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Cholesterol: It's All About The Numbers, Even The Patents

Grace Teoh discusses a dispute on a patent for cholesterol medication

Dave Barry, a Pulitzer Prize-winning American author and columnist, was quoted as saying, "It is a scientific fact that your body will not absorb cholesterol if you take it from another person's plate". On 3 April 2014, the New Straits Times reported in the article "More than a third of Malaysians suffer from high cholesterol" that over one-third of Malaysians suffer from high cholesterol due to unhealthy lifestyles.

Lovers of nasi lemak in Malaysia with high cholesterol levels requiring treatment may now have access to cheaper generic drugs, as a result of the Malaysian High Court's recent decision in Winthrop Pharmaceuticals (Malaysia) Sdn Bhd v AstraZeneca UK Ltd (KLHC CS No. D-22IP-57-10/2011) ("Suit 57") to invalidate a particular patent.

CHEM 101, PHARMA 301

One of the treatments for hypercholesterolemia, or colloquially known as high cholesterol, is the use of drugs containing the cholesterol-lowering agent known as statins. Statins reduce the level of low-density lipoprotein (LDL) cholesterol (also known as "bad cholesterol") in the blood by inhibiting the production of it in the liver. One of these statins is "rosuvastatin". Drugs containing rosuvastatin may be administered in various forms, including via injections and orally.

AstraZeneca UK Limited ("AstraZeneca") was the registered proprietor of Malaysian Patent No. MY-136382-A ("Patent 382") for a particular oral dosage form of rosuvastatin; specifically, a drug composition containing 5 to 10 mg of rosuvastatin (or 5.2 to 10.4 mg of rosuvastatin calcium)("Claimed Dosage Range") to be administered to patients orally once daily. Put simply, the patent allowed AstraZeneca to monopolise the right to manufacture and market medicine capsules containing any amount between 5 and 10 mg of rosuvastatin in Malaysia.

AstraZeneca had applied to register the equivalents of Patent 382 in various jurisdictions, including the United Kingdom, Europe, and Australia. The validity of these patent applications or registrations has been attacked by various generic pharmaceutical companies. In AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99, a five-member panel sitting in the Federal Court of Australia held that the Australian Patent No. 769897 (the equivalent of Patent 382) was invalid.

In Suit 57, Winthrop Pharmaceuticals (Malaysia) Sdn Bhd ("Winthrop"), the Malaysian arm of Sanofi's generic pharmaceuticals business, filed an action in court against AstraZeneca, seeking, inter alia, a declaration that the patent was invalid, whether as-filed or as-amended. Winthrop challenged Patent 382 on several grounds: invalid claim to priority dates, lack of novelty, lack of inventive step, lack of support, insufficiency, and invalid claim to entitlement.

DOCTOR WHO? : THE SKILLED NOMINEE

In order to consider the issues before the Court, the Court first had to establish the "person having ordinary skill in the art", or "the skilled person", to assist the Court in donning the mantle of the notional skilled but unimaginative person faced with the available set of facts and information.

Winthrop and AstraZeneca each tendered their own expert witness in Court. After considering both parties' written submissions on the notional skilled person, and which expert's evidence the Court should prefer, the Court agreed with Winthrop's submissions that the notional skilled addressee should be clinicians working in the area of lipidology, particularly the treatment of high cholesterol.

EENY, MEENY, MINEY, MOE: ARBITRARY SELECTION

It was not AstraZeneca's claim that it invented rosuvastatin; it was agreed that the compound existed before the priority date of Patent 382. Instead, Patent 382 claimed the invention for the selection of the single daily starting dose of rosuvastatin within the Claimed Dosage Range, which according to AstraZeneca, was more efficacious than any other dosage range in the alteration of lipid levels or ratios. The priority dates claimed for Patent 382 were 6 February 1999 and 8 September 1999.

The main thrust of Winthrop's contentions in relation to lack of novelty and lack of inventive step was that the essential elements in Patent 382 were already known to the notional skilled person, long before Patent 382 was filed. Specifically, European Patent Application Publication No. 0521471 published on 7 January 1993 ("Shionogi prior art"), an article in the Journal of the American Medical Association, 269(23):3015-3023 published in 1993, and an article in Bioorganic and Medicinal Chemistry, 5(2):437-444 published in 1997 ("Watanabe prior art"), had already disclosed the alleged invention claimed in Patent 382.

