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.

F. Hoffmann La Roche vs CIPLA- A Digest

The long pending patent dispute ensuing between CIPLA and F. Hoffmann La Roche over Roche’s lung cancer drug Erlotinib hydrochloride (sold under the name of Tarceva) has been resolved after the Division bench of the Delhi High Court pronounced in its judgement that CIPLA  infringes Roche’s patent.

This judgement has contributed in establishing Indian jurisprudence with regard to various legal principles relating to not only the validity of a patent, but also in extending the scope of a composition of matter patent.

The History so far:

  1. Roche sued Cipla in early 2008 for infringement of their Patent IN ‘774, claiming [6, 7-bis(2- methoxyethoxy) quinazolin-4-yl]- (3-ethynylphenyl) amine hydrochloride’ also known as ‘Erlotinib Hydrochloride’.
  2. No interim relief granted to Roche in the early stages of the suit and the main matter was decided after the trial vide an order dated 7th September 2012.
  3. The Single Judge’s decision was that while Roche’s patent IN ‘774 was valid (the counter claim for revocation could not be proved), there was no evidence that the alleged infringing product does, in fact, infringe their patent.
  4. An appeal was filed before the Division Bench by Roche challenging the non-infringement aspect of the order of the Single Judge and a cross appeal was filed by CIPLA in respect of primarily the validity aspect of 774.
  5. The main issues decided by the Division Bench are:
  1. Whether Roche’s compound patent, i.e. IN ‘774, is valid; and
  2. Whether CIPLA’s product, Erlocip which is polymorphs B of the compound Erlotinib, infringes Roche’s patent for the compound Erlotinib;

The Division Bench held that CIPLA’s product Erlocip, which is claimed to be a polymorph B form of the compound Erlotinib, infringes the compound patent IN ‘774 and affirmed the validity of the patent as well. The Division Bench set the correct legal principle for establishing infringement  i.e  mapping the infringer product with the patented claims.

The Bench held that “an infringement analysis involves comparison of each and every limitation of the claim with the allegedly infringing product/device. The analysis cannot be performed by comparing the product manufactured by the patentee with the allegedly infringing product.

The Defendant alleged that their product Erlocip is a polymorph B form of the compound Erlotinib Hydrochloride and since patent application for the polymorphs B of Erlotinib Hydrochloride is rejected, and hence Cipla is free to make polymorph B form.

The Division Bench of the Delhi High Court held that Indian Patent IN ‘774 claimed the compound, [6,7-bis (2-methoxyethoxy) quinazolin-4-y1]-(3-ethynylphenyl) amine hydrochloride], is clearly not limited to any polymorphic form of Erlotinib Hydrochloride, but to Erlotinib Hydrochloride itself. “This compound may exist in several polymorphic forms, but any and all such forms will be subsumed within this patent. Therefore as Cipla’s Erlocip is admittedly one particular polymorphic form of the Erlotinib Hydrochloride compound (Polymorph B), it will clearly infringe the IN’774 patent”.

The Division Bench while interpreting claims of the Suit Patent also summarizes principals of claims construction as follows:-

  1. Claims define the territory or scope of protection.
  2. There is no limit to the number of claims.
  3. The broad structure of set of claims is an inverted pyramid with the broadest at the top and the narrowest at the bottom (Manual of Patents Office – Practice and procedure). An independent Claim can be the broadest scope claim. It has fewer limitations than any dependent claim which is dependent upon it’.
  4. Where claims are ‘dependent’, they incorporates by reference ‘everything in the parent claim, and adds some further statement, limitations or restrictions’.
  5. Where claims are ‘independent’ although relating to the same inventive concept this implies that the ‘independent claim stands alone, includes all its necessary limitations, and is not dependent upon and does not include limitations from any other claim to make it complete.
  6. Different claims define different embodiments of the same inventive concept.
  7. If subsidiary claims contain an independent inventive concept different from the main claim then the Patent office will insist on the filing of a divisional application.
  8. Subject matter of claims can be product, substances, apparatus or articles; alternatively methods or process for producing said products etc. They may be formulations, mixtures of various substance including recipes. Dosage regimes or in some countries methods of use or treatment may also be claimed.
  9. To invalidate a patent, the challenger must invalidate each claim separately and independently as it is quite likely that some claims may be valid even while some are invalid.
  10. In an infringement action, first define the scope and meaning of the claims including its terms. Herbert Markman Vs. Westview 52 F.3d 967 also 517 US 370), the Courts held that an infringement analysis entails two steps:-
  1. to determine the meaning and scope of the patent claims asserted to be infringed.
  2. to compare the properly construed claim with the device accused of infringing.

