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Ph20 Polypeptide Variants With A Modification At Position 309 Of The Ph20 Polypeptide And A Method Of Making Thereof

Patent No. US12077791 (titled "Ph20 Polypeptide Variants With A Modification At Position 309 Of The Ph20 Polypeptide And A Method Of Making Thereof") was filed by Halozyme Inc on Jun 22, 2023.

What is this patent about?

’791 is related to the field of hyaluronidase enzymes , specifically modified PH20 hyaluronidases. Hyaluronan, a key component of the extracellular matrix, plays a role in various physiological processes. Hyaluronidases, like PH20, degrade hyaluronan and are used to treat diseases associated with hyaluronan accumulation and to enhance the dispersion and delivery of therapeutic agents. Existing hyaluronidases, often derived from ovine or bovine sources, can be immunogenic in humans, creating a need for improved hyaluronan-degrading enzymes.

The underlying idea behind ’791 is to engineer PH20 hyaluronidase variants with improved properties, particularly increased stability and activity . This is achieved through specific amino acid modifications, such as replacements, deletions, or insertions, within the PH20 polypeptide sequence. The goal is to create modified PH20 enzymes that retain or enhance their hyaluronidase activity while exhibiting greater resistance to degradation under various conditions, such as elevated temperature, agitation, or the presence of denaturing agents.

The claims of ’791 focus on a modified PH20 polypeptide with at least 95% sequence identity to SEQ ID NO: 35, featuring an amino acid replacement at position 309 (relative to SEQ ID NO:3). The replacement must be selected from E, G, H, L, M, N, Q, R, S, or T. Crucially, the modified polypeptide must exhibit increased hyaluronidase activity compared to the unmodified polypeptide of SEQ ID NO:3 when measured under identical conditions.

In practice, the invention involves identifying specific amino acid residues within the PH20 polypeptide that, when modified, lead to enhanced stability or activity. This can be done through directed mutagenesis and high-throughput screening. The resulting modified PH20 polypeptides can then be produced recombinantly in host cells, such as CHO cells, and purified for use in pharmaceutical compositions.

’791 differentiates itself from prior approaches by providing specific PH20 variants with enhanced stability and activity. Unlike previous hyaluronidases, which may be prone to degradation or immunogenicity, the modified PH20 polypeptides of this invention are engineered to withstand denaturing conditions and maintain their enzymatic function. This makes them particularly suitable for use in pharmaceutical formulations requiring long shelf lives or exposure to harsh conditions, and for enhancing the delivery of co-administered therapeutic agents.

How does this patent fit in bigger picture?

Technical landscape at the time

In the early 2010s when ’791 was filed, hyaluronan-degrading enzymes were typically implemented using recombinant protein expression and purification techniques at a time when protein engineering commonly relied on site-directed mutagenesis to improve enzyme properties. At that time, protein stability was a significant concern, especially for therapeutic applications, when hardware or software constraints made high-throughput screening of protein variants non-trivial. At that time, formulations commonly relied on preservatives to maintain sterility and stability, and protein denaturation under various conditions was a well-known challenge.

Novelty and Inventive Step

The examiner approved the claims because the modified PH20 polypeptide, which includes a specific amino acid sequence and modifications, was not described or suggested in the prior art. The examiner also noted that the double patenting rejection was withdrawn because the applicant submitted an acceptable terminal disclaimer.

Claims

This patent contains 10 claims, with claim 1 being independent. Independent claim 1 focuses on a modified PH20 polypeptide with specific amino acid sequence characteristics and increased hyaluronidase activity. The dependent claims generally elaborate on specific features, compositions, and manufacturing methods related to the modified PH20 polypeptide described in the independent claim.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)Support for SpecificationInterpretation
Amino acid modification
(Claim 1)		“The modifications include amino acid replacement, deletion and/or insertions. For purposes herein, amino acid replacements are denoted by the single amino acid letter followed by the corresponding amino acid position in SEQ ID NO:3 in which the replacement occurs. For example, replacement with P at a position corresponding to position 204 in a PH20 polypeptide with reference to amino acid residue positions set forth in SEQ ID NO:3 means that the replacement encompasses F204P in a PH20 polypeptide set forth in SEQ ID NO:3, or the same replacement at the corresponding position in another PH20 polypeptide.”An amino acid replacement at a specific position in the PH20 polypeptide sequence.
Increased hyaluronidase activity
(Claim 1)		“Also provided are modified PH20 polypeptides that contain at least one amino acid replacement in a PH20 polypeptide, where the modified PH20 polypeptide exhibits increased hyaluronidase activity compared to the PH20 polypeptide not containing the amino acid replacement. When comparing activity among polypeptides, activity is compared under the same conditions. Among the modified PH20 polypeptides are those that that exhibit at least 120%, 130%, 135%, 140%, 145%, 150%, 160%, 170%, 180%, 200%, 250%, 300%, 350%, 400%, 500%, 1500%, 2000%, 3000%, 4000%, 5000% or more of the hyaluronidase activity of the PH20 polypeptide not containing the amino acid replacement.”The modified PH20 polypeptide exhibits a higher level of hyaluronidase activity compared to the unmodified polypeptide of SEQ ID NO: 3, when measured under the same conditions.
Modified PH20 polypeptide
(Claim 1)		“Provided are modified PH20 polypeptides that have an altered property or properties compared to the PH20 polypeptide that do not have the modification(s). The modifications include amino acid replacement, deletion and/or insertions. Included are modified PH20 polypeptides that have at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to the sequence of amino acids set forth in SEQ ID NO:3.”A PH20 polypeptide with at least 95% sequence identity to SEQ ID NO: 35, containing a specific amino acid replacement at position 309 (with reference to SEQ ID NO: 3), and exhibiting increased hyaluronidase activity compared to SEQ ID NO: 3.

Litigation Cases New

US Latest litigation cases involving this patent.

Case NumberFiling DateTitle
2:25-cv-03179Apr 10, 2025People Co. Ltd. V. Lakeshore Learning Materials, Llc

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US12077791

HALOZYME INC
Application Number
US18339829
Filing Date
Jun 22, 2023
Status
Granted
Expiry Date
Dec 28, 2032
External Links
Slate, USPTO, Google Patents