IPAB begins the hearings over the ‘Glivec’ pre-grant rejection

The special IPAB bench has commenced hearing Novartis’s appeal against the decision of the Asst. Controller of Patents rejecting its patent application for the beta-crystalline form of Imatinib Mesylate, popularly known as ‘Glivec’, during a pre-grant patent opposition proceedings initiated by the the Cancer Patient Aid Association (CPAA) and Natco amongst other parties. For a detailed explanation of the facts as also the Section 3(d) issues, please feel free to download this paper co-authored by Shamnad and me and which was published in Script-ED. The paper can be downloaded at the SSRN database over here.

Once again we would like to express our appreciation for the factual and balanced reporting by Lawyers Collective. The proceedings can be viewed here. Mr. Anand Grover the head of LC is representing the CPAA in this particular case. Respected Supreme Court, Senior Advocate Shanti Bhushan is appearing on behalf of Novartis.

A brief recap of the milestones in the development of Glivec, as mentioned in our paper:

1. Synthesizing imatinib as its free base, a compound that was patented in the US, EU and several other countries. However, this could not be patented in India, owing to the fact that in 1993, India did not provide product patents for pharmaceutical substances.

2. Converting the free base to a particular salt form, imatinib mesylate, by adding methanesulfonic acid.

3. Crystallising the imatinib mesylate to obtain the beta crystalline form, which is allegedly the most stable polymorphic form of the salt. A patent application was filed for this and it is this application that is the subject matter of dispute.

4. Formulating the beta crystalline form of imatinib mesylate into a pharmaceutically useful drug, Glivec.

The main issues in this appeal

Anticipation of the beta-crystalline form of Imatinib Mesylate

One of the reasons for the rejection of Novartis’s patent application was the Patent Office’s conclusion that the ‘beta-crystalline form of Imatinib Mesylate’ was anticipated by the ’93 US Patent 5521184 as also a patent term extensions certificate issued by the USPTO which specifically mentions Imatinib Mesylate as the product. At pre-grant stage Novartis had unsucessfully attempted to argue that this patent covered only the Imatinib free base and that the beta-crsytalline form of Imatinib Mesylate was not obvious from a reading of the ’93 patent. We have noted at p.22 of our article that:

“It is interesting to note that the international search report for a PCT application claiming the beta crystalline form (filed on 16^th July, 1998 and claiming a priority date of 18^th July 1997) suggested that imatinib mesylate is anticipated from the ‘184 patent (filed in 1993 in the US):

“Methanesulfonic acid addition salts of the present compound….are disclosed in D1(D1: US Patent Application)….However, no mention is made of a particular crystalline form of the monomethanesulfonic acid addition salt of said compound. The novelty of the present claim can therefore be acknowledged.”

In other words, while imatinib mesylate may be “known”, the same cannot be said for the beta crystalline form of imatinib mesylate.

The LC reports that Mr. Shanti Bhushan has approached this issue from the angle of ‘selection patents’ and has only warmed up the Bench by discussing the basics as laid down in an EIPR article.

[Julian Jeffs, “Selection Patents”, 1988 European Intellectual Property Review 10(10), 291–296].

“Quoting from the article, he said that a selection patent involves the selection for a useful and special property of a particular compound or class of compounds.” By broaching on the topic of ‘selection patents’ it appears that Novartis will attempt to argue that although the beta-crystalline form was as obvious from the ’93 patent as several other salt groups, it still deserves patent protection for narrowing down on the beta-crystalline form and discovering those special properties of the beta-crystalline form which were not obvious from the prior art on the subject.

Putting it simply: it is broadly known as to what will be the various salt groups that will result from the addition of a particular acid and a person skilled in the art usually know the properties of these various salts. Such a disclosure from a prior patent is referred to as enabling disclosure. However if in case the inventor discovers a special property, in one of the salts, which was not obvious from the prior art then in that case he is entitled to patent protection for his efforts in selecting that one salt and testing it to get the unexpected results. Although such protection is at times controversial it is thought necessary in some quarters to grant such incentives failing which the inventors will lack an incentive to explore these various salts.

Mr. Bhushan has not seemed to have go into much detail into ‘selection patents’ at this stage and will probably do so at the later stage.

The standard of ‘efficacy’ demanded by Section 3(d)

Section 3(d) of the Patent Act grants patent protection to only those new forms of known substances which demonstrate an increased efficacy. The LC website reports that Mr. Bhushan argued that the beta-crystalline form of imatinib mesylate was 30% more bioavailable, thermo-stable at room temperature and less hygroscopic than other forms of imatinib and imatinib mesylate,he said that these advantageous properties made the beta-crystalline form more efficacious. He added that for cancer drugs, which are attendant with serious side-effects, such increase in bioavailability was crucial as it meant that a greater quantity of the drug could reach the target site with the same or lesser dosage. The bench however observed that the term “efficacy” has a fixed understanding in the pharmaceutical field and asked Mr. Bhushan to provide documents to support his explanation of efficacy.

At the pre-grant stage the patent office held that Novartis had failed to demonstrate increased efficacy in this case. The pre-grant opposition order of the patent office notes that:

As per the affidavit the technical expert has conducted studies to compare the relative bioavailability of the free base with that of beta crystalline form of imatinib mesylate and has said that the difference in bioavailability is only 30% and also the difference in bioavailability may be due to the difference in their solubility in water. The present patent specification does not bring out any improvement in the efficacy of the beta crystal form over the known substances – rather it states the base can be used equally in the treatment of diseases of in the preparation of pharmacological agents wherever the beta crystal is used. Even the affidavit submitted on behalf of the Applicant does not prove any significant enhancement of known efficacy.

In this regard I reproduce an extract, from p.9 of our paper, below:

“As can be seen from the above, the decision of the patent office is not very illuminating and the patent controller did not give any detailed reasons as to why he thought the beta crystalline form lacked enhanced “efficacy.” The following questions remain unanswered.

1. What did the term “efficacy” mean? Did it connote only “therapeutic efficacy”? Assuming this is the case, would “bioavailability” qualify? Would advantages such as heat stability and increase in manufacturing efficiency qualify?

2. What would constitute a “significant enhancement in efficacy” under the Explanation to section 3(d)? Would a 30% increase in bio-availability suffice?”

What should qualify as the ‘known’ substance against which the comparison under section 3(d) ought to be made?

“In the case at hand, would the “known” substance be the imatinib free base (in relation to which it is far easier to show increased efficacy) or the later salt, imatinib mesylate? Or the alpha crystalline form of imatinib mesylate?” In an earlier post Shamnad had discussed how the Patent Manual had attempted to pre-judge the matter by expressly stating at para 4.5.3 that: “The examiner makes comparison with regard to properties or enhancement of efficacy between the known substance and the new form of known substance. In case the new form is further converted into another new form, the comparison is made between the already existing form and another new form but not between the base compound and another new form.” At the IPAB, Novartis is arguing against this proposition by demanding that the comparison be made between the free base and the beta-crystalline form. It would be interesting to see the stand taken by the IPAB especially since the Patent Manual does not have the force of the law and is merely an indicator of patent office practices.

Can Novartis introduce new expert evidence in front of the IPAB?

The LC reports that Mr. Anand Grover has objected, strongly, to the introduction of new expert evidence at the appellate stage. Technically he does have a point since expert evidence should typically be introduced only at the trial stage where it can be adequately cross-examined by the opposing party. It remains to be seen how exactly the Bench rules on this point. So far the LC has put up proceedings for only the 17^th of November. We’ll continue to bring you updates on this case: so do watch this space.