Each claim has a priority date and hence a group of claims in a specification may have multiple priority dates. This only means that if a patent application with certain priority date and claims was followed by another application with different claims and different priority dates, then if they were consolidated or cognate with another application, each claim would retain the original priority date [Section 11(1)].

On the question of obviousness, the Division Bench held that “to test obviousness” the first test required to be applied is to see who is an ordinary person skilled in art (POSA) and its characteristics. The features of a person skilled in the art are;

      1. that of a person who practices in the field of endeavour,
      2. belongs to the same industry as the invention,
      3. possesses average knowledge and ability, and
      4. is aware of what was common general knowledge at the relevant date.

The Division Bench crafted the steps to determine obviousness/lack of inventive step in the nature of following queries:-

  1. To identify an ordinary person skilled in the art,
  2. To identify the inventive concept embodied in the patent,
  3. To impute to a normal skilled but unimaginative ordinary person skilled in the art what was common general knowledge in the art at the priority date.
  4. To identify the differences, if any, between the matter cited and the alleged invention and ascertain whether the differences are ordinary application of law or involve various different steps requiring multiple, theoretical and practical applications, and
  5. To decide whether those differences, viewed in the knowledge of alleged invention, constituted steps which would have been obvious to the ordinary person skilled in the art and rule out a hindsight approach.

The Division bench held that the teaching of the prior art document should be considered as a whole and that similarity of structure alone was insufficient for prima facie unpatentability. To show obviousness besides structural similarity, there should be a reason or motivation shown in the prior art to make the particular structural change in order to achieve the properties that the applicant was seeking. CIPLA’s expert witness who was presented as a Person Skilled in the Arts (POSA), was not a medicinal Chemist and could not be considered as a POSA and the court held that CIPLA has been unsuccessful in satisfying the tests laid down above to establish prima facie that the suit patent was obvious.

CIPLA also sought revocation of the suit patent for violation of Section 8 of the Patents Act and contented that if Polymorph B of Erlotinib Hydrochloride is presumed to have been covered in the suit patent, this would imply Polymorph B of Erlotinib Hydrochloride to be same and substantially the same as the suit patent. Roche was then under an obligation to have disclosed before the patent office while prosecuting its application resulting in IN `774 that it had filed an application for grant of patent for Polymorph B of Erlotinib Hydrochloride resulting in US `221 which fact was not disclosed.

The Division Bench rejected this ground as well as it held that CIPLA did not prove that inventions in IN774 and US 221 are same and substantially the same.

Further the Bench held that, when Roche was prosecuting its application for grant of Suit Patent IN `774 separate application for grant of patent for Polymorph B form of Erlotinib Hydrochloride was filed on February 06, 2002. The Suit Patent was a product patent relating to the new molecule Erlotinib Hydrochloride whereas US`221 was an improvement patent application relating to certain polymorphic structure. The Court attributed the non-filling of the details of the application resulting in grant of patent US ‘221 by Roche to the bona-fide belief of Roche that the application resulting in patent US’221 is not same or substantially the same compound.

To conclude, the Division Bench affirmed the validity of Roche patent, IN ‘774, and set aside the single judge decision dismissing suit for injunction filed by Roche. However, keeping in view the fact that the IN ‘774 patent would expire in March, 2016, the Bench did not grant injunction against CIPLA. Importantly, the Division Bench of the Delhi High Court directed CIPLA to render accounts concerning manufacture and sale of Erlocip for the calculation of damages.

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.