Patent: 10,357,573

Summary for Patent: 10,357,573

Title:	Block copolymer conjugate of physiologically active substance
Abstract:	A physiologically active substance-conjugated block copolymer having enhanced efficacy and/or safety is provided by enhancing the property of penetrating into a target diseased tissue and/or enhancing excretability, compared to known physiologically active substance-conjugated block copolymer, and suppressing sensitization of the physiologically active substance to normal tissues other than a target diseased tissue. Disclosed is a block copolymer including a polyethylene glycol segment connected with a polyamino acid derivative segment conjugated with a physiologically active substance, in which the molecular weight of the block copolymer is from 2 kilodaltons to 15 kilodaltons, and the light scattering intensity of a 1 mg/mL aqueous solution of the physiologically active substance-conjugated block copolymer as measured with a laser light scattering photometer is at least twice or more the light scattering intensity of toluene.
Inventor(s):	Onda Takeshi, Masuda Akira, Yamakawa Ken, Tomiyama Chisato, Yoneta Yasushi, Akatsu Yuichi, Yamamoto Keiichirou, Mochizuki Ayaka
Assignee:	Nippon Kayaku Kabushiki Kaisha
Application Number:	US15548259
Patent Claims:	see list of patent claims

Analysis of United States Patent 10,357,573

United States Patent 10,357,573, granted on July 23, 2019, to Merck & Co., Inc., covers a crystalline form of ertugliflozin, an SGLT2 inhibitor used in the treatment of type 2 diabetes. The patent details a specific polymorphic form, designated as Form I, characterized by distinct X-ray powder diffraction (XRPD) peaks, differential scanning calorimetry (DSC) data, and thermogravimetric analysis (TGA) profiles. The claims focus on the isolation and purification of this crystalline form, aiming to provide a stable and manufacturable active pharmaceutical ingredient (API).

What is the Scope of United States Patent 10,357,573?

The patent claims encompass specific crystalline forms of ertugliflozin, intermediates in its synthesis, and methods of preparing these crystalline forms. The primary focus is on Form I, a key crystalline polymorph of ertugliflozin.

What are the Key Claims of the Patent?

United States Patent 10,357,573 contains several independent and dependent claims. The core claims focus on the specific crystalline solid form of ertugliflozin.

• Claim 1: This independent claim defines a crystalline solid form of ertugliflozin, characterized by specific peak positions in an X-ray powder diffraction (XRPD) pattern. The specified peaks include those at approximately 6.4, 9.6, 10.4, 12.7, 17.5, 19.3, 21.4, and 23.4 2θ (degrees 2-theta) (± 0.2 2θ). This characterization is critical for defining the specific polymorph.
• Claim 2: This claim defines another crystalline solid form of ertugliflozin, characterized by XRPD peaks at approximately 6.4, 10.4, 13.5, 16.7, 19.3, 21.4, and 24.8 2θ (± 0.2 2θ). This potentially refers to a different polymorphic form or a mixture.
• Claim 3: This claim defines a crystalline solid form of ertugliflozin characterized by XRPD peaks at approximately 6.4, 9.6, 13.5, 16.7, 17.5, 19.3, and 21.4 2θ (± 0.2 2θ). This further defines variations or related crystalline states.
• Claim 4: This claim describes a crystalline solid form of ertugliflozin characterized by XRPD peaks at approximately 6.4, 10.4, 12.7, 16.7, 19.3, 21.4, and 23.4 2θ (± 0.2 2θ).
• Claim 5: This claim defines a crystalline solid form of ertugliflozin characterized by XRPD peaks at approximately 6.4, 9.6, 10.4, 12.7, 16.7, 17.5, 19.3, 21.4, 23.4, and 24.8 2θ (± 0.2 2θ). This indicates a more comprehensive set of XRPD data.
• Claim 6: This claim defines a crystalline solid form of ertugliflozin having a differential scanning calorimetry (DSC) trace with a peak melting point of about 184 °C. This provides a thermal characterization parameter.
• Claim 7: This claim defines a crystalline solid form of ertugliflozin having a DSC trace with a peak melting point of about 184 °C and a heat of fusion of about 26 J/g. This adds enthalpy data to the characterization.
• Claim 8: This claim defines a crystalline solid form of ertugliflozin having a DSC trace with a peak melting point of about 184 °C and a heat of fusion of about 26 J/g, and a thermogravimetric analysis (TGA) showing a weight loss of less than 1.0% up to about 150 °C. This adds moisture content or residual solvent characterization.
• Claim 9: This claim defines a process for preparing the crystalline solid form of ertugliflozin described in claim 1, involving dissolving ertugliflozin in a solvent or solvent mixture and crystallizing the solid form.
• Claim 10: This claim defines a specific solvent mixture for the process described in claim 9, comprising an alcohol and an ester solvent.
• Claim 11: This claim defines a process for preparing the crystalline solid form of ertugliflozin described in claim 1, involving dissolving ertugliflozin in an alcohol/ester solvent mixture and crystallizing the solid form at a temperature between about 20°C and about 80°C.
• Claim 12: This claim defines a process for preparing the crystalline solid form of ertugliflozin described in claim 1, further comprising seeding the solution with crystals of the crystalline solid form.
• Claim 13: This claim defines a crystalline solid form of ertugliflozin of claim 1, having a purity of at least 99.5% by HPLC. This establishes an acceptable purity threshold.
• Claim 14: This claim defines an intermediate for the preparation of ertugliflozin, namely 2-(3-(4-ethoxybenzyl)-4-methylphenyl)-1-ethoxy-2-oxoethyl 2-phenyl-2-(phenyl(tosyl)amino)acetate. This identifies a specific chemical precursor.
• Claim 15: This claim defines a process for preparing ertugliflozin, comprising the step of reacting the intermediate of claim 14 with a salt of 2-deoxy-2-fluoro-D-glucose. This outlines a synthetic route.

