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.

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.

 

 

IPO REJECTS PATENT APPLICATION FOR RELATING TO ATOMIC ENERGY

In a decision given by the Kolkata patent office for Applicant Merck and CIE, the IPO refused the patent application for falling within the ambit of invention relating to atomic energy.

Section 4 of the Indian Patents Act reads as follows: “Inventions relating to atomic energy not patentable. -No patent shall be granted in respect of an invention relating to atomic energy falling within sub-section (1) of section 20 of the Atomic Energy Act, 1962 (33 of 1962).”.

This application was first filed with the Department of Atomic Energy (DAE) to seek their approval however the DAE denied the same stating that the invention relates to Atomic Energy.

The patent applicants at the IPO, contended in their submissions that the instant invention relates to novel folate conjugates and the corresponding metal-chelate complexes as well as pharmaceutical compositions thereof, their methods of production and use in diagnostic and therapeutic medical applications, such as in diagnostic imaging and radiotherapy. The novel folate conjugates according to the invention can form a stable chelate with venous radio nuclides suitable for diagnostic imaging and radio therapeutic applications. The present invention is directed towards a new method of synthesis of 18 – folate radio pharmaceuticals, wherein at least one L8F-isotope is attached to a folic acid or derivative thereof, through direct radio labeling with 18F.

The applicants held that the invention has no relevance or use in the field of atomic energy and do not attract the provisions of Section 4 of the Patents Act. The applicants also referred to some instances wherein patent applications relating to similar subject matter, i.e. the use of radio nuclides in compounds, complexes or conjugate for different purposes, including medical applications such as for radio imaging, diagnostics and radiotherapy amongst others have been granted by the IPOs in the past.

They also submitted that it is obvious from the disclosure that the complexes according to the invention are used only for radiotherapy and diagnosis and not for the production of atomic energy in any form. The invention does not, in any way relate to the production, control, use of disposal of atomic energy or the prospecting, mixing, extraction, production, physical and chemical treatment, fabrication, enrichment, canning or use of any prescribed substance or radioactive substance as required by section 20(1) of the Atomic Energy Act. They pleaded to waive off said objection, submitting that there is no link between compounds according to the instant invention and the “Prescribed Substance” as defined in Section 2, item (i), paragraph (g) of the Atomic Energy Act, and therefore the claims do not attract Section 4 of the Patents Act.

However, the IPO did not give a reasoned order elaborating upon its reasons to refuse the patent application but cited the refusal of the instant application by DAE as their conclusive decision.

Delhi DB raises the bar of burden of proof on the Defendant to establish a credible challenge

A bench comprising of Justice BD Ahmed and Justice Sanjeev Sachdeva recently passed an order granting an injunction in a patent matter. The DB reversed an order of Justice Manmohan Singh who had denied the injunction.

The Court has also hinted at a presumption of validity of the patents holding that the grant of the patent by the IPO and the USPTO heightens the burden for establishing a credible challenge (see point IV. below)

The principles laid down by the Division Bench are culled out below:

  1. The principles governing patentability of an invention have been summarized as under:
    • it must be the inventor’s own discovery;
    • it should not be a mere verification of what was already known before the date of the patent;
    • it is a manner of new manufacture and includes an improvement and an allied invention;
    • must also be useful;
    • not only the art, process or manner of providing, preparing or making an article but also the article prepared or produced by the manufacture can be patented;
    • should be more than a mere workshop improvement;
    • the improvement or the combination must produce a new result, or a new article or a better or cheaper article than before;
    • a combination of old, known integers may be so combined that by their working inter-relation they produce a new process or improved result;
    • mere collection of more than one integer or things, not involving the exercise of any inventive faculty, would not qualify for the grant of a patent;
    • there must be novelty in the mode of application and the novelty must show invention;
    • the new subject-matter must involve “invention” over what is old;
    • must involve something which is outside the probable capacity of a craftsman;
    • it must not be the obvious to a skilled worker, in the field concerned,
    • it must not be a natural suggestion of what was previously known;
    • Prior public knowledge of the alleged invention would disqualify the grant of a patent and prior public knowledge can be by word of mouth or by publication through books or other media;

     

  2. Merely because the prior art and the subject patent use the same term for a feature does not necessarily mean that the feature is the same. The said term may have two different meanings in the prior art reference and the subject patent. For the invention to be anticipated, the feature disclosed in the prior art must pertain to the same concept as claimed in the patent.
  3. The entire specification and teaching of the prior art must be considered while determining patentability. Mere reference to the abstracts of the prior art documents without considering the teaching of the prior art in the detailed description is erroneous.
  4. The Indian Patent Office and the United States Patent Office have granted the patent and have not found that the patent is obvious in view of the cited prior art. Since these expert bodies have found the patent to be non – obvious, the burden of proof on the Defendant to establish a credible challenge is even greater.

