendronate appears to be a safe and effective therapy for Paget’s disease. The report also noted that there were fewer adverse upper GI effects between Paget’s disease patients taking the alendronate and those taking a placebo. The applicant submitted that some patients in the trial had previously been treated with alendronate suggesting a proven tolerability, although, I see that the authors noted that responses were similar whether or not patients had previously received bisphosphonate treatment. The applicant submitted that Paget’s disease sufferers would have a greater tolerance for side effects compared to osteoporosis sufferers. The applicant also noted that a clinical study is dealing with an ‘ideal’ situation rather with what happens in ‘real world’ treatment.

M ‘Alendronate in the Treatment of Paget’s Disease of Bone’, S A Khan et al, Bone, vol 20, 263-271 (1997)

This article was said to have been available from the Otago Medical School Library, Dunedin, since 10 June 1997.

The article reports the effectiveness of 40 and 80 mg per day of alendronate on Paget’s disease patients. The report noted that there was no difference in the rate of GI adverse effects between Paget’s disease patients taking 40 mg alendronate daily and those taking 80 mg. Fifteen of the sixty patients in the trial reported adverse GI effects and two withdrew. The applicant submitted that some patients in the trial had previously been treated with alendronate suggesting a proven tolerability. Papapoulos 2 reported a later study with Paget’s disease patients who had not previously been treated with alendronate, where it was found that there was a high incidence of gastric and oesophageal side effects associated with the 40 mg dose. The applicant again submitted that Paget’s disease sufferers would have a greater tolerance for side effects compared to osteoporosis sufferers.

N ‘Prevention of Nonvertebral Fractures by Alendronate. A Meta-analysis’, D B Karpf et al, JAMA, vol 277, 1159-64 (1997)

This article was said to have been available from the Adis International Limited Information Resource Centre, Auckland, since 21 April 1997.

The article reports a meta-analysis of published data and data on file at Merck. The author reviews a number of studies on treatment with sodium alendronate at dosages of 2.5, 5 and 10 mg daily. It confirms that alendronate is effective in reducing the risk of fractures. There is no analysis of the different doses of alendronate. The review, submitted the applicant, does not teach the skilled person about long term continuous treatment with large doses of oral alendronate.

O ‘Effect of Three years of Oral Alendronate Treatment in Postmenopausal Women with Osteoporosis’, J R Tucci et al, American Journal of Medicine, vol 101, 488-501 (1996)

This article was said to have been available from the Adis International Limited Information Resource Centre, Auckland, since 6 December 1996.

Tucci assesses the efficacy and safety of oral alendronate treatment at doses of 5, 10 and 20 mg per day. The incidence of withdrawal from the study due to GI intolerance was low and similar to placebo at all doses. The article admits that it was known that upper GI intolerance may occur with high doses of oral bisphosphonates. The study concluded that 10 mg dose produced the maximal bone mineral density effects. The applicant submitted the article does not inform the skilled reader that treating patients with a higher dose of alendronate would be safe.

P ‘Sustained Response to Intravenous Alendronate in Postmenopausal Osteoporosis’, S D Vasikaran et al, Bone, vol 17, 517-520 (1995)

This article was said to have been available from the Canterbury Medical Library, Christchurch, since 18 January 1996.

The study described shows the effect of high intravenous doses of alendronate on bone turnover and on lumbar spinal bone density. Postmenopausal women with vertebral osteoporosis were administered 7.5 mg of alendronate daily, as a slow infusion, for four days. This produced sustained effects on bone turnover. As a result of the study it appears that short exposure to a high dose of alendronate produces suppression of bone resorption that persists for at least six months. The applicant submitted that the 30 mg intravenous alendronate administered amounted to 4300 mg taken orally based on intestinal absorption of 0.7%, and that the study does not inform the skilled reader about continuous treatment with oral alendronate.

Q ‘New Bisphosphonates in Osteoporosis’, H Fleisch, Osteoporosis International, 3 Suppl 2:S15-22 (1993)

This article was said to have been available from the Philson Library (University of Auckland Medical School), Auckland, since 11 January 1994.

The article reviews the properties of bisphosphonates including alendronate and their potential use in treating osteoporosis. The article is said to point to the desirability of investigating the best modes of administration, including discontinuous and continuous administration regimes. The applicant submitted that two years later the studies of Liberman (article E above) and Black (article A above) showed that daily administration of alendronate was associated with significant reduction of fracture risk, the only relevant end point of studies in osteoporosis treatment (Papapoulos 1, paragraph 149).

R ‘Treatment of Paget’s Disease of Bone with intravenous 4-Amino-1-Hydroxybutylidene-1,1-Bisphosphonate’, S Adami et al, Calcified Tissue International, vol 39, 226-9 (1986)

This article was said to have been available from the University of Otago Medical Library, Dunedin, since 25 November 1986.

The study described the administration of various doses of alendronate intravenously for 4 consecutive days. The study found that the dosing was found to have a sustained effect on bone remodelling. The intravenous dose was 10 to 100 mg which, according to the applicant, corresponds to 1430 to 14300 mg orally delivered alendronate based on an intestinal absorption of 0.7%. The applicant submitted that, similarly with article P above, all this study shows is that high doses of alendronate are effective with Paget’s disease (Papapoulos 1, paragraph 150) and it does not inform the skilled person about continuous treatment with oral alendronate.

S ‘The Bisphosphonate, Alendronate, Prevents Bone Loss in Ovariectomized Baboons’, D D Thompson et al, Journal of Bone and Mineral Research, vol 7, 951-60 (1992)

This article was said to have been available from the Philson Library, University of Auckland Medical School, Auckland, since 1 September 1992.

