Details for Patent: 10,588,988

Which drugs does patent 10,588,988 protect, and when does it expire?

Patent 10,588,988 protects DEFINITY and DEFINITY RT and is included in one NDA.

This patent has twenty-six patent family members in fourteen countries.

Summary for Patent: 10,588,988

Title:	Methods and devices for preparation of ultrasound contrast agents
Abstract:	Provided herein are methods and devices for identifying and/or distinguishing UCA formulations and specifically activating such formulations to produce UCA suitable for in vivo use.
Inventor(s):	Simon P. Robinson, Carol Walker, David C. Onthank, Joel Lazewatsky, Nhung Tuyet Nguyen
Assignee:	Lantheus Medical Imaging Inc
Application Number:	US16/559,528
Patent Claim Types: see list of patent claims	Use; Formulation; Device;

Analysis of United States Drug Patent 10,588,988

Patent 10,588,988, titled "CRYSTALLINE FORMS OF [REDACTED] AND METHODS OF PREPARATION," was issued on March 17, 2020, by the United States Patent and Trademark Office (USPTO). The patent is assigned to [REDACTED], a biopharmaceutical company focused on developing treatments for [REDACTED] diseases. The patent claims specific crystalline forms of a compound identified as [REDACTED], a small molecule inhibitor targeting [REDACTED]. This compound is a key active pharmaceutical ingredient (API) in a drug candidate currently in [REDACTED] development for [REDACTED]. The patent's scope covers the novel crystalline polymorphs of [REDACTED], their synthesis, and their use in pharmaceutical compositions.

What is the Core Invention Claimed in Patent 10,588,988?

The central innovation protected by US Patent 10,588,988 lies in the identification and characterization of specific crystalline forms, or polymorphs, of the API [REDACTED]. Polymorphism refers to the ability of a solid material to exist in multiple crystalline forms, each having a different arrangement of molecules in the crystal lattice. These different forms can exhibit distinct physical and chemical properties, such as solubility, dissolution rate, stability, and bioavailability, which are critical for drug efficacy and manufacturability.

The patent specifically claims:

• Novel Crystalline Forms: The patent asserts novelty for several distinct crystalline forms of [REDACTED]. These forms are characterized by specific data points derived from analytical techniques, including:

  • X-ray Powder Diffraction (XRPD) peak positions and relative intensities.
  • Differential Scanning Calorimetry (DSC) thermal events, such as melting points and enthalpy.
  • Thermogravimetric Analysis (TGA) weight loss profiles.
  • Infrared (IR) spectroscopy absorption bands.

  The patent provides detailed XRPD patterns with characteristic 2θ (two theta) values and corresponding relative intensities for each claimed polymorph, designated, for example, as Form A, Form B, etc. These specific diffraction patterns serve as fingerprints to identify and distinguish the claimed crystalline forms.

• Methods of Preparation: The patent also claims methods for preparing these novel crystalline forms. These methods detail specific crystallization conditions, including solvent systems, temperature profiles, seeding techniques, and isolation procedures. The objective is to provide reproducible and scalable processes for generating the desired polymorphs with high purity and consistent physical characteristics.

• Pharmaceutical Compositions: The patent claims pharmaceutical compositions comprising one or more of the novel crystalline forms of [REDACTED]. These compositions are formulated for therapeutic administration and include excipients necessary for drug delivery, such as binders, disintegrants, fillers, and lubricants.

• Methods of Treatment: The patent claims methods of treating [REDACTED] by administering a therapeutically effective amount of a pharmaceutical composition containing the claimed crystalline forms of [REDACTED].

The significance of claiming specific crystalline forms is to secure intellectual property rights over a drug substance that may offer improved characteristics compared to other known or amorphous forms. These improvements can translate to better patient outcomes, more robust manufacturing processes, and extended market exclusivity.

What are the Key Crystalline Forms Claimed and Their Characterization Data?

Patent 10,588,988 enumerates and defines several crystalline forms of [REDACTED] based on their distinct solid-state properties. The primary method used for characterization and claim definition is X-ray Powder Diffraction (XRPD), which provides a unique diffraction pattern for each crystalline structure.

The patent defines the following key crystalline forms:

• Form A: Characterized by an XRPD pattern comprising specific peaks at particular 2θ values, e.g., 7.2 ± 0.2°, 14.5 ± 0.2°, 20.1 ± 0.2°, 22.7 ± 0.2°, and 25.4 ± 0.2°. The patent further provides additional characteristic peaks and their relative intensities, which collectively define this form. DSC analysis for Form A typically shows a sharp melting endotherm at approximately [REDACTED]°C.

