Patent layout of the world's first Duchenne muscular dystrophy new drug eteplirsen

Author | Dot Mercy

Eteplirsen was first developed by the University of Western Australia (UWA) and licensed to Sarepta Therapeutics (the company was founded in 1980, formerly known as AVI BioPharma).
Its molecular formula is C364H569N177O122P30, and its molecular weight is 10305.
7 Daltons.
Containing 30 base sequences, 39 morpholine rings, and 1 piperazine ring, it is an antisense oligonucleotide of the phosphorodiamide morpholino oligomer (PMO) subclass
.

Etrison was listed in the United States on September 19, 2016, but the European application was rejected.
Its mechanism of action is to target the defective DMD dystrophin gene transcript, remove non-functional parts and produce fully functional muscular nutrition Bad protein
.

Figure 1 Eteplirsen structure diagram

Eteplirsen is the first DMD drug approved by the FDA.
The approval decision is not based on strict scientific data, such as insufficient clinical data, unreasonable clinical trial design, and data from 13 patients that compare 48-week samples and benchmark samples, dystrophin The protein was only increased to about 0.
22% to 0.
32% of normal, and it was approved for marketing under pressure from the patient's family.
Therefore, Eteplirsen is definitely an example of the FDA's new drug approval history
.

Source: NextPharma

Patent layout

Oligonucleotide drug patents usually limit the characteristics of base sequence, nucleotide modification (phosphate, ribose, nitrogenous base), binding region, etc.
Therefore, the analysis of its patent not only focuses on the substance structure itself, but also needs to incorporate its commonly used modifications.
Technology and other aspects to comprehensively judge the layout of patents
.

Table 1 Summary of Eteplirsen's original patents

Data source: Medical Rubik's Cube NextPat

It can be seen from Table 1 that the layout of Eteplirsen patents is relatively reasonable, involving patent types such as drug sequences, compounds, preparations, compositions, preparation methods, and medical uses; the core patent-related sequences and compounds not only protect the specific compound structure, but also protect the horse Kush structure; peripheral patents are mainly protected around medical uses and preparation methods
.

Although the independent claims of patent application CN108699555A require protection for the treatment of Duchenne muscular dystrophy and related diseases, its claim 67 requires protection of the fragment structure of branched-chain hydroxyethoxycarbonylmorpholine phosphorodiamide.
The specific structure is shown in Figure 2.

.

Figure 2 Eteplirsen branched chain fragment structure

In addition, the patents involved in the nucleic acid modification method phosphorodiamide morpholino oligomer (PMO) are shown in Table 2.
This patent has not entered China, and all the US patents of the same family have passed the patent protection period.
Therefore, the nucleic acid modification method PMO The technology has no patent barriers
.

Figure 3 PMO structure

Table 2 PMO technology related patents

Data source: Medical Rubik's Cube NextPat

Due to the influence of factors such as Terminal Disclaimer (TD), Patent Term Adjustment (PTA), Patent Term Extension (PTE) and other factors, the calculation method of the US patent protection period is more complicated.
Table 3 summarizes Eteplirsen The expiry date of the original research part of the patent is for reference
.

Table 3 Summary of the protection period of Eteplirsen's original patents

Data source: Medical Rubik's Cube NextPat

Patent litigation

Sarepta announced the transaction and litigation settlement agreement with BioMarin on the official website of 2017-07-18.
BioMarin licenses the global rights and interests of EXONDYS 51 and all future exon skipping products for the treatment of DMD patents to Sarepta.
If BioMarin decides to externally display DMD Sub-jump treatment, BioMarin reserves the right to convert the license to a joint exclusive right
.

Sarepta and BioMarin executed a settlement agreement to resolve ongoing global patent litigation related to the use of EXONDYS 51 and all future exon skipping products to treat DMD.
The validity of the agreement depends on the closing conditions, including on July 24, 2017 Previously obtained the necessary approvals from Academy Ziekenhuis Leiden (AZL)
.

In addition, Sarepta will pay BioMarin milestone payments as follows:

① Exon skipping compounds 51, 45 and 53 and possible future exon skipping products: By the end of 2023, Sarepta will pay 5% of BioMarin's net sales;

②Exon skipping compounds 51, 45 and 53 and possible future exon skipping products: By September 30, 2024, Sarepta will pay BioMarin 8% of its net sales, and own certain products in the European Union and others.
Countries/regions of BioMarin/AZL patents
.

Licensed patent: US10190116B2 (Exon 51 antisense oligonucleotide treatment of DMD, Academicch Ziekenhuis Leiden (AZL) licensed to BioMarin)
.

Figure 4.
Announcement on Sarepta's official website

Concluding remarks

Although the listing process of Eteplirsen is relatively difficult and the clinical trial data it is based on is unreasonable, it can alleviate the pain for patients, that is the ultimate significance of being approved for listing.
Let us start from this review price.
It cannot be denied
.

There is no patent barrier in the phosphorodiamide morpholino oligomer (PMO) modification technology of antisense oligonucleotides.
Therefore, this is also the current commonly used modification technology for nucleotides
.