Cancer drug (Enzalutamide) Patent application refused

5 Oppositions were filed against Indian patent application No. 9668/DELNP/2007 covering the drug product Enzalutamide and the same have been decided by Controller Umesh Chandra Pandey in an order dated 8th November 2016. The Controller has refused the application and held that the invention though is novel however the same lacks inventive step and is not patentable under section 3(d) and 3(e) of the Act.

 The claims of the application were directed to Enzalutamide. Claim 2 and 3 were directed to a composition and method of preparation of the same compound respectively.  The main highlights of the decision are as follows:-

Novelty: As per the Controller none of the cited documents specifically discloses the structure of the compound as claimed in either a claim or in an example and therefore the same is novel. Rather a person has to pick some suitable substituents from the definition given in markush structure as given in prior art and suitably put them to arrive at the structure of the claimed compound, Enzalutamide. This type of picking and putting is not allowable to ascertain the Novelty of the claimed invention.

Inventive step:  US’981, one of the prior art cited by the Opponent discloses a compound of example 15 which is represented herein below

1.png

The difference between the compound of example 15 and Enzalutamide is FLUORO-N-METHYLBENZAMIDE at 1st Nitrogen of thiohydantoin moiety.

Another cited document, J Med Chem. 2004 Jul15;47(15), 3765-16, (D1) motivates the selection of fluoro-N-methylbenzamide. Although D1 does not talk about methylcarbamoyl group instead it suggested acetamido group which is different than the methylcarbamoyl group. But the controller accepted the Opponents argument, that D1 suggests that, only a moderately sized group can be accommodated specifically at para position. Further, D1 suggests that groups such as acetamido (molecular formula C2H4NO) can be favored. Therefore, in view of teachings of D1 the applicant has selected aryl ring substituted with methylcarbamoyl specifically at para-position.

The controller also held that the invention is obvious when US’981 is seen in view of US’257 in combination with D1. The controller also considered US’257 which describes a compound of the formula as shown below:

2

Taking in view of teachings of D1 a person skilled in the art will think of replacing the moiety sown in rectangle of US’257 compound with hydrogen attached to N of hydantoin moiety of the compound 15 of US’981. The invention was therefore considered as obvious.

Section 3(d): As per the Controller the claimed compound Enzalutamide is lacking novelty and inventive step and therefore the said compound is a new chemical entity is not acceptable and falls under section 3(d)

Section 3(e): As per the Controller invention fails to show any surprising synergistic effect when the said compound is used as a composition. Therefore opponent’s objection regarding section 3(e) of Patent Act is found to be acceptable.

Lack of Sufficiency: As per the controller the impugned invention has been sufficiently disclosed in the patent application. Enzalutamide is specifically disclosed as Example 56 and its process for preparation is also disclosed. Data for Enzulatamide has been given in the specification and also in-vivo data has been provided in clinical trials.

Requirement of Section 8(1) and 8(2) was complied on different dates by filing the information about filing detail in other jurisdiction.

An objection was also raised by one of the opponents on insufficient fees for the claims paid at the time of filing of the application. But the controller held that at the time of entering in to the national phase the applicant may delete the claims and pay fees for less claims. In this regard reliance on honorable IPAB decision 17 of 2013 was made by the applicant. Moreover as per the amendment Rules 2006 and new rule 20(1) the patent application may be filed by deleting the claims form the claims filed in PCT application. The Controller therefore rejected this ground.

Second generation Tygacil granted a Patent

The Indian Patent Office issued its order dismissing two pregrant oppositions filed by NATCO and Lupin against Wyeth for their commercial product, Tygacil.

The application claims a composition comprising: (a) tigecycline; (b) a carbohydrate chosen from lactose, mannose, sucrose and glucose; and  (c) and an acid or buffer, the molar ratio of tigecycline to the said carbohydrate is between about 1:0.2 to about 1:5 and the pH of the composition is between 3.0 and 7.0.

The Controller opined that the application claims a second generation formulation with selective carbohydrate at a low pH with tigecycline. Experimental results in the specification point to epimerization of tigecycline in presence or absence of lactose and also show that in presence of lactose, the epimerization of tigecycline is less and therefore tigecycline is stabler.

The Controller therefore held that the formulation of the instant invention is not a mere admixture but shows synergism /surprising result and therefore cannot be held under section 3(e) of the Act . The results are not predictive from prior art and hence it is inventive too.

The Controller also held that the composition claim does not attract section 3(d) and in this regard relied on the decision of the IPAB in Allergan Inc. Vs. Ajanta. section 3(d) of the Act considers the following not Patentable: –

“(d) the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.

Explanation.—For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy;”.

The Controller held that the combination mentioned in the explanation of section 3(d) can only mean a combination of two or more of the derivatives mentioned in the Explanation or combination of one or more of the derivatives with a known substance which may result in a significant difference in efficacy. The claimed composition of the instant invention cannot be stated to be a new form of a known substance and therefore does not attract section 3(d).

The order also discussed legal issues, and in particular discussed if a delay of 28 days to file the reply statement and evidence when considering rule 55(4) of the Patent rules should be condoned. The Controller held that the applicant desired to contest the opposition to safeguard their rights (they timely filed a petition for extension of time and correction of irregularity) and for only a little late in filing the reply statement and evidence, and it would not be proper to debar them to contest on this highly technical issues and that will be against the natural justice.