API and IP Newsletter
Contents
Pharma Battling Legal Precedent in Medicare Drug Price Lawsuits
Digital Vision Pharma: Drug regulatory reforms will ensure safer healthcare.
FDA approval- Ritlecitinib
We generally follow FDA approvals of small molecules. The focus is mainly on chemistry, relevant IP filed by the innovator. We briefly comment on imports of raw materials which would require to synthesise API. We try and estimate active players and their development status. This month, one of the approvals by FDA is Ritlecitinib.
Ritlecitinib, an oral capsule is sold under the brand name Litfulo, is a medication used for the treatment of severe alopecia areata (hair loss). Ritlecitinib is a kinase inhibitor which inhibits Janus kinase 3 and tyrosine kinase. In simple terms it is used to treat severely patchy hair loss.
Chemical name of ritlecitinib is 1-[(2S,5R)-2-Methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-piperidinyl]-2-propen-1-one
Patent families
WO2015083028A1
Example 129 describes the compound.
Example 5 describes the process.
The US equivalent of this family would expire in 2034 but it could perhaps be extended till 2037.
The clinical studies were conducted with oral administration of Ritlecitinib at two different doses (10 and 50 mg tablets) using the material sparing tablet (MST) formulation. However, the MST formulation was found to be unstable as Ritlecitinib readily underwent dimerization and oligomerization. In addition, a noticeable transformation in appearance was also observed for blends and tablets with samples turning from white to yellow/brown over time or exhibiting an intense localized color change. The poor stability profile necessitated the use of refrigerated storage and foil packaging.
To overcome this Pfizer developed stable immediate release formulations comprising Ritlecitinib and filed patent application WO2021137160A1.
There are couple of other Chinese patent applications on processes and polymorphs of ritlecitinib.
Basic RM is 3-amino picoline and there are many CDMOs in India who are importing this basic intermediate in small quantities. Syngene, TCG, Sai, Jubilant, Albany, GVK. It seems many CROs are working on the API development or advance intermediate development for various clients.
General information
Pharma Battling Legal Precedent in Medicare Drug Price Lawsuits
Federal courts have struck down similar arguments
Drug companies eye Supreme Court to resolve dispute
Decades of legal precedent defending the authority of Congress and the Medicare agency threaten to stand in the way of the pharmaceutical industry’s pursuit to stop the federal government from negotiating lower drug prices, lawyers and drug pricing analysts say.
News here.
Digital Vision Pharma: Drug regulatory reforms will ensure safer healthcare.
As a global powerhouse in the production of generic drugs, the Indian pharmaceutical industry plays a vital role in meeting the healthcare needs of millions worldwide. However, instances of substandard and harmful drugs have underscored the urgent need for regulatory reforms to ensure enhanced safety and patient well-being. These concerns have prompted the industry to undertake regulatory improvements, with companies like Digital Vision Pharma leading the charge in prioritizing compliance and patient safety.
News here
Intellectual Property
Boehringer Ingelheim International GmbH (BI) Vs Teva et al.
Pharmaceutical dosage form for immediate release of nintedanib esilate
European patent 2 313 087 was issued to Boehringer Ingelheim International GmbH and granted on the basis of ten claims. Claim 1 of the patent read as follows:
"Pharmaceutical dosage form of the active substance nintedanib esilate, which delivers an immediate release profile in which not less than 70% (Q65%) of the active substance is dissolved in 60 minutes in vitro under the following in vitro dissolution conditions according to European Pharmacopeia 6.2: Apparatus 2 (paddle), dissolution medium with 0.1 M HCl (pH 1) and stirring speed of 50 to 150 rpm, at a temperature of 37°C and which comprises a viscous lipid suspension formulation comprising 10 to 50 weight% of the active substance, 10 to 70 weight % of medium chain triglycerides, 1 to 30% weight % of hard fat and 0.1 to 10 weight % of lecithin, based on the total weight of the viscous lipid suspension formulation."
MCT refers to medium chain triglycerides.
Three oppositions were filed against the patent on the grounds that its subject-matter lacked novelty and inventive step, it was not sufficiently disclosed and it extended beyond the content of the application as filed.
There were initially three opponents
Teva Pharmaceutical Industries Ltd.
Generics (U.K.) Limited
Ter Meer Steinmeister & Partner Patentanwälte mbB
Ter Meer withdrew the opposition later.
In this write-up we will discuss inventive step.
The auxiliary request filed and in claim 1 of this auxiliary request 1, the definition of the viscous lipid suspension formulation was amended to “a viscous lipid suspension formulation of 10 to 50 weight% of the active substance in 1 to 70 weight % of medium chain triglycerides, 1 to 30 weight % of hard fat and 0.1 to 10 weight % of lecithin, based on the total weight of the viscous lipid suspension formulation”.
