API and IP Newsletter
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List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic
List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic
The FDA maintains a list of approved new drug application (NDA) drug products that are no longer protected by patents or exclusivities and for which the FDA has not approved an abbreviated new drug application (ANDA) referencing that NDA product. The FDA updates this list every six months (in June and December).
The new list is updated last week.
Starting in December 2021, FDA publishes two versions of the list, one for prescription drug products and one for over-the-counter drug products that are approved and marketed under an NDA.
The prescription and over-the-counter lists are both separated into three sections:
Part I identifies those drug products for which FDA could immediately accept an ANDA without prior discussion.
Part II identifies drug products for which ANDA development or approval may raise potential legal, regulatory, or scientific issues that should be addressed with the Agency prior to considering submission of an ANDA.
The Appendix identifies NDA drug products that were removed from Part I or Part II of the list because one or more ANDAs referencing such NDA drug products have been approved since the previous list publication.
More details could be found here.
We have identified tablet dosage forms from these lists, where there’re approved NDA drug products that are no longer protected by patents or exclusivities, and for which the FDA has not approved an ANDA. The list is as follows.
Now, why this information is important?
These could be the potential products where generic manufacturer could apply for CGT designation at FDA ie Competitive Generic Therapies (CGT).
The CGT designation provides manufacturers with the approval pathway to review of generic drugs which lack competition. Above table is a representative of products which lack competition.
The CGT approval process includes pre-ANDA meetings that help applicants understand FDA’s expectations. These meetings could reduce the number of review cycles.
The most importantly, it provides the applicant with an opportunity of 180 day Competitive Generic Therapies (CGT) exclusivity to reward the efforts and investments made by the applicant.
General information
USFDA highlights quality concerns over drugs manufactured in India
Data integrity problems were found in bioavailability and bioequivalence studies conducted by contract research organisations (CROs). These data integrity issues found in Indian manufacturers, included falsified pharmacokinetic (PK) data which is the study of how the human body interacts with administered substances, deliberate distribution of subject data into distinct cohorts to pass the bioequivalence study, questionable practices in reanalysing samples schemes and deficiencies poor quality management of systemic procedures.
News here
The top 5 emerging startups fuelling drug discovery with AI
Artificial intelligence is showing great promise in the quest to unearth new drug candidates and disease targets faster than ever before.
News here
Intellectual Property
T 0091/22 Pharmaceutical Composition of Raltegravir Containing An Anti-Nucleating Agent
EP 1819323 is Assigned to Merck Sharp and Dohme LLC
Independent claim 1 as granted read as follows:
"1. A pharmaceutical composition for oral administration as a solid dose, which comprises:
(a) from 0.5 to 20 wt.% of an anti-nucleating agent which comprises hydroxyalkylcellulose, and
(b) an effective amount of from 5 to 75 wt.% of a potassium salt of Compound A, wherein Compound A is: Raltegravir
Cited prior art documents
The appeal lies from the decision of the opposition division finding that the patent in amended form meets the requirements of the EPC.
This is a lengthy decision, we will analyse only Inventive Step discussion (From Auxiliary Request-3)
The claimed invention relates to a composition for oral administration that includes the potassium salt of compound A that converts to a less soluble form under certain acidic conditions. The composition comprises an anti-nucleating agent for solving this problem
D1 was considered to represent the closest prior art by the opposition division in its decision. Both parties agreed to this choice.
D1 relates to N-substituted hydroxypyrimidinone carboxamide as inhibitors of HIV integrase. One of the compound disclosed in D1 is compound A in its free acid form, namely compound 24 on page 161, which is also exemplified on page 130 (example 19), and is mentioned in claim 28 on page 207, lines 18-20. Said Compound A is disclosed in D1 among a great number of alternative N-substituted hydroxypyrimidinone carboxamide.