By 1993, the Shionogi prior art had already disclosed the three essential elements of Patent 382: (i) the use of rosuvastatin to treat hypercholesterolemia, (ii) the fact that rosuvastatin-containing drugs can be administered orally, and (iii) the administration of rosuvastatin in the dosage range of 1 to 100 mg per day, depending on the patient's characteristics, to treat hypercholesterolemia would be more beneficial than any other dosage range.

Winthrop contended that the selection of the Claimed Dosage Range by AstraZeneca was arbitrary as there was no data within the patent specification which demonstrated clearly that the range would have clinical advantages over other ranges.

TIGER CAUGHT BY ITS TOE: LACK OF NOVELTY

The High Court agreed with Winthrop's submissions on the issue of novelty, or the lack thereof, in Patent 382.

The Court found that all the allegedly novel features of Patent 382 had been previously disclosed by the Shionogi prior art, namely that (i) rosuvastatin can be used in the treatment of cholesterolemia, (ii) rosuvastatin may be given in, amongst others, a single once daily dose, (iii) the dosage range claimed by Patent 382 is within the 1 to 100 mg range disclosed in the Shionogi prior art, (iv) the Shionogi prior art did not distinguish between a starting dose and a continuing dose, and (v) there are clear directions in the Shionogi prior art that the dosage may be administered orally. The Court observed that the rosuvastatin calcium compound, used in Claim 2 of Patent 382, had been described in Example 7 of the Shionogi prior art.

Additionally, the Shionogi prior art also disclosed the fact that clinicians could alter the doses within the 1 to 100 mg range, in accordance with the needs and characteristics of the patient.

The Court was mindful of two further pieces of evidence from AstraZeneca's expert in coming to its conclusion of lack of novelty: first, that the specification in Patent 382 did not disclose any safety data and held no promise as to the safety of rosuvastatin, even though Patent 382 claimed that the Claimed Dosage Range of rosuvastatin was safe for consumption, and second, that the Claimed Dosage Range was no more efficacious than 2.5 to 4 mg.

In the absence of data which demonstrated that the Claimed Dosage Range was particularly efficacious, the Court agreed with Winthrop's contention that AstraZeneca's selection of that range was arbitrary. The selection was motivated by the knowledge that the lower-end of a given statin dosage range was likely to be more effective, that it was safer for statin doses to be prescribed from the lower-end to avoid side effects, and that 5 to 10 mg were historically typical doses of many other statins administered for the treatment of hypercholesterolemia.

WATCHING YOUR DIET: IT'S OBVIOUS

The High Court, donning the mantle of the skilled person, examined Patent 382 through the four steps elucidated in Windsurfing International Inc v Tabur Marine (Great Britain) Ltd [1985] RPC 59:

  1. First step: The identification of the inventive concept in the patent. Patent 382 claimed that the Claimed Dosage Range of rosuvastatin (or 5.2 to 10.4 mg of rosuvastatin calcium) provided significantly greater results than any other dosage ranges.
  2. Second step: The identification of the common general knowledge at the priority date of Patent 382. The Court found, amongst others, that statin drugs had varied recommended dosages including 5 and 10 mg, that the dose-response relationship for statins is non-linear, that the efficacy of higher doses of statin may plateau, and that it was safer to titrate up from lower starting doses.
  3. Third step: Comparison of the inventive concept against the background of common general knowledge. The Court determined that the dosage range expounded in the Shionogi prior art clearly encompassed the Claimed Dosage Range.
  4. Fourth step: To consider whether the differences would have been obvious to the skilled person. The Court agreed with Winthrop's submissions that the Claimed Dosage Range would be obvious to the skilled person in light of the Shionogi and Watanabe prior art documents, and given that it is common knowledge that the dose-response relationship for statins is non-linear where there is an initial sharp fall in LDL-C levels at lower doses.

Having done so, the Court found that the selection of the Claimed Dosage Range did not require any degree of inventiveness.

TRIMMING THE FATS: INVALID AMENDMENTS

On 4 February 2000, Patent 382 was filed. Patent 382 claimed the priority date of 6 February 1999 based on GB Patent Application No. 99025900 and 8 September 1999 based on GB Patent Application No. 99210627. Patent 382 was amended on 5 October 2004 and again on 22 January 2008.