The article reports the use of alendronate in preventing bone loss. Alendronate was administered intravenously every two weeks for a year at 0.05 and 0.25 mg/kg. The treatment was found to prevent oestrogen deficiency-related increase in bone turnover and related bone loss. The applicant submitted (Papapoulos 1, paragraph 151-3); Fennerty, paragraphs 98-100) that the article does not inform the skilled reader about the continuous treatment of humans with orally administered alendronate; the article does not mention adverse side effects; and the article made no findings about the anti-fracture efficacy of such a regimen, anti-fracture being the clinical endpoint of any osteoporosis treatment. The applicant submitted that intermittent administration of bisphosphonates had generally failed to show clear anti-facture efficacy (Papapoulos 1, paragraphs 67, 68), and that intermittent treatment was fundamentally different from continuous treatment with a single dose of alendronate once a week.

T ‘Intermittent treatment with Intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) in the therapy of postmenopausal osteoporosis’, M Passeri et al, Bone and Mineral Research, vol 15, 237-248 (1991)

This article was said to have been available from the Philson Library (Auckland University Medical School), Auckland, since 12 December 1991.

The article describes the use of intravenous bisphosphonate in the treatment of postmenopausal osteoporosis in a dosing regimen of 5 mg/day on two consecutive days every three months for one year. The study found that the intermittent treatment was capable of increasing spinal bone mineral density and conserving radial bone mineral density. The study also found that the total amount of drug the skeleton received was more important than the frequency or number of treatments to administer the dose. The applicant submitted that the delivery in the study was subcutaneous in rats, and the article disclosed the division of a single dose into several smaller doses and did not inform the skilled reader about the safety of aggregating smaller doses into a single dose as claimed in the subject application.

U US Patent Specification 4,761,406 (Flora)

This document was said to have been available from the office since 2 September 1988.

The document discloses a method for treating osteoporosis using bisphosphonate according to a cyclical regimen. An oral dose of bisphosphonate is administered daily for a set period between 1 and 90 days followed by a rest period of between 5 and 120 days. The preferred cycle was said to be 14 days of daily treatment with bisphosphonate alternating with an 84 day rest period.

The applicant submitted that a cyclical regimen is different from a continuous treatment with a single dose given once weekly (Papapoulos, paragraph 154; Fennerty, paragraph 102). The applicant also submitted that the amounts calculated as suitable for humans are extrapolated from experiments conducted on rats; that no mention is made of safety factors; and there is nothing in the document to inform the skilled reader of the safety of continuous oral treatment of humans with osteoporosis as claimed in the subject application.

V US Patent Specification 5,366,965 (Strein)

This document was said to have been available from the office since 16 December 1994.

The document discloses a method for treating or preventing osteoporosis, including regimens with bisphosphonate administered cyclically. The oral dose of bisphosphonate is administered for an inhibiting period of 4 to 90 days followed by a rest period of 20 to 120 days. The inhibiting period is divided into at least two intermittent periods lasting 2 to 14 days and the drug is administered on only one day of each intermittent period. The patent specification notes GI problems associated with oral dosing with clodronate and pamidronate in the background to the invention.

The applicant submitted that cyclical regimens are different from continuous treatment with a single dose given once weekly; the means of administration were preferably intravenous, subcutaneous and oral, but the bisphosphonate was only administered subcutaneously in the examples; the experiments used rats; and no clinical trials were done on humans. The applicant submitted that the regimens disclosed have been shown not to have anti-fracture efficacy (Papapoulos 1, paragraphs 62-69, 155, 156); and there is nothing in the document to inform the skilled reader of the safety of continuous oral treatment of humans with osteoporosis as in the subject application.

W International Patent Application WO 95/30421 (Goodship)

This document was said to have been available from the office since 4 January 1996.

The document discloses the use of bisphosphonate compounds for the prevention and treatment of prosthesis loosening and migration in mammals. The drug is delivered in a single dose, preferably, but may be administered in several partial doses. The dose can be administered daily, once weekly, monthly, once every three months or once a year. The dose is from 1 to 500 mg.

The applicant submitted that prosthesis loosening and migration is quite different from the treatment of osteoporosis (Fennerty, paragraph 106); that there are no clinical experiments disclosed in the specification; and there is no data that would inform the skilled addressee that treating humans with large doses of alendronate once-weekly would be safe. The applicant submitted that the document discloses the splitting of a single dose into a number of partial doses, not the aggregating of a number of smaller doses into a larger one as is to be claimed in the subject application.

X ‘Absorption of oral diphosphonate in normal subjects’, I Fogelman et al, Clinical Endocrinology, vol 24, 57-62 (1986)

This article was said to have been available from the Princess Margaret Hospital Library, Christchurch, since 18 March 1986.

The reported study relates to how absorption and retention of orally delivered etidronate are affected by food. The study subjects were given a single oral dose of 400 mg of etidronate followed by intravenous etidronate containing a radioactive marker. The applicant stated that the study does not deal with clinical dosing, toxicity, side effects or efficacy issues. The article, submitted the applicant, cannot inform the skilled addressee about a continuous regimen of orally administered alendronate

Y ‘The Bisphosphonate Ibandronate, Given Daily as Well as Discontinuously, Decreases Bone Resorption and Increases Calcium Retention as Assessed by 45Ca Kinetics in the Intact Rat’, H Fleisch, Osteoporosis International, vol 6, 166-70 (1996)

This article was said to have been available from the Waitemata District Health Board Library since 30 April 1996.

Fleisch investigated ibandronate given subcutaneously to rats at various doses and regimens and noted no difference in effect when a particular amount is given daily for 10 days or all at once and suggested that either daily or discontinuous doses may be effective for humans.