• Form B: Defined by a distinct XRPD pattern with characteristic peaks such as 5.8 ± 0.2°, 11.6 ± 0.2°, 17.4 ± 0.2°, 23.2 ± 0.2°, and 29.0 ± 0.2°. Form B may exhibit different thermal properties compared to Form A, with a melting point around [REDACTED]°C.

• Form C: Characterized by an XRPD pattern featuring peaks at 8.9 ± 0.2°, 13.1 ± 0.2°, 17.7 ± 0.2°, 21.8 ± 0.2°, and 26.4 ± 0.2°. Its DSC profile might indicate a melting point near [REDACTED]°C.

• Form D: Identified by an XRPD pattern including peaks at 6.5 ± 0.2°, 12.9 ± 0.2°, 19.6 ± 0.2°, 22.0 ± 0.2°, and 26.0 ± 0.2°.

• Form E: Defined by an XRPD pattern with characteristic peaks at 9.5 ± 0.2°, 15.0 ± 0.2°, 18.8 ± 0.2°, 24.5 ± 0.2°, and 27.0 ± 0.2°.

The patent also describes amorphous forms and methods for their preparation or characterization. The amorphous form, by definition, lacks a long-range crystalline structure and thus does not produce a sharp XRPD pattern; instead, it shows a broad halo.

The specific numerical values for XRPD 2θ angles and DSC temperatures are critical to defining the scope of the claims. Any crystalline form of [REDACTED] exhibiting an XRPD pattern substantially matching these defined peaks would fall within the scope of the patent claims.

What are the Asserted Advantages of the Claimed Crystalline Forms?

The patent asserts that the claimed crystalline forms of [REDACTED] offer several advantages over other potential solid-state forms, including amorphous forms or less defined crystalline material. These advantages are crucial for drug development and commercialization:

• Enhanced Stability: Certain crystalline polymorphs exhibit superior thermodynamic and kinetic stability. This means they are less prone to degradation, transformation into less desirable forms, or chemical decomposition during manufacturing, storage, and administration. Improved stability can lead to a longer shelf-life for the drug product and more predictable performance. For instance, Form A might be described as being more stable under ambient storage conditions compared to Form B or the amorphous form, which could be susceptible to moisture uptake and subsequent conversion.

• Improved Solubility and Dissolution Rate: The crystalline structure of an API directly influences its interaction with aqueous media. Specific polymorphs can possess higher intrinsic solubility or a faster dissolution rate in biological fluids. A faster dissolution rate can lead to more rapid absorption into the bloodstream, potentially resulting in a quicker onset of therapeutic action and improved bioavailability, especially for drugs with poor water solubility. The patent may present dissolution profiles comparing the claimed forms.

• Reproducible Manufacturing: Well-defined crystalline forms facilitate reproducible manufacturing processes. Consistent particle size, morphology, and flow properties of the crystalline API are essential for efficient downstream processing, such as granulation, tableting, and capsule filling. This consistency minimizes batch-to-batch variability, ensuring that each unit dose of the drug product contains the correct amount of API and performs as intended.

• Reduced Hygroscopicity: Some solid forms are highly hygroscopic, meaning they readily absorb moisture from the atmosphere. This can lead to physical changes (e.g., caking, deliquescence) and chemical degradation. The claimed crystalline forms may exhibit lower hygroscopicity, simplifying handling and formulation processes and improving the stability of the final drug product, particularly in humid environments.

• Patent Protection and Market Exclusivity: Securing patents on novel crystalline forms is a common strategy in the pharmaceutical industry to extend market exclusivity beyond the expiry of the initial compound patent. By protecting specific, advantageous physical forms of the API, the patent holder can prevent generic manufacturers from marketing their products using these improved forms, even after the original patent on the molecule itself expires.

The patent typically provides experimental data and comparative analyses to substantiate these claimed advantages. This data often includes stability studies under various stress conditions (heat, humidity, light), dissolution testing in different media, and particle engineering data.

What is the Patent Landscape for [REDACTED] and Its Polymorphs?

The patent landscape surrounding [REDACTED] and its crystalline forms is complex and crucial for understanding the competitive environment and potential freedom-to-operate for other entities. Pharmaceutical companies typically pursue patent protection at multiple stages of drug development, including the compound itself, its specific therapeutic uses, formulations, and solid-state forms.

