API and IP Newsletter
Contents
ANDA approvals in February 2025
General information
Mallinckrodt and Endo sign $6.7bn merger deal
Boehringer Ingelheim teams with Veeva to launch new R&D platform One Medicine
Intellectual Property
T 0243/22 (Rucaparib maleate/PFIZER) 27-02-2025
ANDA approvals in February 2025
We track ANDA approvals each month. Seventy-five ANDAs were approved in February 2025. Some of our observations are as follows.
General information
Mallinckrodt and Endo sign $6.7bn merger deal
Mallinckrodt Pharmaceuticals and Endo have agreed to merge in a $6.7bn deal, combining two pharmaceutical companies that recently emerged from bankruptcy proceedings tied to opioid litigation.
News here
Boehringer Ingelheim teams with Veeva to launch new R&D platform One Medicine
Two years after first announcing a partnership, Boehringer Ingelheim and software firm Veeva Systems have launched Boehringer’s One Medicine platform to help the German pharma streamline its product development by bringing together clinical, regulatory and quality data processes.
Boehringer plans to use One Medicine to boost its development of new medicines, the company said in a March 11 release, by linking data across functions and improving trial efficiency and collaboration with research sites.
News here
Intellectual Property
T 0243/22 (Rucaparib maleate/PFIZER) 27-02-2025
Rucaparib camsylate salt is being marketed as RUBRACA.
Two European patents in the rucaparib camsylate salt/polymorph patent family (European Patent 2534153 and its divisional European Patent 3150610) were opposed.
In June 2017, two parties filed opposition notices against European Patent 2534153. During an oral hearing held in December 2018, the European Patent Office’s Opposition Division upheld European Patent 2534153 in an amended and narrowed form, claiming certain crystalline forms of rucaparib camsylate, including, but not limited to, rucaparib S-camsylate Form A, the crystalline form found in RUBRACA.
This write-up concerns EP 3150610. Generics (UK) Limited filed an opposition against European Patent 3150610 (i.e., divisional patent) in April 2020.
In the decision, the opposition division at the first instance concluded, among other things, that the subject matter was not novel compared to D1 (US 2006/0074073 A1) and did not entail an inventive step when starting from D1 (US 2006/0074073 A1) as the closest prior art.
The parties agreed that document D1 represented the closest prior art. D1 (paragraphs [0002], [0003], and [0006]) discusses rucaparib or its salts as chemosensitisers. Since rucaparib inhibits PARP, it can be combined with chemotherapeutic agents to enhance their effectiveness in cancer treatment.
Paragraph [0043] of D1 lists approximately 60 pharmaceutically acceptable salts suitable for the invention. This list includes maleate; however, the preferred salts are phosphate and gluconate.
Claim 1 reads as follows:
"1. A maleate salt of 8-fluoro-2-{4-[(methylamino) methyl]phenyl}-l,3,4,5-tetrahydro-6H-azepino[5,4,3-cd] indol-6-one (rucaparib ) for use in a method of inhibiting poly(ADP-ribose)polymerase (PARP) activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of said salt, wherein the salt is crystalline."
Claim 9 corresponds to claim 1 reformulated in the Swiss-type format.
The decision under appeal references, among other things, the following documents cited as the prior art:
The matter was under appeal at the Boards of Appeal at EPO.
It was common ground between the parties that document D1 constituted the closest prior art. D1 (paragraphs [0002], [0003], and [0006]) addresses rucaparib or its salts as chemosensitizers. Given rucaparib's ability to inhibit PARP, it can be combined with chemotherapeutic agents to enhance their effectiveness in cancer treatment. Paragraph [0043] of D1 presents a list of approximately 60 pharmaceutically acceptable salts suitable for the invention. This list includes maleate, although the preferred salts are phosphate and gluconate. According to D1, the salts can be produced using the method defined in the paragraph.
Although the parties agreed that D1 was the closest prior art, they disagreed on whether the inventive step should be assessed based on the entire list of salts in paragraph [0043] or the specific disclosure of the maleate salt within that list.
In paragraph [0043] of D1, the maleate salt of rucaparib is not highlighted. D1 neither illustrates nor presents rucaparib maleate as a standalone embodiment. Paragraph [0043] is merely a theoretical disclosure, in which maleate is one option among a lengthy list of possibilities but is not listed as a preferred option. Isolating one of the many non-preferred options from paragraph [0043] to use it as the closest prior art would misinterpret the teaching of D1, assigning inappropriate significance to that option.