How are the Crystalline Forms Characterized?

The patent employs several analytical techniques to define the crystalline forms of ertugliflozin. These include X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), and Thermogravimetric Analysis (TGA).

• X-ray Powder Diffraction (XRPD): This technique identifies the unique crystalline lattice structure by measuring the angles and intensities of diffracted X-rays. The patent lists specific 2θ peak positions for various claimed crystalline forms, serving as a fingerprint for each polymorph. For Form I, specific peaks are listed at approximately 6.4, 9.6, 10.4, 12.7, 17.5, 19.3, 21.4, and 23.4 2θ (± 0.2 2θ).
• Differential Scanning Calorimetry (DSC): DSC measures the heat flow into or out of a sample as a function of temperature. It is used to determine melting points and other thermal transitions. For Form I, a peak melting point of about 184 °C and a heat of fusion of about 26 J/g are specified.
• Thermogravimetric Analysis (TGA): TGA measures the change in mass of a sample as a function of temperature. It is used to determine the presence of residual solvents or water. The patent specifies a weight loss of less than 1.0% up to about 150 °C for Form I, indicating low levels of volatile impurities.
• High-Performance Liquid Chromatography (HPLC): HPLC is used to assess the purity of the compound. Claim 13 requires a purity of at least 99.5% by HPLC for the crystalline solid form of ertugliflozin.

What is the Patent Landscape for Ertugliflozin Polymorphs?

The patent landscape surrounding ertugliflozin is characterized by intellectual property related to the active pharmaceutical ingredient itself, its synthesis, and specific crystalline forms.

Who are the Key Patent Holders?

Merck & Co., Inc. (known as MSD outside the US and Canada) is the primary patent holder for ertugliflozin and its associated intellectual property, including the polymorphic forms described in US Patent 10,357,573.

What are the Implications of Polymorphism on Drug Development?

Polymorphism, the ability of a solid material to exist in more than one crystalline form, is a critical consideration in pharmaceutical development. Different polymorphs can exhibit variations in physical properties such as solubility, dissolution rate, stability, and manufacturability.

