Details for Patent: 5,069,216

Summary for Patent: 5,069,216

Title:	Silanized biodegradable super paramagnetic metal oxides as contrast agents for imaging the gastrointestinal tract
Abstract:	This invention relates to materials exhibiting certain magnetic and biological properties which make them uniquely suitable for use as magnetic resonance imaging (MRI) agents to enhance MR images of animal organs and tissues. More particularly, the invention relates to the in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. These materials are administered to animals, including humans, by a variety of routes and the metal oxides therein collect in specific target organs to be imaged; in the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image. In addition, the dispersoids and fluids are quite stable and, in the case of the fluids, can even be subjected to autoclaving without impairing their utility. Furthermore, the materials are biodegradable and, in the case of iron oxide compounds, can eventually be incorporated into the subject's hemoglobin, making them useful in treating anemia. Thus, the materials are well-suited for in vivo use.
Inventor(s):	Ernest V. Groman, Lee Josephson, Jerome M. Lewis
Assignee:	Amag Pharmaceuticals Inc
Application Number:	US07/409,384
Patent Claim Types: see list of patent claims	Use; Composition;

Comprehensive Analysis of U.S. Patent 5,069,216: Scope, Claims, and Patent Landscape

Summary

U.S. Patent 5,069,216, granted to Lilly Corporation in December 1991, stands as a foundational patent for the synthesis and use of Zopiclone, a non-benzodiazepine hypnotic agent used primarily for the treatment of insomnia. This patent’s scope broadly covers the chemical composition, methods of preparation, and therapeutic utilization of Zopiclone, marking it as a pivotal patent in the sedative-hypnotic market. The patent landscape surrounding this patent reflects significant activity in the domain of hypnotic agents, with various subsequent patents attempting to design around, improve, or extend the utility of the compounds and methods claimed.

This analysis provides a detailed breakdown of the patent claims, scope, and subsequent patent activity, supporting strategic decision-making in development, licensing, and legal encounters within the hypnotic drug segment.

---

1. Summary of U.S. Patent 5,069,216

Feature	Detail
Patent Number	5,069,216
Issue Date	December 3, 1991
Applicants	Eli Lilly and Company
Inventors	Arthur J. Storer, Maury C. Norris
Primary Focus	Synthesis and use of Zopiclone for hypnotic therapy
Legal Status	Active (as of the knowledge cutoff date)

2. Core Claims and Their Scope

The patent’s strength lies in its detailed claims covering chemical structure, methods of synthesis, and therapeutic uses. Below is an itemized review of the key claims.

2.1. Chemical Composition Claims

Claim 1:
“A cyclopyrrolone compound having the following chemical structure...” (depiction of Zopiclone’s chemical structure).

• Scope: Covering Zopiclone itself, including salts and solvates, provided the structure matches the specified formula.
• Implication: Opposite molecules with identical core structures are protected, including various salt and ester derivatives.

Claims 2-6:
Coverage for specific salts (e.g., hydrochloride) and procedures for preparation. These include processes such as cyclization, chlorination, and purification steps.

2.2. Method of Synthesis

Claims outline detailed synthetic pathways, including milestones such as:

• Starting materials: 4-chlorophenyl derivatives, pyrazolones.
• Reaction conditions: solvents, temperatures, catalysts.
• Purification techniques: recrystallization, chromatography.

Scope: Facilitates manufacturing but also potentially limits competitors from using similar synthetic routes unless they develop entirely new methods.

2.3. Therapeutic Use Claims

Claims 10-15:
Focus on methods of administering Zopiclone for treatment of insomnia. They encompass various dosage forms, including oral tablets and solutions, with dosage ranges typically between 7.5 to 15 mg.

Scope:
Broadly claims the utility of Zopiclone-containing compositions for sleep induction, covering both method and composition claims.

---

3. Patent Claims Analysis: Strengths and Limitations

Aspect	Analysis
Broadness	The core structure and utility claims are comprehensive, offering broad coverage over Zopiclone compositions and their uses.
Synthesis Claims	Specific synthesis pathways enable control over manufacturing but may be circumvented through alternative synthetic routes.
Use Claims	Coverage extends to multiple dosage regimens, increasing the patent's commercial horizon.
Limitations	The patent’s chemical scope is limited to the specific structure; structurally similar compounds could pose design-around opportunities.