D1 mentions the possibility to administer the compounds disclosed therein in the form of pharmaceutically acceptable salts, such as inter alia potassium salts, but also sodium, calcium, magnesium, quaternary ammonium salts. Some ways and forms of administration are disclosed on page 62, lines 27-33. Page 63, lines 24-30 refers to tablets, capsules, nasal sprays, injectable suspensions as possible dosage forms.
The opposition division concluded in its decision that the differences between claim 1 and the closest prior art were the use of a specific potassium salt of compound A in the specific amount and in its combination with a specific amount of an anti-nucleating agent comprising hydroxyalkylcellulose. The Board agreed with this conclusion, since document D1 does neither disclose compound A as potassium salt nor the presence of an anti-nucleating agent in the claimed amounts.
The opposition division defined the problem as the provision of a novel pharmaceutical formulation comprising compound A having certain suitable bioavailability.
The appellant-opponent (Kraus & Lederer PartGmbB) disagreed with the opposition division and defined the problem as the provision of an alternative formulation of the potassium salt of compound A.
Examples 4 and 5 and D15 were cited to support the existence of an effect by the patentee Merck Sharp and Dohme.
D15 shows that tablets comprising HPMC provide a quick dissolution.
An improvement in solubility and bioavailability linked with the presence of HPMC is shown in examples 4 and 5 of the patent.
Example 4 shows a comparison among tablets comprising 0, 5, 10 or 15wt% HPMC, and show indeed a two-fold improvement in the dissolution for tablets containing HPMC in comparison to the tablets with 0 wt% of HPMC; tablets with 10 or 15 wt% exhibited a slower dissolution than the tablets with 5 wt% of HPMC, but achieved prolonged supersaturation.
Example 5 is a pharmacokinetic study and a comparison between a tablet comprising the potassium salt of Compound A ie Raltegravir and either 5 wt.% of HPMC or 5 wt.% of methlycellulose. It shows a 2-fold improvement in the AUC value for the tablet with 5 wt.% of HPMC versus the tablet comprising 5 wt.% of methylcellulose.
In the Board's view, the improvement shown in examples 4 and 5 is extrapolable to any hydroxalkylcellulose. Hence, already in view of the examples of the patent, the problem can be as defined as the provision of a novel pharmaceutical formulation comprising compound A ie Raltegravir having suitable bioavailability.
With regard to obviousness, it is known from the teaching of several cited documents, such as D3, D4 or D5, that hydroxyalkylcellulose polymers were known and used for improving the water solubility of drugs or as anti-nucleating agents.
D3 teaches the inhibitory effect of HPMC on the precipitation of a poorly water soluble drug PNU-91325.
D4 discloses the effects of water-soluble polymers on precipitation of the drug RS-8359. D4 discloses explicitly that the polymers inhibited the nucleation of the compound in the supersaturated solution (see page 64).
D5 discloses HPMC as anti-nucleating agent for decreasing the crystallization of hydrocortisone acetate.
The Board does not contest that it was known that hydroxyalkylcellulose polymers were known and used for improving the water solubility of drugs or as anti-nucleating agents.
The question with regard to obviousness is in the present case whether the skilled person, starting from D1 as closest prior art, would have been incited to choose all the features disclosed therein and combine them with the teaching of the other cited documents to arrive at the claimed subject-matter, in order to provide a pharmaceutical formulation comprising compound A ie Raltegravir and having certain suitable bioavailability, and not whether the skilled person could have done so.
There is however no incentive in D1 or any other cited document to combine the potassium salt of Raltegravir with an anti-nucleating agent comprising hydroxyalkylcellulose.
The fact that Raltegravir and its potassium salt is a drug that converts to a less soluble form of the drug under certain acidic conditions was not known at the effective filing date of the contested patent. There was therefore no reason to envisage an option to improve the solubility of the claimed compound, even the use of anti-nucleating agents which is one option among many others. For this reason alone, the claimed solution is not obvious.
Accordingly, the Board concluded that auxiliary request 3 meets the requirements of Article 56 EPC.
Decision here