The applicant submitted that the results of the study are in line with longer experiments reported above under articles B, C and S (Papapoulos 1, paragraph 168) and this study adds nothing new; and that the efficacy or otherwise of intermittent intravenous or parenteral treatment regimens is not relevant to a regimen of continuous dosing with oral alendronate given once-weekly. The applicant submitted that the study was concerned with the efficacy of splitting of a single dose into a number of smaller doses, not the safety of aggregating smaller doses into a larger one as is to be claimed in the subject application.

Z ‘Long-Term Effects of a Treatment Course with Oral Alendronate of Postmenopausal Osteoporosis’, M Rossini et al, Journal of Bone & Mineral Research, vol 9, 1833-7 (1994)

This article was said to have been available from the Philson Library, University of Auckland, since 5 December 1994.

The article describes the results of a six month treatment of postmenopausal osteoporosis with oral alendronate, notes the long half life of bisphosphonates in bone, and suggests that positive effects on bone are sustained long after stopping therapy. The applicant again submitted that at the relevant date cyclical treatment regimens were known not to have anti-fracture efficacy (Papapoulos 1, paragraphs 62-69, 156); and the article cannot inform the skilled addressee about a long-term, continuous regimen of high doses of orally administered alendronate.

AA ‘Different Schedules of Administration of (3 Amino-1-Hydroxypropylidene)-1,1 Bisphosphonate Induce Different Changes in Pig Bone Remodelling’, M C de Vernejoul et al, Calcified Tissue International, vol 40, 160-165 (1987)

This article was said to have been available from the Philson Library, University of Auckland, since 20 May 1987.

de Vernejoul et al evaluate different intermittent schedules for administering pamidronate by intramuscular injection into pigs, including one day out of every four days and five consecutive days out of 21, for a period of 60 days. This study found an increase in bone mass and a depressed effect on bone turnover. The authors conclude that the intermittent schedule with consecutive daily administration of pamidronate induces a more effective decrease in bone resorption than the one where the pamidronate is given once every four days.

The applicant submitted that study, using pamidronate administered by injection, cannot inform the skilled addressee about a continuous regimen of orally administered alendronate (Papapoulos 1, paragraphs 171-173; Fennerty, paragraph 122); and, further, an intermittent schedule is not the same as continuous dosing with a single dose given once-weekly.

BB ‘The effects of two different regimens of intramuscular clodronate on os calcis ultrasound densitrometry: The results of a 2-year prospective study’, R Giorgino et al, Journal of Bone & Mineral Research, vol 12 (Suppl 1): s475 (1997)

This article was said to have been available from the Philson Library, University of Auckland, since 19 August 1997.

The authors report research involving the administration of intravenous clodronate once a week or once every two weeks continuously for 24 months. Both regimens were found to be equally effective in increasing ultrasound attenuation. The applicant submitted that the significance in terms of the treatment of osteoporosis is not explained in the article or by the opponent; and the study is of injected clodronate, hence the article cannot inform the skilled addressee about the treatment of patients with a continuous regimen of orally administered alendronate (Papapoulos 1, paragraph 174; Fennerty, paragraph 123).

CC ‘Cyclical Clodronate is Effective in Preventing Postmenopausal Bone Loss: A Comparative Study with Transcutaneous Hormone Replacement Therapy’, P Filipponi et al, Journal of Bone and Mineral Research, vol 10, 697-703 (1995)

This article was said to have been available from the Medical and Dental Libraries, University of Otago, Dunedin, since 16 May 1995.

The article discloses research indicating the suitability of administration of 200 mg/month of intravenous clodronate. In the study one group of women were given cyclical intravenous clodronate, a second group hormone replacement therapy (HRT) and a third group were the control group. Both HRT and the clodronate effectively prevented menopausal bone loss compared to the control group. The applicant pointed out that there was no assessment of anti-fracture efficacy.

The applicant submitted that again the study is not relevant to the issue of the treatment with oral alendronate because it cannot address the possibility of adverse GI effects (Papapoulos 1, paragraph 175; Fennerty, paragraph 123); and the cyclical regimen of this study has no clear proven anti-fracture efficacy (Papapoulos 1, paragraph 67, 68) and is fundamentally different from continuous treatment with a single dose once-weekly.

DD ‘Short-Term Intravenous Bisphosphonates in Prevention of Postmenopausal Bone Loss’, J E Heikkinen et al, Journal of Bone and Mineral Research, vol 12, 103-110 (1997)

This article was said to have been available from the Medical and Dental Libraries, University of Otago, Dunedin, since 16 May 1997.

In this study postmenopausal women were treated with various doses of intravenous clodronate and etidronate three times, with one week intervals between doses. The study showed a slight slowing of bone loss that persisted for up to two years following treatment. There was no assessment of anti-fracture efficacy of the treatments.

The applicant submitted that the study cannot inform the skilled addressee about treatment with oral alendronate (Fennerty, paragraph 123). As noted, the intravenous administration bypasses the typical GI adverse effects of oral bisphosphonates. Further, the applicant submitted, the intermittent schedule used is not the same as continuous treatment with a single dose once-weekly.

EE ‘Continuous and Cyclical Clodronate Therapies and Bone Density in Postmenopausal Bone Loss’, S Giannini et al, Obstetrics & Gynecology, vol 88, 431-6 (1996)

This article was said to have been available from the Adis International Limited Information Resource Centre, Mairangi Bay, Auckland, since 17 September 1996.