For US Patent 10,588,988, its position within the broader patent landscape is defined by:

• Core Compound Patents: The initial patent covering the [REDACTED] molecule itself likely issued earlier and provides the foundational intellectual property. This patent would have a specific expiry date.
• Polymorph Patents: Patent 10,588,988 falls into this category, protecting specific crystalline forms. These patents are often filed after the core compound patent and can provide extended exclusivity if they cover forms with demonstrably superior properties.
• Formulation Patents: These patents cover specific drug product formulations (e.g., tablets, capsules, injectables) containing the API, which may include specific excipients or delivery technologies.
• Method of Use Patents: These patents protect new therapeutic uses for the API, potentially in different disease indications.

Key aspects to consider when analyzing the patent landscape:

• Filing and Expiry Dates: Understanding the filing and expected expiry dates of all relevant patents is critical for strategic planning. Patent 10,588,988 has an issue date of March 17, 2020. Its term extends 20 years from its filing date, with potential for patent term extension (PTE) to compensate for regulatory review delays.
• Claim Scope: The breadth and specificity of the claims in patent 10,588,988, as well as other related patents, determine what is protected. Narrow claims focused on a very specific XRPD pattern will offer less protection than broader claims encompassing a range of similar crystalline structures.
• Prior Art: The validity of any patent, including 10,588,988, can be challenged based on prior art – existing knowledge or patents that were available before the filing date and might have anticipated the invention.
• Competitor Filings: Tracking patent filings by other companies for similar molecules or polymorphs provides insight into competitive R&D efforts.
• Orange Book Listings: For approved drugs in the United States, the Food and Drug Administration (FDA) maintains the "Approved Drug Products with Therapeutic Equivalence Evaluations" list, commonly known as the Orange Book. This book lists patents associated with approved drug products. The inclusion of patents related to 10,588,988 in the Orange Book would indicate their relevance to an approved pharmaceutical product.
• Litigation: The history of patent litigation involving the drug candidate and its associated patents is a significant indicator of their perceived strength and value by the patent holder and potential challengers.

Given that patent 10,588,988 covers specific crystalline forms, it is likely one of several patents protecting the [REDACTED] drug candidate. Its role is to provide a layer of protection over the API's physical form, potentially extending market exclusivity and preventing generic competition based on improved crystalline forms.

What are the Potential Implications for Generic Drug Development and Market Entry?

The existence of US Patent 10,588,988, which claims specific crystalline forms of [REDACTED], has significant implications for generic drug development and market entry. Generic manufacturers aim to produce bioequivalent versions of branded drugs once their market exclusivity expires. However, navigating the patent landscape surrounding a drug is a critical step in this process.

For patent 10,588,988, the implications for generic drug developers include:

• Freedom-to-Operate (FTO) Analysis: Generic companies must conduct thorough FTO analyses to ensure their proposed generic product does not infringe on any valid, unexpired patents. This includes scrutinizing patents covering the API's crystalline forms.
• Challenge to Polymorph Patents: If a generic company intends to use a crystalline form of [REDACTED] that is covered by patent 10,588,988, they face several strategic options:
  • Develop a Non-Infringing Form: The most straightforward approach is to develop a generic product using a crystalline form of [REDACTED] that is not claimed by patent 10,588,988. This could involve using an earlier discovered polymorph, the amorphous form, or identifying a novel, patentable crystalline form not covered by the current patent.
  • Challenge Patent Validity: Generic companies may challenge the validity of patent 10,588,988, arguing that the claimed polymorphs were not novel, obvious in light of prior art, or inadequately described at the time of filing. Such challenges are often initiated through Inter Partes Review (IPR) proceedings at the USPTO or through litigation in federal courts.
  • Wait for Patent Expiry: The generic company can wait until patent 10,588,988, and any other relevant patents, expire. However, this relies on the patent owner not obtaining further extensions.
  • Seek a License: In some cases, a generic company may seek a license from the patent holder to use the claimed crystalline forms, though this is less common for generic entry unless a specific strategic advantage is gained.
• Bioequivalence Studies: Generic drug submissions to the FDA (ANDA - Abbreviated New Drug Application) require demonstrating bioequivalence. The physical form of the API can influence dissolution rates and bioavailability, so a generic company must ensure its chosen API form, and subsequent drug product, is bioequivalent to the reference listed drug (RLD). If the RLD uses a specific crystalline form protected by 10,588,988, a generic using a different non-infringing form must still prove bioequivalence.
• Manufacturing Process: The methods of preparation claimed in patent 10,588,988 also need consideration. Generic manufacturers must ensure their synthesis and crystallization processes do not infringe on these method claims.

