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.

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Etanercept applications granted by the IPO

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:-

  1. 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.
  2.  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.
  3.  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:-

    1. 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.
    2. 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.

 

 

Gilead granted a Patent for Sofosbuvir

After a roller coaster ride from the patent office to the High Court and back to the Patent Office, the application for Patent for Sovaldi (Sofosbuvir) has now finally seen the sun. The Indian Patent Office has upheld the patent application of Gilead for Sofosbuvir. The Dy. Controller of Patents and Designs, Mr. Rajesh Dixit, in a 58 page order has found the application for patent to be novel, inventive and outside the prohibitory ambit of Section 3(d).

The Indian Patent office had earlier in January 2015 rejected the same application under Section 3(d) of the Indian Patents Act. Instead of appointing hearings on the pre-grant oppositions, the erstwhile Controller appointed a hearing under Section 15. The Controller did not consider the data on reduced toxicity and rejected Gilead’s patent application under Section 3(d). Gilead had filed a Writ Petition before the Delhi High Court against the Order of the Controller stating that the same was biased and was largely influenced by the opposition filed to the extent that typographical errors in the oppositions filed were incorporated as it is in the order. Gilead further claimed that the order was biased as no opportunity of being heard was given to the Petitioner with regard to the grounds raised in the oppositions. The order was set aside and the matter was remanded back for a fresh hearing by the Delhi high Court.

Dr. Rajesh Dixit heard the matter at length between 23rd to 29th February 2016 and vide an order dated 9th May 2016 reversed the previous order refusing the grant. The following are noteworthy findings in the decision of the Controller:-

(a)             Novelty

1)      The application discloses (2’R)-21-deoxy-2’-fluoro (down)-2’-C-methyl (up) nucleosides, as well as their corresponding monophosphate, diphosphate and triphosphate forms. The claimed compounds require methyl group at the 2’(up) position and a fluorine at the 2’(down) position of the sugar ring, a cytosine or uracil base attached to the sugar ring at 1 position nitrogen in the base ring.

2)     The Controller noted that this substitution is unique and there is neither exemplification  nor enabling disclosure in any of the cited prior art documents, including the closest prior art WO425, of the compounds claimed in the present application. The claimed compounds which have not be exemplified in any prior art cannot be deemed to be a part of the prior art.

3)     Cherry picking of substituents from prior art is not allowed and the substituent in the Markush formulae provided in the prior arts have to be understood in the context of the invention contained in the examples, process for preparation and overall teaching of the document. Arbitrary selection of the substituents to arrive at hypothetical compounds is not possible without hindsight.

(b)            Inventive Step

4)     The Controller held that the compounds enabled by the prior art do not have 2’-fluoro (down)-2’-C-methyl (up) substitution pattern, which has been claimed in the present application. From the teachings of prior art, in particular WO425, it is difficult for POSA to arrive at a substitution pattern as presently claimed. There is no motivation or guidance towards the unique substitution pattern of the compounds of the present application in WO425 or any other prior art document.

5)     A person skilled in the art would not be motivated to select a compound for further research from prior art unless the same is enabled or listed as a promising compound. Selecting a hypothetical compound requires some motive. The opponent has not provided any motivation for selecting said imaginary compound for the inventive step analysis.

6)     POSA was further well aware of the unpredictability of fluorination on drug metabolism and unpredictability of fluorination using reagents such as DAST and substantial experimentation would have been required at the priority date to arrive at the claimed compounds which therefore, cannot be obvious.

(c)             Section 3(d)

7)     The Controller held that the compounds claimed are outside the prohibitory ambit of Section 3(d).

8)     Nucleosides and other analogues are known in the art and in further research in the field there is bound to be similarity in core structure of any new nucleoside analogue invented. This cannot be understood to mean the structural similarity in field of chemistry. Further if such compounds are considered to be structurally similar and a derivative then the issue will be that what would be the known substance against which the enhanced therapeutic efficacy has to be shown.

9)     The compounds argued to be known substances for the present case are hypothetical compounds which are not exemplified. The processes described in the prior art will not lead to the claimed compounds. In other words, the claimed compounds can be visualized in the prior art only by way of hindsight. An applicant cannot be required to make a compound which was not in existence as on the priority date for showing comparative activities.

10)  Further, the claimed compounds are not polymorphs, isomers, salts etc. of a known compound and therefore are not derivatives of any known compounds. The process for the preparation of the claimed compounds shows that the claimed compounds are not derived from compounds having 2’methyl (up) or 2’-hydroxyl (down) substitutions.

11)   In addition, the applicant has provided comparative activity and toxicity data vis-à-vis compounds having 2’methyl (up) substitution and 2’-hydroxyl (down) substitution i.e. 2’-C-methylcytidine and 2’-C-methyladenosine. The drug cover by the claims of the present application has shown excellent efficacy as against all the known medicines for HCV.

(d)            Insufficiency

12)  Though the Opponents argued that the claimed compounds are not sufficiently described in the complete specification this claim has not been supported by any reason. The specification provides examples, schemes of synthesis, experimental data, figures, comparative activity and toxicity data. Therefore, a person skilled in art will able to perform the invention in view of the description of the patent application.

 

IPAB ADMITS APPEALS ON ORDERS ISSUED UNDER NON-APPEALABLE PROVISIONS

In two landmark cases,the Intellectual Property Appellate Board treated orders issued under non-appealable provisions of section 11(B) (4) and 77(f) as appealable.

The first such order was issued under section 11(B) (4) treating an application for patent as ‘deemed withdrawn’ for failure to file the request for examination within the prescribed time period of 48 months from the date of priority of the application. The case of the petitioner was that the Indian Patent Office (IPO) made an incorrect entry in the cash receipt stating that the fee for examination was filed after the expiry of the prescribed period in spite of the timely filing of the same. The Petitioner brought the incorrect entry to the notice of the Patent Office. In what can be seen as a gross violation of the principles of natural justice, the Controller of Patents issued an order treating the application as withdrawn without issuing a hearing notice to the Applicant.

Statutorily, orders passed under section 11(B) (4) are not appealable but the attorneys of the Appellant argued that since the Applicant had timely filed the request for examination, said order should be taken as an order under section 15 of the Indian Patents Act which bestows upon the Applicant a right to appeal. The Appellate Board agreed with the submissions of the Appellant and allowed the appeal.

In the second case, an order issued in a pre-grant opposition, which was treated as a review petition under orders of the Delhi High Court to correct a procedural irregularity that had ensued due to a patent being granted without processing of a pre-grant opposition, was treated as patentable by the IPAB. The IPAB held that the order issued in the review petition under section 77(f), was in effect an order in a pre-grant opposition that was being treated as a review petition under directions of the High Court and since orders in pre-grant oppositions are appealable, the order in this case was also held appealable.

These orders have brought in their wake a stand to draw curative measures to address administrative errors.