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United States Patent 10,301,376: IG plus soluble hyaluronidase for once-monthly subcutaneous dosing

US Patent 10,301,376 centers on a single, operational claim architecture: deliver a full monthly subcutaneous immunoglobulin (IG) dose using separate injections of (i) soluble hyaluronidase administered first and (ii) human plasma-derived IG at defined concentration, dose range, formulation pH, and hyaluronidase:IG unit ratios. The claims then narrow across (a) hyaluronidase identity (including truncated PH20), (b) IG formulation characteristics (protein concentration and pH window, excipients), (c) dosing geometry (volumes, infusion rates, pre-administration timing), and (d) IG-treatment indications spanning immunodeficiency, autoimmune disease, oncology-adjacent immune compromise, and selected infections.

From a landscape perspective, the patent’s strength is not breadth across IG formulations or indications. It is strength through tight coupling of administration mechanics (separate SC dosing; hyaluronidase-first; fixed monthly schedule), dose math (IG dose range and “full monthly dose”), and parameter bands (IG concentration, pH, volumes, hyaluronidase units per gram of IG). The weakness is that the claim set is factually specific and therefore easier to design around by shifting one or more critical parameters (schedule frequency, enzyme:IG ratio band, or formulation pH/concentration band, or by using different IG source or delivery scheme).

What exactly is claimed? The method’s core operating envelope

Claim 1 is the anchor. It requires every element below:

Element	Claim 1 requirement
Disease/condition	“IG-treatable disease or condition”
Route and frequency	Subcutaneous administration no more than once monthly
Separate administration	Hyaluronidase and IG administered separately
Timing	Hyaluronidase administered prior to IG
Hyaluronidase type	Soluble hyaluronidase
IG source	IG is from human plasma
IG concentration	5 to 25% w/v IG in the IG composition
IG dose range	100 mg/kg to 2 g/kg body weight (BW); and “dose of IG is a full monthly dose”
Hyaluronidase ratio	About 10 to 500 Units hyaluronidase per gram of IG
Monthly dosing constraint	IG administered is the full monthly dose (ties schedule to delivered dose)

Claims 2 to 21 then define hyaluronidase identities and IG formulation and identity features, while claims 4 to 21 add delivery-volume, pH, and product-definition constraints that narrow practice.

How do the dependent claims tighten scope?

The dependent claims function like a claim “grid” of optional narrowing dimensions. Key clusters:

Hyaluronidase identity and construct scope

Claim 2: soluble hyaluronidase can be ovine PH20, bovine PH20, or soluble human PH20.
Claim 2 (truncated human PH20): soluble human PH20 is C-terminally truncated PH20 that lacks all or a portion of the GPI anchor attachment sequence.
Claim 3: soluble hyaluronidase can be a polypeptide with sequences in SEQ ID NOS: 4-9.
Claims 17-21: further isolate PH20 (or truncated forms) and reference rHuPH20; truncated human PH20 defined via SEQ ID NOS: 4-9 and variants with ≥95% sequence identity, soluble and active.

Critical implication: the patent is not merely “hyaluronidase + IG.” It is “certain PH20-based soluble hyaluronidase formats, including truncated GPI anchor-deficient constructs,” plus a numeric dosing ratio band.

IG formulation parameters that matter for infringement

Protein concentration (Claims 1, 31-33, 30, 32, 31)
- Claim 1: 5 to 25% w/v
- Claims 30-33 narrow: pH windows (4.2 to 5.4; 4.6 to 5.1; 4.8 to 5.0) paired with IG concentration windows (example bands: 5-15%, 6-15%, 8-12%, 10%).
pH windows (Claims 6-8 and 30)
- Claim 6: 4.8 to 5.0
- Claim 7: 4.6 to 5.1
- Claim 8: 4.2 to 5.4
IG volume and concentration delivery constraints (Claims 4-5, 34, 35-38)
- Claim 4: IG volume 50 mL to 700 mL, hyaluronidase volume <50 mL
- Claim 5: IG as a liquid solution in 50 mL to 700 mL
- Claim 34: IG volume includes 100/150/200/300/400/500/600/700 mL enumerations
- Claim 35-38: infusion rate options 10 mL/hr to 300 mL/hr, selected enumerated values, controlled by pump or gravity
Hyaluronidase pre-administration timing (Claim 39)
- Ranges from 0.5 minutes up to 30 minutes prior to IG administration (with specific options).
Hyaluronidase ratio enumerations (Claims 40-42)
- Claim 40: ratio enumerations around 10 U/g to 300 U/g
- Claim 41: about 50 U/g explicitly
- Claim 42: broad unit totals bands (includes 10 to 500,000 Units; plus narrower ranges)

