API and IP Newsletter

 

Contents

• Analysis of 505 (b) (2)s approved in the year 2018
• General information
• FDA grants fast track status to Rznomics’ RZ-001 for HCC
• Sandoz to pay $275 million to settle drug price-fixing case
• Intellectual Property
• T 0295/22 (Orally administered apremilast/AMGEN)

 

Analysis of 505 (b) (2)s approved in the year 2018

 

From time to time, we analyse the 505 (b) (2) applications approved each year. Recently, we analysed the applications approved in 2018. The details of our analysis are provided below.

1. In 2018, there were around seventy-eight NDA (505 (b)(2)) approvals. Additionally, six tentative approvals (TA). They (TAs) are not included in this analysis.

2. Of the 78 NDAs, 36 are oral solids, including tablets, capsules, films, oral suspensions, and three sublingual forms.

3. Of the 36 approved NDAs for oral solid dosages [505 (b) (2)], 12 were discontinued, including all three sublingual dosage forms. Approximately 33% of oral solid dosage form NDAs [505 (b) (2)] never reach the market or are discontinued for various reasons. This may be due to market conditions or technical issues.

4. Three NDA [505 (b) (2)] approvals were for oral solutions, and three were for oral suspensions. All six NDAs [505 (b) (2)] are in the market, and oral solutions and suspensions approved in 2018 have not been discontinued.

5. A total of 21 injectable dosage forms were approved, and seven were discontinued. Thus, 33% of injectable NDAs [505 (b) (2)] have been discontinued.

 

We will publish our detailed analysis later.

General information

 

FDA grants fast track status to Rznomics’ RZ-001 for HCC

The US Food and Drug Administration (FDA) has granted fast track designation to Rznomics’ RZ-001 for the treatment of hepatocellular carcinoma (HCC), a form of liver cancer.

This is the second such designation for the gene-therapy-based drug, following a previous status for glioblastoma in November 2023.

 

News here

 

Sandoz to pay $275 million to settle drug price-fixing case

Swiss generic drug manufacturer Sandoz has agreed to pay $275 million to resolve claims by U.S. consumers and others who accused the company of conspiring with industry rivals to illegally fix prices.

Sandoz denied any wrongdoing in agreeing to settle. The company said it will cooperate with the plaintiffs as they pursue claims against other drugmakers.

 

News here

Intellectual Property

 

T 0295/22 (Orally administered apremilast/AMGEN)

 

This opposition is regarding EP 2962690. SPC granted till March 2028. The patent was issued to Amgen.

 

Fifteen oppositions were filed against the patent grant, arguing that its subject matter lacked novelty and an inventive step, that the claimed invention was not sufficiently disclosed, and that the patent covered subject matter extending beyond the application's originally filed content.

 

The opposition division (first instance) determined that the patent, amended according to auxiliary request 3, fulfilled the requirements of the EPC. The patentee, Amgen (Europe) GmbH, and 12 opponents filed appeals against this interlocutory decision.

 

This write-up will briefly discuss arguments concerning inventive step. Two sets of claims were considered by the Boards of Appeals.

 

“Main Request A”

 

Claim 1 of the new main request defines:

"A compound which is stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione (apremilast) comprising greater than 80% by weight of the (+) enantiomer and less than 20% by weight of the (-) enantiomer, or a pharmaceutically acceptable polymorph, salt, solvate or hydrate thereof for use as a medicament, wherein the medicament is administered orally."

 

Claim 4 of the new main request defines:

"Use of stereomerically pure apremilast comprising greater than 80% by weight of the (+) enantiomer and less than 20% by weight of the (-) enantiomer, or a pharmaceutically acceptable polymorph, salt, solvate or hydrate thereof, for the manufacture of a medicament for the treatment or prevention of an inflammatory disease, wherein the medicament is administered orally."

 

"Main request B"

The auxiliary request "Main request B" only comprises claims in the format of the use of the compound in the manufacture of a medicament. Independent claim 1 of this request defines:

"Use of stereomerically pure apremilast comprising greater than 97% by weight of the (+) enantiomer and less than 3% by weight of the (-) enantiomer, or a pharmaceutically acceptable polymorph, salt, solvate or hydrate thereof, for the manufacture of a medicament for the treatment or prevention of an inflammatory disease, wherein the medicament is administered orally, and wherein the inflammatory disease is psoriasis or Behçet's disease."

