API and IP Newsletter

 Contents

• Recent P-IV filings

• General information

• 1910 Genetics Launches CANDID-CNS™, an AI Model for Blood-Brain Barrier Permeability Prediction that Outperforms the Industry Standard

• Amicus Therapeutics Announces Settlement of Galafold® (migalastat) Patent Litigation with Teva

• Intellectual Property

• EP 3256472: Ensifentrine (Verona Pharma PLC)

Recent P-IV filings

We follow P-IV filings on the USFDA website. 

As readers of this newsletter would know about paragraph IV (P-IV) certifications.  

Under the Hatch-Waxman Amendments, a company can seek FDA approval to market a generic drug before the expiration of patents related to the brand-name drug that the generic seeks to copy.

To seek this approval, a generic applicant must provide in its application a "certification" that a patent submitted to FDA by the brand-name drug's sponsor and listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) is, in the generic applicant's opinion and to the best of its knowledge, invalid, unenforceable, or will not be infringed by the generic product. This certification is called a "paragraph IV certification."

More information about P-IV filings can be found here.  

Drug Name	Comments
Isavuconazonium Sulfate Dosage Form For Injection Strength 372 mg/vial RLD/NDA: Cresemba/ 207501	As per the FDA website, 2 ANDAs were submitted on 06 September 2024.  The Brand is planning a paediatric label extension for the US, with the potential to extend market exclusivity in the US by six months to September 2027.  The public domain does not indicate US sales of Cresemba, but global sales of this anti-fungal medicine are about USD 400 million.  Glenmark, Cipla, Hetero, MSN, and Lupin imported innovator samples, and two of them could have filed ANDAs post-GAIN exclusivity.
Clascoterone Dosage Form Cream Strength 1% RLD/NDA: Winlevi/ 213433	As per the FDA website, 1 ANDA was submitted on 26 August 2024.  Sun Pharma and Cassiopea, a subsidiary of Cosmo Pharmaceuticals N.V., signed the License and Supply Agreements for WINLEVI (clascoterone) cream 1%, expanding the territory to include Japan, Australia, New Zealand, Brazil, Mexico, and Russia, along with the USA. The analyst is maintaining a below-street expectation for Winlevi and peak sales at ~US$60mn. Here. Glenmark signed with the innovator for supply in Europe and South Africa.  WINLEVI is approved in the U.S. for the topical treatment of acne vulgaris in people aged 12 and older.  Dr. Reddys, Macleods, Aurobindo, Lupin, and EnCube imported innovator samples, and one of them could have filed an ANDA on the NCE-1 date.  The brand must be using crystalline form IV, and it is protected till 2029. Generic would have circumvented this patent.

General information

1910 Genetics Launches CANDID-CNS™, an AI Model for Blood-Brain Barrier Permeability Prediction that Outperforms the Industry Standard

CANDID-CNS™ achieved an 83% success rate for predicting small molecule brain penetration and distribution versus a 64% success rate for the industry standard, CNS Multiparameter Optimization (CNS-MPO) score. Importantly, CANDID-CNS™outperformed all other industry benchmarks, regardless of the metric used for CNS penetration and distribution, e.g., site of action, 

News here

Amicus Therapeutics Announces Settlement of Galafold® (migalastat) Patent Litigation with Teva

Amicus Therapeutics (Nasdaq: FOLD) has announced a settlement in the Galafold® (migalastat) patent litigation with Teva Pharmaceuticals. The key points of the agreement are:

1. Amicus grants Teva a license to market a generic version of Galafold® in the United States starting January 30, 2037, subject to FDA approval.

News here 

Intellectual Property 

EP 3256472: Ensifentrine (Verona Pharma PLC)

This decision concerns the appeal filed by the patent applicant (Verona Pharma PLC) against the examining division's decision to refuse European patent application No. 16 704 896.6, ie EP 3256472. 

The patent relating to Ensifentrine and its composition. The EMEA has not yet approved Ensifentrin, but the USFDA approved it in June 2024 for the maintenance treatment of chronic obstructive pulmonary disease (COPD). 

This invention relates to certain salts of Ensifentrine, which have been found to have desirable intrinsic dissolution rates, which can lead to improved bioavailability. 

Particular salts of Ensifentrine, claimed in this invention, have also been well suited to pressurised metered dose and dry powder formulations.

Certain salts of RPL554/ Ensifentrine have also been found to have better thermal stabilities than other salts. Such salts are desirable as they are resistant to temperature variation without changes in form and stable to changes in humidity.

Accordingly, the present invention provides a pharmaceutically acceptable acid addition salt of:

(i) 9, 10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2- aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6, l-a]isoquinolin-4-one (RPL554/ Ensifentrine); and

(ii) ethane- 1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid

The decision under appeal is based on a single claim request. 

The examining division considered that the subject matter of claim 1 was not novel over the D1-WO 2012/020016 A1. About the inventive step, the examining division expressed a positive opinion in an obiter dictum on the subject matter of claim 3.

This write-up will discuss the arguments for the novelty and inventive step. 