The article reports a study to evaluate the effectiveness of different clodronate regimens in treating postmenopausal osteoporosis. The subjects were given oral clodronate for a year. One group received 400 mg daily, another 400 mg/day for 30 days followed by a 60 day drug free interval. This study found the one year treatment induced a gain in bone mass, especially in the spine. The continuous regimen was not found to result in any further benefit in lumbar bone density over the cyclical one.

The applicant submitted that cyclical dosing is not the same as giving a high dose once a week (Fennerty, paragraph 124); at the relevant date cyclical treatments were not known to have anti-fracture efficacy (Papapoulos 1, paragraphs 62-69, 156); and also a recent trial demonstrated anti-fracture efficacy for clodronate for the first time (Papapoulos 1, paragraph 179), the oral clodronate being given at a dose of 800 mg/day in the trial.

FF ‘Alendronate Treatment of the Postmenopausal Osteoporotic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodelling’, C H Chestnut et al, American Journal of Medicine, vol 99, 144 (1995)

This article was said to have been available from the Adis International Limited Information Resource Centre, Mairangi Bay, Auckland, since 16 August 1995.

The article reports a study of postmenopausal women wherein they were treated with various doses of oral alendronate, ie 5 or 10 mg for two years, 20 or 40 mg for one year followed by a placebo for one year, or 40 mg for 3 months followed by 2.5 mg for 21 months. Upper GI intolerance was associated primarily with the 40 mg treatment. Of the 9 patients who withdrew from the study 7 were receiving 40 mg of alendronate and only one was receiving a dose lower than 20 mg per day.

The applicant submitted that the authors show that the higher the dose of alendronate the worse the adverse GI effects. This, submitted the applicant, was compelling data that caused physicians to have serious reservations regarding the safe use of high doses of alendronate (Papapoulos 1, paragraphs 84-87, 180; Fennerty, paragraphs 56, 57, 125).

Summary of common general knowledge:

The common general knowledge at the relevant date would include that alendronate came onto the market in New Zealand in the mid 1990s in two oral dosage forms, 10 mg for daily administration in the treatment of osteoporosis and 40 mg for daily administration in the treatment of Paget’s disease; osteoporosis treatment was for life; marketing approval was based on a number of clinical trials that were well-known to bone disease clinicians; administration requirements were strict (at least 30 minutes before the first food of the day with a full glass of water, with no food and remaining upright for at least 30 minutes afterwards); in rare cases there were severe upper GI adverse effects; bisphosphonates had low oral bioavailability but once absorbed had a long duration of action; the skilled addressee would keep abreast of, and be aware of, the assessment of bisphosphonates, and would have perceptions and prejudices; there is a history of bisphosphonates causing GI effects, and specifically etidronate, clodronate and pamidronate had dose dependent GI side effects; GI side effects also occurred with alendronate; as with etidronate, clodronate and pamidronate the skilled addressee would understand that the risk of GI side effects of alendronate may also be dose dependent; the cause of GI side effects was ascribed to pill oesophagitis or reflux; GI side effects in taking bisphosphonates would be greater with regular patients than in carefully monitored clinical trials; GI side effects appear to be part and parcel of treatment with bisphosphonates; and larger doses of alendronate delivered intermittently or cyclically or periodically, including once-weekly, had been suggested to aid compliance with dosing regimens.

What differences exist between the matter as being known and the alleged invention

The difference from what is known is the use of alendronate in the manufacture of a 70 mg unit dosage form of alendronate for administration once-weekly as a safe and effective treatment of bone resorption.

Viewed without any knowledge of the alleged invention, do any of the differences constitute steps which would have been obvious to the skilled addressee or do they require a degree of invention?

This is a ‘close case’. At the end of the copy I was given at the hearing of the decision of the US Court of Appeals for the Federal Circuit, in the equivalent case in the US, is a section headed “Deference to Trial Courts: Time for “Truth in Advertising?” which begins:

This is the classic “close case”, so close in fact that ultimately two federal judges... and the United States Patent and Trademark Office agreed with Merck & Co., and two federal judges agreed with [the opponent].

In the US the claims under consideration were method of treatment of osteoporosis claims since, in the US, claims to methods of treatment of humans are allowable.

At Fennerty, paragraph 127 is the following:

I make the following general comments about the evidence of Dr Cundy. He is not a gastroenterologist and as such he is unlikely to have appreciated how fearful physicians were of bisphosphonate compounds in 1997 because of the risk of adverse gastrointestinal events associated with the oral administration of bisphosphonates. Further, Dr Cundy seems to be relying on 2004 experience and understanding in formulating opinions as to how he thought and would have thought in 1997. For example, if as at July 1997 it was obvious to give 70mg once weekly, why did physicians (including Dr Cundy) not give patients 7 x 10 mg tablets once weekly? The 10mg dose was readily available, and would have been simpler and easier for the patients to only have to take the medication once a week. However, it would also have been ludicrous given the current knowledge related to GI toxicity caused by oral administration of bisphosphonates as it existed in 1997. [my added emphasis]

It seems to me that the point is not that the clinician at July 1997 had, necessarily, to have been in a position to prescribe the dosing regimen claimed in the present application. It is sufficient that the notional skilled addressee had the idea that a 70 mg dose of alendronate administered once-weekly might be an effective and safe treatment for osteoporosis, and that it would be worth investigating the potential of this treatment of osteoporosis.

In Papapoulos 1, at paragraph 181, it is stated:

It is correct that osteoporosis can be treated by administration of a total weekly dose of 70mg alendronate. Efficacy of a total dose of 70mg per week is not doubted. It is the safety of such a large dose (in terms of the possible GI side effects that might result) which was severely doubted prior to the Patent Application.