The appealed decision cited the following documents among others:
D2: L. Lachman, "The Theory and Practice of Industrial Pharmacy", 3**(rd) edition, Lea & Febiger, 1986, pages 398-412
D3: W. Fahrig, U. Hofer, "Die Kapsel - Grundlage, Technologie und Biopharmazie einer modernen Arzneifom", Wissenschaftliche Verlagsgesellschaft mbH, 1983, pages 60-63
D4: R. C. Rowe, "Handbook of pharmaceutical excipients", 5**(th) edition, Pharmaceutical Press, 2006, pages 409-411
D6: WO 2004/013099 A1
D7: US 4829057 A
D15: Oral lipid-based formulations, Drugs and pharmaceutical sciences, vol. 170, David J Hauss, 2007, page 88
D16: Protein based films and coatings. Chapter 16: Soft Gelatin Capsules, edited by A. Gennadios, 2002, pages 393-443
The opposition division first instance decided that:
(a) Claim 1 of the main request introduced added subject-matter.
(b) Auxiliary request 1 met the requirements of Article 123(2) EPC. Its subject-matter was sufficiently disclosed.
The closest prior art : D6
Starting from the closest prior art D6, the subject-matter of claim 1 differed in that it defined a dosage form which comprised a viscous lipid suspension of nintedanib esilate in MCT, hard fat and lecithin, in the amounts claimed, and that the dosage form delivered a specific release profile as claimed.
Objective Technical Problem
The technical problem was the provision of a pharmaceutical dosage form comprising nintedanib esilate having acceptable bioavailability, low inter-individual variation, and delivering an immediate release as claimed. The claimed solution involved an inventive step.
The matter then went into appeal, ie 2nd instance.
Following documents added as prior art in appeal proceedings.
D26: GB395546
D27: US 2,720,463
D28: US 2,870,062
D29: Fiedler Encyclopedia of Excipients, 6**(th) edition, 2007, pages 1326-1327 (filed by appellant O1 as D26)
Obviousness discussions in appeal proceedings
It is not contested that the carrier components recited in claim 1 (MCT, hard fat and lecithin), and their use for formulating suspensions for soft gelatine capsules, were part of common general knowledge at the priority date.
The relevant question is however, whether the prior art would have motivated the skilled person to combine the claimed components in the claimed amounts in the expectation of solving the technical problem.
This question must be answered in the negative, because the prior art contains no hint that the addition of lecithin in the claimed amounts would have such a significant effect on dissolution and would allow the achievement of the claimed immediate release properties.
There is in particular no basis in Teva and Generic UK’s contention that the wetting properties mentioned in D2 would be equated with an effect on solubilisation, as opposed to being related to contact angle on surfaces.
Teva and Generic UK further argued that the skilled person reading D6 would have turned to the document D7 cited therein as regards the soft gelatine capsule formulation, and that D7 disclosed the claimed ingredients.
The Board did not share this view either.
Firstly, the relevant passage of D6 states:
"An especially suitable pharmaceutical formulation for the compounds in accordance with the present invention is soft gelatine capsules. Suitable soft gelatine capsules for the encapsulation of pharmaceutical compounds and the process for their preparation are described, for example,…" followed by references to D26, D27, D28 and D7 among others.
As argued by Patentee BI, the wording "for the encapsulation" does not indicates that the subsequent references relate to the formulation of the capsule filling (i.e. in the present case, the liquid suspension), but rather to the composition of the encapsulating gelatine shell.
This is confirmed by the fact that most references in this passage of D6 only disclose shell compositions, and processes for their preparation, but no filling formulation.
In this list, only example 3 of D7 discloses a soft gelatine capsule filling formulation, albeit applied to a different active pharmaceutical ingredient (namely oxytetracycline).
Accordingly, there is no motivation in D6 for the skilled person to turn to any of the references therein for the formulation of the liquid suspension filling, or to use the formulation of example 3 of D7 as such for the different active ingredient nintedanib esilate.
Secondly, example 3 of D7 describes soft gelatine capsules of crystalline oxytetracycline containing an inert fill comprising Miglyol 812 (an MCT in the sense of the patent, see paragraph [0042]), bees wax, hydrogenated vegetable oils and soy lecithin.
D7 however neither discloses the amounts of these components, nor the use of a hard fat. There is no evidence that the hydrogenated vegetable oils mentioned in D7 generally qualify as hard fat.
Accordingly, the board decided that the subject-matter of auxiliary request 1 involves an inventive step.
Case here
