1.) Development activities of Neuland Laboratories Limited (NLL) 2.) Otsuka: Freeze-dried cake composition of Aripiprazole

Contents

Development activities of Neuland Laboratories Limited (NLL) General information

Amgen prevails over Sanofi at UPC Court of Appeal with Brinkhof and Bardehle

CCRAS launches SIDDHI 2.0 to strengthen research-driven innovation in Ayurveda pharma sector

Intellectual Property Otsuka: Freeze-dried cake composition of Aripiprazole

Development activities of Neuland Laboratories Limited (NLL)

We monitor the exports of many companies and then attempt to analyse their development activities. Some inferences that can be drawn from NLL's export data about its development capabilities are as follows.

General information

Amgen prevails over Sanofi at UPC Court of Appeal with Brinkhof and Bardehle

Amgen's most important cholesterol-lowering patent EP 797 is valid after all, according to a landmark ruling by the UPC Court of Appeal yesterday. The decision allows Amgen to proceed with its infringement action against Sanofi and sets important precedents for future revocation actions at the UPC. News here

CCRAS launches SIDDHI 2.0 to strengthen research-driven innovation in Ayurveda pharma sector

The Central Council for Research in Ayurvedic Sciences (CCRAS), Ministry of Ayush, launched the second edition of Scientific Innovation in Drug Development, Healthcare and Integration (SIDDHI) 2.0 in Vijayawada, positioning it as a national platform to strengthen industry research collaboration and accelerate evidence-based innovation in Ayurveda.

News here

Intellectual Property

Otsuka: Freeze-dried cake composition of Aripiprazole

The subject of the decision, which relates to a medical device containing a freeze-dried cake composition comprising aripiprazole, is associated with the patent proprietor, Otsuka Pharmaceutical Co., Ltd. The patent proprietor, Otsuka, manufactures and markets long-acting injectable (LAI) formulations of aripiprazole, such as ABILIFY MAINTENA (aripiprazole prolonged-release aqueous suspension for intramuscular injection), a monthly formulation. Another product is ABILIFY ASIMTUFII (aripiprazole), a once-every-two-months long-acting injectable (LAI) formulation provided in a single-chamber prefilled syringe. The patent at issue, European patent No. 2667856, has the title: "MEDICAL DEVICE CONTAINING A CAKE COMPOSITION COMPRISING ARIPIPRAZOLE AS AN ACTIVE INGREDIENT, AND A CAKE COMPOSITION COMPRISING ARIPIPRAZOLE AS AN ACTIVE INGREDIENT". The patent claims a medical device (such as a dual-chamber syringe) containing a separately prepared, freeze-dried cake composition of aripiprazole. This description closely relates to the formulation type of the long-acting injectable aripiprazole products. Though exact sales information in Europe for LAI is not available, Given that the European market is a significant, high-growth region for this product, and that the total antipsychotic market size for the region is second only to North America, attributing $300 million to $500 million USD to the European LAI Aripiprazole market is a reasonable estimate for its current annual value, especially as new two-month formulations launch. Hence, this decision had a significant impact on Otsuka’s European business. The decision addresses appeals filed by three opponents (Instone Terry, Hamm&Wittkopp Patentanwalte PartmbB, and Maiwald GmbH) against the Opposition Division's decision rejecting their oppositions and maintaining the patent as granted. The opponents sought to revoke the patent in its entirety, primarily on grounds of lack of inventive step and insufficient disclosure. Prior art

Key Patent Claims: The patent was granted with twenty-two claims. The core independent claims relevant to this decision are:

• Claim 1: A medical device containing a separately prepared freeze-dried cake composition comprising aripiprazole in a storage container whose inner wall is treated with silicone, wherein there is a space between the inner wall and the cake composition.
• Claim 11: A cake composition comprising aripiprazole, having a strength of 5 to 100 N, a cylindrical shape, and a sloped side surface with an angle of 0.1 to 10°.
• Claims 18 and 22: Methods for producing the device of claim 1 and the cake composition of claim 11, respectively.

Procedural Background: Four oppositions were filed against the patent, arguing lack of inventive step and insufficient disclosure. The Opposition Division rejected these oppositions, prompting appeals from three of the opponents. Opponents' Arguments: The opponents argued that:

• D28 (a press release) should be admitted as evidence of common general knowledge regarding intramuscular aripiprazole, making it relevant for inventive step, especially starting from document D12.
• The patent lacked sufficiency because it did not provide clear instructions on measuring the 5-100 N cake strength or how to obtain a "raised top-surface" mentioned in the dependent claims.
• The invention lacked inventive step. They proposed D12, D11, and D18 (medical devices) as equally promising starting points as D2 (aripiprazole composition), arguing that the only difference was the active ingredient. They contended that the "separately prepared" and "space" features were not sufficiently defined to differentiate or be effective. They suggested that the prevention of agglomeration was not conclusively demonstrated and that any observed effects were due to the absence of silicone during freeze-drying, not the separate preparation or space. For claim 11, they argued its shape and strength were obvious from D3 (conical shape for removal) and D12 (motivation for separate preparation), and that the strength was not a differentiating feature, as D2's method would yield sufficient strength.