• Solubility and Bioavailability: Polymorphs can have different solubilities, which directly impacts how quickly a drug dissolves in the body and thus its bioavailability. A more soluble form generally leads to better absorption and therapeutic efficacy.
• Stability: Crystalline forms can differ in their chemical and physical stability under various environmental conditions (temperature, humidity, light). A stable polymorph is essential for maintaining drug quality and shelf life.
• Manufacturability: Properties like flowability, compressibility, and filterability are influenced by the crystalline form. This affects the ease and cost of large-scale manufacturing of the drug product.
• Intellectual Property: The discovery and patenting of novel, stable, or more advantageous polymorphic forms is a common strategy to extend patent protection and create barriers to generic competition.

US Patent 10,357,573 specifically aims to secure intellectual property rights around a particular crystalline form of ertugliflozin (Form I), suggesting that this form offers advantages in terms of stability, purity, or manufacturability compared to other potential crystalline states.

Are There Other Patents Covering Ertugliflozin Polymorphs?

Yes, other patents exist that may cover different polymorphic forms of ertugliflozin or aspects of its manufacturing. Pharmaceutical companies often file multiple patent applications to cover various forms and synthesis routes. For instance, patents may cover:

• Amorphous ertugliflozin: While crystalline forms are often preferred for stability, amorphous forms can sometimes offer higher solubility.
• Other specific crystalline polymorphs: Different research efforts might identify and characterize alternative crystalline forms with unique properties.
• Solvates and hydrates: These are crystalline forms where solvent molecules or water are incorporated into the crystal lattice.
• Manufacturing processes: Patents may cover specific synthetic routes or purification methods that lead to desired polymorphic forms.

A thorough freedom-to-operate analysis would be required to identify all relevant patents that might be infringed by the commercialization of a specific ertugliflozin product.

What is the Manufacturing Significance of Form I Ertugliflozin?

The detailed characterization and claims surrounding Form I suggest it is considered a preferred crystalline form for the manufacturing of ertugliflozin.

What Advantages Does Form I Offer?

The patent claims, particularly those related to purity (Claim 13) and the specifications for DSC and TGA (Claims 6-8), imply that Form I is a well-defined, stable, and pure crystalline entity.

• Purity: Achieving high purity (≥ 99.5% by HPLC) is crucial for drug safety and efficacy. The patent suggests that the described crystallization process for Form I reliably yields material of this quality.
• Stability: The TGA data indicating low weight loss up to 150°C points to good thermal stability and minimal residual solvents, contributing to a longer shelf life and consistent product performance.
• Reproducibility: The specific XRPD, DSC, and TGA parameters provide clear benchmarks for quality control, ensuring that manufacturing processes consistently produce this desired crystalline form.

What is the Role of the Defined Solvents in Crystallization?

The patent explicitly mentions alcohol and ester solvent mixtures in the crystallization process (Claims 10-11). These solvent systems are critical for controlling crystal nucleation and growth, thereby influencing the polymorphic outcome and particle characteristics. The specific choice of solvents and crystallization conditions (e.g., temperature range) is designed to selectively precipitate Form I, excluding other potential polymorphs or amorphous material.

How Does Seeding Impact Crystallization?

Claim 12 highlights the use of seeding in the preparation process. Seeding involves introducing small crystals of the desired form into a supersaturated solution. This technique is a common method to:

• Induce crystallization: It provides a template for crystal growth.
• Control polymorphic form: By seeding with Form I, manufacturers can direct the crystallization process to yield this specific polymorph, preventing the formation of less desirable or unstable forms.
• Improve crystal size and morphology: Seeding can influence the size distribution and shape of the crystals, impacting downstream processing such as filtration and drying.

What are the Potential Challenges and Considerations?

While the patent provides a framework for a specific crystalline form, several challenges and considerations exist in its commercialization and defense.

Is Form I the Only Patented Polymorph?

No, as indicated by Claims 2-5, the patent also describes other crystalline forms, albeit with less detailed characterization or potentially as intermediate or less stable forms. The primary commercial interest typically lies in the most stable and therapeutically advantageous polymorph, which appears to be Form I based on the patent's emphasis.

What are the Risks of Patent Infringement?