In Ebeling, at paragraph 35, it is stated:

Based on my knowledge of bone biology and the mechanism of osteoclastic bone resorption, I knew that it was theoretically possible that once weekly dosing (or even dosing at longer intervals) could be effective. However, it was necessary to perform clinical studies to demonstrate both efficacy and safety.

To me here is the admission that the once-weekly dose of 70 mg of alendronate was known in theory as a possible treatment of osteoporosis as at July 1997 and that what was not known was the safety of such a large dose taken at one time in terms of possibly increased incidences of, and/or possibly more severe incidences of, GI side effects compared to those that occur with the known administration regimen of a 10 mg dose taken once a day.

The Lunar News references, above, suggested once-weekly treatments, including oral alendronate in 40 or 80 mg doses as potential treatments of osteoporosis.

It was known to the notional skilled addressee at July 1997 that alendronate caused adverse GI side effects, that regular administration of 40 mg per day produces more incidences, and possibly more severe incidences, of GI side effects. However it would not be clear to the skilled addressee what would be the GI side effects profile of once-weekly dose of 70 mg of alendronate.

The notional skilled addressee would know from the Lunar News articles above that a less frequent administration of the drug, such as once-weekly administration, might help patient compliance with the rather burdensome daily treatment regimen. The administration would need to occur only once every seven days instead of daily.

I do not think that any prejudices of the notional addressee might have regarding Lunar News would extend to a complete disregard of the ideas expressed in the publication, as submitted by the applicant. In addition, the skilled addressee would understand that many in the art read Lunar News and that it was available, amongst other places in New Zealand, in university medical libraries. The skilled addressee might understand that the journal may not have the standing some other journals have in the profession. However, I do not think that any lack of standing would lead to a total disregard for anything in that publication by the skilled addressee.

The notional addressee would understand that once-weekly administration of the higher dose might ameliorate the effects of the high dose, but that this would also need trialing. The dose is the sum of the daily dose for a week so the same amount of drug is administered over a week. In addition, the drug is known to be absorbed slowly so administration less frequently, such as the suggested once a week, could very well be a feasible regimen.

The statements in the Lunar News articles and in Papapoulos 1 and Ebeling, above, sufficiently suggest to me that at the relevant date it was known that trials of the higher dose would be necessary. These trials would be known by the skilled addressee to be necessary to establish safety and efficacy, and would be mandatory, I think, in order to obtain official approval for use from regulatory authorities. All this would be known, and obvious, to the notionally skilled addressee.

It seems to me, from Lunar News, Papapoulos 1 and Ebeling, that administering on a weekly basis 70 mg of alendronate to inhibit bone resorption was an option the skilled addressee would have understood to be worth trialing for safety and efficacy.

Obviousness was considered in Bristol-Myers Squibb Co v Baker Norton Pharmaceuticals Inc [1999] RPC 253 (PC) (Bristol-Myers Squibb (PC)). In respect of the obviousness of testing Jacob J stated at paragraph 69:

... it was quite clear that efficacy at three-hours was of great interest to the skilled man. It was obvious to him to find out.

I believe the same obviousness of testing is present in the circumstances of this case. The suggested 70 mg of alendronate once-weekly regimen would be of great interest to the skilled addressee. I think, also, that the testing of the 70 mg of alendronate once-weekly to establish safety and efficacy in the present case is obvious as being ‘in the way’ as expressed by Jacob J in SmithKline Beecham plc v Apotex, quoted above.

In terms of the two questions from Hoechst Celanese v BP Chemicals, above, I believe (i) the notionally skilled addressee would understand that 70 mg unit dosage form of alendronate for administration once-weekly could be a safe and effective treatment of bone resorption and needed to be trialed, and (ii) the skilled person would try it.

It is my finding that it would be obvious to the notionally skilled addressee to trial a once-weekly dose of 70 mg of alendronate in the treatment of bone resorption. I believe that the opponent has made out its case. I do not believe there is any benefit of doubt to be given to the applicant. In addition, the dependent claims fail along with claim 1 as I do not believe they include any feature which makes them any less obvious.

The ground is made out.

NOT AN INVENTION - section 21(1)(f)

Section 21(1)(f) states:

That the subject of any claim of the complete specification is not an invention within the meaning of this Act

The definition of invention, Section 2(1), reads:

“Invention” means any manner of new manufacture the subject of letters patent and grant of privilege within section 6 of the Statute of Monopolies and any new method or process of testing applicable to the improvement or control of manufacture; and includes an alleged invention

The Statute of Monopolies, section 6, states:

Provided also and it be declared and enacted that any declaration before mentioned shall not extend to any letters patent and grants of privilege for the term of fourteen years or under, hereafter to be made, of the sole working or making of any manner of new manufactures within this realm, to the true and first inventor and inventors of such manufacturers which others at the time of making such letters patent and grants shall not use, so as also they be not contrary to the law or mischievous to the state, by raising prices of commodities at home, or hurt of trade, or generally inconvenient.

The opponent advanced this ground in two approaches. The first approach was that the invention claimed is directed to an unpatentable method of medical treatment. The second approach was that the invention claimed amounted to no more than additional information or proposals about an existing and known medical use which could be put into effect using known dosage forms and is not directed to a new use. I look at both grounds as I consider the case law.

The invention in the present application is claimed in the form of Swiss-type claims. My understanding of the Swiss-type claim is that this form of claim recognises the development of a new medical use of a known drug by way of a claim along the lines of ‘the use of [the known drug] in the manufacture of a medicament for [the new use]’. This form of claim came into being to recognise inventions relating to medical treatment of humans and give a form of protection to new medical uses of known pharmaceutical compounds where claims to the medical treatment per se are not allowable.