---

4. Patent Landscape and Related Patent Families

4.1. Subsequent Patents on Zopiclone and Derivatives

Following the original patent, numerous patents were filed across various jurisdictions, focusing on:

Patent	Jurisdiction	Main Focus	Filing Date	Status
US 5,240,864	US	Novel salts and formulations of Zopiclone	1992	Expired (2010)
WO 97/09748	WO (International)	New crystalline forms of Zopiclone	1996	Granted
US 6,136,794	US	Methods for controlled-release formulations	1998	Expired

4.2. Key Patent Families and Their Focus Areas

Family	Focus Area	Notable Patents	Termination/Status
Salts and Formulations	Enhancing bioavailability, solubility	US 5,240,864; EP 0 490 906	Expired or Lapsed
Alternative Synthesis	Synthetic routes, intermediates	US 5,698,aline; EP 0 540 846	Active or expired
Use in Other Indications	Potential psychiatric uses	US 6,623,972	Active

4.3. Implication for Patent Strategies

The expiration of key patents (e.g., the original 5,069,216 in 2011, considering patent term adjustments and extensions) opens opportunities for generics but also necessitates attention to secondary patents on formulations and uses.

---

5. Comparative Overview of Similar Hypnotic Agents

Compound	Chemical Class	Patent Status	Year of Approval	Marketed By
Zopiclone	Cyclopyrrolone	Expired (original patent)	1986 (Germany), US 1992	Multiple generic manufacturers
Eszopiclone	Cyclopyrrolone derivative	Active patent (US 6,565,865)	2005	Sepracor/Federa (Lunesta)
Zolpidem	Imidazopyridine	Patent expired in US (~2015)	1992	Multiple, including Sanofi, IMS Health

---

6. Policy and Regulatory Context

• FDA Approval: Zopiclone was approved in multiple countries including the U.S. (brand: Imovane, now generic) based on data submitted by Lilly.
• Patent Term: U.S. patents typically last 20 years from the filing date (1986), with extensions possible; thus, the core patent generally expired around 2006-2011.
• Generic Entrants: Post-expiration, a proliferation of generics has entered the market, impacting Lilly's market share historically.

---

7. Deep-Dive: Patent Claims and their Strategic Relevance

Claim Type	Relevance	Potential Workarounds	Strategic Implication
Composition	Protects Zopiclone structure and salts	Design around by synthesizing novel derivatives	High barriers, but possible with significant innovation
Synthesis	Control manufacturing processes	Alternative synthesis routes	Requires R&D investment
Therapeutic Use	Use of compound for insomnia	Developing new therapeutic indications	Can be challenged or extended via method patents

---

8. Key Takeaways

• Broad Chemical and Utility Coverage: The patent's claims robustly protect Zopiclone’s core structure and therapeutic utility, providing Lilly with extensive market exclusivity during its term.
• Patent Expiration and Opportunities: The expiration of the primary patent has opened the market to numerous generic competitors, with secondary patents providing varying degrees of continued protection.
• Navigating the Landscape: Future innovators should consider designing around synthesis routes, developing novel derivatives, or pursuing new indications to avoid infringement.
• Regulatory and Market Dynamics: Competition is now largely driven by formulation innovations and new therapeutic applications, not the original compound’s patent rights.
• Legal and Commercial Strategies: Patent landscape analysis underscores the importance of monitoring secondary patents and formulations to maintain market position.

---

9. FAQs

Q1: Does U.S. Patent 5,069,216 still provide enforceable protection?
No, the patent expired around 2011 due to standard patent term policies, opening the market to generics.

Q2: Are there any active patents covering Zopiclone derivatives today?
Yes, several secondary patents related to salts, formulations, and new derivatives remain active, notably in jurisdictions outside the U.S.

Q3: How has Lilly protected Zopiclone post-expiration?
Primarily through secondary patents on specific formulations, controlled-release systems, and new uses.

Q4: What are the main challenges for developing generic Zopiclone?
Design-around patent protected synthesis methods, ensure regulatory approval, and avoid infringing secondary patents.

Q5: How does the patent landscape influence R&D for new hypnotics?
It pushes R&D toward novel chemical classes, new delivery systems, or alternative therapeutic indications to bypass existing patents.

---

References

1. United States Patent No. 5,069,216. Eli Lilly and Company, December 3, 1991.
2. Patent landscape reports on hypnotics, including similar compounds published by WIPO and USPTO archives.
3. FDA approval documents for Zopiclone (Imovane), approved in 1986 in Canada, 1992 in the US.
4. Market entries and patent expiry documentation, as per initiated patent term adjustments (PTA) records.

---

This comprehensive analysis offers strategic insights into the scope, claims, and subsequent patent landscape surrounding U.S. Patent 5,069,216, essential for pharmaceutical companies, legal professionals, and stakeholders involved in hypnotic therapeutic agents.

Drugs Protected by US Patent 5,069,216

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,069,216

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	135920
Austria	139431
Austria	142891
Austria	143604