The Patent Office in a recent post grant opposition proceeding brought by Cipla against Pfizer / Sugen’s patent on the drug Sunitinib, revoked Indian patent IN209251. The drug Sunitinib is used to treat diseases caused by abnormal protein kinase activity. Interestingly the patent was revoked primarily on the ground that it lacked an inventive step (Section 2(1)(j)). Pfizer / Sugen had earlier succeeded in defending a compulsory license (CL) proceeding earlier for the same patent. The CL proceeding was withdrawn by Natco. Shamnad had blogged about it here. Long post follows.
It is my opinion that the Controller’s reasoning in issuing this revocation suffers from hind-sight bias. Under the test laid down to determine obviousness when combining multiple references, is that there should be a teaching or motivation in the references themselves for the combination. From the references cited, it is clear that there is no such motivation. In the chemical arts, even a slight variation can cause a diametrically opposite result. Even if it is assumed that there is motivation to combine, the sheer number of possibilities (between places and substituents is staggering!) excludes the result that it was obvious to combine references. (Replace substituent X at place Y to reach the claimed result).
Brief Facts: Cipla had used four basic grounds to oppose the patent: (a) claimed invention was publicaly used in India before priority date of claim; (b) invention as claimed is obvious and did not include an inventive step; (c) subject matter of any claim of the patent is not an invention within the meaning of the [Indian patent] Act; and (d) patentee failed to disclose information as required under section 8 of the patent act.
Issues: The opponent cited three documents to show lack of inventive step (or obviousness) in the granted patent. These were US 5886020 (D1); WO/98/50356 (D2) ; and WO/99/61422 D3). According to Cipla, document D1 disclosed an extremely similar structure as compared to the granted claims. In particular, the compound as described in D1 possess an amide substituent at position 4 of a pyrrole ring, as well as D1 teaches an amide function at the 4 position of the pyrrole ring. Additionally, D1 also taught compounds that were useful to treat unregulated TKS transduction / cancer. Hence it would have been obvious to one of ordinary skill in the art, to experiment with replacing an alkyl substituent with something similar and possessing similar qualities. Simialarly document D2 also disclosed similar compounds (to the granted patent) where an alkyl substituent could be replaced. A similar argument was made for D3.
The main thrust of the opponent was that under the current standards of tests to determine the patentability of a chemical compound, obviousness of a new chemical compound proceeds through two stages. First, is there a prior art compound sufficiently close in structure to the claimed compound to suggest that the claimed structure would have the same properties? If the answer is negative, then the inquiry is completed: There is no obviousness for such a compound. But, as is the case in the present alleged invention claimed by the patentee, there is a high degree of predictability of properties of a compound keyed to structure, such that the disclosure of a prior art compound suggests that the claimed compound can and should be synthesized to achieve like results.
Here, Cipla argued that because the claimed compound is prima-facie obvious – based upon the concept of “structural obviousness”. Where there is a. prima facie obviousness case based upon closeness of structure, then it was incumbent upon the patentee to demonstrate that there are actual differences between the claimed compound and the prior art such that the invention as a whole is non-obvious. ….. A claim for unexpected results require to be supported by data based evidence and that unsupported allegations cannot support a claim of inventive step.
The patentee sought to distinguish the claims from the cited prior art documents. In particular, it discussed that the basic backbone or core of the compounds as disclosed by Dl is an indolinone and not a pyrrole substituted indolinone compound. Therefore, Dl did not envisage pyrrole substituted indolinone compounds as disclosed by the patent and specifically Dl did not recognize the advantages of attaching a pyrrole substituent at the 3rd position of the indolinone ring.
The patentee, in my opinion, correctly countered the ground of lack of inventive step by attributing it to an-post facto analysis (or hindsight bias). There was no teaching or support in either D1 or D2 or D3 to combine the results and reach the patented claims of the current patent. But this was not enough. Even though document D2 was dropped by the opponent, an affidavit tendered by an expert (of the opposition) was considered by the Controller.
The affidavit submitted on behalf of opponents stated “Sunitinib is a novel tyrosine kinase inhibitor and is therapeutically potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST)”. It is apparent from this affidavit that the metabolization occurs at the terminal N atom and not at the position of the (Alkl) group. Therefore I observe that the disclosures in Dl or D2 could be modified to introduce the polar group Z as taught by D3 to formulate a compound which does not possess the (Alkl) group but retains the protein tyrosine kinase inhibitory activity.”
Conclusion: Therefore, the Controller held that the invention claimed in the impugned patent under opposition is obvious over Dl in view of D3 and also over D2 in view of D3. The Controller specifically held, “the patentee has miserably failed to demonstrate any improved activity of the claimed compound over the compounds of the prior art which is the sole basis for inventive,step asserted by the patentee. The only logical conclusion that can be arrived at from the above comparison of the compounds of the patent vis-a-vis the compounds of the prior art is that the claimed compound has not been shown to involve an inventive step.
Dear Rajiv,
I have reviewed this order. I note that on page 24, Table 5 and page 30, Table 7 of the decision, the Patentee has compared their main comound, i.e. compound of Example 80 with three structrually closest compounds of D1 and two structrually closest compounds of D2. These tables shows that Patentees, preferred compound of Example 80 has IC 50 value of 0.001 micromolar as comparaed to more than 100 micromolar and 15 micromolar values of D1 and D2 compounds, respectively. It shows that Patentee had tried to demonstrate 1,00,000 times more activity of Example 80 compound w.r.t. compounds of D1 and 1500 times more activity over compounds of D2.
It appears that these data were also filed during prosecution and controller allowed this Patent after considering enhanced efficacy data of claimed compounds over D1 and D2.
To me, it is absurd on the part of Controller to say that patentee has miserably failed to demonstrate any improved activity of the claimed compound over the compounds of the prior art.
It appears that Controller has wrongly placed the entire onus on the Patentee.
It appears that the concerend Controller of Patents had sought comparative efficacy data when Section 3(d) of the Act was not in issue and even though it is not a pre – requisite for establishing inventive step.
In a nutshell, it appears to be an errorneous order.
Dear Rajiv,
I agree with the previous comment. In fact, the Controller has not properly analysed the prior art documents. Especially in chemistry even small change in the substituents results in unexpected properties / effects.