The claims which were contested read as follows: 

Claim 1

"A pharmaceutically acceptable acid addition salt of:

(i) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2- aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,l-a]isoquinolin-4-one (RPL554/Ensifentrin); and

(ii) ethane-1,2-disulfonic acid,

or a solvate thereof, wherein the pharmaceutically acceptable acid addition salt or solvate thereof is a solid."

Claim 3

"A pharmaceutical composition which is a dry powder comprising a pharmaceutically acceptable acid addition salt as defined in claim 1 or 2 and a pharmaceutically acceptable excipient or carrier."

Claim 4

"A pharmaceutically acceptable acid addition salt as defined in claim 1 or 2 for use in the treatment of the human or animal body."

Claim 5

"A pharmaceutically acceptable acid addition salt as defined in claim 1 or 2 for use in the treatment or prevention of a disease or condition selected from asthma and chronic obstructive pulmonary disease (COPD)."

2. Thus, the independent claims essentially relate to the solid acid addition salt of RPL554, i.e.

 with ethane-l,2-disulfonic acid (claim 1), a pharmaceutical dry powder composition comprising it (claim 3), and its first (claim 4) and second medical use (claim 5).

Novelty (Article 54 EPC)

1. Claim 1 of the set of claims on which the decision under appeal is based relates not only to a pharmaceutically acceptable acid addition salt of RPL554/ Ensifentrin and ethane-1,2-disulfonic acid but also to salts formed between RPL554/ Ensifentrin and other acids, namely ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, phosphoric acid and sulfuric acid. 

2. The examining division objected to claim 1 as not being novel only for some other acids. 

3. It considered the acid addition salt formed between RPL554/ Ensifentrin and ethane-1,2-disulfonic acid to be novel.

4. The board agreed. D1 does not disclose ethane-1,2-disulfonic acid or salts derived from it.

Thus, the Board said the subject matter of claim 1, the other independent claims 3 to 5, and the dependent claims 2 and 6 are novel over the cited prior art.

Inventive step 

1. The board agreed with the examining division's view, expressed in its obiter dictum, that D1 represents the closest prior art.

2. D1 (e.g. claim 1) relates to RPL554 and its solid forms.

3. The subject matter of claim 1 is distinguished from solid RPL554/ Ensifentrin as disclosed in D1 in that it relates to a salt of RPL554 with ethane-1,2-sulfonic acid.

4. The application (table 6) discloses that RPL554 (Ensifentrin) ethane-1,2-disulfonate has a much higher solubility in 0.7 w/w% and 0.9 w/w% saline than RPL554.

5. Of the numerous RPL554 (Ensifentrin ) salts tested (phosphate, methane sulfonate, ethane-1,2-disulfonate, hydrochloride, sulfate, benzenesulfonate, ethanesulfonate, hydrobromide, p-toluenesulfonate, naphthalene-2-sulfonate and naphthalene-1,5-disulfonate), RPL554/ Ensifentrin ethane-1,2-disulfonate has the third and second highest solubility in 0.7 w/w% and 0.9 w/w% saline, respectively.

6. The application (tables 14 and 22) also evaluates the performance of RPL554/ Ensifentrin and various salts of it in a dry powder inhaler. 

7. To this end, RPL554/ Ensifentrin and its salts were micronised to a degree required for formulation as a respiratory product (D(0.9) < 5 μm) and mixed with lactose, and the formulations were aerosolised. 

8. The formulation containing RPL554 ethane-1,2-disulfonate had a significantly higher percentage of fine particles (< 5 μm) in the aerosol output (fine particle fraction, FPF) than that containing RPL554/Ensifentrin alone (RPL554 ethane-1,2-disulfonate, 40.39%; RPL554, 35.20%). 

9. Of the numerous RPL554/Ensifentrin salts tested (methane sulfonate, ethane-1,2-disulfonate, hydrochloride, sulfate, benzenesulfonate, ethanesulfonate, hydrobromide and p-toluenesulfonate), RPL554/ Ensifentrin ethane-1,2-disulfonate had the second highest FPF.

10. The appellant (Verona Pharma ) argued that a high FPF was beneficial, allowing more of the formulation to penetrate deep into the lungs. 

11. The Board, therefore, decided, starting from RPL554/ Ensifentrin as disclosed in D1, the objective technical problem is to provide a form of RPL554/ Ensifentrin that makes it more suitable for the treatment of respiratory diseases with a dry powder formulation.

12. Even if the skilled person had contemplated the formation of the ethane-1,2-disulfonate of RPL554/ Ensifentrin to increase its solubility in general and in various salt solutions (0.7 w/w% and 0.9 w/w% saline), the skilled person would not have had a reasonable expectation of success of obtaining a form of RPL554/ Ensifentrin with such a beneficial combination of properties as shown in the application, i.e. in terms of solubility and FPF.

13. This reasoning applies mutatis mutandis to the subject matter of the other independent claims 3 to 5 and the dependent claims 2 and 6.

Therefore, the Board said the subject matter of the main request involves an inventive step, and the main request is allowable. The case was remitted to the examining division with the order to grant a patent. 

Decision here