API and IP Newsletter

 

Contents

• ANDA approvals in January 2025
• General information
• GDUFA And Facility Readiness: A New Era for Generic Drug Approvals
• Advised by former Novo Nordisk boss: Biotech company turns weight-loss drug into robotic tablet
• Intellectual Property
• Melinta Therapeutics, LLC v. Nexus Pharm

 

ANDA approvals in January 2025

 

We follow ANDA approvals every month.

This month, the FDA reported 64 ANDA approvals and 23 tentative approvals. These 23 products cannot be made available to patients immediately. A tentative approval is a notification issued by the FDA for drugs that otherwise meet the statutory and regulatory requirements for approval but cannot be marketed in the United States due to patents or exclusivities related to the reference-listed drug. Additional information about tentative approvals can be found on the FDA site.

Here

General information

 

GDUFA And Facility Readiness: A New Era for Generic Drug Approvals

Under GDUFA III, the concept of facility readiness has taken center stage in the goal date assignment process for ANDAs. The FDA now considers a facility ready for inspection when it meets the following criteria:

1. cGMP Compliance: The facility must adhere to current good manufacturing practice (cGMP) requirements as outlined in section 501(a)(2)(B) of the FD&C Act and 21 CFR Parts 4, 210, and 211.

2. Consistency with Application Data: The facility's operations, methods, and product formulation must align with the descriptions provided in the ANDA. Moreover, the data at the facility must be complete, accurate, and consistent with the application.

3. Readiness for Commercial Manufacturing: The facility must demonstrate that it has a quality system designed to achieve sufficient control over commercial manufacturing operations for the product.

 

News here

 

Advised by former Novo Nordisk boss: Biotech company turns weight-loss drug into robotic tablet

US-based Rani Therapeutics, with advice from a former Novo Nordisk executive, has developed a robotic tablet that can deliver semaglutide orally without wasting active ingredients.

 

News here

Intellectual Property

 

 

Melinta Therapeutics, LLC v. Nexus Pharm

 

This matter is before the Court (United States District Court, Northern District of Illinois) for decision on the infringement and validity of Claims 1, 7, and 18 of the U.S. Patent No. 9,084,802 (the “ '802 Patent”) and Claim 27 of the U.S. Patent No. 9,278,105 (the “ '105 Patent”).

 

These are OB listed patents.

 

The patents cover the intravenous administration of Minocin®(minocycline) as an injection product. This aqueous solution, consisting of minocycline and magnesium, is used to treat bacterial infections. 

 

Melinta Therapeutics’ (Rempex) own New Drug Application No. 050444 (NDA) for the FDA-approved Minocin product.

 

The priority date of the patents-in-suit is May 12, 2010

 

Nexus Pharm owns the ANDA, which it submitted to the FDA on October 16, 2020, seeking to develop a generic version of Minocin before the expiration of the patents in suit.

 

Melinta filed this lawsuit.

 

Melinta’s Minocin product replaced an old intravenous (IV) minocycline formulation (the prior art minocycline) approved in 1972 to treat bacterial infections caused by the Acinetobacter baumannii bacteria.

 

The prior art minocycline was removed from the market in 2005 but returned in 2009 because no other similar product existed to treat bacterial infections. 

 

During that period, the inventors started development (later filed US 9084802 and US 9278105), aiming to enhance the prior-art minocycline. Several years later, Melinta obtained the NDA for the prior-art minocycline and submitted a supplemental NDA to substitute it with their new Minocin formulation.

 

Both the prior art minocycline and Minocin are intended to be administered to a patient intravenously, i.e., injected into the patient's vein. An intravenous product begins as a powder or other dried substance.

 

After reconstitution, the reconstituted solution must be further diluted with an additional diluent for intravenous administration. The existing minocycline label instructs a POSA to dilute the reconstituted solution in 500 mL to 1,000 mL of a compatible diluent.

 

The inventors of the patents-in-suit aimed to improve the previous formulation of minocycline. While the prior art minocycline successfully treated bacterial infections, it had several shortcomings. First, it possessed a low pH level. Second, it necessitated a large injection volume.

 

While Defendant Nexus Pharm disputes this, the low pH level and high injection volume posed a risk of irritation, tolerability, and other issues related to injection site hemolysis.

 

First, the prior-art minocycline had a low pH level, ranging from 2.0 to 6.

 

Dr. Friedman testified that the prior-art minocycline pH levels were low and that a pH level closer to 7.35 to 7.45 is necessary for safe administration to patients. A pH level that is too low, and thus more acidic, can trigger hemolysis at the injection site.

 

Melinta argued that Nexus is liable for indirect infringement because a physician using the generic ANDA product would directly infringe on the patents in question. Because the allegedly infringing generic product's label instructs a physician on how to use the product, the physician's following the ANDA product label would meet the claim elements at issue in this case, thereby directly infringing on the patents in question.

 

Nexus argued that Melinta has not demonstrated that the ANDA product directly infringes on the osmolality element of the '105 Patent and the injection site hemolysis element of the '802 Patent.

 

Two prior art references cited

 

Prior Art Reference CN'268

CN'268 discusses improving doxycycline (a tetracycline similar to minocycline) by adding magnesium ions to increase pH values and minimise irritability when administered. By adding magnesium ions to the formulation, CN'268 achieved better solubility, stability, and tolerability. The formulation's increased solubility allowed for a lower administration volume. CN'268 used magnesium ions in higher molar ratios to doxycycline and had a pH value between 3 and 7.

