This post examines the April 1, 2016 decision issued by the Indian Patent Office involving patent application 1399/MUMNP/2010 entitled, “Anti-retroviral Combination”, (the ‘1399 application) owned by Cipla Limited. The ‘1399 application was filed on June 30, 2010, and claims a pharmaceutical composition for treating HIV comprising ritonavir and darunavir. The application was filed with the following twenty-two claims:

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

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

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

2. A pharmaceutical composition according to claim 1, which is a tablet formulation comprising said ritonavir in a first layer of the formulation and said darunavir in a second layer of the formulation.

3. A pharmaceutical composition according to any preceding claim, further comprising a water insoluble polymer and/or a water soluble polymer.

4. A pharmaceutical composition according to claim 3, wherein the ratio of the weight of the ritonavir or darunavir to the weight of the polymer is from 1:1 to 1:6.

5. A pharmaceutical composition according to claim 3 or 4, wherein the polymer is present in at least the layer containing the ritonavir.

6. A pharmaceutical composition according to any preceding claim, further comprising at least one pharmaceutically acceptable excipient.

7. A pharmaceutical composition according to claim 6, wherein the excipient includes a plasticizer.

8. A pharmaceutical composition according to any preceding claim, wherein the darunavir is present in an amount from 300 to 800 mg.

9. A pharmaceutical composition according to any preceding claim, wherein the ritonavir is present in an amount from 50 to 100 mg.

10. A pharmaceutical composition according to any preceding claim for use in treating HIV or AIDS.

11. A pharmaceutical composition according to any one of claims 2 to 10, when dependent on claim 2 and 3, wherein the layer containing the ritonavir is obtainable by hot melt extruding said ritonavir with the polymer.

12. A method of treating HIV or AIDS comprising administering a therapeutically effective amount of a pharmaceutical composition as defined in any preceding claim.

13. A method of making a pharmaceutical composition as defined in any one of claims 2 to 11, when dependent on claim 2, comprising hot melt extruding the ritonavir to form an extrudate, then formulating the extrudate into said first layer; formulating said darunavir into said second tablet layer; and combining said first and second layer to provide a single unitary multiple layer tablet formulation.

14. A method according to claim 13, wherein the ritonavir is mixed with a water soluble polymer and/or a water insoluble polymer prior the hot melt extrusion step.

15. A method according to claim 13, wherein the darunavir is mixed with a water soluble polymer and/or a water insoluble polymer and extruded by hot melt granulation process, or melt granulation process.

16. A method according to claim 13 or 14 or 15, comprising preparing a substantially homogeneous melt of the ritonavir or darunavir and optionally one or more excipients, extruding the melt, and cooling the melt until it solidifies.

17. A method according to claim 16, wherein the melt is formed at a temperature from substantially 50ºC to substantially 200ºC.

18. A method according to claim 13 or 14, wherein the ritonavir, the polymer, and optionally one or more excipients are processed to form a powder blend which is transferred through the heated barrel of the extruder, whereby the powder blend melts and a molten solution product is formed, which is allowed to cool to form an extrudate.

19. A method according to claim 18, comprising processing the cooled extrudate into a desired pharmaceutical dosage form.

20. A pharmaceutical dosage form according to claim 19 in the form of a tablet or capsule or tablet in capsule.

21. A method according to any one of claims 13, 14, 18, 19, 20 wherein the layer containing the darunavir is prepared by direct compression or by wet granulation.

22. A composition prepared by a method according to any one of claims 13 to 21 for use in the treatment of HIV or AIDS.

A request for examination was filed in 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 following five prior art references were cited:

