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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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).

 

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.

 

Tofacitinib caught in section 3(d) turmoil

The Controller of Patents, Mumbai  issued an order rejecting a patent application of Pfizer for Tofacitinib for the second time. The primary ground for rejection of Tofacitinib was Section 3(d) and the Controller relied on the Supreme Court’s order on the Glivec case. The Controller said that the claimed form is an enantiomer of a compound (known compound) and the Applicant has failed to establish the enhanced therapeutic efficacy of the claimed compound over the base compound.  The Controller held that the base compound is a “known compound” for the purpose of section 3(d) even if the prior art which discloses it was not published before the priority date. The said prior art being Applicant’s own patent application was known to the them.

The Controller also held that the advantage of the claimed form over other possible enantiomer forms of the base compound does not prove enhanced efficacy over base compound.

The Controller also rejected the application on the grounds of Anticipation by prior claiming. The controller held that Example 14 of WO 01/42246 (D1) discloses the compound of present claim without reference to the stereo chemical configuration (base compound) which is also claimed in the prior art. Further the controller held that D1 teaches that the compounds have asymmetric centres and exist in different enantiomeric and diastereomeric forms. D1’s reference to enantiomeric and diastereomeric forms of the compounds was held to represent an unambiguous technical teaching making available to the public all four stereo chemical configurations of the compounds according to example 14. Therefore the form (3R, 4R) of the compound claimed by the applicant was considered disclosed in the prior art. The Controller also considered present form to be anticipated as he held that the Applicant has failed to compare the compound claimed with the compound of prior art D1 to overcome lack of novelty.

This is the second time that the same application has been rejected by the Indian Patent Office. The patent application was rejected for the first time by a different Controller and the Patent office in Mumbai was directed by Intellectual Property Appellate Board (IPAB) to re-consider Pfizer’s patent application on account of flagrant violation of principles of natural justice. The matter was heard afresh by Controller of patents  on January 2015. The application has been rejected again by the recent order on the 3rd of September, 2015

Second generation Tygacil granted a Patent

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.