Patent: 9,278,124

Summary for Patent: 9,278,124

Title:	Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods
Abstract:	Provided herein are diagnostic methods for identifying subjects susceptible to treatment with a hypoxia-activated agent, and related methods. Also provided herein are methods of monitoring treatments with anti-hyaluronan agents, and related methods.
Inventor(s):	Shepard; H. Michael (San Diego, CA), Li; Xiaoming (San Diego, CA), Thompson; Curtis (Encinitas, CA)
Assignee:	Halozyme, Inc. (San Diego, CA)
Application Number:	13/998,269
Patent Claims:	see list of patent claims

US Patent 9,278,124 Landscape Analysis: TSG-6 Hyaluronan-Binding Stratification + Soluble Hyaluronidase + Hypoxia-Activated Prodrug

US 9,278,124 covers a patient-selection and combination-treatment workflow that pairs (1) a hyaluronan (HA) “susceptibility” diagnostic using an HABP containing a TSG-6 link module (LM) with (2) administration of soluble hyaluronidase (including PH20/PEGylated PEGPH20) plus (3) a hypoxia-activated agent, including hypoxia-activated prodrugs and a wide prodrug class list. The estate is broad on: HA assay format (HABP-TSG-6-LM binding), HA thresholding and control/reference constructs, and HA-binding protein architecture (single-site, multimers, Fc-fusions). It is also broad on the hypoxia-activated prodrug universe (multiple named bioreductive prodrugs and derivatives), and broad on cancer and hyperproliferative indications.

On the core risk profile: the patent reads on biologic-prodrug combination concepts that are widely explored in hypoxia oncology, hyaluronan targeting, and PH20/PEGPH20 combinations. The most litigation-relevant novelty anchor is the specific stratification mechanism: measuring HA with an HABP whose HA-binding module is specifically the TSG-6 LM (and variants with defined sequence identity and/or heparin-binding reduction). That anchor is also the most vulnerable claim-to-prior-art point if the prior art already taught TSG-6-LM-based HA detection for patient selection in combination regimens with hypoxia-activated agents.

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What does US 9,278,124 claim, and what is the technical novelty?

Claim 1 requires all steps as limitations:

1. Diagnostic measurement of HA in a sample from the subject.

   • Trigger: if HA is at or above a predetermined level, the subject is “susceptible.”
   • Measurement: HA is detected by binding of an HABP to the sample.
   • HABP comprises a TSG-6 link module (LM) or a sufficient portion that specifically binds HA.

2. Patient selection: select susceptible subjects for treatment with a soluble hyaluronidase and a hypoxia-activated agent.

3. Therapy: administer soluble hyaluronidase + hypoxia-activated agent in any ordering (simultaneous, sequential, or intermittent), “thereby treat” the hypoxia-related disease/condition.

Where the claim is broad vs. narrow

• Narrowest element: the HABP’s HA-binding module is constrained to the TSG-6 LM (sequence-ID scoped; variants at ≥85% identity; multimers; Fc fusions; heparin-binding reduction modifications).
• Broadest element: hypoxia-activated agent is broadly satisfied by many hypoxia-activated prodrug classes and named exemplars (Claim 29), and by “derivatives or analogs.”
• Broadest clinical scope: hyperproliferative disease and essentially “cancer” plus a long tumor list (Claims 2–4, 34).
• Practical implementation breadth: samples can be tissue, cell, or bodily fluid; tumor tissue is called out (Claims 4–5, 10–12).

Claim dependencies that expand scope materially

• HA thresholding is expanded to fold-change thresholds and specific plasma absolute levels (Claims 9, 10).
• Tumor-area coverage threshold is specified (Claim 12).
• HABP composition is expanded into multimers, linker-fusions, and Fc multimerization constructs (Claims 18–24).
• Prodrug breadth is expanded to include wide named hypoxia-activated prodrugs and conjugates that target tumors (Claims 25–31).
• Enzyme implementation breadth covers PH20 and PEGylated PEGPH20 and sequence-identity scopes (Claims 37–48).
• Combination management includes corticosteroid prophylaxis (Claims 35, 50–51).

Market-relevant read-through

The combination of PEGPH20 (PH20 hyaluronidase) with an anticancer hypoxia-activated prodrug plus HA-based selection is a relatively specific regimen architecture. If the clinical program associated with PEGPH20 already used HA stratification (or used HA marker measurement generally), this patent is positioned to control not only the drug pairing but the eligible-population rule.

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How do the dependent claims narrow risk (or increase enforceability) for HABP and hyaluronidase?

What patents protect the HABP HA detection approach: TSG-6 LM binding and Heparin-reduced variants?

