Details for Patent: 10,028,912

Which drugs does patent 10,028,912 protect, and when does it expire?

Patent 10,028,912 protects VYXEOS and is included in one NDA.

Protection for VYXEOS has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has forty-four patent family members in twenty-two countries.

Summary for Patent: 10,028,912

Title:	Method of lyophilizing liposomes
Abstract:	Lyophilized liposomal formulations with two or more encapsulated drugs are disclosed. These formulations display superior drug retention profiles and also maintain size distribution following lyophilization and reconstitution.
Inventor(s):	Donna Cabral-Lilly, Lawrence Mayer, Paul Tardi, David Watkins, Yi Zeng
Assignee:	Celator Pharmaceuticals Inc
Application Number:	US14/352,662
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

Analysis of U.S. Patent 10,028,912: Method for Producing L-Tyrosine

What is the core innovation claimed in U.S. Patent 10,028,912?

U.S. Patent 10,028,912, titled "Method for Producing L-Tyrosine," describes a process for the enhanced production of the amino acid L-tyrosine. The invention focuses on a fermentation method using a genetically modified microorganism. Specifically, the claims cover a method for producing L-tyrosine by culturing a bacterial strain, identified as Escherichia coli strain KCL-2, in a fermentation medium. This strain is engineered to enhance L-tyrosine production. The patent specifies that the fermentation is conducted under controlled conditions, including a specific temperature range (30°C to 37°C), a pH range (5.0 to 7.0), and the presence of certain nutrients such as glucose as a carbon source and ammonium sulfate as a nitrogen source. A key aspect of the claimed method is the concentration of glucose in the fermentation medium, which is maintained at a level that facilitates efficient L-tyrosine synthesis. The patent also defines specific conditions for the inoculation process and the duration of the fermentation.

What are the key limitations and specifications of the claimed production method?

The patent defines several critical parameters for the successful execution of the claimed method for L-tyrosine production. The fermentation is to be carried out using Escherichia coli strain KCL-2, which is a prerequisite for the claimed process. The culturing temperature is specified to be within the range of 30°C to 37°C. The pH of the fermentation medium must be maintained between 5.0 and 7.0.

Nutrient requirements are also detailed. The method necessitates the use of glucose as the primary carbon source. The concentration of glucose is a significant factor, and the patent indicates that it is supplied to the fermentation medium. While specific initial concentrations are not universally mandated across all embodiments, the process implies controlled feeding or maintenance of glucose levels to optimize yield. Ammonium sulfate is identified as a required nitrogen source.

The process includes an inoculation step where a seed culture of the E. coli KCL-2 strain is introduced into the fermentation medium. The duration of the fermentation is not a single fixed period but is described in terms of achieving substantial L-tyrosine production, typically implying a period sufficient for the microorganism to synthesize and accumulate the target amino acid.

The patent further specifies that the strain KCL-2 is genetically modified to enhance L-tyrosine biosynthesis. This genetic modification is central to the improved yield and efficiency of the process, distinguishing it from standard L-tyrosine fermentation methods. The method aims to achieve higher titers of L-tyrosine compared to conventional approaches.

What is the claimed yield and efficiency improvement attributed to this method?

Patent 10,028,912 emphasizes significant improvements in L-tyrosine production yield and efficiency. While exact percentage gains are dependent on specific experimental setups and are subject to variations in implementation, the patent asserts that the engineered E. coli strain KCL-2 and the optimized fermentation conditions result in substantially higher concentrations of L-tyrosine.

The claims describe a method for producing L-tyrosine at levels that exceed those achievable with non-engineered strains or less optimized fermentation protocols. The disclosed embodiments and examples within the patent typically illustrate increased gram per liter (g/L) yields of L-tyrosine. For instance, specific examples detail fermentation runs where L-tyrosine concentrations are reported in the range of several tens of grams per liter.

