Invalidation of Cubist Pharmaceuticals, cubicin

unitary-patent-articleAlthough methods of (medical) treatment claims are accepted in the US and Europe, such claims are still not accepted in China. Currently such claims have to be rewritten into so called Swiss-type claims. However, Swiss- type claims are not suitable for inventions involving merely changes in the dosage regimen and/or timing of administration. This was the problem faced by Cubist Pharmaceuticals, Inc. with its Chinese patent covering its block-buster drug cubicin. This is also the first ruling from the Supreme Court on its position regarding the dosage amount and timing of administration on determination of patentability in China.

Before discussing the current case, there was a previous High Court decision (in the case of Chinese Patent No. ZL94194471.9) that a limitation on unit dose should be considered as a technical characteristic in evaluating patentability. In that case, the distinguishing feature of the Swiss-type claim was the “0.05 to 3.0mg dosage amount” of the medicament, and the drug is administrated orally. The current Supreme Court decision does not appear to contradict this High Court decision; rather this Supreme Court decision distinguishes the unit dose in Chinese Patent No. ZL94194471.9 from treatment dose in Cubist’s Chinese patent.

Claim  1  of  the  Cubist’s  Chinese  Patent  (No.  ZL 99812498.2) read:

Use of daptomycin for the manufacture of a medicament for treating a bacterial infection in a patient in need thereof without generating skeletal muscle toxicity, wherein a dose for said treatment is 3-75 mg/kg of daptomycin, wherein said doses are administered repeatedly at a dose interval of once every 24 hours or 48 hours.

It was determined that the following features were distinctions, as daptomycin was known to be used in treating bacterial infection, particularly those infected by gram-positive bacteria:

  1. Skeletal muscle toxicity did not result
  2. A treatment dose of 3-75 mg/kg of daptomycin
  3. The above treatment dose is administered repeatedly at a dose interval of once every 24 hours or 48 hours

Before the decision of the Supreme Court, the Chinese patent was first invalidated at the Patent Re-examination Board (PRB) of the Chinese SIPO, then in an appeal at the Beijing Intermediate People’s Court, and in a second appeal at the Beijing High People’s Court. In short, the three People’s Courts affirmed the invalidation decision from the PRB of the SIPO. Specifically, the feature of “not generating skeletal muscle toxicity” was considered to be not limiting as such is an effect occurred after the drug is administered on the patient. The significance of the dose of the treatment and the dosage interval were also dismissed as these two limitations were considered to be not related to the manufacturing of the medicament. More specifically, the PRB and the three Chinese People’s Courts considered that a Swiss-type claim is a “method of manufacturing” claim, more specifically a method of manufacturing a medicament, and therefore, the above limitations relating to the administration itself or effects of the administration were considered to be carrying no weight on determination of patentability of a Swiss-type claim.

The Supreme Court decision has additional comments on these points, which will be discussed below.

As expected, Cubist tried to argue for the patentability of the above two features at various stages. Attempts from Cubist included the following:

•  Skeletal muscle toxicity in prior art composition resulted in the suspension of Eli Lily’s clinical trials of daptomycin at the US FDA, and therefore, the non- generation of skeletal muscle toxicity feature should be considered when evaluating patentability.

•   The process of manufacturing a medicament does not only include raw materials, drug treatment dosage, method manufacturing and equipment, but also include specification of the drug, drafting a specification of the labels and packaging, and all processes involved before the drug is shipped out of the factory. As such, the treatment dosage amount and dosage interval recited in the current patent claims will directly affect the drug specification and labels, and therefore should be considered as limiting.

•   The prior art did not disclose the less frequent dosage interval of 24 to 48 hours but higher administration dose of 3-75 mg/kg of daptomycin.

•   At the application date of this patent, daptomycin is still at the research and development stage, and is very distant from actually being used as a medicine. As such, doctors will strictly follow the treatment dosage and dosage interval according to the specification without any freedom.

•   Cubicin has received huge commercial success, and Cubist presented various pieces of evidence including news reports that Cubist major income is from cubicin, annual reports from Cubist, and so on.

•   The Chinese Patent Examination Guideline 1993 edition should be used, while the 2006 edition was used instead. The main difference between the two editions is that the 2006 edition recited that distinguishing features only realized at drug administration cannot be used to confer novelty to the use for Swiss-type claims, while such statement is absent in the 1993 edition.

All the above attempts failed: it was decided that Swiss- type claims are in fact a claim directed to method of manufacturing of a medicament, and features relating to administration of such medicament and/or effect after administration should be disregarded.