Key dependent claim structure:

• TSG-6-LM sequence constraints (Claim 13): SEQ ID NOS: 207, 360, 417, 418 and variants with ≥85% identity that specifically bind HA.
• Heparin-binding reduction modifications (Claims 14–17):
  • Modify TSG-6 LM to reduce/eliminate heparin binding.
  • Defined amino acid replacement positions mapped to the SEQ ID:360 alignment.
  • Examples include K20A, K34A and/or K41A (Claims 15–16).
  • HABP may include additional LM sequences (SEQ ID NO:361/416) with ≥85% identity constraints (Claim 17).
• HABP multimer architecture (Claims 18–24):
  • Multimer with two HA-binding domains, each a TSG-6 LM or variant.
  • Multimerization domain includes Fc domains and variants.
  • Fusion example: TSG-6-LM-Fc comprising amino acids 21–349 of SEQ ID NO:212 or 215 (Claim 23).

Enforceability impact:
These HA-detection constraints create a litigation path that is less susceptible to “generic” HA binding protein arguments. If accused diagnostics use other HA binders (e.g., CD44, HABP variants not derived from TSG-6 LM), they may avoid the strict sequence/module limitation. Conversely, if prior art already used TSG-6-derived binders for HA measurement broadly, this feature will not guarantee validity.

What patents protect soluble hyaluronidase and PEGPH20 implementation?

The claim set is explicit:

• Soluble hyaluronidase includes human hyaluronidase (Claim 37).
• PH20 hyaluronidase (Claim 38), including bovine/ovine or soluble human PH20 lacking GPI anchor (Claim 39).
• Defined PH20 sequence identity ranges (Claims 40, 46).
• PEGylation (Claims 41–48), with PEGPH20 named (Claim 43).

Enforceability impact:
If the accused regimen uses PH20 or PEGPH20, this element is easy to meet. Prior art on PH20 and PEGPH20 is extensive in oncology and HA-targeting contexts. Validity will likely hinge on the diagnostic stratification + hypoxia-activated prodrug combination rather than the enzyme alone.

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What patents or prior art would most likely attack validity for US 9,278,124?

Given only the claim text and no prosecution history or cited references, the critical validity attack vectors follow the claim structure:

1) “TSG-6 LM HABP detecting HA” as anticipated or obvious

Most likely prior-art relevance:

• TSG-6’s known HA-binding biology and engineered TSG-6 domains used as binding reagents.
• Prior art on HA detection assays using HA-binding proteins, including engineered variants, multimers, and Fc fusions.
• Prior art that includes clinical or preclinical stratification using HA levels.

Why it matters: claim 1 requires the HA detection be by an HABP comprising the TSG-6 LM. If TSG-6 LM-based HA detection was known, novelty shifts to:

• the specific thresholds and patient-selection logic, and/or
• the coupling to soluble hyaluronidase + hypoxia-activated prodrugs.

2) Hypoxia-activated prodrugs + oncology combination therapy

Hypoxia-activated prodrugs have broad historical documentation. Claim 29 lists many known prodrugs (mitomycin C derivatives, tirapazamine, EO9, RH1, etc.). The broad prodrug list can be attacked as:

• lacking a specific inventive feature tied to each prodrug; and/or
• being obvious substitutions within a known class.

Why it matters: if PH20/PEGPH20 combinations with any hypoxia-activated prodrug were already taught, claim 1’s “hypoxia-activated agent” limitation becomes easy to meet and harder to distinguish.

3) Synergy rationale tied to HA stratification

The combination appears to be a stratified approach: HA-high tumors are more susceptible to HA degradation by hyaluronidase, which then improves delivery or therapeutic effect for hypoxia-activated cytotoxins.

Attack vector: if prior art describes HA-targeting and improved penetration generally but does not use TSG-6-LM HABP detection to define susceptibility, then the diagnostic specificity can preserve validity. If prior art used HA markers in general (not via TSG-6-LM HABP binding), then claim 1 can still remain novel due to the specific assay mechanism, even if the therapy concept is known.

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When does the patent lose exclusivity (expiration timing) and how does that affect generic/Paragraph IV risk?

No filing, priority, or patent term data is provided in the prompt. Without:

• earliest priority date,
• maintenance fee status,
• any patent term adjustment (PTA) or terminal disclaimers, the exclusivity timeline cannot be computed.

Result: a complete and accurate “expiration date” and “generic launch window” assessment cannot be produced from the supplied information.

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What is the Orange Book status of US 9,278,124 and which FDA products could trigger Paragraph IV?

The prompt does not provide:

• the listed active ingredient(s) covered by the assignee/applicant,
• associated FDA application numbers (NDA/BLA),
• or the Orange Book publication link/entries.

Result: the Orange Book listing status and Paragraph IV risk map cannot be generated accurately from the provided claim text alone.

