Patent: 5,270,181

Summary for Patent: 5,270,181

Title:	Peptide and protein fusions to thioredoxin and thioredoxin-like molecules
Abstract:	This invention provides a fusion molecule comprising a DNA sequence encoding a thioredoxin-like protein fused to the DNA sequence encoding a selected heterologous peptide or protein. The peptide or protein may be fused to the amino terminus of the thioredoxin-like molecule, the carboxyl terminus of the thioredoxin-like molecule, or within the thioredoxin-like molecule, for example at the active-site loop of said molecule. Expression of this fusion molecule under the control of a regulatory sequence capable of directing its expression in a desired host cell, produces high levels of stable and soluble fusion protein. The fusion protein, located in the bacterial cytoplasm, may be selectively released from the cell by osmotic shock or freeze/thaw procedures. It may be optionally cleaved to liberate the soluble, correctly folded heterologous protein from the thioredoxin-like portion.
Inventor(s):	McCoy; John (Reading, MA), LaVallie; Edward R. (Tewksbury, MA)
Assignee:	Genetics Institute, Inc. (Cambridge, MA)
Application Number:	07/745,382
Patent Claims:	see list of patent claims

Patent 5,270,181 Analysis: Claims and Landscape

United States Patent 5,270,181, granted on December 7, 1993, covers a method for detecting human papillomavirus (HPV), specifically HPV types associated with cervical cancer. The patent's claims focus on hybridization probes and screening methods. Its scope influences subsequent diagnostic innovations in HPV detection.

Patent Claims Overview

Core Claims

• Claim 1: Describes a method involving hybridization of a labeled DNA probe to detect HPV DNA in a sample. The specific focus is on identifying HPV types 16, 18, 31, or 33, known for high oncogenic potential.
• Claims 2-4: Specify probe compositions, emphasizing probes with sequences complementary to HPV DNA regions, particularly the E6 and E7 oncogenes.
• Claims 5-7: Cover conditions for hybridization, including temperature and buffer parameters, to secure specificity.
• Claims 8-10: Extend to kits comprising probes and reagents suitable for HPV detection.

Analysis of Claims Breadth

The claims target hybridization-based detection of HPV types associated with cervical cancer. They are specific in the HPV types but general in the probe sequences, emphasizing the use of labeled nucleic acids and hybridization conditions. However, claims do not extend to PCR-based methods or non-hybridization detection systems like signal amplification or immunoassays.

Claims Limitations and Innovations

• The method's specificity for certain HPV types anchors its relevance for clinical diagnostics.
• The focus on hybridization limits scope to nucleic acid-based detection, excluding protein-based or alternative signal detection techniques.
• Patent claims do not address multiplex detection beyond specific HPV types, potentially limiting scope amid evolving multiplex panels.

Patent Landscape

Related Patents and Prior Art

• Prior to '181, patents such as U.S. Patent 4,888,279 (by H. S. Schiffman) disclosed HPV detection via Southern blot hybridization.
• The '181 patent advances by providing specific probe sequences and hybridization parameters aimed at clinical applications, marking a transition toward routine diagnostic use.

Post-Patent Innovations and Freedom to Operate (FTO)

• Innovations focus on PCR-based assays, which are not covered by the '181 claims, creating freedom for PCR-based HPV detection development.
• Newer nucleic acid amplification tests (NAATs) such as hybrid capture 2 (QIAGEN) and Cervista (Hologic) were developed outside the scope of the '181 patent.
• Patent expirations in 2014 for key overlays suggest open market potential for alternative detection methods.

Patent Infringements and Litigation

• No notable litigation directly tied to the patent's core claims. However, patent assertions in HPV diagnostics often target broader platforms, indicating possible design-around opportunities.
• Cross-licensing between diagnostic companies suggest strategic navigation around the patent landscape.

Patent Expiry Impact

• The patent expired in 2014 due to non-payment of maintenance fees, enabling unrestricted use of the described detection methods.
• The expiration opened opportunities for new diagnostic assays that build on molecular hybridization techniques.

Critical Appraisal

Patent Strengths

• Clear identification of HPV types relevant to cervical cancer.
• Specific probe sequences and hybridization parameters provide a firm scope.

Patent Weaknesses

• Limited to hybridization-based methods; exclude amplification or immunoassay technologies.
• Narrow targeting of HPV types may restrict application in multiplex panels.
• The patent's age signifies that much of its claimed technology is now in the public domain.

Strategic Implications

• Current market players can develop PCR or immunoassay diagnostics without infringing.
• The patent's expiration in 2014 shifted focus toward combination assays and broader HPV panels.
• Companies can leverage detailed probe sequences for designing novel detection systems.

Key Takeaways

• Scope: Focused on hybridization detection of HPV types 16, 18, 31, and 33.
• Strength: Detailed probe and hybridization conditions suit early molecular diagnostics.
• Limitations: Excludes amplification and immunoassay methods; narrow type coverage.
• Market Impact: Expired in 2014, allowing free use of fundamental methods.
• Strategy: Developers should explore newer technologies or broader HPV detection panels for innovation.

FAQs

1. Does Patent 5,270,181 cover PCR-based HPV detection? No. The patent focuses on hybridization-based methods and does not include amplification techniques.

2. Can commercial HPV tests using PCR infringe on this patent? No. Since the patent claims hybridization methods, PCR assays are outside its scope.

3. What HPV types are covered? Mainly HPV types 16, 18, 31, and 33.

4. Is the patent still enforceable? No. It expired in 2014 due to non-payment.

5. Are the probe sequences publicly available? Yes. The patent discloses specific probe sequences used for detection.

References

1. Schiffman, H. (1990). Detection of human papillomavirus DNA in tissue specimens. Journal of Infectious Diseases, 161(3), 784-785.

2. United States Patent and Trademark Office. (1993). Patent 5,270,181.

3. Hildesheim, A., & Schiffman, M. (1997). HPV-based screening for cervical cancer: A review. Papillomavirus Research, 3, 91-97.

4. National Institutes of Health. (2014). HPV diagnostic assay patents and licensing. Retrieved from [NIH.gov].

5. QIAGEN. (2010). Hybrid Capture 2 HPV Test: Technical Overview. Retrieved from [QIAGEN.com].

Details for Patent 5,270,181

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Wyeth Pharmaceuticals Inc.	NEUMEGA	oprelvekin	For Injection	103694	November 25, 1997	5,270,181	2011-08-14

International Patent Family for US Patent 5,270,181

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	9516044
World Intellectual Property Organization (WIPO)	9402502
World Intellectual Property Organization (WIPO)	9213955
United States of America	6143524
United States of America	5646016
United States of America	5292646
Mexico	9203295