In a well-reasoned order, the Indian Patent Office dismissed two pre-grant oppositions filed by Indian Pharmaceutical Alliance (first opponent) and Pankaj Kumar Singh (second opponent), against Immunogen Inc.’s Indian Patent Application no. 885/CHENP/2008. The application was opposed on the grounds of lack of novelty, lack of inventive step, lack of utility, non-patentable subject matter u/s 3(d), lack of clarity and sufficiency, failure to disclose information u/s 8 and failure to disclose or wrongful disclosure of biological material used for the invention.
(a) The application relates to a process for preparing antibody-maytansinoid conjugates comprising the steps of antibody modification by contacting the antibody with a bifunctional crosslinking reagent to covalently attach a linker to the antibody and thereby prepare a first mixture comprising antibodies having linkers bound thereto,
(b) Purification of first mixture by subjecting the first mixture to tangential flow filtration, selective precipitation, adsorptive filtration, or adsorptive chromatography and thereby prepare a purified first mixture of antibodies having linkers bound thereto,
(c) Conjugating maytansinoid to modified antibody in the purified first mixture by reacting the antibodies having linkers bound thereto with a maytansinoid in a solution having a pH of 4 to 9 to prepare a second mixture comprising (i) an antibody chemically coupled through the linker to the maytansinoid, (ii) free maytansinoid, and (iii) reaction by-products produced during step (c), and
(d) Purification of second mixture by subjecting the second mixture to tangential flow filtration to purify the antibodies chemically coupled through the linkers to the maytansinoid from the other components of the second mixture and thereby prepare a purified second mixture of antibodies chemically coupled through the linkers to the maytansinoid.
The advantage of this process was stated to be the use of tangential (TFF) flow filtration for removal of impurities from the second reaction mixture. TFF is easier to scale up and is also more economical as compared to non-adsorptive chromatography.
Some key findings of the Controller are as follows:
On the ground of novelty the Controller concluded that none of the documents cited by the first Opponent disclosed the invention claimed in Immunogen’s application. Particularly, none of the documents disclosed the use of TFF for purification of the antibody-maytansinoid conjugates as claimed in the step-d) of Immunogen’s application.
Furthermore, noting that the second opponent had admitted to the novelty of the claims of Immunogen’s application during the hearing and had not argued said ground, the Controller rejected all arguments submitted by the second opponent in their hearing submissions. The Controller held that written submissions must be based on the matter argued in the hearing.
The Controller observed that there was no dispute on the knowledge of TFF technique on the priority date of Immunogen’s application. He noted that documents D1 and D2 which related to antibody-maytansinoid conjugates and D4 which related to antibody-effector conjugates were the only relevant documents as the remaining documents either discussed the technique of TFF or concentrating solutions using TFF in their respective field of technology.
The Controller assessed:
- If TFF was known, why did the inventors of D1 use TFF only in step (b) but not in step (d) of the process?
- If TFF was known, why did the inventors of D2 use TFF only to concentrate the antibody conjugate but used Sephadex G-25™ column to separate the unreacted maytansinoids from the antibody conjugate?
- Why was D4 silent on maytansinoids?
The Controller concluded that the inventors of D1, D2 and D4 did not find TFF relevant for use in the purification of antibody-maytansinoid conjugates. Disagreeing with the Opponent’s generalized conclusion that since TFF was known for purifying or concentrating antibody use of the same for purification of antibody-maytansinoid conjugates would be obvious, the Controller held that there is no prior teaching that TFF can be used for the purification of antibody-maytansinoid conjugates. The invention was therefore, held to be non-obvious over the cited documents.
Non patentability u/s 3(d)
The Controller noted that the word ‘mere use of a known process’ implies that the known process should have been used as such without any change and held that section 3(d) does not apply in view of the novelty and inventive step of the claims.
The second opponent argued that the invention claimed in Immunogen’s application was a selection invention- a ground that was not pleaded by them. At the outset the Controller held that arguing a ground at the hearing stage without pleading is not permissible. The Controller further concluded that the invention claimed was not a selection as the application of a known technique like TFF in the antibody-maytansinoid conjugate process of the invention was inventive. The Controller further held that the pH used during the conjugation of the antibody and maytansinoid in step (c) was also important since it had its own advantages and was different from the pH for the same step taught by the cited documents. Accordingly, this ground of the Opponent was also dismissed.
Agreeing with the Applicant’s submissions, the Controller also dismissed the grounds of lack of utility, lack of clarity and sufficiency, failure to disclose information u/s 8 and failure to disclose or wrongful disclosure of biological material and granted a patent.