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What patent estate surrounds US 9,278,124: continuations, family members, and overlapping claims?

US 9,278,124 claim coverage is unusually modular: it spans

• HA assay chemistry (TSG-6 LM),
• enzyme form (PH20 and PEGylated PEGPH20),
• prodrug class list (many named hypoxia-activated agents),
• and clinical selection thresholds.

This indicates that related family members (or continuations) often exist that narrow to:

• specific prodrug exemplars,
• specific HA thresholds,
• specific HABP embodiments (TSG-6-LM-Fc),
• specific disease indications,
• and specific corticosteroid regimens.

Result: without the patent’s bibliographic record and family/patent citation graph, the patent estate cannot be enumerated in a complete and accurate way.

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How does US 9,278,124 compare with other PEGPH20 and hypoxia-prodrug patent strategies?

Competitive strategy dimensions implied by claim scope

• Regimen-level: PH20/PEGPH20 + hypoxia-activated cytotoxic.
• Biomarker-level: HA measurement to select susceptible subjects.
• Assay-level: TSG-6-LM-based HABP binding detection with specific sequence identity and structural options (multimers, Fc fusions).
• Mitigation-level: corticosteroid prophylaxis to reduce hyaluronidase adverse effects.

Practical implication for design-around

A competitor can attempt to avoid literal infringement by altering at least one required element:

• use a different HA-binding protein not comprising TSG-6 LM, or
• measure HA using non-binding detection methods (not meeting “detecting binding of HABP comprising TSG-6 LM”), or
• avoid the “select susceptible subjects based on HA at or above predetermined level” structure (e.g., different clinical selection criterion), or
• use a different hyaluronidase (not “soluble hyaluronidase” as constrained by the claim embodiments), or
• use non-hypoxia-activated agents (or agents not meeting the definition of hypoxia-activated prodrugs).

But because claim 1 uses “administering ... in any order” and broadly defines both sample types and hypoxia-activated agents, design-around likely focuses on the assay modality or the HA-binding module identity.

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How strong is the patent estate for US 9,278,124 across likely litigation themes?

Strength drivers (based on claim architecture)

• Defined diagnostic mechanism: TSG-6-LM HABP binding is a specific technical limitation that can be powerful against broad HA biomarker prior art.
• Assay embodiment specificity: sequence identity thresholds and heparin-binding reduction mutations create concrete claim scope hooks.
• Combination specificity: pairing hyaluronidase with hypoxia-activated agents is not a purely abstract synergy; it is operationally constrained.

Weakness drivers (based on claim breadth)

• Hypoxia-activated agent list breadth: inclusion of many known prodrugs can be attacked as obvious class coverage with limited functional distinction.
• Disease breadth: “cancer” and an extensive tumor list can raise enablement or obviousness concerns if the specification does not support every tumor with the same rationale.
• Prevalence of enzyme combination prior art: PH20/PEGPH20 is heavily studied; the estate may be vulnerable if the combination with hypoxia-activated therapy was known and HA stratification was routine.

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Key Takeaways

• US 9,278,124 centers enforceability on a TSG-6-LM HABP-based HA measurement used to select patients for treatment with soluble hyaluronidase (including PH20/PEGPH20) plus a hypoxia-activated agent/prodrug.
• The claim is diagnostic-constrained (TSG-6 LM module, specific sequence identity and modifications) and therapy-broad (large hypoxia-prodrug set; wide cancer indications; multiple HA thresholding constructs).
• Validity risk is most likely concentrated in prior art that already taught: (a) TSG-6-LM HA binding reagents/assays for HA measurement and (b) hyaluronidase plus hypoxia-activated prodrug combination strategies.
• A defensible exclusivity and Paragraph IV/Orange Book risk map cannot be produced because the prompt does not include patent bibliographic/term data or FDA linkage.

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FAQs

1. Does US 9,278,124 protect HA measurement using any HA-binding protein, or only TSG-6-LM-based HABPs?
2. Can a competitor avoid infringement by measuring HA without a HABP binding assay?
3. Is the claim limited to PEGPH20, or does it also cover other soluble hyaluronidases and PH20 variants?
4. Does US 9,278,124 require the hypoxia-activated agent to be a prodrug, or can other hypoxia-activated modalities qualify?
5. How do the sequence-identity limitations and heparin-binding reduction mutations affect design-around risk for HABP embodiments?

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References (APA)

1. United States Patent 9,278,124, “Method of treating a subject having a hypoxia-related disease or condition,” claims as provided in prompt.

Details for Patent 9,278,124

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	May 05, 2004	9,278,124	2033-10-16
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	December 02, 2004	9,278,124	2033-10-16
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	October 26, 2004	9,278,124	2033-10-16