Stay tuned for detailed analysis of the order!
Controller Nilanjana Mukherjee on 7th November 2016 allowed two applications of Pfizer Ireland (2315/DELNP/2007 (IN 2315) and 2317/DELNP/2007 (IN 2317)) covering their commercial method for production of Etanercept, dismissing Oppositions filed by Biocon Ltd. (1,2), and Mylan Laboratories Ltd (1,2).
The claims currently on record in respect of Indian patent application no. 2315/DELNP/2007 are directed to production of Polypeptide, and claim 1 reads as follows:
A method of producing a polypeptide in a large-scale production cell culture comprising the steps of:
roviding a cell culture comprising;
mammalian cells that contain a gene encoding a polypeptide of interest, which gene is expressed under condition of cell culture; and
a medium containing glutamine, having a cumulative amino acid amount per unit volume greater than 70 mM, a molar cumulative glutamine to cumulative asparagine ratio of less than 2, and wherein the cumulative total amount of histidine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, and proline per unit volume in said medium is greater than 25 mM;
maintaining said culture in an initial growth phase under a first set of culture conditions for a first period of time sufficient to allow said cells to reproduce to a viable cell density within a range of 20%-80% of the maximal possible viable cell density if said culture were maintained under the first set of culture conditions; changing at least one of the culture conditions, so that a second set of culture conditions is applied;
maintaining said culture for a second period of time under the second set of conditions and for a second period of time so that the polypeptide accumulates in the cell culture.
The observation of the controller in respect of the grounds raised by the opponents are as follows:-
- Novelty:- There is neither an unambiguous, clear and direct disclosure of the claims nor all the features claimed are present in the same order in any prior document. None of the prior art documents are in relation to a method for the large/ commercial scale production of polypeptides; the combination of medium characteristics recited in the claims; change in culture conditions when the viable cell density is in the range of 20-80% of the maximal possible viable cell density.
- Inventive step: The Controller considered the method to be inventive as she found that there was no teaching, suggestion or motivation in any of the prior art documents either alone or in combination to arrive at the method claimed; the significance of the cumulative amino acid amount per unit volume being greater than 70mM; molar cumulative glutamine to cumulative aspargine ratio less than 2; cumulative total amount of histidine isoleucine, leucine, methioxine, phenylalanine; tryptophan, tyrosine and proline per unit volume of greater than 25nM. The calculations of the cumulative value claimed made by the opponent were incorrect according to the controller as stated by the inventor and were based on hindsight.
- Section 3(d): The Controller held that Section 3(d) is not attracted as the claims of IN 2315 are not in relation to a new use of a known process but is a combination of several features and aspects of each step and parameters disclosed therein.
2317/DELNP/2007 relates to an improved process for large scale production of TNFR-Ig that allows high level of protein production and lessens the accumulation of undesirable factors and/or lactate. The main culture conditions according to the claim 1 and highlighted by the Applicant are:
(a) The following media characteristics:
(i) cumulative amino acid amount per unit volume being greater than 70mM;
(ii) molar cumulative glutamine to cumulative asparagine ratio less than 2;
(iii) a molar cumulative glutamine to cumulative total amino acid ratio of less than 0.2;
(iv) a molar cumulative inorganic ion to cumulative total amino acid ratio between 0.4 to 1;
(v) a combined cumulative amount of glutamine and asparagine per unit volume of greater than 16 mM or a combination thereof; and
(b) that the cell culture is maintained in an initial growth phase for a first period of time to allow the cells to reproduce to a viable cell density between about 20% to 80% of the maximal possible viable cell density under the first set of culture conditions; Thereafter, there is a culture shift in the condition, where at least one of the culture conditions to a second set of culture conditions and maintaining the said culture for a period of time under the second set of conditions so that the polypeptide accumulates in the said culture.
The highlights of the decision are as follows:-
- Novelty: The controller held that there is no disclosure with regard to the media characteristics and the change in culture conditions from the first set to the second set conditions as claimed. Therefore, the claims of the Indian Patent Application No. 2317/DELNP/2007 do not lack novelty. Also, the calculations of the Opponent were considered to be incorrect.
- Inventive step: The controller held that the prior art does not teach or suggest the medium and cultural characteristics outlined by claims of IN ‘2317. The prior art does not disclose the significance of any media characteristics, asparagine or its significance, the importance of glutamine and the fact that the process of IN ‘2317 can be scaled up. The controller therefore was of the opinion that none of the prior art documents either alone or in combination teaches or motivates a person skilled in the art to arrive at the invention claimed by IN ‘2317.
A ground of double patenting was also raised during the hearing in respect of the two applications 2315/delnp/2007 and 2317/delnp/2007, however the controller also dismissed said ground as she considered that the scope covered by applications 2315/DELNP/2007 and 2317/DELNP/2007 are different. The inventions claimed in 2315/DELNP/2007 and 2317/DELNP/2007 are patentably distinct and do not involve any issue of ever greening or double patenting. In 2315/DELNP/2007, three specific media conditions are needed in the method of production of polypeptides whereas in 2317/DELNP/2007 specific media characteristics and their combinations in methods for the production of TNFR-Ig have been claimed in 2317/DELNP/2007.
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.