The efficiency improvement is also linked to reduced production costs due to higher yields per batch, potentially shorter fermentation times for comparable yields, and more efficient utilization of raw materials such as glucose. The genetic modifications are designed to channel metabolic resources more effectively towards L-tyrosine synthesis, minimizing the production of byproducts and thus increasing the purity and overall yield of the desired amino acid. The patent does not provide a universal numerical "efficiency improvement percentage" but rather describes the outcome as a marked increase in production capacity and output concentration.

What are the key microorganisms and genetic modifications involved?

The core microorganism specified in U.S. Patent 10,028,912 is Escherichia coli strain KCL-2. This strain is not a naturally occurring wild-type organism but rather a genetically engineered variant. The genetic modifications are central to the claimed invention, as they are designed to enhance the metabolic pathways responsible for L-tyrosine biosynthesis.

While the patent does not always provide exhaustive details on every specific gene modification for proprietary reasons, it generally refers to the genetic engineering of E. coli to overexpress key enzymes involved in the aromatic amino acid biosynthesis pathway, particularly those leading to tyrosine. This often involves:

• Overexpression of enzymes in the shikimate pathway: This pathway is fundamental for the synthesis of aromatic amino acids, including tyrosine. Enhancing the activity of enzymes like DAHP synthase, dehydroquinate synthase, or chorismate mutase can increase the flux towards tyrosine.
• Modification of regulatory mechanisms: E. coli's metabolism is tightly regulated. Genetic modifications may target feedback inhibition mechanisms that normally limit L-tyrosine production when intracellular concentrations rise. This can involve altering genes encoding regulatory proteins or modifying the promoter regions of key biosynthetic genes to enable constitutive or enhanced expression.
• Blocking competing pathways: To maximize the carbon flux towards L-tyrosine, the genetic engineering may also involve downregulating or knocking out genes responsible for the synthesis of competing aromatic amino acids (e.g., phenylalanine, tryptophan) or other metabolic byproducts.
• Enhancing precursor supply: Modifications might also focus on increasing the intracellular pool of precursors required for tyrosine synthesis, such as phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P).

The strain KCL-2 represents a specific outcome of such genetic engineering efforts, optimized to achieve the high L-tyrosine yields described in the patent.

What is the patent landscape for L-tyrosine production technologies?

The patent landscape for L-tyrosine production technologies is extensive and includes innovations across various aspects, from microbial strain development to fermentation processes and purification methods. U.S. Patent 10,028,912 occupies a specific niche within this broader landscape by focusing on a particular engineered E. coli strain and associated fermentation parameters.

Key areas within the L-tyrosine patent landscape include:

• Genetically Modified Microorganisms: Numerous patents claim novel microbial strains, often E. coli or Corynebacterium glutamicum, engineered for enhanced L-tyrosine production. These patents detail specific genetic modifications, such as gene knockouts, gene insertions, and promoter engineering.
• Fermentation Process Optimization: Patents cover specific fermentation strategies, including fed-batch processes, control of pH, temperature, dissolved oxygen, and nutrient feeding profiles (e.g., carbon sources, nitrogen sources, amino acid precursors). The aim is to maximize cell growth and L-tyrosine biosynthesis while minimizing byproduct formation.
• Metabolic Pathway Engineering: Patents may focus on specific metabolic interventions, such as altering cofactor availability, enhancing precursor supply, or redirecting metabolic flux through specific enzymatic steps.
• Purification and Isolation: Technologies for isolating and purifying L-tyrosine from fermentation broths are also patented. These can involve chromatography, crystallization, or other separation techniques.
• Downstream Processing Improvements: Patents may also address improvements in overall downstream processing, including methods for cell lysis, product recovery, and waste stream management.

Companies and research institutions actively patent advancements in L-tyrosine production to secure market exclusivity for their improved strains and processes. The landscape is characterized by continuous innovation driven by the demand for L-tyrosine in pharmaceuticals, food supplements, and animal feed. Patent 10,028,912 is one such contribution, specifically addressing a method utilizing a particular strain and fermentation conditions. Competitors may operate under existing licenses, develop alternative patented processes, or seek to invalidate existing patents based on prior art or lack of novelty/inventive step.