Patent Proprietor's Arguments: The patent proprietor contended that:

• D28 should not be admitted as it was not common general knowledge and lacked prima facie relevance.
• The patent was sufficient, providing clear instructions for cake preparation, strength measurement, and obtaining the specified top-surface.
• The invention involved an inventive step. They asserted D2 was the closest prior art because it related to the same purpose (aripiprazole formulation), unlike D12, D11, and D18 which were general medical devices without specific reference to aripiprazole or its formulation problems. They emphasised that "separately prepared" meant outside the storage container and "space" excluded form-locking. Experimental data (Tables 1 & 4) demonstrated that separate preparation and the space prevented silicone-induced agglomeration, which otherwise occurred with in-syringe freeze-drying. The technical effects were interrelated, justifying a combined objective technical problem. They argued the prior art offered no suggestion for the claimed solution, and specifically that D22, D12, D11, D18, and D3 did not address aripiprazole agglomeration issues or provide motivation for the specific combination of features in the patent.

Reasons for the Decision – Focus on Inventive Step:

1. Admittance of Document D28: The Board upheld the Opposition Division's decision not to admit D28, agreeing that it did not represent common general knowledge and offered no new information responsive to the preliminary opinion.
2. Sufficiency: The Board confirmed the patent sufficiently disclosed the claimed invention, citing specific paragraphs and examples for preparing cakes of varying strengths, measuring strength, and achieving a raised top-surface. Opponents' objections were deemed unsubstantiated.
3. Inventive Step:

• Starting Point : The Board affirmed that the patent addresses the specific problem of aripiprazole agglomeration upon resuspension when stored in silicone-treated medical devices. The solution involves reducing contact between the cake and silicone through separate preparation and providing space. Crucially, the Board emphasised that the closest prior art must be directed to the same purpose or effect as the claimed invention. Document D2, describing aripiprazole formulation by freeze-drying, was identified as the most reasonable starting point due to its similar purpose. Documents D12, D11, and D18, which describe general silicone-treated medical devices with freeze-dried formulations but do not mention aripiprazole or related silicone-induced problems, were not considered reasonable alternative starting points. The Board found that selecting aripiprazole from general medical device documents would require a "clueless choice" and thus constituted hindsight.
• Objective Technical Problem for Claim 1: The differences between granted claim 1 and D2 were identified as: (i) separate preparation of the cake, (ii) a space between the cake and the silicone-treated inner wall of the container, and (iii) the inner wall being silicone-treated. The Board clarified that "space" implies a void preventing form-locking and that "separately prepared" means outside the storage container, which D2's examples (in-vial freeze-drying) do not describe. The silicone treatment was acknowledged to enhance device functionality. The Board accepted the patent's experimental results (Tables 1 & 4) demonstrating that separate preparation and space prevented agglomeration, which occurs when freeze-drying happens directly in the silicone-treated syringe. The opponents' argument regarding lack of correlation and contamination during freeze-drying was rejected; the Board found a fair correlation between silicone and agglomeration, attributing outliers to contamination during resuspension, not storage. Therefore, the technical effects were interrelated, justifying a combined objective technical problem: providing a medical device for an injectable aripiprazole formulation with improved use properties and no particle agglomeration upon resuspension.
• Objective Technical Problem for Claim 11: The differences between granted claim 11 and D2 were the defined shape (cylindrical with sloped side surface) and strength (5-100 N). The Board rejected the opponents' argument that D2 implicitly disclosed the required strength, noting that D2's aripiprazole concentration differed from the patent's examples, making D2's resulting strength speculative. The Board concluded that the specific shape and strength of claim 11 facilitated easy removal and handling, making it particularly suitable for use in the claim 1 device and thus contributing to the prevention of agglomeration. Consequently, the objective technical problem for claim 11 was essentially the same as for claim 1, but focused on the cake formulation itself.
• Assessment of the Solution: The Board concluded that the skilled person would not have arrived at the claimed invention in an obvious manner from the available prior art. The prior art (D2, D22, D12, D11, D18, D3) neither recognised the specific problem of silicone-induced aripiprazole agglomeration nor suggested the solution involving separate preparation and space. The Board deemed the opponents' arguments for combining different prior art documents (e.g., D2 with D12 for the device, or D2 with D3 for the cake shape) to be driven by "impermissible hindsight," as there was no compelling motivation in the prior art to make such combinations to solve the identified technical problem.

Conclusion: The Board ruled that the patent as granted complied with the requirement of inventive step under Article 56 EPC. Order: The appeals were dismissed, meaning the European patent EP 2 667 856 remains valid as granted. Decision here