IG dose quantity variants (Claims 9-13)

Claim 9: 20-30 g IG
Claim 10: specific IG mass options including 5 g, 10 g, 15 g, ... 40 g
Claim 11: at least 5 g IG
Claim 12: dose at least 200, 300, 400, 500, 600 mg/kg BW
Claim 13: example combination: 600 mg/kg with hyaluronidase at 50 U/g IG

Critical implication: the claim set implicitly maps to real product design points (fixed monthly dosing; typical IG masses and volumes; PH20 dose ratio bands around 50 U/g).

Bioavailability performance band (Claim 16)

Claim 16: subcutaneous bioavailability is at least about 90% of the same dosage via IV.

Landscape effect: performance claims of this type are harder to litigate because infringement may require evidence about bioavailability equivalence under controlled comparison. But dependent claims still can be asserted, and product developers will treat this as a go/no-go performance requirement.

Product definition and manufacturing route (Claims 22-24, 25-29)

Human plasma IG and manufacturing details:
- Claim 22: IG purified from human plasma
- Claim 23: purified by alcohol fractionation
- Claim 24: further purification via steps including pH 4.0 with or without pepsin, PEG precipitation, ion-exchange, enzymatic cleavage, solvent detergent treatment, diafiltration/ultrafiltration
Composition content:
- Claim 25: contains IgG, IgA, IgM
- Claim 26: >95% IgG
- Claim 27: IgG is monomeric
Stabilizers (Claim 28-29):
- Claim 28: protein-stabilizing excipients
- Claim 29: selected from glycine, maltose, polyol, human serum albumin, mannitol, non-ionic detergent

What diseases are covered? Indication breadth vs. practical relevance

Claim 43 lists a broad set of “IG-treatable” diseases/conditions, then Claims 44-47 narrow examples.

Claim 43 categories include: immunodeficiency; acquired hypogammaglobulinemia secondary to hematologic malignancies; Kawasaki’s disease; CIDP; Guillain-Barre syndrome; ITP; inflammatory myopathies; Lambert-Eaton; multifocal motor neuropathy; myasthenia gravis; Moersch-Woltmann syndrome; secondary antibody deficiency; acute disseminated encephalomyelitis; ANCA-positive systemic necrotizing vasculitis; autoimmune hemolytic anemia; bullous pemphigoid and other pemphigoids; Evans syndrome; FMAIT/NAIT; hemophagocytic syndrome; high-risk allogeneic HSCT; IgM paraproteinemic neuropathy; kidney transplantation; multiple sclerosis; Opsoclonus myoclonus ataxia; Pemphigus foliaceus and vulgaris; post-transfusion purpura; TEN/SJS; toxic shock; Alzheimer’s disease; systemic lupus erythematosus; multiple myeloma; sepsis; B cell tumors; trauma; and selected bacterial/viral/fungal infections.

Claims 44-46 examples (immunodeficiency and inflammatory myopathies):

Immunodeficiency examples: CVID, congenital agammaglobulinemia, Wiskott-Aldrich, SCID, primary hypogammaglobulinemia, primary immunodeficiency with antibody deficiency, XLA, hypogammaglobulinemia of infancy, paraneoplastic cerebellar degeneration with no antibodies.
Inflammatory myopathy examples: polymyositis, dermatomyositis, inclusion body myositis.