 

Dr. Klibanov testified that CN'268 would be relevant to a researcher looking to enhance prior art minocycline because CN'268 studies doxycycline, a close relative of minocycline with structural similarities. Although CN'268 is not an intravenous formulation, it remains pertinent from Dr. Klibanov's perspective since CN'268 is also an injectable formulation, albeit administered into the muscle rather than the vein. He testified that a POSA seeking to modify the prior art minocycline would, upon examining CN'268, be inclined to add magnesium to a minocycline intravenous formulation to enhance stability, solubility, tolerability, and pH. 

https://patents.google.com/patent/CN101301268A/en?oq=9084802

 

Dr. Klibanov also testified about a second publication, the Gibbs reference. Gibbs studied the addition of magnesium ions to minocycline at a molar ratio ranging from 1:1 to 8:1, a formulation that led to improved formulation properties.

https://patents.google.com/patent/EP0337733A2/en?oq=9084802

 

 

Claim 27 of the '105 Patent depends on Claim 1, which specifies that administering Minocin according to the specified instructions will cause an osmolality of less than 500 mOsmol/kg.

 

Neither the Minocin label nor the ANDA label explicitly mentions osmolality. Melinta argued that even though neither label explicitly mentions osmolality, a physician following the ANDA label nevertheless infringes because the product will inevitably have an osmolality of less than 500 mOsmol/kg due to its chemical composition.

 

Melinta cited numerous direct measurements of the osmolality of the ANDA product that they performed, all of which showed an osmolality of less than 500 mOsmol/kg. Thus, Melinta argued that the ANDA product falls within the scope of the '105 Patent's osmolality claim.

 

Nexus countered that Melinta’s experiments utilised a different composition volume (10 mL) than what was specified in the ANDA (5 mL); therefore, the test results cannot demonstrate an infringement of the osmolality limitation. However, Plaintiff Melinta insisted they relied on experimental data using 5 mL of composition.

 

Osmolality is a characteristic of a composition, which means it is determined through straightforward calculations based on the ingredients present. Therefore, a POSA examining the ingredient amounts listed on a product's label would be able to decide on the osmolality of the solution. The parties agree on three key facts: (1) osmolality is a characteristic of the composition that can be calculated by reviewing the ingredients on the label; (2) the standard of care for osmolality is a level below 500 mOsmol/kg; and (3) the Minocin and ANDA product labels are identical, using the same ingredients in the same amounts, as mandated by the FDA.

Thus, a physician following the ANDA label will perform the same process as one adhering to the Minocin label. There is no evidence to suggest that a physician using Nexus's ANDA product will deviate from the standard of care; therefore, a physician administering either product will ensure that the osmolality level remains below 500 mOsmol/kg. Just as administering Minocin will inevitably result in an osmolality of less than 500 mOsmol/kg, so too will administering the ANDA product ensure an osmolality below 500 mOsmol/kg. Nexus Pharma did not dispute this.

 

Nexus Pharma argued that it does not infringe upon the osmolality element of the '105 Patent because osmolality is not explicitly mentioned on the Minocin product label. However, it does not need to be stated on the label for Nexus to infringe. Osmolality is a property of the composition, as both parties agree. Infringement occurs if the physician follows the ANDA label due to the amounts of ingredients listed on the label. 

 

Nexus Pharma also argued that there would be no direct infringement because Melinta did not rely on any experimental data or osmolality measurements for a product reconstituted with 5 mL of water. Nexus Pharma emphasised Dr. deVries's testimony, claiming that she admitted using 10 mL of water in reconstitution and speculated that a 5 mL measurement would “double.” However, Nexus mischaracterises Melinta's tests and Dr. deVries's testimony.

 

All experimental osmolality measurements for Minocin resulted in an osmolality of less than 500 mOsmol/kg, thus falling within the claim element of the '105 Patent. All measurements utilised a composition of 5 mL of water for reconstitution. Dr. deVries never admitted to using 10 mL in an experiment; instead, she stated that a 10 mL-sized vial was used. She never acknowledged relying on data that used 10 mL of water but instead relied on data that utilised 5 mL of water.

 

Melinta argued that Nexus's decision to copy the Minocin product instead of the prior art minocycline product indicates that Nexus recognised some advantages of the Minocin product over the prior art minocycline. According to Melinta, this choice suggests non-obviousness. While it may be true that Nexus opted to replicate Minocin because it believed that Minocin offered benefits absent in the prior art minocycline, such copying serves as less convincing evidence of non-obviousness in Hatch-Waxman litigation. This is because the FDA mandates that an ANDA product must be identical to the patented product, making copying necessary.

 

Based on the foregoing findings of fact and conclusions of law, the Court concludes that Melinta have shown by a preponderance of the evidence that Nexus has infringed on the '105 Patent and the '802 Patent, and that Nexus has failed to show by clear and convincing evidence that the Asserted Claims of the patents-in-suit are invalid for obviousness.

 

The court also found that a skilled artisan would not be motivated to combine CN’268 and Gibbs with the prior art minocycline product. Both concern doxycycline formulations rather than minocycline formulations. Additionally, both disclose only intramuscular formulations and not intravenous formulations. Neither mentions hemolysis or the significance of an increased magnesium to minocycline molar ratio. Therefore, Nexus had not demonstrated by clear and convincing evidence that a skilled artisan would have been motivated to combine the prior art to create the claimed invention.

 

With this decision, Nexus should wait for the generic launch until 2031.

 

Decision here