India: Indian Patent Office Rejects Cipla's Patent Application For HIV Drug

The Indian Patent Office on April 1, 2016 denied Cipla (Applicant) limited a patent for its HIV drug comprising "ritonavir" and "darunavir" involving the patent application 1399/MUMNP/2010 entitled, "Antiretroviral Combination". The IPO rejected the Patent Application on the grounds of lack of inventive step in view of the prior published documents as well as on basis of Section 3(d) of the Patents Act.

BRIEF BACKGROUND

Cipla Limited filed Indian patent application 1399/ MUMNP/2010 entitled "Anti-retroviral Combination" in the Indian Patent Office (IPO) on June 30, 2010. The '1399 application describes a pharmaceutical composition comprising of ritonavir and darunavir for treating HIV or AIDS. The application was filed with 22 claims. A request for examination was filed for the '1399 application on November 22, 2011, and a first examination report was issued on October 27, 2014. In the examination report, all twenty-two claims were found to lack novelty and inventive step over the prior art.

The examiner cited the prior art documents as follows1, D1 (WO 2006/055455), D2 (WO 2006/005720), D3 (Sekar, V. J. et al, Antimicrobial Agents Chemotherapy, American Society for Microbiology (2007); 51(3):958- 961), D4 (US 2005/084529), D5 (WO 2006/091529).

According to the examiner, D1 discloses a single solid dosage comprising of darunavir, tipranavir and optionally ritonavir. D2 discloses an anti-HIV combination comprising tenofovir or its disoproxil fumarate derivative, ritonavir and TMC 114(darunavir) useful for the treatment or prevention of HIV infections. Considering D1 and D2, the claims 1, 8, 10, 12 and 22 of the present invention lacked novelty in view of the examiner.

D3 discloses the co-administration of ritonavir and darunavir for the treatment of HIV. Though D3 does not disclose a bi-layer tablet or the use of a polymer as excipient but only refers to the combined application of drugs. D4 and D5 mention that pharmaceutical compositions comprising one or more HIV protease inhibitor can be prepared in form of bi-layer tablets with a polymer as excipient.

The examiners in view of the aforementioned disclosures declared that it would have been obvious for any skilled person to combine the teachings of D3 with that of D4 and D5 to arrive at the present invention. Therefore the claims 1 to 22 were rejected due to lack of inventive step and do not constitute an invention u/s 2(1)(j) of the Patents Act 1970.Further the examiner pointed that Claims 10 and 22 are use claims, which are not permissible u/s 2(1)(j) of the Act. Claim 12 is directed to methods of treatments which are barred from being patentable u/s 3(i) of the Indian Patents Act.

The applicant filed a response with amended claims. In response to the examination report, the Applicant argued that the counterpart European Patent (EP2242482 B1) had been issued after taking into consideration all of the cited documents listed above (excluding D2), and after the insertion of the limitation of original claim 2 into original claim 1, such that the new independent Indian claim read like the granted claim in the corresponding European application:

"1. A pharmaceutical composition comprising a solid dosage form comprising:

(i) ritonavir or a pharmaceutically acceptable salt and ester thereof;

(ii) darunavir or a pharmaceutically acceptable salt and ester thereof;

(iii) Optionally, at least one pharmaceutically acceptable excipient, which composition is a tablet formulation comprising said ritonavir in a first layer of the formulation and said darunavir in a second layer of the formulation."

APPLICANT'S ARGUMENTS

The applicant argued that the present invention relates to a solid, unit dosage form comprising ritonavir in a first layer and darunavir in the second layer. The applicant submitted that none of the cited prior art documents disclosed such dosage forms hence there exist a novelty. Further, the applicant identified that D3 is the closest cited prior whose teachings were directed to a clinical trial involving administering the combination of darunavir and ritonavir, thereby supervising the administration of actives. The applicant argued that though HIV protease inhibitors taken in combination with cytochrome P450 inhibitors such as ritonavir and darunavir have improved pharmacokinetics as compared to taking HIV protease inhibitors alone, it becomes impractical to supervise the administration of active compounds involving different dosage schedules. Such administration and supervision would result in an increase of "pill burden" and poor patient compliance.

It was further argued by the Applicant that in order to overcome the above said, the present invention provided a single unit dosage form comprising darunavir and ritonavir that simplify the dosage schedule and decreases the 'pill burden'.

The Applicant submitted that D1 and D2 do not provide any further information regarding the incompatibility of ritonavir and darunavir. D4 and D5 describe multilayer forms that allow the combination of active ingredients which are otherwise non-compatible and require separate processing steps.

After the receipt of response for FER, the patent office further conducted an extensive examination and found that the response did not comply with the objections raised in the examination report. The Patent Office scheduled a hearing on 19th February 2016, and issued a letter citing an additional prior art reference, D6 (US 2005/0048112).

