An important decision was published at the beginning of February in “Unipharm vs. Lundbeck”, which relates to an Opposition to Grant Patent Term Extension for IL 90465.
The application was filed by Dr. Shlomo Cohen and Partners, and the opposition was filed by Unipharm represented by Adv. Adi Levit, and by the Chemical and Pharmaceutical Association of the Union of Industrialists, by Adv. Tal Band (S. Horowitz and Partners).
There were two main grounds for opposition:
1. The request for patent term extension was filed late, albeit with permission from the Commissioner of Patents
2. The patent was not for a first use of an active ingredient, since the patented medicine, Spiraled®, is an antidepressant comprising the S-enantiomer of Citalopram®, a previously patented composition comprising the S and R enantiomers in equal proportions (racemic mixture).
Following the US precedent of Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) of 1984, Israel’s 1994 amendment provides patent holders on approved patented products with an extended term of protection under the patent to compensate for the delay in obtaining FDA approval. Thus Israel is a Bolar country which allows the patent term for pharmaceutical patents to be extended beyond the normal 20 years, for up to an additional 5 years, if the protected composition is not commercially exploitable for at least 9 years due to regulatory considerations.
A request for extension was filed late: 13 Sept 2004, after the period allowed by Law Section 64(o) but in accordance with an extension given in a ruling dated 15 June 2005 which was published on 5 October 2006 and against which an opposition was filed on 4 January 2007.
Grounds for Opposition
- The opponents claimed that once the deadline had passed, the decision to provide a patent term extension was unreasonable, and regardless of substantive issues, the deadline had been missed.
- Since the patent for Cipralex® was not the first patent for the active ingredient, which was found in previously patented Cipramil®, this wasn’t a first use patent as required by Section 64d(3).
- The applicant’s failure to report the Cipramil® patent should be considered as bad faith and in accordance with general principles of Israel Law (Former Head of Supreme Court, Aharon Barak’s extension of bad faith from Contract Law into, well, everything else), could, in and of itself, invalidate the request.
Following the ruling, I will relate to the first use issue first, and then address the late request and extension. The bad faith issue, is essentially an “also ran” consideration and won’t be related to substantively.
The main question is whether where the racemic mixture of left and right hand molecules is known to have a physiological effect, one or other of the stereo-enantiomers can be considered to be a new material under the wording and spirit of the Amended Pharmaceutical Term
Extension of the Israel Patent Law
Cipramil® is used for treating clinical depression. The S-Citalopram in Cipralex® is claimed to be more effective for treating severe depression. Is this because the R-form is simply less effective or non-effective and thus the pure S-form is twice as good as an equal mixture of the two? Or is there something surprising in the efficacy of the pure S-form, i.e. does the R-form inhibit the effect of the S-form by bonding with Serotonin and preventing S-form uptake? Should the extracted S-form be considered a new active ingredient? Should the wording of Section 64a which lists materials, their salts, esters, hydrates, crystalline forms but doesn’t relate to stereo-enantiomers be considered an exhaustive list or a list that is designed to be inclusive of different forms and can be interpreted as including stereo-enantiomers despite these not being mentioned?
Dr Ron Tomer, expert witness and director of Unipharm® – the main Opposer to granting extension, , pointed out that if the R-enantiomer has no significant effect, it is not an active ingredient and S-Citalopram is thus the active ingredient of Cipramil®, an earlier patented compound. Even if the R-enantiomer is an inhibitor, the Cipralex® patent under consideration should be considered as being a patent for a purer, cleaner version of S-Citalopram and not a first use. Furthermore, since Cipralex® benefitted from the extensive, earlier clinical trials of Cipramil®, there was no justification for a patent term extension. In a clever twist, Tomer showed that the risk-benefit of the two compositions was identical. Finally, Tomer claimed that Lundbeck acknowledged that the S-enantiomer was the main active ingredient during the regulatory process for Cipramil®, rendering it obvious.
