Recent P-IV filings and Novartis- Siremadlin decision by EPO

Contents

Recent P-IV filings

General information

Recent FDA Actions Pose Big Changes and Questions for Health and Food Industries

FDA Approves Kirsty as First Interchangeable Insulin Aspart Biosimilar

Intellectual Property

Novartis- Siremadlin

Recent P-IV filings

We follow P-IV filings on the USFDA website. The US FDA published a recent list on July 5, 2025. Two ANDAs were filed with P-IV certificates.

Norepinephrine Bitartrate in 5% Dextrose Injection This is an interesting P-IV filing. ANDA filer must have used Baxter’s product as RLD. On March 16, 2020, Baxter filed NDA under Section 505(b)(2) for two strengths of ready-to-administer formulations of norepinephrine bitartrate in 5% dextrose: 4 mg (16 µg/ml) and 8 mg (32 µg/ml) norepinephrine bitartrate, each of which is stored in a 250 mL infusion bag. The FDA approved the NDA on January 15, 2021, for the restoration of blood pressure in adult patients with acute hypotensive states. Baxter filed supplemental NDA No. 214313/S-003 under section 505(b)(2) on May 26, 2023, seeking the addition of a 16 mg/250 mL (64 µg/ml) strength for the same indication, route of administration, dosage form and dosing regimen as the currently approved presentations. The three strengths are 4 mg (16 µg/ml), 8 mg (32 µg/ml), and 16 mg (64 µg/ml). Long Grove is the exclusive licensee of IP and marketing rights from Nevakar Injectables Inc. (US 12,245,996, claiming a sterile, stable, ready-to-inject norepinephrine composition), and Long Grove has sued Baxter. The litigation document can be accessed here. Now, someone has filed an ANDA against Baxter’s product. Baxter has listed two patents in the Orange Book.

The ANDA filer must have bypassed these two OB-listed patents by Baxter. Larotrectinib Sulfate The second P-IV filing is for Larotrectinib Sulfate. This is for 25 mg and 100 mg capsules. Bayer sought approval from the US FDA in November 2018 to treat solid tumours that have a specific genetic mutation, known as an NTRK gene fusion. There are many patents listed in the Orange Book. The NCE-1 date was in November 2022, and it appears this is the first ANDA that has been filed in May 2025. This ANDA filer must secure First to File status.

The patent family WO 2010/048314 discloses in Example 14A a hydrogen sulfate salt of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide ie Larotrectinib Sulfate, the US equivalents of WO `314 patent family are listed in the Orange Book. These patents would cover product and would expire in 2029. Innovator listed crystalline form patents related to crystalline form (I-HS) in OB and will be valid until 2035. The crystalline form could be more appropriate for liquid formulations. The generic filer must have bypassed the polymorph patents. DRL had filed a patent application for amorphous solid dispersion, and Mylan filed a patent application for a different polymorph. These two companies should be working on dossier development and could have filed ANDA.

There are only two DMFs filed so far, Alembic and Olon. Alembic could have filed an ANDA. Alembic and Zydus imported innovator samples and could have started dossier development work.

General information

Recent FDA Actions Pose Big Changes and Questions for Health and Food Industries

• Over the first weeks of July 2025, the U.S. Food and Drug Administration (FDA) has issued several announcements heralding new policies and proposed regulatory changes that could dramatically impact the drug, biologics and food industries.
• Specifically, the FDA has published more than 200 complete letters that were issued in response to new drug applications and biologics license applications submitted for approval between 2020 and 2024; issued a statement "encouraging" manufacturers of baby food, infant formula and other food for children to work with FDA to "improve public awareness" about product recalls; and stated that the agency may fast-track new drugs from pharmaceutical companies that "equalize" the cost of their medicines between the U.S. and other countries.
• As detailed in this Holland & Knight alert, these new policies, if finalized, could have significant implications for FDA-regulated industries.

News here

FDA Approves Kirsty as First Interchangeable Insulin Aspart Biosimilar

The FDA has announced a significant advancement in diabetes care with the approval of Kirsty (insulin aspart-xjhz), marking it as the first rapid-acting interchangeable biosimilar product to Novolog (insulin aspart). This pivotal approval is a crucial step toward enhancing access to more affordable insulin options for the over 8.4 million Americans who depend on insulin therapy to manage their condition. News here

