India: Indian Patent Office Rejects Bayer’s Tosylate Salt Form Of Drug Sorafenib

On 24th February 2015, the Indian Patent office refused Bayer Healthcare AG'S attempt to patent tosylate salt form of its anticancer drug Sorafenib, known under the brand name Nexavar. The application had earlier been opposed through 2 pre-grant oppositions – by generic pharmaceutical company NATCO and as well as by Fresenius Kabi Oncology Ltd1.


Bayer Healthcare filed an application for patent with application number 1960/DELNP/2007 IN Delhi Patent office on March 14, 2007 entitled "THERMODYNAMICALLY STABLE FORM OF A TOSYLATE SALT". The Applicant amended the set of claims in reply to FER on 4th March, 2014. Subsequently two pre-grant oppositions were filed against this application, first one by NATCO Pharma Limited, Hyderabad and second one by Fresenius Kabi Oncology Limited, Gurgaon.


Ground I: Section 3(c): Claims 1-18 drawn to polymorphic forms of 4-{4-[({[4-chloro-3-trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy}-N-methyl pyridine-2- carboxamide also known as Sorafenib is a known compound from WO 00/42012, WO 03/068228 and WO 03/047579.

Section 3(d): Claims 1-18 drawn to polymorphic forms of 4-{4-[({[4-chloro-3-trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy}-N-methyl pyridine-2- carboxamide also known as Sorafenib is a known compound. The alleged invention of polymorphic form I, as claimed, is not supported by any examples or any other data of enhanced efficacy over that of known substances, including the metastable form. Moreover the process for the preparation of Sorafenib tosylate polymorph I as claimed in claims 2-4 neither involve any new reactant nor result in any new product. Thus the claimed invention falls within the scope and mischief of Section 3 (d).

Section 3(e): Claims 7, 8 and 12 and 15-18 are drawn to a pharmaceutical compositions, the composition comprises of the polymorphs of claims 1 along with a pharmaceutically acceptable excipient. But as there are no examples to shoe their synergism, the composition is called a mere admixture.

Section 3(i): Claims 5-6 and 9-11 correspond to method of treatment and are not patentable under sec 3(i).

Ground II: Section 25(1) (b)/(c): None of the claims of 1960/DELNP/2007 are novel.

Ground III: Section 25(1)(e) Lack of inventive step

1. The conversion of one polymorphic form to another polymorphic form is well known in prior art.

2. The use of the inert solvent and seeding technology for the conversion one polymorphic form to another polymorphic form is known from the prior art.

Hence, the process of conversion of polymorphs and the resultant polymorphic form is well known from prior art.

Ground IV: Section 25(1)(f), 2(1)(ja): The invention is devoid of inventive step.

Ground V: Section 25(1)(g): Complete specification of 1960/DELNP/2007 does not describe the invention claimed or the method by it is performed.

Ground VI: Section 25(1)(h): The applicant has failed to furnish the details of National Phase applications filed in USA, Europe, etc which are still under examination and not granted.


Section 25(1)(b) Novelty/Anticipation: The invention so far claimed in any claimed of the complete specification has been published before the priority date of the claim.

Section 25(1)(d) Prior Knowledge/Prior Use: That the invention so far as claimed in any claim of the complete specification was publicly known or publicly used in India before the priority date of that claim.

Section 25(1)(e) Obviousness/Lack of inventive step: That the invention so far as claimed in any claim of the complete specification is obvious and clearly does not involve any inventive step, having regard to the matter published as mentioned in clause (b) or having regard to what was used in India before the priority date of the applicant's claim.

Section 25(f) Not Patentable subject matter: That the subject of any claim of the complete specification is not an invention within the meaning of this Act, or is not patentable under this Act.

Section 25(1) Insufficient Disclosure: That the complete specification does not sufficiently and clearly describe the invention or the method by which it is to be performed.


Bayer Healthcare refuted all the grounds of oppositions raised by both the opponent companies. The Applicant argued that the polymorphic form I of the tosylate salt of Sorafenib as claimed in the present application is not disclosed in any of the earlier cited documents by the Opponents. It also further submitted that the complete specification of the patent application sufficiently and clearly described the invention as well as the method by which it is to be performed and the opponent's objection on this ground as well should be rejected out rightly.


Ground I (Section 3(C)): With regards to this ground the Assistant Controller concluded that the document WO 00/42012 relates Sorafenib base & does not describe any polymorphic form of sorafenib tosylate salt. Though the documents WO 03/047579 and WO 03/068228 describe a tosylate salt of sorafenib but as such there is no mention of any polymorphic form. Therefore, this ground is not validly established by Opponent. Further, the polymorphic forms of Sorafenib tosylate are sufficiently and clearly described in the description in the tables 2 to 6 by X-Diffractometry, IR Spectroscopy, Raman Spectroscopy and NIR Spectroscopy. Hence the ground II (Section 25(1) (g)) Insufficient Disclosure is not validly established by the Opponents.

With regards to Section 3(e) the Controller concluded that the claims of the present lack inventive step on the basis of cited documents, the combination or composition claims does not have any relevance and are not patentable under Section 3(e) of the Patents Act 1970. The Controller further acknowledged that the present invention is novel as the document WO 00/42012 does not describe any polymorphic form of sorafenib tosylate salt. WO 03/068228 and WO 03/047579 describe a tosylate salt of sorafenib but without any specification of the polymorphic form. Further, none of the prior art mentioned the use of any polymorphic form of sorafenib tosylate, nor does any concrete evidence provided by the opponent for prior use of the polymorphic form I of sorafenib tosylate. Therefore, the grounds of opposition under section 25(1) (d) (Prior use) were not validated by the Controller.


The Applicant had mentioned in their arguments that there is a need to find the most stable form of a compound because only the most stable form can ensure that all properties and characteristics regarding stability, dissolution rate, shelf life, efficacy and bioavailability remain constant during manufacturing, storage and administration. The applicant addresses the problem by providing a polymorphic form I of sorafenib tosylate which is surprisingly more stable than the other polymorphs found and ensures a constant and reliable efficacy, therapeutic or otherwise. The Controller had pointed that combining the teachings of the cited documents of the prior art for a skilled artisan, it is a clear cut motivation to prepare stable polymorphic form of sorafenib tosylate as claimed in the impugned patent with enhanced properties with reasonable success by combing the teachings of the references as mentioned in the cited documents no inventive step resides in the same. For the contentions raised by Fresenius Kabi Oncology Ltd, the Controller stated that stirring or shaking and seeding technology is very well known in prior art can be used top prepare a thermodynamically stable polymorph. By combing the teachings of the annexed documents, a skilled artisan could practically arrive at a process of converting one polymorph to another using the already mentioned solvents in the prior art. Thus the Controller concluded that claims of the present invention lacked inventive merit.

With regards to Section 3(d), the Controller opined that the invention failed to demonstrate therapeutic efficacy and therefore fails to fulfill the requirement of patentable invention u/s 3(d) of the patents Act. Further, the Controller noted that the Applicant has creatively attempted to escape liability by furnishing the required details at the last moment and filing a petition for obviation for delay. Therefore, in the present case the Applicant has failed to comply with the provisions of Section 8(1) of the Patents Act.


After considering the representation and expert evidence of opponents, reply of the Applicant, expert evidence in support of the applicant, written submissions and arguments in the hearing made by both the parties, the Controller refused the application 1960/DELNP/2007 on the ground of lack of inventive step (Section 2(1)(ja), Section 3(d),Section 3(e) and Section 25(1)(h) of the Patents Act, 1970.



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