During the evolvement of the case and in this decision from the Chinese Supreme People’s Court, the writer notes the following interesting points:

Whether medical use approved by drug administrations in various countries like the US FDA is relevant to use in drug manufacturing was discussed. The invalidation petitioner, whom was an individual, argued that these are irrelevant, as, if use in manufacturing of a medicament under patent law is the same as use of the drug licensed by drug administration, this would lead to the incorrect conclusion that obtaining patent grant for Swiss-type claims must mean first obtaining approval from the relevant drug administration.

•   Cubist actively abandoned priority claim of certain claims during the invalidation hearing, presumably due to inconsistencies between the priority document and the specification as filed.

•   During the first appeal at the Beijing Intermediate People’s Court, Cubist admitted that a person skilled in the art could not distinguish two medicaments of daptomycin if the distinction is based on the above three distinguishing features a) to c). The writer believes this admission is Cubist’s Achilles heel in this case.

•  Cubist tried to argue that the medicament of the invention is particularly used to treat gram-positive bacterial infection. However, this was dismissed, as the specification itself mentioned that various bacterial infections could be treated, and the current claims did not limit to treatment for gram-positive bacterial infection.

•   The Supreme Court decision specifically discussed the distinction between unit dose and an administration or treatment dose. The decision recited that current claim 1 does not specify the dosage of 3-75 mg/kg is unit dose or treatment dose. The Supreme Court ruled that according to the specification, the above dosage is the treatment dose as would be understood by a person skilled in the art. The Supreme Court decision specifically stated that treatment dose does not necessarily affect the manufacturing process of a medicament, so that it changes the composition of the drug, and therefore it is not limiting to a Swiss-type claim.

•   With regard to the use of the 2006 edition of the Chinese Patent Examination Guideline, the Supreme Court ruled that this does not affect the ruling in this case, as the standards of patentability evaluation for a product manufacturing claim are maintained to be the same.

This ruling is disturbing to companies having inventions involving change of dosage regimens or dosage intervals of existing drugs. However, this is not surprising with the current Chinese interpretation of Swiss-type claims being method of manufacturing a medicament claims. The writer considers that it would be strange if limitations on “mere drug administration” would be considered as limitation of manufacturing of the medicament itself. This is a deadlock, and will only be resolved if attitude towards method of treatment claims is changed in China. In this respect, the USPTO and EPO are encouraged to talk to the SIPO to introduce such changes of allowing method of treatment claims to be granted in China.

The following lessons can be learned from this case:

1)      If the improvement of the medicament is in its dosage, it would be helpful to specify that the dosage in the Swiss- type claim is the unit dose. Although not specified, this Supreme Court decision seems to imply that what is the unit dose would affect the composition of the final medicament manufactured, as opposed to treatment dose (which it decided would not). This would help to confer patentability on Swiss-type claims.

2)      Cubist’s current issue is that they only have Swiss-type claims covering their second medical use. Then would a claim like the following help?

“An article of manufacture comprising a package material, daptomycin, and a  label of package insert contained within the packaging material indicating that the daptomycin is administered at a  dosage of 3-75 mg/kg of daptomycin, and is administered repeatedly at a dose interval of once every 24 hours or 48 hours.”

Similar claims have been granted for inventions involving new chemical compounds or new compositions in which the compound/composition is different from the  prior  art,  for  example  in  Chinese  patent  nos. 200580018660.1, 200580028061.8,  200680042380.9,  and 200980112242.7. Whether the above exemplary claim for daptomycin could be properly granted for a medicament is unknown, as the only distinctions from the prior art are treatment dosage and/or dose interval.  The writer ’s experience is that these are determined on a case-by-case basis. Some examiners may allow such a claim, while other examiners do not. However, the format of the above claim could at least solve the issue of the product manufactured by the Swiss-type claim remaining unchanged if the limitations are only directed to treatment dose and dose interval. The next question to be resolved is whether these distinctions, which in this case lie in the label and draft of the specification of the package only, would be considered as technical? The writer is interested to receive views from fellow readers.

Author: Toby Mak, Tee  &  Howe Intellectual Property Attorneys. ©2014.

These articles were published in the August 2014 issue of the UK Chartered Institute of Patent Attorneys (CIPA) Journal, and are re-posted here with the kind permission from the UK CIPA. The UK CIPA Journal covers updates, articles and case law reviews on IP in the UK, Europe, and around the world. The Journal is available for subscription at GBP130 per year.

Further articles of the author can be accessed here.