 

Prior Art

Following, prior art documents were cited.

 

D1: US 6,020,358

D72: Exp. Opin. Ther. Patents (2002) 12(1): 93-111

D73: Exp. Opin. Ther. Patents (1999) 9(8): 1101 -1118

D74: Declaration by Prof. R. Knowles, 19 August 2020

D76: Current Pharmaceutical Design (2002), 8(14):1255- 1296

D92: Chemical Biology (2001), vol. 5:432-438.

 

 

Document D1 describes compounds with a general formula exemplified by various specific compounds, including, in example 12, the racemate of apremilast. It discloses that these compounds act as inhibitors of PDE3 and PDE4, decrease levels of TNF-alpha, and are useful in the treatment of inflammatory diseases, among other things. Additionally, Document D1 specifically teaches that the individual enantiomers of the disclosed compounds, which may have an optical purity of over 95%, fall within the scope of the disclosed invention.

 

Difference with the prior art

The claimed subject matter differs from the teaching in document D1, in particular, the disclosure of apremilast in a form with an optical purity of more than 95% as an example of compounds described as inhibiting PDE3 and PDE4, decreasing the levels of TNFalpha, and being useful in treating inflammatory diseases. This difference concerns the feature of the oral administration of this particular compound.

 

The opponents contested this difference, arguing that oral administration was disclosed in document D1 as the preferred route of administration due to the prominent references to specific oral dosage forms and the fact that out of six examples of actual pharmaceutical formulations, five pertained to compositions for oral administration. 

 

The patent proprietor argued, referencing the considerations in the previous decision of the Boards of Appeals (T 1126/19), that selecting apremilast from the list of exemplified compounds and their enantiomers in document D1 constituted an additional distinction from the closest prior art.

 

Formulation of the objective technical problem

The EP opposition places a lot of emphasis on the problem-solution approach.

Any conclusion that extends beyond what a skilled person would have objectively inferred from the prior art, without the benefit of hindsight regarding the invention, necessarily conflicts with a proper application of the problem-solution approach.

 

The opponents described the objective technical problem as finding an alternative or suitable administration route for stereomerically pure apremilast. The Board disagreed with this definition, stating that it does not take the relevant effects into account.

 

The patent proprietor formulated the objective technical problem as the provision of a compound that, when administered via the chosen route, provides a safe, well-tolerated, and effective treatment for PDE4-mediated diseases.

 

The Board also disagreed with this formulation because it pertains to the provision of a compound, while stereomerically pure apremilast, recognised as an anti-inflammatory compound with PDE4 inhibitory activity, was already established as the starting point in the prior art.

 

The Board defined the objective technical problem as providing an administration route for stereomerically pure apremilast that enables safe and well-tolerated effective treatment for PDE4-mediated diseases.

 

Decision

The Board considered that the reported challenges related to the oral administration of PDE4 inhibitors highlight the skilled person's strong motivation to pursue this route, as it typically represents their first choice for the systemic delivery of pharmaceutical agents due to its ease of administration.

 

Documents D72 and D76 evidence this, reporting positive results concerning the oral administration of the PDE4 inhibitors cilomilast and roflumilast. Therefore, no established prejudice against the oral administration of PDE4 inhibitors would have prevented the skilled person from administering apremilast via the oral route.

 

The Board considered that the prior art gave the skilled person a reasonable expectation that the oral administration of stereomerically pure apremilast would ensure a safe and well-tolerated treatment for PDE4-mediated diseases.

 

The Board determined that, in this case, the reasonable expectation that orally administered apremilast provides safe and tolerable effective treatment takes precedence over any unforeseen levels of PDE4 selectivity, the therapeutic index concerning emesis, or the solubility of stereomerically pure apremilast as reported in the patent, considering the compelling motivation to administer PDE4 inhibitors via the oral route.

 

Consequently, the Board determined that the subject matter of "Main request A" does not involve an inventive step.

 

The patent proprietor submitted "Main Request B" on the second day of the oral proceedings after the Board determined that the subject matter of "Main Request A" lacked an inventive step. 

 

The submission of "Main request B" is not warranted by any extraordinary circumstance. Consequently, the Board has decided not to include this request in the appeal proceedings.

 

The patent has been revoked. This decision increases the likelihood that generic launches of apremilast in Europe could occur after the expiration of market exclusivities by July 2025.

 

Decision here