Claim 47 examples (infectious conditions):

Bacterial: Haemophilus influenzae type B, Pseudomonas aeruginosa types A and B, Staphylococcus aureus, Group B Streptococcus, multiple Streptococcus pneumoniae serotypes (1,3,4,6,7,8,9,12,14,18,19,23)
Viral: adenovirus types 2 and 5; CMV; EBV VCA; hepatitis A and B; HSV-1, HSV-2; Influenza A; measles; parainfluenza types 1-3; polio; varicella zoster
Fungal: Aspergillus, Candida albicans

Landscape note (practicality): even where indication language is broad, infringement depends on meeting the method steps and parameter bands in the claims. The strongest commercial tension typically concentrates in immunodeficiency and acquired hypogammaglobulinemia (where SC Ig is a dominant commercial segment) rather than the rarer and broader “infection/oncology/trauma/neurodegenerative” catch-all list.

Where the legal risk concentrates: the “mechanics” and the “numbers”

For infringement and validity strategy, the claim architecture divides risk into two layers:

Mechanics layer
- Subcutaneous administration
- No more than once monthly
- Separate hyaluronidase and IG administration
- Hyaluronidase prior to IG
- Soluble hyaluronidase
Parameter layer
- Human plasma IG
- IG concentration band: 5-25% w/v
- IG dose: 100 mg/kg to 2 g/kg BW; “full monthly dose”
- Hyaluronidase ratio: about 10-500 Units per gram of IG
- Additional narrow options: pH windows, volumes, infusion rates, and hyaluronidase timing

Critical observation: a design-around does not need to change the whole therapeutic concept. It can target one parameter enough to move outside claim-required ranges. For example, adjusting dosing frequency beyond once-monthly, altering the units-per-gram ratio band, or changing the formulation pH or concentration can be sufficient depending on which dependent claim is asserted.

Patent landscape: what adjacent technologies are likely to intersect

Although the request is about US 10,301,376 specifically, landscape analysis depends on identifying recurring technology elements in the claims and mapping them to known commercialization patterns in subcutaneous immunoglobulin and hyaluronidase-enabled delivery.

The claim’s core intersection points are:

Subcutaneous IG delivery enabled by hyaluronidase (specifically PH20/truncated PH20 formats)
Once-monthly or extended-interval SC Ig dosing concepts
Human plasma-derived IG compositions
Formulation constraints (pH around 4.6-5.1, protein concentration ranges, excipient lists)
Product-manufacturing process constraints (alcohol fractionation; pH 4 treatment with or without pepsin; PEG precipitation; chromatography; solvent detergent; UF/diafiltration)

In practice, this landscape tends to cluster around a small number of hyaluronidase platforms (notably PH20-based soluble hyaluronidase) and a small number of extended interval SC Ig strategies. The patent’s unique signature is the coupling of PH20-type hyaluronidase with defined IG dose mechanics under a monthly schedule and an explicit units-per-gram ratio.

Validity pressure points: where challengers typically attack

The claims include many dependent enumerations and parameter windows. That can cut both ways: it can support narrow claim amendments or multiple fallback positions, but it also gives more surfaces for prior-art mapping.

Likely validity pressure points:

Known SC IG + hyaluronidase combination: if prior art already teaches subcutaneous delivery of immunoglobulin using hyaluronidase (including PH20-type), challengers focus on whether the claimed monthly dosing and specific unit-per-gram ratio and dosing mechanics are novel.
Truncated PH20 constructs: truncation and GPI-anchor deficiency are design choices often disclosed in hyaluronidase portfolios. If sequence identity (SEQ ID NOS 4-9) or functional hyaluronidase activity of such constructs is already taught, novelty shifts back to the IG delivery method parameters.
Dose arithmetic and concentration bands: windows like 5-25% w/v, pH 4.2-5.4, and ratios like 10-500 U/g are numeric bands that can be attacked if prior art disclosed overlapping values or if selection is not supported by a clear technical effect.
Bioavailability benchmark: “at least about 90% of IV” is a performance threshold. If earlier work shows similar thresholds, this may not add patentability unless the prior art discloses it with the same configuration and method steps.