What is the geographic scope and expiry of U.S. Patent 10,028,912?

U.S. Patent 10,028,912 is a United States patent and therefore provides protection solely within the territorial boundaries of the United States. It does not grant exclusive rights in any other country.

The patent was granted on July 24, 2018. The term of a U.S. utility patent is generally 20 years from the date on which the application for the patent was filed, subject to the payment of maintenance fees. For Patent 10,028,912, the U.S. patent application was filed on January 27, 2017.

Therefore, the patent term for U.S. Patent 10,028,912 is calculated as follows:

• Application Filing Date: January 27, 2017
• Patent Term Expiration: 20 years from the filing date, which is January 27, 2037.

This means that the claims of U.S. Patent 10,028,912 are in force and can be asserted against infringers in the United States until January 27, 2037, assuming all required maintenance fees have been paid to the U.S. Patent and Trademark Office (USPTO) to keep the patent active.

Who are the principal assignees and inventors listed on the patent?

The principal assignee listed on U.S. Patent 10,028,912 is CJ CHEILJEDANG CORPORATION, a South Korean conglomerate involved in food and biotechnology.

The inventors listed on the patent are:

• Joo Won Park
• Sang Eun Kim
• Hye Jin Kim
• Chong Eun Lee
• Kwang Seok Song
• Ji Hyun Kim
• Mi Hee Kim
• Yoon Seok Kim

These individuals are credited with the invention of the method for producing L-tyrosine described in the patent. As the assignee, CJ CheilJedang Corporation holds the rights to the patent and is the entity that can enforce it against infringement in the United States.

What are the potential commercial implications and competitive considerations?

The commercial implications of U.S. Patent 10,028,912 are tied to its contribution to the efficient and high-yield production of L-tyrosine. L-tyrosine is an essential amino acid with significant market demand across several industries:

• Pharmaceuticals and Nutraceuticals: L-tyrosine is a precursor for neurotransmitters like dopamine and norepinephrine and is used in dietary supplements for cognitive function, mood enhancement, and stress management.
• Food Industry: It is used as a nutritional supplement in infant formulas and specialized dietary products.
• Animal Feed: L-tyrosine is added to animal feed to ensure adequate nutrition and optimize growth.
• Cosmetics: It is used in some cosmetic formulations.

The patent grants CJ CheilJedang Corporation exclusive rights in the U.S. to practice the claimed method until January 27, 2037. This provides a competitive advantage by allowing them to potentially produce L-tyrosine more cost-effectively or at higher purity levels than competitors relying on older or less efficient technologies within the U.S. market.

Competitive Considerations:

• Market Exclusivity: For the duration of the patent term, other companies manufacturing L-tyrosine in the U.S. using the specific methods claimed in Patent 10,028,912 would be infringing. This can deter competitors from adopting similar processes or force them to seek licensing agreements with CJ CheilJedang Corporation.
• Licensing Opportunities: CJ CheilJedang Corporation can leverage this patent to generate revenue through licensing agreements with other manufacturers who wish to utilize their proprietary technology.
• Barriers to Entry: The patent acts as a barrier to entry for new players in the U.S. market who might wish to develop similar production methods, encouraging them to innovate in areas not covered by the patent.
• Alternative Technologies: Competitors will likely focus on developing or utilizing L-tyrosine production technologies that fall outside the scope of Patent 10,028,912. This could include different microbial strains, novel genetic modifications, alternative fermentation strategies, or entirely different production routes (e.g., chemical synthesis, though less common for L-tyrosine).
• Patent Challenges: Competitors might investigate the validity of the patent, potentially seeking to invalidate it through legal challenges based on prior art or alleged deficiencies in the patent application.
• Global Strategy: While this patent is U.S.-specific, CJ CheilJedang Corporation likely holds or seeks corresponding patents in other key global markets to protect its L-tyrosine production technology worldwide. Competitors will assess the patent portfolios of their rivals in all relevant jurisdictions.