Patentable or not? : IPO gives a reasoned order.

The Controller of Patents A.RAJA, rejected an application of Yahoo, numbered 1833/CHE/2007, directed to method of scheduling and displaying an online presence status of a user of an instant messaging application. In particular, presented claim 1 recites:

A method of scheduling and displaying an online presence status of a user of an instant messaging (IM) application, comprising: setting, by presence management server (PMS) (500)containing a processor and a memory, a routine online schedule of the user, the routine including a start time, an end time, a time zone, and a routine status that indicates a preference of the user to appear online or offline in the IM application between the start time and the end time; determining, by the presence management server (PMS), the online presence status of the user in the IM application as user and a current time, wherein the online presence status is set to be equal to the routine status when the current time is between the start time and the end time for said time zone regardless of the user being online or offline in the IM application, wherein the online presence status is not equal to the routine status when the current time is not between the start time and the end time, wherein the user appears online in the IM application if the user desires to appear online according to the routine status even if the user is offline in the IM application, the routine online schedule of the user being stored to enable the determining of the online presence status of the user; and displaying, by the presence management server PMS),the determined online presence status of the user in an IM control panel (350) of other users.

The claims have been rejected under section 3(k) and 3(n). The reasons provided by the Controller are as follows:-

  • Independent claim 1 recites a presence management server (PMS) for performing various operations (setting, determining, displaying) related to scheduling and displaying an online presence status of a user of an instant messaging (IM) application. The steps of setting, determining, displaying have been held to be nothing but computer algorithmic steps for giving a solution to the detailed problem related to scheduling an displaying an online presence status of a user of an instant messaging application.
  • The Controller has held that the algorithm related claims are even wider than the computer programmes claimed by themselves, as a single algorithm can be implemented through different programmes in different computer languages. If, in substance, claims in any form such as method/process, apparatus/system/device, computer program product/ computer readable medium belong to the said excluded categories, they would not be patentable. Even when the issue is related to hardware/software relation, (e.g., when the claims recite ‘processor is programmed to… or ‘apparatus comprising a processor and configured / programmed to…..) the expression of the functionality as a ‘method’, is judged on its substance.The independent claim 1 which seek to protect a method of scheduling and displaying an online presence status of a user of an instant messaging application clearly indicates that the subject matter intent to claim only the computer programming instructions.
  • The presence of hardware components such as a presence management server containing a processor and a memory are general purpose computer containing processor and a memory.
  • The Controller held that the independent claim 1 recites displaying the determined online presence status of a user in an IM control panel of other users. The claim further recites that the determination of the presence status is based on routine online schedule of the user and a current time, with the routine online schedule of the user being stored to enable the determining of the online presence status of the user. The displayed online presence reflects the status of the instance messaging system. Therefore, the present invention indicates that the presentation of information which fall under section 3(n) of the Patents Act.

 

Cipla’s Patent Application For HIV Drug rejected

The Indian Patent Office rejected Cipla’s patent application for its HIV drug composition comprising combination of “ritonavir” and “darunavir”. The application, in particular, was directed to a pharmaceutical composition comprising a solid unit dosage form comprising: (i) ritonavir; (ii) darunavir; (iii) a water insoluble polymer and/or water soluble polymer, wherein the ratio of the weight of the ritonavir or darunavir to the weight of the polymer is from 1:1 to 1:6. Further, the claimed composition was a tablet composition comprising ritonavir and polymer in first layer and darunavir in second layer. The first layer is obtainable by hot melt extruding, and the second layer is obtainable by direct compression or by wet granulation.

The application was rejected on the grounds of lack of inventive step in view of the prior published documents. The controller cited 6 prior art documents and heavily relied on one particular D6: US 2005/0048112 in his inventive step analysis which describes that solid pharmaceutical dosage forms comprising ritonavir and, a second species of HIV protease inhibitor, including TMC-114 (darunavir). Therefore, according to the Controller, D6 provides strong motivation to formulate a solid pharmaceutical dosage form that comprises both ritonavir and darunavir. D6 additionally discloses that dosage may be provided as dosage forms consisting of several layers and such “multilayer forms have the advantage of processing  two active ingredients which are incompatible with one another  or controlling the release characteristics of the active ingredient(s). The claims were therefore considered obvious by the Controller. in addition to this, the Controller held that the claimed subject matter does not clearly show advantage/surprising effect over prior art composition to show non-obviousness (no comparative data being provided by the Applicant).

The Controller also rejected the application under section 3(d) as he considered the  new layered form of a known combination of prior art, as being statutorily barred from the patentability u/s 3 (d).