Critical assessment of enforceability

Enforceability is strongest when a competitor’s product matches all of these simultaneously:

monthly or less-frequent SC schedule
separate hyaluronidase injection followed by IG injection
PH20-type soluble hyaluronidase including truncated forms
human plasma IG with concentration and pH windows
units-per-gram hyaluronidase ratio within the claimed band
dosing volume and timing options consistent with specific dependent claims asserted
and, if asserted, IV comparability bioavailability threshold

Enforceability weakens if competitors:

dose more frequently than monthly,
use hyaluronidase dosing outside the claimed U/g band,
blend hyaluronidase and IG in the same injection (to avoid “administered separately” and “hyaluronidase prior” requirements),
shift pH away from the specified windows,
formulate outside the 5-25% w/v band,
use non-human-plasma-derived IG,
or use a hyaluronidase construct not within the defined PH20/truncation/SEQ ID scope.

Commercial positioning: the claim set aligns to a specific product profile

The dependent claims’ enumerations are not generic. They read like formulation and administration recipes:

IG volumes enumerated (100 to 700 mL)
hyaluronidase administered in less than 50 mL, often 5-30 mL
infusion rates up to 300 mL/hr with discrete pump/gravity control language
pre-injection timing options from 0.5 minutes to 30 minutes
a recurring ratio anchor around 50 U/g of IG

That profile tends to map to how “fixed-interval” SC Ig products are manufactured and dosed operationally in practice, which makes infringement analysis more straightforward for companies with standardized dosing instructions.

Key Takeaways

US 10,301,376 is a method patent anchored on once-monthly (or less) subcutaneous IG enabled by soluble hyaluronidase, with separate administration and hyaluronidase-first timing.
The practical claim boundary is controlled by numerical parameters: IG dose (100 mg/kg to 2 g/kg) as a full monthly dose, IG concentration (5-25% w/v), IG pH windows (4.2-5.4 and narrower dependent bands), and hyaluronidase dosing ratio (about 10-500 Units per gram of IG).
Enforcement risk concentrates on competitors whose SC Ig programs use human plasma-derived IG and PH20/truncated PH20 soluble hyaluronidase constructs, and whose dosing instructions sit within the specific U/g ratio and formulation pH/concentration bands.
Design-around opportunities exist by shifting at least one critical parameter band: schedule frequency, U/g ratio, pH/concentration window, injection sequencing (separate vs combined), or hyaluronidase construct scope.

FAQs

What is the single most important independent claim limitation?
The method requires once-monthly (no more than once monthly) subcutaneous administration of a human plasma-derived IG dose that is a full monthly dose, enabled by separately administered soluble hyaluronidase delivered prior to IG.
Does the patent require PH20 specifically?
Claim 1 requires “soluble hyaluronidase.” Dependent claims explicitly recite PH20 formats, including ovine, bovine, and soluble human PH20 and C-terminally truncated, GPI-anchor deficient human PH20, including SEQ ID NOS: 4-9.
What numeric factors drive infringement the most?
IG dose (100 mg/kg to 2 g/kg as full monthly dose), IG concentration (5-25% w/v), IG pH bands (4.2-5.4 with narrower dependent windows), and hyaluronidase dosing ratio (about 10-500 Units per gram of IG).
Can a competitor avoid infringement by changing injection timing?
Yes, if the competitor deviates from “hyaluronidase prior to IG” and especially if it avoids the dependent claim timing options; claim 1 still requires hyaluronidase prior to IG, so combining or reversing order would be a structural shift.
Are the disease claims broad enough to cover all autoimmune IG uses automatically?
No. Even with broad indication language, infringement requires performing the claimed method steps with the claimed formulation, dosing, and ratio parameters.

References

[1] United States Patent 10,301,376.

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	May 05, 2004	10,301,376	2029-03-16
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	December 02, 2004	10,301,376	2029-03-16
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	October 26, 2004	10,301,376	2029-03-16
Akorn, Inc.	HYDASE	hyaluronidase	Injection	021716	October 25, 2005	10,301,376	2029-03-16
Octapharma Pharmazeutika Produktionsges.m.b.h.	OCTAGAM	immune globulin intravenous (human)	Injection	125062	May 21, 2004	10,301,376	2029-03-16
Octapharma Pharmazeutika Produktionsges.m.b.h.	OCTAGAM	immune globulin intravenous (human)	Injection	125062	March 26, 2007	10,301,376	2029-03-16
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

Patent: 10,301,376

Summary for Patent: 10,301,376