D1 – WO 2006/055455

D2 – WO 2006/005720

D3 – Sekar, V. et al, Antimicrob Agents Chemother (2007); 51(3):958-961

D4 – US 2005/084529

D5 – WO 2006/091529

Specifically, claims 1, 8, 10, 12, and 22 were found to lack novelty in view of D1 and D2, the former disclosing a single solid dosage form comprising darunavir, tipranavir, and optionally ritonavir, and the latter disclosing an anti-HIV combination comprising tenofovir (or its disoproxil fumarate derivative), ritonavir, and darunavir (TMC 114), and pharmaceutical formulations containing such combinations. According to the examination report, D3 disclosed the co-administration of ritonavir and darunavir for the treatment of HIV. While this reference did not disclose a bi-layer tablet or the use of a polymer as an excipient, D4 and D5 disclosed that pharmaceutical compositions comprising one or more HIV protease inhibitors could be prepared in the form of a bi-layer tablet with a polymer as an excipient. In view of these references, claims 1-22 were rejected as lacking inventive step under 2(1)(j) of the Indian Patents Act, 1970 (Act). Additionally, “use” claims 10 and 22 were rejected as not constituting patentable subject matter. Moreover, claim 12 was rejected as not constituting patentable subject matter under Section 3(i) of the Act for being directed to a method of treatment.

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.”

The Applicant further identified D3 as the closest cited prior art. D3 disclosed a clinical trial which involved administering separate pills of darunavir and ritonavir to patients, and which required supervision to ensure patient compliance with the treatment regimen. Applicant argued that it was impractical to supervise the administration of the biological actives involving different dosage schedules, which increases the “pill burden” for patients and can lead to poor patient compliance. Additionally, the Applicant argued that darunavir and ritonavir are incompatible, thus preventing the two drugs from being combined into a single pill. As a result, the objective technical problem of the instant application was to provide a stable unit dosage form comprising both drugs, and the Applicant argued that the instant invention overcame the pill burden by providing a single tablet comprising darunavir and ritonavir, simplifying the dosing schedule. The Applicant further argued that D1 and D2 failed to teach any further information regarding the formulation of the tablet, while D4 and D5 did not disclose that multilayered forms of tablets may overcome the incompatibility of two active drugs.

After submission of the response, the Patent Office conducted a further examination and found that the response did not comply with the objections raised in the examination report. Because the Applicant had requested a hearing in the event that all of the rejections in the examination report were not overcome, the Patent Office scheduled a hearing, and issued a letter citing an additional prior art reference:

D6 – US 2005/0048112

According to the Patent Office, D6 disclosed a solid pharmaceutical dosage form comprising ritonavir, and optionally a second HIV protease inhibitor. D6 identified 24 species of protease inhibitors in addition to ritonavir, including darunavir (TMC-114). The Patent Office argued that D6 provided strong motivation to formulate a solid pharmaceutical dosage comprising both ritonavir and darunavir, and that D6 additionally disclosed that a dosage form may consist of several layers, such as a multilayer tablet. Specifically, D6 disclosed 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)” (para. [0080]).

As a result, 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 instant 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. Specifically, Section 3(d) recites that “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. According to the Controller, only the therapeutic effect of the claimed invention was relevant when assessing inventive step and patentability under Section 3(d). Physical properties were irrelevant.

Following the hearing, the Applicant submitted a written reply and amended the claims. The Applicant argued that the prior art references 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. Additionally, the Applicant provided evidence that mixing ritonavir and darunavir in the same layer adversely affected the release of both drugs. Interestingly, the data also demonstrated that providing the drugs in separate layers provided an optimal dissolution profile for both active compounds. The Applicant argued that neither D3, nor any of the other cited prior art, suggested improving the dissolution profile for the combination of ritonavir and darunavir, using a multilayer tablet with ritonavir and darunavir occupying separate layers. The Applicant concluded by arguing that only hindsight would have permitted one of skill to arrive at the instant invention. In addition, the Applicant amended claim 1 to recite:

“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.”

The Controller maintained the inventive step and Section 3(d) rejections. Regarding inventive step, the Controller held that the claims lacked inventive step in view D3 in combination with D1 and D4-D6. In particular, the Patent Office identified that D6 disclosed “a copolymer of about 60% by weight of the copolymer, N-vinyl pyrrolidone, and about 40% by weight of the copolymer, vinyl acetate” as the “particularly preferred polymer,” and that “multilayer forms have the advantage that 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” (para. [0080]). Specifically, the Controller stated that D6 disclosed 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)” (para. [0080]).” Additionally, the Controller held that the claimed invention did not show any advantage or surprising effect over the prior art. Regarding Section 3(d), the Controller held that “…[the] claimed composition consider [sic] the new layered form of a known combination of prior art, which are statutorily barred from the patentability u/s 3(d) of the Act…”