IP Verse

Ph20 Polypeptide Variants, Formulations And Uses Thereof

Patent No. US12054758 (titled "Ph20 Polypeptide Variants, Formulations And Uses Thereof") was filed by Halozyme Inc on Dec 15, 2022.

What is this patent about?

’758 is related to the field of hyaluronidase enzymes , specifically modified versions of the PH20 hyaluronidase. Hyaluronidases degrade hyaluronan, a key component of the extracellular matrix. This degradation can be used to treat diseases associated with hyaluronan accumulation or to increase tissue permeability for drug delivery. Existing hyaluronidases, often derived from ovine or bovine sources, can be immunogenic in humans, creating a need for improved enzymes.

The underlying idea behind ’758 is to engineer PH20 hyaluronidase variants with improved properties, particularly increased stability . This is achieved by introducing specific amino acid substitutions into the PH20 polypeptide chain. The goal is to create enzymes that are more resistant to denaturation under various conditions, such as elevated temperature, agitation, low salt concentrations, or the presence of preservatives, while maintaining enzymatic activity.

The claims of ’758 focus on a modified PH20 polypeptide that includes one or more amino acid modifications in an unmodified PH20 polypeptide, where the unmodified PH20 polypeptide consists of the amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 7 and 32-66; amino acid modifications are selected from the group consisting of amino acid replacements(s), deletion(s), and/or insertion(s); the modified PH20 polypeptide comprises an amino acid replacement at a position corresponding to residue 317, with reference to amino acid positions set forth in SEQ ID NO:3; the replacement at the position corresponding to residue 317 is selected from the group consisting of A, I, K, M, Q, and R; corresponding amino acid positions are identified by alignment of the PH20 polypeptide with the polypeptide having the amino acid sequence of SEQ ID NO:3; and the modified PH20 polypeptide has at least 91% sequence identity to a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 7 and 32-66.

In practice, the invention involves identifying specific amino acid positions within the PH20 sequence where substitutions can enhance stability. This is done through mutagenesis and screening , creating libraries of PH20 variants and testing their activity and stability under different conditions. The patent identifies numerous specific amino acid substitutions that confer increased stability, particularly in the presence of phenolic preservatives or at elevated temperatures.

The modified PH20 polypeptides can be produced recombinantly in cells like CHO cells, purified, and formulated into pharmaceutical compositions. These compositions can be used to treat hyaluronan-associated diseases or to enhance the delivery of other therapeutic agents. The key advantage is the improved stability of the modified PH20, allowing for more robust formulations and potentially improved therapeutic efficacy.

How does this patent fit in bigger picture?

Technical landscape at the time

In the early 2010s when ’758 was filed, hyaluronan was known as a major component of the extracellular matrix, and at a time when hyaluronidases were typically used to degrade hyaluronan for therapeutic purposes. At that time, many hyaluronidases used therapeutically were ovine or bovine forms, when systems commonly relied on these animal-derived enzymes rather than engineered or modified versions. When hardware or software constraints made protein engineering and modification non-trivial, at a time when protein stability was typically achieved through formulation adjustments.

Novelty and Inventive Step

Claims were rejected for nonstatutory double patenting over prior art. Arguments were made, and the application proceeded to allowance. The prosecution record does NOT describe the technical reasoning or specific claim changes that led to allowance.

Claims

This patent contains 40 claims, with claim 1 being the only independent claim. Independent claim 1 is directed to a modified PH20 polypeptide with specific amino acid modifications. The dependent claims generally elaborate on the characteristics, modifications, compositions, and uses of 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 modifications
(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.”Alterations to the amino acid sequence of a PH20 polypeptide, including amino acid replacements, deletions, and/or insertions.
Amino acid replacement
(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.”The substitution of one amino acid residue for another at a specific position in the PH20 polypeptide sequence.
Corresponding amino acid positions
(Claim 1)		“These include modified PH20 polypeptides that contain one or more amino acid replacements, where at least one replacement is at an amino acid position corresponding (i.e., by alignment) to a position selected from among 10, 12, 20, 22, 26, 34, 36, 46, 50, 52, 58, 68, 70, 74, 82, 83, 84, 86, 97, 127, 131, 138, 142, 143, 144, 166, 169, 174, 193, 195, 196, 204, 205, 206, 213, 219, 234, 237, 238, 240, 249, 261, 267, 277, 279, 291, 309, 310, 314, 315, 317, 318, 347, 367, 375, 376, 399, 401, 407, 416, 419, 421, 431, 433, 439, 440, 443 or 445 with reference to amino acid positions set forth in SEQ ID NO:3, wherein corresponding amino acid positions are identified by alignment of the PH20 polypeptide with the polypeptide set forth in SEQ ID NO:3.”Amino acid positions in different PH20 polypeptides that align with each other when the sequences are aligned, using the sequence of SEQ ID NO:3 as a reference.
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. The modified PH20 polypeptide can be one in which the unmodified form thereof has at least about 68% sequence identity to SEQ ID NO: 3 and further contains modifications that alter stability and/or can be a PH20 polypeptide that includes as many as about up to 100, 110, 120, 130, 150 amino acid differences from PH20 but retains enzymatic activity, particularly, at least about 40% of the activity of the unmodified PH20 polypeptide and exhibits increased stability, such as stability under denaturing conditions.”A PH20 polypeptide that has been altered by at least one amino acid replacement, deletion, or insertion, compared to an unmodified PH20 polypeptide. The unmodified PH20 polypeptide has the amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 7 and 32-66.

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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US12054758

HALOZYME INC
Application Number
US18066960
Filing Date
Dec 15, 2022
Status
Granted
Expiry Date
Dec 28, 2032
External Links
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