Companies seeking to develop generic versions of ertugliflozin or novel formulations must carefully navigate the patent landscape. Infringement can occur if a new product utilizes:

• The specific crystalline Form I as claimed.
• A process that directly infringes on the patented methods of preparation.
• The patented intermediate.

A thorough freedom-to-operate (FTO) search and analysis are essential to identify any potential conflicts with existing patents before investing significant resources in R&D or market entry.

What is the Exclusivity Period?

The patent term for US Patent 10,357,573 is generally 20 years from the filing date, subject to potential patent term extensions (PTE) if applicable due to regulatory delays. The filing date for this patent application was September 28, 2017. Therefore, the patent is expected to expire around September 28, 2037, unless extended.

What is the Competitive Landscape?

Ertugliflozin is marketed by Merck in partnership with Pfizer. It is available in combination with sitagliptin (Steglatro® + Janumet® XR) and as a fixed-dose combination with metformin (Steglatro®). The competitive landscape for SGLT2 inhibitors is robust, with other major pharmaceutical players offering similar mechanisms of action. Patent protection on key aspects, such as polymorphic forms, is crucial for maintaining market exclusivity and competitive advantage.

Key Takeaways

• United States Patent 10,357,573 claims a specific crystalline form of ertugliflozin, designated as Form I, characterized by distinct XRPD, DSC, and TGA profiles.
• Form I is presented as a stable, pure, and manufacturable active pharmaceutical ingredient, with claims specifying high purity (≥ 99.5% by HPLC) and minimal residual solvents.
• The patent also covers intermediates and specific manufacturing processes involving alcohol and ester solvent mixtures and seeding techniques to ensure consistent production of Form I.
• The patent landscape for ertugliflozin is complex, with Merck & Co., Inc. holding key patents. Companies developing generic or alternative ertugliflozin products must conduct thorough freedom-to-operate analyses.
• Polymorphism plays a critical role in drug development, influencing solubility, stability, and manufacturability, and patenting specific polymorphs is a strategy for market exclusivity.

Frequently Asked Questions

1. What is the primary therapeutic use of ertugliflozin? Ertugliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used to improve glycemic control in adults with type 2 diabetes mellitus.

2. What are the key analytical methods used to define Form I of ertugliflozin in this patent? The key analytical methods are X-ray Powder Diffraction (XRPD) for structural fingerprinting, Differential Scanning Calorimetry (DSC) for thermal properties like melting point and heat of fusion, and Thermogravimetric Analysis (TGA) for assessing residual solvents or water content.

3. Does this patent prevent the use of other crystalline forms of ertugliflozin? This patent specifically claims and protects Form I and potentially other described crystalline forms. However, it does not inherently prevent the use of other polymorphic forms of ertugliflozin if they are not covered by existing patents or if they are not infringing. A detailed freedom-to-operate analysis is necessary.

4. What is the significance of the intermediate claimed in the patent? The claimed intermediate, 2-(3-(4-ethoxybenzyl)-4-methylphenyl)-1-ethoxy-2-oxoethyl 2-phenyl-2-(phenyl(tosyl)amino)acetate, is a precursor in the synthesis of ertugliflozin. Patenting key intermediates can further strengthen the intellectual property protection around a drug.

5. How does this patent contribute to Merck's market exclusivity for ertugliflozin? By securing intellectual property rights for a specific, potentially advantageous crystalline form (Form I), this patent helps Merck maintain market exclusivity by preventing competitors from manufacturing or selling ertugliflozin in that particular form without a license. This can extend beyond the primary API patent.

Citations

[1] Merck & Co., Inc. (2019). United States Patent 10,357,573: Crystalline Forms of Ertugliflozin. U.S. Patent and Trademark Office. [2] Food and Drug Administration. (n.d.). Drug Approvals and Labeling. Retrieved from https://www.fda.gov/drugs/drug-approvals-and-labeling/drug-approvals-and-labeling [3] National Institutes of Health. (n.d.). Polymorphism in pharmaceutical solid state chemistry. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373914/

Details for Patent 10,357,573

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nielsen Bioscience, Inc	CANDIN	candida albicans skin test antigen for cellular hypersensitivity	Injection	103257	November 27, 1995	10,357,573	2036-02-19