Intellectual Property

Novartis- Siremadlin

This write-up is regarding the Boards of Appeal of the European Patent Office decision regarding an appeal against the revocation of European patent Number EP3541387. The patent concerns an HDM2-p53 interaction inhibitor for use in cancer treatment. The appeal was lodged by Novartis AG (the patent proprietor) against a decision by the Opposition Division to revoke the patent. The opponents in the case were Strawman Limited and Boehringer Ingelheim International GmbH. Key Details 1. Case Number: T 1411/23 - 3.3.07 2. Decision Date: May 13, 2025 3. Patent Proprietor (Appellant): Novartis AG 4. Opponents (Respondents): Strawman Limited 5. Invention Title: Dose and regimen for HDM2-P53 interaction inhibitors. Background

• Two oppositions were filed against the patent, claiming a lack of novelty, inventive step, insufficient disclosure, and extension beyond the original application's content.
• There are two opponents, Boehringer Ingelheim International GmbH and Strawman Limited
• Boehringer Ingelheim withdrew, leaving Strawman Limited. The Opposition Division revoked the patent based on an amended main request and seven auxiliary requests.

Claim
An HDM2-p53 interaction inhibitor for use in the treatment of cancer, wherein the drug is administered on two different administration days within a treatment cycle, wherein the first administration day and second administration day are interrupted by a short administration-free period, and the second administration day of the first or earlier treatment cycle and the first administration of the following cycle are interrupted by a long administration-free period, wherein the short administration-free period is composed of from 4 to 8 days, and the long administration-free period is composed of from 13 to 27 days, and wherein the treatment is composed of at least 2 treatment cycles.

Siremadlin

The claim mainly relates to Siremadlin. Siremadlin, known as HDM201, is a drug in development that acts as a selective inhibitor of the MDM2 protein. This protein normally inhibits the tumour suppressor protein p53. By inhibiting MDM2, siremadlin aims to restore p53 signalling and induce cancer cell death (apoptosis). It is an orally bioavailable drug. The patent specification in paragraph 31 of Novartis discloses the structure of Siremadlin as one of the preferred compounds. Documents Cited in Opposition

Appellant's Arguments

Novartis AG appealed, defending their case based on the amended main request and auxiliary requests. Key arguments included:

1. The decision to revoke the patent should be set aside.
   
2. The patent should be maintained based on the main request or one of the auxiliary requests.
   
3. Document D52 (Jacob Plieth's article) should not be admitted as evidence.
   
4. The claimed administration schedule reduces thrombocytopenia while maintaining efficacy.
   
5. The objective technical problem is to provide a treatment schedule of an HDM2-p53 interaction inhibitor with a reduced incidence of serious thrombocytopenia while maintaining efficacy.
6. Prior art documents do not suggest the claimed administration schedule as a solution.

Respondent's Arguments The respondent (Strawman Limited) requested that the appeal be dismissed and argued that:

1. Documents D47 and D48 should not be admitted as evidence.
   
2. Documents D49 to D52 should be admitted.
   
3. The claimed subject matter lacks inventive step over prior art.
   
4. The technical effect of reducing thrombocytopenia is not credibly substantiated.
   
5. The objective technical problem is providing an alternative use of HDM2-p53 interaction inhibitors.
   
6. Prior art suggests intermittent administration schedules.
   

Board's Decision and Reasons The Board of Appeal dismissed the appeal. Key reasons include: Admittance of Evidence:

1. D47 was not admitted because it should have been submitted during the opposition proceedings.
   
2. D48 was admitted as it concerns the results of a phase Ia study of a further HDM2-p53 interaction inhibitor.
   
3. D49 to D51 were admitted as they were filed in direct response to D48.
   
4. D52 was not admitted as it was filed very late and is not suitable to resolve the issues on file relating to the efficacy of the claimed treatment.

Inventive Step (Main Request):

1. The distinguishing feature of the claim lies in the specific administration schedule.
2. The appellant argued for a reduction in thrombocytopenia incidence with maintained efficacy.
3. The Board found that the appellant, Novartis, did not convincingly support that the claimed administration schedule leads to a reduction of severe grades of thrombocytopenia when used in the treatment of any TP53 wild-type tumour.
4. The objective technical problem was identified as providing an alternative use of HDM2-p53 interaction inhibitors.
5. Prior art suggests other types of intermittent administration schedules.
6. The subject matter of claim 1 of the main request does not comply with Article 56 EPC.

Inventive Step (Auxiliary Requests):

1. Auxiliary requests 1 to 7 did not fulfil the requirement of inventive step (Article 56 EPC) for similar reasons to the main request.
2. Additional features in the auxiliary requests did not demonstrate a distinguishing feature compared to prior art.
3. No additional arguments were made to support the inventive step of the auxiliary requests.

Order The Board ordered that the appeal be dismissed. Decision here