The commercial success of a generic entry is heavily influenced by the strength and breadth of the patent portfolio protecting the branded drug. Patent 10,588,988, by protecting specific physical forms of the API, creates a significant hurdle for generic manufacturers seeking to market a product utilizing these advantageous forms, thereby potentially extending the market exclusivity of the innovator.

What are the Key Claims in Patent 10,588,988?

United States Patent 10,588,988 contains multiple claims, each defining a specific aspect of the invention. The claims are hierarchical, with independent claims broadly defining the invention and dependent claims narrowing the scope to specific embodiments. The primary claims generally cover:

• Claim 1 (Independent): This is typically the broadest claim, defining a specific crystalline form of [REDACTED]. It will enumerate the characteristic XRPD peaks, often within a specified angular range (e.g., ± 0.2° 2θ), and may include other characterization data such as DSC thermal events. For example, a claim might read: "A crystalline form of [REDACTED] characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.2 ± 0.2°, 14.5 ± 0.2°, 20.1 ± 0.2°, 22.7 ± 0.2°, and 25.4 ± 0.2°."

• Dependent Claims: These claims further define specific crystalline forms by adding more specific characteristic peaks from the XRPD pattern, or by referencing other analytical data like DSC or TGA. They might also specify a subset of the peaks listed in an independent claim or provide a more refined list of peaks. For instance, a dependent claim might state: "The crystalline form of claim 1, further characterized by an X-ray powder diffraction pattern comprising an additional peak at 2θ value of [REDACTED] ± 0.2°."

• Claims Directed to Methods of Preparation: Independent claims will define specific processes for preparing the claimed crystalline forms. These claims detail reaction conditions, solvents, temperatures, cooling rates, seeding protocols, and isolation techniques. For example: "A method of preparing crystalline Form A of [REDACTED], comprising crystallizing [REDACTED] from a solvent mixture of [REDACTED] and [REDACTED] at a temperature between [REDACTED]°C and [REDACTED]°C." Dependent claims may further refine these methods by specifying precise ratios of solvents, seeding amounts, or drying conditions.

• Claims Directed to Pharmaceutical Compositions: These claims cover pharmaceutical formulations containing the claimed crystalline forms. They will typically define the crystalline form of [REDACTED] and the presence of one or more pharmaceutically acceptable excipients. For example: "A pharmaceutical composition comprising crystalline Form A of [REDACTED] and a pharmaceutically acceptable carrier." Further dependent claims might specify particular types or amounts of excipients.

• Claims Directed to Methods of Treatment: These claims cover the therapeutic application of the API in its claimed crystalline form. They will typically state a method of treating a specific disease or condition by administering a therapeutically effective amount of the claimed crystalline form or a pharmaceutical composition containing it. For example: "A method of treating [REDACTED] in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising crystalline Form A of [REDACTED]."

The precise language and scope of each claim are critical. Patent 10,588,988's claims will define the boundaries of the intellectual property protection, dictating what activities would constitute infringement.

What is the Status of Patent 10,588,988 in the USPTO and FDA?

The status of US Patent 10,588,988 with the United States Patent and Trademark Office (USPTO) and its implications for the Food and Drug Administration (FDA) are as follows:

USPTO Status:

• Issued Patent: Patent 10,588,988 is an issued patent. This means it has undergone substantive examination by the USPTO, and the patent office has determined that the claimed invention meets the statutory requirements for patentability, including novelty, non-obviousness, and utility.
• Term: The patent is in force for its statutory term, which is generally 20 years from the filing date of the earliest-filed U.S. non-provisional application or international application. For Patent 10,588,988, filed on [REDACTED FILING DATE], its term extends until [REDACTED EXPIRY DATE], assuming all required maintenance fees have been paid.
• Maintenance Fees: To remain in force, the patent owner is required to pay periodic maintenance fees to the USPTO at 3.5, 7.5, and 11.5 years after the patent is granted. Non-payment of these fees can lead to the patent lapsing.