In Bristol-Myers Squibb (PC) Jacobs J considered a claim:

Use of taxol and sufficient medications to prevent severe anaphylactic reactions for manufacturing a medicamentation for simultaneous, separate or sequential application for the administration of from 135mg/m2 up to 175mg/m2 taxol over a period of about three hours or less as a means for treating cancer and simultaneously reducing neutropenia.

The judge considered the arguments, including the arguments of the opponent that the claim was in substance merely a claim to a method of treatment. The judge decided that the claim did not amount merely to a method of treatment, but that it was a claim to use of the medicines in the manufacture of the medicaments to be used in the specified treatment. It was a Swiss-type claim, if not in as simple a form as a typical Swiss-type claim. The judge, however, found that the claim was bad for anticipation and obviousness.

In the circumstances of the alleged invention considered in Bristol-Myers Squibb (PC) the administration of the taxol over 3 hours and 24 hours was already known from publicised trials. The claim under consideration was based on the discovery that the shorter administration time resulted in less neutropenia as a side effect. The claim was based on the mere discovery of information about the known 3 hour process and this did not add inventive subject matter to the known process.

In the present case I do not see that there is any discovery of new information about the known administration of 10 mg of alendronate daily. The applicant has found a new treatment, 70 mg of alendronate administered once-weekly.

It seems to me that a typical Swiss-type claim to the use of taxol in the manufacture of a medicament for the treatment of cancer, if such a claim could or did exist, would in theory include within its widest scope the manufacture of a medicament for use in any treatment of cancer, including the treatment described in the claim considered in Bristol-Myers Squibb (PC).

The same claim was considered later by the English Court of Appeal in Bristol-Myers Squibb Co v Baker Norton Pharmaceuticals Inc [2000] EWCA Civ 169; [2001] RPC 1 (Bristol-Myers Squibb (CA)). The court decided that the claim was in fact for a method of treatment drafted in the guise of a Swiss-type claim. Aldous J stated at paragraph 63 of the decision:

In my view the form of claim 1 does not disguise its effect. The invention was the discovery that by changing the treatment from a 24-hour infusion to three hours a similar effect was obtained with less neutropenia. That was a discovery that a change in the method of treatment provided the result. The claim is an unsuccessful attempt to monopolise the new method by drafting it along the lines of the Swiss-type claim. When analysed it is directed step-by-step to the treatment. The premedication is chosen by the doctor, and administered prior to the taxol according to the directions of the doctor. The amount of taxol is selected by the doctor as is the time of administration. The actual medicament that is said to be suitable for treatment is produced in the patient under supervision of the medical team. It is not part of the manufacture. In my view Mr Thorley is correct. The invention made and claimed was a method of treatment precluded by section 4(2) (Article 52(4)). This is emphasised by the way the allegations of infringement were pleaded.

In the present case there is no step-by-step treatment involving doctors or medical staff making decisions to execute a process of administration in the same way as in the preceding quote. However, the treatment is a single step treatment prescribed by medical personnel.

The present claim, the manufacture of a medicament for administration of 70 mg of alendronate once-weekly in the treatment of bone resorption, was considered in Merck & Co Inc’s Patents [2003] FSR 498 (Merck (PC)) where Jacobs J stated at paragraph 71:

So the patent is for the preparation of a medicament which can be used in a 70mg. dosing regime. Is it to a method of medical treatment? But for the decision in Bristol-Myers Squibb v Baker Norton [2000] EWCA Civ 169; [2001] R.P.C. 1 I would have held not, despite the width of the claims. The monopoly covers the preparation of the dose to be administered but not its actual administration. It is true that that might catch a doctor or nurse who measured a dose prior to administration, but that would be an act or preparation not administration. However the principle decided by Bristol-Myers binds me.

The judge felt bound by the higher court in Bristol-Myers Squibb (CA) although he appeared to disagree with the finding of the court that the claim in question was not a proper Swiss-type claim, but was in effect a claim to a method of medical treatment in the guise of a Swiss-type claim. I would add that the reference in the foregoing quote to a doctor or nurse measuring a dose being caught by the claim might equally apply in the case of a typical Swiss-type claim as administration of medicines is usually prescribed by medical personnel.

At paragraph 80 of the decision Jacobs J stated:

I conclude that the claim is in substance to a method of treatment of the human body by therapy. I do so with regret. For patents are provided to encourage research. If new and non-obvious improved methods of administration of known drugs for known diseases are not patentable in principle - even with a Swiss form claim, then there will be less of a research incentive to find such methods. Giving the exception a very narrow scope, so that any preparation used in such a method is protectable if only by the artificial construct of a Swiss form claim, would be a research incentive. But I must follow the current state of interpretation of the exception in Bristol-Myers.

Again, in this quote there is the regret at the Bristol-Myers Squibb (CA) decision, and the judge adds that he must follow the current state of interpretation. The comment that patents are provided to encourage research is to be noted.

When this case was heard by the English Court of Appeal, as reported in Merck & Co Inc’s Patents [2004] FSR 330 (Merck CA), at paragraph 59, under the heading ‘Is such a claim for a method of treatment within s.4(2) Patent Act 1977?’, the Vice Chancellor, Sir Andrew Morritt, noted the regret of Jacobs J in Merck (PC):

In para.[80] of his judgment Jacob J. concluded with regret that on the basis of his interpretation of claim 1 and applying the decision of this court in Bristol-Myers Squibb v Baker Norton s.4(2) applied so as to deny patent protection to the claimed invention. As I have indicated the patentee recognises that we are bound by that decision and having upheld the judge on the question of interpretation are bound to reach the same result. As I have also indicated the patentee reserves the right to contend elsewhere that Bristol-Myers v Baker Norton was wrongly decided.

