In its latest rejection of a pharmaceutical patent, on March 4 2015 the Patent Office rejected Patent 254813, granted to Boehringer Ingelheim Pharma Gmbh, in a post-grant opposition initiated by Cipla.

The patent related to "crystalline tiotropium bromide monohydrate and process thereof” for the treatment of conditions such as chronic obstructive bronchitis and asthma, and was granted in 2012. The patent was rejected for lack of inventive step and for not being patentable under Section 3(d) of the Patents Act 1970.

Interestingly, the patent had previously survived a pre-grant opposition initiated by Intermed Labs. Further, some of the prior art documents cited in the post-grant opposition had also been cited in the pre-grant opposition, and the patentee was able to overcome objections relating to inventive step and Section 3(d) of the act in respect of such prior art documents.

The pre-grant opposition was determined by the deputy controller, while the post-grant was decided by the assistant controller. Both offices exercise power on behalf of the controller and thus are considered to be on the same legal footing. Therefore, it is interesting to compare the patentee’s failure at post-grant stage as compared to its success at pre-grant stage.

Order
The two independent claims in issue were as follows:

"1) Crystalline tiotropium bromide monohydrate characterised by an endothermic peak at 230 ± 5°C occurring during thermal analysis using DSC, at a heating rate of l0K/mm.

4) Process for preparing crystalline tiotropium bromide monohydrate as claimed in one of claims 1, 2 or 3, wherein the said process comprises following steps;

(a) tiotropium bromide is taken up in water,

(b) the mixture obtained is heated,

(c) activated charcoal is added

and

(d) after the removal of the activated charcoal, tiotropium bromide monohydrate is slowly crystallised with slow cooling of the aqueous solution."

Inventive step

The patent was found to lack inventive step by a mosaic of prior arts. Document D4 cited in the opposition, published in 1995 and used to invalidate the product claims, and Document D7, published in 1994 and used to invalidate the process claims, did not refer to tiotropium bromide. The assistant controller rejected the patentee’s argument that these prior art documents were irrelevant:

The position of the patentee that non-analogous prior art is irrelevant while judging obviousness is incorrect since all knowledge before the priority date of the patent which is not specific to this field will be held to constitute common general knowledge.

With regard to the question of common general knowledge, the decision rendered by the Technical Board of Appeals in Case T777/08 (Atorvastatin Hydrate) was important. In that decision the Technical Board of Appeals concluded that the following were matters of common general knowledge as of 1995:

  • The skilled person would know that polymorphism is commonplace in molecules of pharmaceutical interest.
  • The skilled person would also know it to be advisable to screen for polymorphs early on in the drug development process.
  • The skilled person would be familiar with routine methods for screening for polymorphs by crystallisation from a range of different solvents under different conditions.
  • The skilled person would be aware that crystalline forms have several physical and chemical advantages over amorphous forms.

Based on these findings, the Technical Board of Appeals arrived at the following conclusions:

"it was... obvious to try [obtaining the crystalline form] with a reasonable expectation of success without involving any inventive ingenuity...

The appellant further argued that the presence of an inventive step was supported by the fact that a specific polymorph was being claimed rather than crystalline forms in general… However, an arbitrary selection from a group of equally suitable candidates cannot be viewed as involving an inventive step."

This decision appears to suggest that, even as of 1995, merely obtaining crystalline forms and polymorphs may not be sufficient; instead, it may be necessary to highlight that one specific polymorphic form shows unexpected properties in comparison to the other possible polymorphic forms. The order in the case at hand did not show that such comparison among the various possible polymorphs was on record or relied on. Perhaps such data might have come to the rescue of the patentee in proving inventive step. Instead, the assistant controller observed that:

"After complete reading of the specification, it is clear that the applicants had failed to provide sufficient comparative data for any unexpected surprising advantageous technical effects verified in the description over the closest prior.

Section 3(d)

The explanation to Section 3(d) states that a polymorph of a known substance is deemed to be the same substance unless shown to differ significantly in properties with regard to efficacy. With respect to the objection under Section 3(d) of the act, the assistant controller observed:

The impugned patent relates to the crystalline tiotropium bromide monohydrate which is a polymorph of tiotropium bromide, however there was no disclosure in the specification as to enhancement in the therapeutic efficacy as compared to its structurally similar compounds i.e. tiotropium bromide as cited in document D3.

From the perspective of a person skilled in the art, solvation and hydration products are considered to be polymorphs (specifically pseudopolymorphs) (ICH Harmonised Tripartite Guideline, Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances, page 8). All references to the improved physical stability and other physical properties were considered irrelevant to the analysis. Although the assistant controller was potentially willing to consider the efficacy of drugs of this nature in terms of the forced expiratory volume of the lungs within one second, the assistant controller observed that this was not supported by clinical trials or research data.

There was also some data on record (part of the pre-grant opposition) suggesting that the percentage and amount of the particles reaching the lungs were higher. However, citing the Supreme Court’s decision in Novartis v UOI ((2013) 6SCC1), the assistant controller observed that this did not necessarily imply any increased therapeutic efficacy.

Comment

The decision is not the end of the matter and the patentee may appeal. However, the decision on the post-grant opposition, specifically with regard to Section 3(d), shows the lack of definitive guidance on the nature of the evidence required to support an assertion of enhanced efficacy. Only time will provide such necessary guidance.

From the perspective of the more fundamental requirement of inventive step, it is clear that the Patent Office is increasingly inclined towards relying on common general knowledge and, by treating certain information as common general knowledge, the question of relevancy becomes moot.

Malathi Lakshmikumaran

This article first appeared in IAM magazine. For further information please visit www.iam-magazine.com.