MOTIVATION FOR THE INGREDIENTS OF THE FORMULATION AS WELL AS THE MULTILAYER DOSAGE FORM BASED ON D6

According to the examiner D6 disclose solid pharmaceutical forms comprising of ritonavir and optionally comprises of second species of HIV protease inhibitor. It was further identified that D6 mention 24 species of HIV protease inhibitor other than ritonavir, including TMC-114(darunavir). Therefore D6 provide a strong motivation to formulate a solid pharmaceutical dosage form that comprises of both ritonavir and darunavir. The examiner pointed that D6 additionally discloses that the solid pharmaceutical dosage form comprises "at least one pharmaceutically acceptable water-soluble polymer".

D6 further discuss that "dosage forms according to the invention may be provided as dosage forms consisting of several layers for example laminated or multilayer tablets. It is mentioned in D6 that "it is possible to provide an initial dose by including an active ingredient in one of the outer layers, and a maintenance dose by including the active ingredient in the inner layers.

After analyzing the reply submissions of the Applicant, the Controller maintained that the claimed subject matter did not clearly show an advantage or surprising effect over the prior art. In addition, the Controller argued that the claims in the present application related to a new layered form of a known combination of the prior art, and thus were not patentable under Section 3(d) of the Patents Act. Section 3(d) reads "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" does not constitute a patentable invention. Further the Controller specifically pointed that only the therapeutic effect of the compounds in question, are relevant in assessing the inventive step and patentability under section 3(d) and not the physical properties of the compounds.

THE APPLICANT'S POST HEARING SUBMISSIONS

Post hearing, the Applicant submitted a written reply and amended the claims. The Applicant argued that the prior art disclosures (D4, D5 and D6) did not disclose the specific combination of ritonavir and darunavir, and that the combination of ritonavir and darunavir in separate layers of a single composition was new. The Applicant strongly focused on the data that showed the mixing ritonavir and darunavir in the same layer adversely affect the release of both active compounds which was overcome in the present invention by providing the two active compounds in separate layers. Such an arrangement provided for an optimal dissolution profiles for both the actives. The Applicant mentioned that neither D3 nor any of the other cited prior art suggested for improving the dissolution profile for the combination of darunavir and ritonavir, in a multilayer form, having the active compounds in separate layers so as to result in the optimal release profile of the separate drugs.

The amended new claim is as follows,

A pharmaceutical composition comprising a solid dosage form comprising:

(i) ritonavir or a pharmaceutically acceptable salt and ester thereof;

(ii) darunavir or a pharmaceutically acceptable salt and ester thereof;

(iii) a water insoluble polymer and/or a 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;

(iv) Optionally at least one pharmaceutically acceptable excipient, which composition is a tablet formulation comprising said ritonavir and said polymer in a first layer of the formulation and said darunavir in a second layer of the formulation; wherein the first layer is obtainable by hot melt extruding, and the second layer is obtainable by direct compression or by wet granulation."

CONTROLLER'S DECISION

The Objections pertaining to inventive step and section 3(d) was maintained by the controller. With regards to D6 the Controller observed that "dosage forms according to the invention may be provided as dosage forms consisting of several layers, for example laminated or multilayer tablets. Further multilayer forms have the advantage that the two active ingredients which are incompatible with one another can be processed, or that the release characteristics of the active ingredient(s) can be controlled".

It was specifically mentioned in D6 that "it is possible to provide an initial dose by including an active ingredient in one of the outer layers, and a maintenance dose by including the active ingredient in the inner layer(s)".

In view of the above the controller rejected the Applicant's reply submissions considering D1-D5 and D6, composition comprising darunavir and ritonavir and its use known from D1-D6. Further claimed subject matter did not clearly exhibit advantage/surprising effect over the prior art composition.

CONCLUSION:

The claim of the present invention consider the new layered form of a known combination of prior art, which are not considered as being patentable under Section 3(d) of the Indian Patents Act. Therefore the subject matter of claims 1-8 were rejected as it falls under Section 3(d) of the Act. Also, in view of the aforesaid disclosures, it would have been obvious for a person skilled in the art to combine the teachings of D3 with that of D4 or D5-D6. Hence the claims 1-8 lack inventive step and do not constitute invention under section 2(1) (j) of the Indian Patents Act, 1970.

Footnote

1 http://ipindiaservices.gov.in/patentdecisionsearch/ Iewdoc.aspx?application_number=/KNSylmn9/JQrFrkvodCFzmmRThoHDPFUArb/7ZWPpzbY8z1fFZBNngfGDGag6oVbl/ Zou2iXODnygMuSH3HfQ==

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