Winthrop challenged the validity of the 2008 amendments to Patent 382. The 2008 amendments had made two vital changes:

  1. Claims 1 and 2 of Patent 382 were amended to include the phrase "single once daily dose"; and
  2. Page 11A was introduced to Patent 382's specification, where it first mentioned "single once daily dose" in relation to the Claimed Dosage Range of rosuvastatin.

Winthrop's challenge was based on the fact that the phrase "single once daily dose" was never disclosed anywhere in Patent 382 as it was originally filed in year 2000. The application form of Patent 382 had only disclosed that the subject matter, the Claimed Dosage Range, was a "suitable starting dose".

The Court found that the 2008 amendments, as revealed by Patent 382's prosecution history, contravened sections 26A and 79A(2) of the Patents Act 1983 as they introduced a concept that would go beyond the initial application as originally filed in year 2000. In consequence, the Court held that the claims of Patent 382 would not be fully supported by the description disclosed in the initial application, and that the description was insufficient to convey the invention in such terms that it can be understood clearly and completely for the skilled person to carry out the invention.

LIMPID LIPIDS: NAME THE INVENTORS

Post-Suit 57, it is clear that patent applicants must be careful in naming the inventor(s) in their patent application. Section 56(2)(d) of the Patents Act 1983 stipulates that the right to the patent must belong to the person to whom the patent was granted.

AstraZeneca had nominated Ali Raza as the inventor of the purported invention claimed in Patent 382. Winthrop's challenge with respect to AstraZeneca's entitlement to Patent 382 was grounded on the fact that the Claimed Dosage Range in the patent was first discovered by the employees of Shionogi Seiyaku Kabushiki Kaisha ("Shionogi Co"). Shionogi Co's employees had in fact, been the authors of the Shionogi and Watanabe prior art documents.

In 1993, Shionogi Co had conducted the first of a series of clinical trials on healthy volunteers using various doses, including the Claimed Dosage Range. In 1994, Shionogi Co had conducted further trials using 5, 10, and 20 mg doses per day. Between 1995 and 1996, Shionogi Co tested the efficacy of rosuvastatin at doses of 1 to 4 mg daily, and noted greater lipid reductions compared to available conventional drugs.

AstraZeneca's involvement only began after it had obtained a licence from Shionogi Co to exploit the rosuvastatin compound in 1998. In the licence agreement, all works relating to the rosuvastatin compound were disclosed by Shionogi Co to AstraZeneca, including the clinical trials conducted by Shionogi Co.

Even after the signing of the agreement, Shionogi Co was still involved in the development of drugs using rosuvastatin. Between September and October 2004, Shionogi Co conducted yet another study using rosuvastatin on patients with mild hyperlipidaemia.

The Court highlighted that AstraZeneca's expert admitted during cross-examination that based on hindsight, it was Shionogi Co who discovered the Claimed Dosage Range. The Court's attention was also drawn to the Australian Federal Court's decision in Apotex Pty Ltd (supra) where the Australian Federal Court had noted that Shionogi Co was the first to discover the effective use of rosuvastatin at doses of 5 and 10 mg.

Given that the efficacy of the Claimed Dosage Range to lower lipid levels was known as early as 1993, thus long before the 1999 priority dates claimed by Patent 382, the High Court found that AstraZeneca was not entitled to the invention as AstraZeneca's nominee, Ali Raza, was not the inventor of the purported invention in Patent 382.

CONCLUSION: EAT THE YOLKS!

In short, the High Court found that Patent 382 was invalid for lack of novelty, lack of inventive step, lack of support due to the invalidity of the amendments, insufficiency, and lack of entitlement by AstraZeneca. As the High Court had found Patent 382 invalid, AstraZeneca's counterclaim for infringement was consequentially dismissed. The High Court further awarded costs to Winthrop and directed that Winthrop's damages arising from AstraZeneca's enforcement of Patent 382 be assessed.

It would appear that that the Court's grounds for finding invalidity will not be challenged, as AstraZeneca had only filed a motion for leave to appeal against the decision on costs. The deadline for AstraZeneca to challenge the Court's decision expired on 15 February 2015.

As cheaper generic drugs for high cholesterol may enter the market, it's time to dig in into your nasi lemak with extra eggs!

Writer's e-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

WRITER'S NAME : GRACE TEOH WEI SHAN

WRITER'S PROFILE:

Grace is an Associate in the Intellectual Property Division of SKRINE. She graduated from the University of Nottingham in 2010.

SUBJECT : CASE COMMENTARY

 
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