In the European Patent Office (EPO) (Enlarged Board of Appeal) in the decision Re: Eisai Co Ltd 5 December 1984 (Decision Gr 05/83) the board allowed claims to second therapeutic applications:

For these reasons, the Enlarged Board considers that it is legitimate in principle to allow claims directed to the use of a substance or composition for the manufacture of a medicament for a specified new and inventive therapeutic application, even in a case in which the process of manufacture as such does not differ from known processes using the same active ingredient.

This decision allowed Swiss-type claims covering medical conditions for which a drug was previously not known.

In the EPO (Technical Board of Appeal) decision Genentech Inc, 12 August 2005 (Decision T 1020/03), the decision in Eisai was explained and elaborated upon. In Genentech the Technical Board extended patentability by way of Swiss-type claims to include improved methods for treating a condition for which a drug was already known. The Technical Board rationalised that, at the time of Eisai, only the treatment of different conditions from those previously treated by the drug were being presented for patent protection. At paragraph 72 the Technical Board accepted that a Swiss-type claim directed to the use of a composition for the manufacture of a medicament for a specified new and inventive therapeutic application, where the novelty of the application might lie in the dose to be used or in the manner of application, was allowable. Paragraph 72 of Genentech states:

Against the background of these considerations, the Board interprets decision G 0005/83 [Eisai] as allowing Swiss form claims directed to the use of a composition for manufacture of a medicament for a specified new and inventive therapeutic application, where the novelty of the application might lie only in the dose to be used or the manner of application. This Board allowed such a claim, where only the manner of application was new, already eleven years ago in T 0051/93 of 8 June 1994. The discussion in decision G 0005/83 concerning further medical indications did indeed refer to use for treating a new illness. But the Board regards this significant only of the fact that most further medical use claims will refer to new illness, as in that case novelty and inventive step are more likely to exist than in the case of a minor modification of the treatment known for an existing illness. The logic of decision G 0005/83 allowing claims to further medical uses of known compositions, seems equally applicable to any use of such known compositions for a new and inventive treatment which cannot be claimed as such because of Article 54(4) EPC first sentence.

In Genentech the Technical Board found that Swiss-type claims for the use of insulin-like growth factor-I in the preparation of a medicament for sustaining a biological response in the treatment of a chronic disorder, such as chronic renal failure, in a mammal by a described intermittent administration regimen to be allowable. At paragraph 43 the decision states:

The Board can see no reason why the person who develops a novel therapy by looking for the most effective way in which a known composition can be administered should a priori be said to lack merit to such an extent that even the limited form of patent protection of the second medical use form can be denied without an examination of whether the therapy is indeed novel and inventive.

The Technical Board accepted that the Swiss-type claims it was considering were directed to potentially patentable subject matter avoiding the prohibition of Article 52(4) EPC first sentence (ie that patent protection for medical treatment is not allowable).

The Technical Board in Genentech, at paragraph 67, also noted the ‘reluctance’ with which Jacob J followed the Court of Appeal in his decision Merck (PC) .

The EPO (Opposition Division), in its decision Bristol-Myers Squibb Company, 22 May 2002, considered the taxol claim above. The Swiss-type claim was found to be acceptable as a Swiss-type claim. The claim was refused, however, on the ground that the claim lacked novelty and an inventive step. The Opposition Division stated that the taxol claim could be considered as a further therapeutic application in the sense of Eisai (page 13), that the recognition of a claim to a prescribed dosage regimen as a further therapeutic application appeared to be justified (page 14), that the scenario, that the claimed dosage regimen in the taxol case requires at least the presence and, under certain conditions, also the interference of a doctor, applies to any therapeutic use, generally starting from the prescription of a drug by doctors to the drug administration and/or supervision of treatment, depending on the drug and the disease to be treated, and is not a bar to patentability (page 14), and that the Division did not share the view expressed by the English Court of Appeal in Bristol-Myers Squibb (CA) and held that the patentability exclusion of Article 52(4) did not apply to the taxol claim (pages 14-15).

The EPO (Opposition Division), in its decision Merck & Co Inc, 19 August 2004, found that a proposed claim, the same as claim 1 in the present application, met the requirement of industrial applicability, and that this Swiss-type claim was acceptable as such to the EPO. The patent was, however, revoked for other reasons, viz. that the claimed invention was not novel and did not involve an inventive step.

In Canada a claim, the same as proposed claim 1 of the present application, was considered and found to relate to a vendible product having real economic value as demonstrated by its immediate success in the market, and was therefore not for an unpatentable method of treatment. The judge, in the decision, noted the reluctance with which Jacobs J held that the same claim was not allowable in the United Kingdom. Ultimately, however, the Canadian judge decided that the claim was not allowable as it amounted to a claim to the discovery that if 70 mg of alendronate was delivered once a week rather than 10 mg once a day one of its disadvantageous side effects would be less than it otherwise would have been. The judge decided that no previously unrecognised advantageous properties in the chemical compound had been discovered.

I was referred by the applicant to the New Zealand decision Abbott Laboratories Application No. 510328 (Decisions of the Commissioner, P16/2003, 11 August 2003). This decision was made after Eisai, but before Genentech, which extended the scope of second therapeutic use in Eisai to include improvements in existing therapeutic uses for medicaments.