Professor Montgomery, expert witness for Lundbeck made some reasonable but not particularly inspiring claims that different enantiomers have different toxicity levels, absorption levels and side effects, and claimed that without extensive clinical trials one cannot ascertain the effect of using an isolated enantiomer. He did give some examples of compositions where a racemic mixture was more effective than one or other enantiomer in isolation. An additional though in my opinion, weak claim, was that the isolation of S-Citalopram was difficult to achieve. Somewhat more convincing was some clinical evidence that the S-Citalopram was twice as effective on rats, when administered neat, than the same dosage of S-Citalopram in the racemic mixture, indicating an inhibitory effect, and also indicated that the pure S-form was more effective for treating the severely depressed than the mixture. Montgomery went on to cite twenty publications that should improved efficacy of S-Citalopram over the mixture.
In cross-examination, Levit showed that in his own book, Montgomery himself had pointed out that the escitalopram, i.e. the S-enantiomer was the active enantiomer and that the R-enantiomer was not active.
Both sides went on to cite peer reviewed research papers and also used favorable rulings in other jurisdictions.
In his ruling, Dr. Noam first examined the definition of the term “material” as far as Section 64a of the Law is concerned. In 1063/06 Novartis AG vs. Commissioner of Patents and Others, the District Court Upheld an earlier decision that a mixture of known active ingredients cannot be considered a “new material”. Noam points out that the current issue is really the mirror image (I’d have used simile of stereo-enantiomer ;-) ).
In that precedent, Re Alcon Laboratories (USPQ2d 1115, 1121) the US Court ruled that the intention of the Hatch-Waxman Act was not intended to include something previously marketed as part of a combinatory product.
As to the claim that the S-enantiomer is superior to the racemic mixture, Dr. Noam drew a distinction between the requirement for patentability, where such an effect could be considered patentable, and the stricter standard for the first use requirement for patent term extension.
In an elegant argument, Noam went on to demolish a British court ruling Generics (UK) Ltd. Vs. Daiichi Pharmaceutical Co. Ltd.  EWHC 2413 (Pat), which was cited by patentee. However, he related to a case cited therein (C-258/99 BASF v. BIE  RPC 9), which relates to relative purities of active ingredients as being patentable but not new materials, per se – using this as analogous to the current case.
Noam went on to cite the Australian Patent tribunal’s decision re patent term extension for the corresponding patent, which was endorsed by the Australian Court and rejected the European and American rulings, and dismissed other arguments including whether the S-enantiomer’s additional efficacy is surprising, whether there are synergistic effects, etc. with various well reasoned opinions.
The Extension for Late Filing
Noam endorsed his earlier decision to allow late filing of the request for patent term extension based on applicant not being familiar with the Israel Law.
As far as the substantive question of first use is concerned, both sides presented their cases well. I was actually present at part of the hearing, and think Adv. Adi Levit performed excellently, though he was a bit hard on Montgomery, the expert witness. Unipharm’s contention is one of “evergreening” – keeping patents alive for ever. I think the Commissioner of Patents, Dr. Noam, came to a correct decision, but wish that he had the resources to rule and publish more quickly.
As far as granting an extension based on applicant missing deadline due to ignorance of the law is concerned, I disagree with the ruling and think that the Patent Office is being inconsistent. In this regard I note a ruling against a Korean client of mine whose Korean counsel mistakenly thought that Israel had a 31 month PCT National Phase Entry. His request for an extension was rejected despite several earlier precedents from the Israel Patent Office where late filing was allowed including one where there was evidence of bad faith with applicant offering alternate excuses for missing deadline, including the CEO being in an ashram and unavailable, this case also being handled by Dr. Shlomo Cohen and Partners.
Although the Commissioner has the authority to make such exceptions, generally the Patent Office pontificates about fairness to third parties and is strict on procedures, and I see no reason to rule differently in this case. It takes a lot of courage to say “I was wrong”. King David was perhaps the last Israeli civil servant to do so (Sam II 12:13). Anyway, since the extension was overturned the issue is moot.
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