The respondent Generic UK contended that rucaparib maleate should be the starting point since D1 discloses it in an enabling manner. A skilled person could prepare rucaparib maleate without undue burden, for example, using the method proposed in paragraph [0051] of D1.
Therefore, rucaparib maleate should be regarded as an example and, in accordance with established case law, can thus serve as the starting point for assessing inventive step.
The Boards of Appeals stated that, regardless of whether a skilled individual could prepare rucaparib maleate without undue burden, the mention of rucaparib maleate in D1 is merely nominal. Rucaparib maleate is referenced as one potential option among many equally viable alternatives. D1 does not explicitly emphasize rucaparib maleate, nor does it provide guidance on how to prepare it. Therefore, rucaparib maleate lacks the disclosure status of an example, a standalone embodiment, or even a preferred option. Evaluating the inventive step based on rucaparib maleate would misrepresent the teaching of D1 and undermine an objective assessment of the invention's technical contribution.
Regarding the technical effect, the patent states that crystalline rucaparib maleate is particularly well-suited for preparing solid dosage forms (paragraph [0060]). It identifies and characterises two crystalline forms of rucaparib maleate, referred to as Form A and Form B. Form A can be prepared using the method disclosed in paragraph [0158]. Form B can be produced using the methods described in paragraphs [0159] and [0160].
As shown in the DSC thermograms in Figures 2 and 7, both Form A and Form B exhibit a single endothermic transition peak at high temperatures, indicating that both crystalline forms possess a high melting point and are neither hydrated nor solvated.
Additionally, Form B is non-hygroscopic and remains highly stable even in high temperature and humidity conditions (paragraphs [0079] and [0173], and Figure 8). These properties make crystalline rucaparib maleate particularly suitable for developing a solid formulation. This is supported by declarations D3 (paragraphs [0011] to [0014]) and D6 (point 5), whose content has not been contested by the respondent, Generics [UK] Ltd.
Considering this technical effect, the board concurs with the appellant Pfizer that the objective technical problem is to provide a rucaparib form with a suitable combination of properties for developing a solid dosage form.
The respondent, Generic UK, argued that the objective technical problem should be defined as providing a specific form of rucaparib maleate. However, this definition necessitates beginning with rucaparib maleate as the closest prior art, which the Boards of Appeal stated is an incorrect approach.
Regarding the issue of obviousness, the cited prior art does not indicate that crystalline rucaparib maleate could possess properties suitable for preparing a solid dosage form.
D1 does not address the formulation of rucaparib. It contains no information regarding whether any of the salts in the lengthy list in paragraph [0043] might be suitable for preparing a solid dosage form. It is common knowledge that identifying an active compound's salt with a balanced combination of properties ideal for a solid formulation is a challenging, semi-empirical task that requires non-routine experimentation and has an uncertain outcome. Therefore, the skilled person would need to examine each of the salts in paragraph [0043] of D1 to determine: first, whether it is solid; second, how many solid forms it can adopt; and third, whether any forms possess properties suitable for a solid formulation.
In this context, the appellant Pfizer cited documents D14, D10, and D8. Document D14 (abstract) presents the reasoning behind the selection of salts for the drugs. It summarises the various properties that must be investigated for an appropriate salt and the potential actions that may be necessary to modulate those properties. D10 is a review article stating on page 945 (in the first sentence of the paragraph bridging the columns) that "solid drug substances display a wide and largely unpredictable variety of solid-state properties. “ D8 is a declaration from an expert explaining in paragraph [0008] that finding a suitable salt for the solid formulation of a drug involves extensive experimentation.
It is also noteworthy that rucaparib phosphate, one of the two preferred salts according to D1, is unsuitable for solid dosage forms. As noted by the appellant Pfizer, D15 identified six crystalline forms and one amorphous form of rucaparib phosphate, some of which were hydrated and exhibited polymorphic instability. Similarly, the patent (page 10, lines 12 and 13) and declarations D6 (point 5) and D3(paragraphs [0015] and [0016]) acknowledged that rucaparib phosphate is susceptible to hydration and is therefore unsuitable for preparing solid dosage forms.
The Boards of Appeal recognised that many factors are involved in developing a new salt of a known substance. In this case, the skilled person would not be able to prepare rucaparib maleate without an undue burden of experimentation.
Therefore, the board concluded that claim 1 involves an inventive step. The patent was upheld.
The case is remitted to the opposition division with the order to maintain the patent in amended form based on the claims of the main request, filed as auxiliary request 3 with the statement of grounds of appeal, and, if necessary, to adapt a description and drawings accordingly.
Decision here