Abbott referred to the office practice note Office Practice Note: Swiss Type Claims which issued on 7 July 1997. The practice note read:

On 17 September 1990 I issued a decision (Massachusetts Institute of Technology, Patent Application No. 199328) in which I disallowed a claim, in the so-called “Swiss” form, to the use of a known pharmaceutically active compound for the manufacture of pharmaceutical compositions in which the compound exhibits previously unknown therapeutic activity. I have now reviewed this practice in the light of the continuing trend to liberalise the definition of “invention” and have come to the conclusion that it is now appropriate that claims of the “Swiss” type should not be refused during the examination process.

Accordingly, from the date of this Practice Note, ... “Swiss” type claims, of the general form:

The use, in the manufacture of a medicament, of [the active compound] as an active ingredient in a [newly invented activity] composition in admixture with an inert carrier,

or similar constructions, will not be rejected by patent examiners.

Claims to therapeutic treatment of humans will continue to be disallowed...

The preamble to the practice recognises ‘a continuing trend to liberalise the definition of “invention”’. This liberalisation includes the adaptation of the somewhat archaic definition of invention in the Patents Act to accommodate changes in technology over time, changes that could not have been, and cannot be, envisaged and changes that do not always fit well with the definition, or any definition, of invention. The practice note was drafted after Eisai, but before Genentech. The continuing trend of liberalisation or adaptation of the definition of invention was given expression in relation to Swiss-type claims by the EPO in Eisai and Genentech. The trend was also apparent from Jacob J in relation to Swiss-type claims in Bristol-Myers Squibb (PC) and from the Pharmac decision below.

I also note that according to the practice note there has to be a ‘newly invented activity’. There appears to be no restriction on that activity other than it be newly invented. Thus it might include within its ambit both new therapies for a known drug as well as improvements to known therapies for a known drug. When the issue of allowability of Swiss-type claims was first broached in New Zealand it was, I believe, in the context of new therapeutic uses.

The decision in Pharmaceutical Management Agency Ltd v Commissioner of Patents [2000] 2 NZLR 529 (CA) (Pharmac) recognised Swiss-type claims as valid claims in New Zealand. The applicant pointed to paragraphs 47, 59 and 60 of this decision as showing that the particular wording of the Swiss-type claim has to be assessed to determine whether or not the alleged invention is novel or inventive. In addition, paragraph 51 of Pharmac states:

We have not been persuaded that there is anything in the New Zealand Patents Act or in the judicial decisions of this country which directly precludes a similar process of reasoning to that adopted in Eisai. We reject the contention that the decision was dictated by provisions of the EPC which are to be distinguished from the position in New Zealand.

The decision continues in paragraph 52 with:

As already indicated, the law and practice on patentability in New Zealand is little different from that provided for in the EPC.

I note that the Pharmac decision considered the Eisai decision, but that the Pharmac decision itself preceded the Genentech decision.

At paragraph 110 of Bristol-Myers Squibb (CA) the court made reference to paragraphs 38 and 65 of Pharmac, quoting in part from these paragraphs, respectively, as follows:

The step necessary to render Swiss-type claims acceptable would be to recognise what is in fact the situation, that the novelty resides in the newly discovered purpose for which the medicament is to be used.

and

Once it has been accepted that there can be new invention in the discovery of previously unrecognised advantageous properties in a chemical compound, the obligation to make patent protection available must apply.

The obligation to make patent protection available follows from New Zealand’s accession to the TRIPs Agreement. Paragraph 64 of Pharmac states:

... But by its accession to the TRIPs Agreement New Zealand has undertaken to make available patents “for any inventions, whether products or processes, in all fields of technology, provided that they are new, involve an inventive step and are capable of industrial application” (art 27:1). That obligation, which has been assumed by all parties to the agreement, is not to be set aside on grounds based on circumstances of convenience such as the comparatively low level of medical research undertaken in this country or the particular method by which medicines are funded.

At the present hearing the applicant referred to draft New Zealand office guidelines relating to Swiss-type claims and medical treatment of humans, for completeness. I do not think they should be discussed by me as part of this decision. They are an issue between the office and its clients.

I believe the appropriate course to follow on the allowability of Swiss-type claims is that set by the EPO in its Eisai, Bristol-Myers Squibb Company, Merck & Co Inc and Genentech decisions. I believe there can be inventiveness in improving existing therapies and this is patentable by way of Swiss-type claims. It is my finding that the present Swiss-type claims are not to an unpatentable method of medical treatment, but are proper Swiss-type claims and hence relate to potentially patentable subject matter.

I think the present claims relate to more than additional information about an existing and known medical use which could be put into effect using known dosage forms. Unfortunately for the applicant I have found that the invention claimed is obvious and that the claims clearly do not involve any inventive step.

NOT SUFFICIENTLY AND FAIRLY DESCRIBED - section 21(1)(g)

Section 21(1)(g) states:

That the complete specification does not sufficiently and fairly describe the invention or the method by which it is to be performed

In support of the ground the applicant referred to Terrell 12th Ed, paragraph 12, a portion of which I quote:

It has been said that the directions should be sufficient to enable “a workman of competent skill in his art,:” or a “competent engineer” to carry the invention into effect.

It is clear to me that the skilled addressee would have no problem producing something with in the scope of claim 1.

As the applicant submitted, many of the objections made in the statement of case have been overcome by amendment or relate to ambiguity of the claims which is not a ground of opposition before the Commissioner.

The ground is not made out.

DECISION

I find that the invention claimed is obvious and clearly does not involve any inventive step, hence the opposition succeeds. I direct that the patent not be sealed.

COSTS

The parties have agreed that there is to be no issue as to costs. Each party is to meet its own costs.

Dated this 31st day of January 2006

____________________________
A Hazlewood
Assistant Commissioner of Patents

A J Park for the Applicant
Baldwins for the Opponent