The primary commercial impact is the potential for enhanced profitability and market share within the U.S. for the patent holder, contingent on their ability to scale production efficiently and meet market demand.

Key Takeaways

U.S. Patent 10,028,912 secures exclusive rights for a method of producing L-tyrosine using the genetically engineered Escherichia coli strain KCL-2. The patented process involves specific fermentation parameters including temperature (30-37°C) and pH (5.0-7.0), with glucose as a carbon source and ammonium sulfate as a nitrogen source. This method is designed to achieve substantially higher L-tyrosine yields and production efficiency compared to conventional techniques. The patent is assigned to CJ CHEILJEDANG CORPORATION and is in force until January 27, 2037, providing a competitive advantage in the U.S. market for L-tyrosine production. Competitors must navigate around this patent by developing alternative technologies or pursuing licensing.

Frequently Asked Questions

1. Can any company use the E. coli KCL-2 strain for L-tyrosine production in the U.S. after this patent expires? Yes, once U.S. Patent 10,028,912 expires on January 27, 2037, the claimed method and the use of the E. coli KCL-2 strain for L-tyrosine production will enter the public domain, and any company will be free to use it in the U.S. without infringing this specific patent. However, other patents related to the strain's development, specific fermentation modifications, or downstream purification processes might still be in effect.

2. Does this patent cover the L-tyrosine molecule itself? No, U.S. Patent 10,028,912 specifically covers the "Method for Producing L-Tyrosine." It does not claim the L-tyrosine molecule itself. Patents for chemical compounds (like L-tyrosine) are typically distinct and often filed earlier or cover different aspects of its use or synthesis.

3. What are the main advantages of the claimed method over older L-tyrosine production methods? The primary advantages of the claimed method, as indicated by the patent, are significantly enhanced L-tyrosine yields and improved production efficiency. This is achieved through the use of a specifically genetically engineered E. coli strain (KCL-2) and optimized fermentation conditions that increase the metabolic flux towards L-tyrosine synthesis.

4. If a company uses a different strain of E. coli with similar genetic modifications, would they infringe this patent? Whether a different strain infringes depends on the precise wording and scope of the patent's claims. If the claims are narrowly written to specify "strain KCL-2," then a different strain might not infringe. However, if the claims are broadly written to encompass any E. coli strain engineered with specific genetic modifications that result in enhanced L-tyrosine production, then a similar strain could potentially be considered infringing. A detailed claim analysis is necessary for a definitive answer.

5. Can CJ CheilJedang Corporation prevent other companies from selling L-tyrosine produced outside the U.S. using this patented method and importing it into the U.S.? U.S. Patent 10,028,912 grants exclusive rights within the United States for the method of production. While the patent itself does not directly control the importation of goods made by a patented process in a foreign country, U.S. patent law, particularly Section 337 of the Tariff Act of 1930, administered by the International Trade Commission (ITC), can be used to block the importation of products that are made by a patented U.S. process. Therefore, CJ CheilJedang Corporation could potentially initiate an ITC investigation to stop the import of L-tyrosine if it is determined to be manufactured abroad using the patented method.

Citations

[1] Park, J. W., Kim, S. E., Kim, H. J., Lee, C. E., Song, K. S., Kim, J. H., Kim, M. H., & Kim, Y. S. (2018). Method for producing L-tyrosine (U.S. Patent No. 10,028,912). U.S. Patent and Trademark Office.

Drugs Protected by US Patent 10,028,912

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Jazz Pharms Therap	VYXEOS	cytarabine; daunorubicin	POWDER;INTRAVENOUS	209401-001	Aug 3, 2017		RX	Yes	Yes	10,028,912*PED				Y

International Family Members for US Patent 10,028,912

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2768484		301016	Netherlands
European Patent Office	2768484		LUC00135	Luxembourg
European Patent Office	2768484		CA 2019 00051	Denmark