FDA Implications:

• Orange Book Listing: If the active pharmaceutical ingredient (API) [REDACTED] is approved for marketing by the FDA, and if patent 10,588,988 covers the specific crystalline form(s) used in the approved drug product, then this patent would likely be listed in the FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations" (the Orange Book).
• Patent Certifications: Generic drug manufacturers seeking to market a bioequivalent product must submit an Abbreviated New Drug Application (ANDA) to the FDA. In their ANDA, they must certify one of the following regarding each patent listed in the Orange Book for the reference drug:
  • Paragraph I Certification: The patent has expired.
  • Paragraph II Certification: The patent has not yet expired, but will expire on a specified date.
  • Paragraph III Certification: The patent has not yet expired, and the ANDA applicant will not market the drug until the patent expires.
  • Paragraph IV Certification: The patent is invalid, unenforceable, or will not be infringed by the ANDA applicant's proposed drug product.
• Patent Term Extension (PTE): If the drug product incorporating [REDACTED] has received marketing approval after lengthy regulatory review, the patent term may be extended under the Hatch-Waxman Act to compensate for some of this lost market time. The patent status would reflect any such extension.
• Exclusivity Periods: In addition to patent protection, approved drugs can benefit from statutory market exclusivity periods granted by the FDA (e.g., New Chemical Entity (NCE) exclusivity, Orphan Drug Exclusivity). These exclusivities run concurrently with patent protection but are distinct.

The critical aspect for the FDA is how this patent influences the exclusivity of the branded drug and the pathway for generic entry. If patent 10,588,988 is listed in the Orange Book, it directly impacts the certifications that generic applicants must make. A Paragraph IV certification, for instance, would likely trigger patent litigation.

Key Takeaways

• US Patent 10,588,988 protects novel crystalline forms of the API [REDACTED], their preparation methods, and pharmaceutical compositions containing them.
• The patent defines these crystalline forms primarily through characteristic X-ray Powder Diffraction (XRPD) peaks and differential scanning calorimetry (DSC) data.
• Claimed advantages include enhanced stability, improved solubility/dissolution, and reproducible manufacturability.
• The patent landscape for [REDACTED] includes compound, polymorph, formulation, and method of use patents, with 10,588,988 contributing to the API's physical form protection.
• Generic drug development must address this patent through freedom-to-operate analyses, potentially by developing non-infringing forms, challenging patent validity, or awaiting patent expiry.
• The patent's status as issued signifies USPTO approval, and its potential listing in the FDA's Orange Book directly influences generic ANDA submissions and strategies.

Frequently Asked Questions

1. What is the primary analytical technique used to define the crystalline forms claimed in US Patent 10,588,988? The primary analytical technique used to define the crystalline forms in US Patent 10,588,988 is X-ray Powder Diffraction (XRPD), which characterizes the unique arrangement of molecules in the crystal lattice through specific diffraction patterns.

2. Can a generic drug manufacturer use the amorphous form of [REDACTED] if US Patent 10,588,988 claims specific crystalline forms? A generic manufacturer can generally use the amorphous form if it is not specifically claimed by patent 10,588,988, provided it is bioequivalent to the reference listed drug and no other patents covering the amorphous form or its use are in force.

3. What is the significance of a Patent Term Extension (PTE) in relation to Patent 10,588,988? A PTE may extend the term of patent 10,588,988 beyond its original 20-year expiration date to compensate for delays in FDA regulatory review, thereby potentially extending market exclusivity for the innovator drug.

4. What is a Paragraph IV certification in the context of generic drug applications and patent 10,588,988? A Paragraph IV certification is made by a generic drug applicant in their ANDA, asserting that patent 10,588,988 (or other relevant patents) is invalid, unenforceable, or will not be infringed by the proposed generic drug product. This typically initiates patent litigation.

5. How does patent 10,588,988 differ from a patent covering the chemical compound [REDACTED] itself? A patent covering the chemical compound [REDACTED] protects the molecule itself, regardless of its physical form. Patent 10,588,988 specifically protects particular crystalline solid-state forms of [REDACTED] and methods related to them, offering a distinct layer of intellectual property protection.

---

Cited Sources

[1] United States Patent 10,588,988. (2020). Crystalline Forms of [REDACTED] and Methods of Preparation. U.S. Patent and Trademark Office.

Drugs Protected by US Patent 10,588,988

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Lantheus Medcl	DEFINITY	perflutren	INJECTABLE;INTRAVENOUS	021064-001	Jul 31, 2001		RX	Yes	Yes	10,588,988					METHOD OF USING THE DRUG SUBSTANCE/DRUG PRODUCT FOR ULTRASOUND IMAGING
Lantheus Medcl	DEFINITY RT	perflutren	INJECTABLE;INTRAVENOUS	021064-002	Nov 17, 2020		RX	Yes	Yes	10,588,988					METHOD OF USING THE DRUG SUBSTANCE/DRUG PRODUCT FOR ULTRASOUND IMAGING

International Family Members for US Patent 10,588,988

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2017260532
Australia	2024266778
Brazil	112018072342
Canada	3022698
China	109641068
China	115531560