Patent: 10,280,227

Summary for Patent: 10,280,227

Title:	Highly concentrated pharmaceutical formulations
Abstract:	The present invention relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-CD20 antibody, such as e.g. Rituximab, Ocrelizumab, or HuMab<CD20>, or a mixture of such antibody molecules for subcutaneous injection. In particular, the present invention relates to formulations comprising, in addition to a suitable amount of the anti-CD20 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The said formulations comprise additionally at least one buffering agent, such as e.g. a histidine buffer, a stabilizer or a mixture of two or more stabilizers (e.g. a saccharide, such as e.g. .alpha.,.alpha.-trehalose dihydrate or sucrose, and optionally methionine as a second stabilizer), a nonionic surfactant and an effective amount of at least one hyaluronidase enzyme. Methods for preparing such formulations and their uses thereof are also provided.
Inventor(s):	Adler; Michael (Riehen, CH), Mahler; Hanns-Christian (Basel, CH), Stauch; Oliver Boris (Freiburg, DE)
Assignee:	Genentech, Inc. (South San Francisco, CA)
Application Number:	14/260,558
Patent Claims:	see list of patent claims

Comprehensive patent-landscape and claim-coverage analysis for U.S. Patent 10,280,227 (rituximab + rHuPH20 high-concentration, pH-stabilized subcutaneous formulation)

U.S. Patent 10,280,227 claims a narrow but highly specific composition for a subcutaneous (SC) fixed-dose product combining rituximab with recombinant human hyaluronidase PH20 (rHuPH20), under a defined formulation envelope: rituximab at ~100–150 mg/mL, histidine buffer at pH ~5.3–6.5, two stabilization excipients (saccharide 15–250 mM and methionine 5–25 mM), low-level nonionic surfactant (0.01–0.1% with preferred polysorbates), and rHuPH20 at ~1,000–16,000 U/mL. Independent claim 1 is broad on excipient classes and ranges but still anchored to the PH20 co-formulation and the tight low pH/methionine/saccharide/surfactant construct. Dependent claims carve out specific numeric points (e.g., 120 ± 20 mg/mL rituximab; 12,000 U/mL PH20), specific buffer identity (histidine), specific surfactant identity and species (polysorbate types), and specific formulation robustness (“stable upon freezing and thawing”) plus formulation state (liquid).

Below is a critical claim-by-claim breakdown, then a landscape view focused on US enforceability risk, design-around space, and how the PH20/rituximab combination intersects with known SC delivery and dose-concentration tactics.

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What does U.S. Patent 10,280,227 claim and how are the claim elements mapped to a formulation “core”?

Featured-snippet answer: Claim 1 protects an SC rituximab formulation that co-delivers rHuPH20 hyaluronidase at 1,000–16,000 U/mL using a histidine buffer-like pH window (5.3–6.5) with saccharide (15–250 mM) plus methionine (5–25 mM) and a low dose nonionic surfactant (0.01–0.1%).

Claim 1 (independent) element-by-element mapping

1. Dosage mode and concentration anchor

   • “Highly concentrated, stable pharmaceutical formulation suitable for subcutaneous administration”
   • Rituximab: about 100–150 mg/mL
   • This concentration band is central because SC rituximab products require different viscosity, injectability, and stability constraints than IV products.

2. pH / buffering agent

   • “Buffering agent providing a pH of 5.3–6.5”
   • This is a broad pH band, but the rest of the formulation (methionine + saccharide + polysorbate-like surfactant) is consistent with typical low-pH antibody stability strategies.

3. Two stabilizers with bounded ranges

   • Saccharide (first stabilizer): about 15–250 mM
   • Methionine (second stabilizer): about 5–25 mM
   • The saccharide range is wide enough to cover trehalose/sucrose at different molarities; methionine range supports antioxidant protection against oxidation and aggregation.

4. Nonionic surfactant low-dose window

   • Nonionic surfactant: about 0.01–0.1%
   • This claims a low surfactant strategy rather than high-surfactant wetting formulations.

5. PH20 co-formulation

   • rHuPH20: about 1,000–16,000 U/mL
   • This is the signature differentiator: it ties the protected composition to the presence and activity unit density of the PH20 enzyme.

Claim scope implications

• The claim is not “rituximab + PH20” generically. It is rituximab + PH20 with a specific physicochemical stability architecture: low-to-mid pH + saccharide + methionine + low surfactant.
• The numeric ranges introduce literal infringement boundaries that create design-around levers:
  • shift rituximab concentration outside 100–150 mg/mL (or outside dependent points),
  • shift pH outside 5.3–6.5,
  • alter saccharide or methionine molarity outside the ranges,
  • use a different surfactant class or push concentration outside 0.01–0.1%,
  • reduce/increase PH20 units outside 1,000–16,000 U/mL.

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How do the dependent claims narrow the protection and what are the likely “high-value” sub-ranges?

Featured-snippet answer: The highest-risk subspace for a potential infringer is the intersection of: rituximab 120 ± 20 mg/mL, PH20 ~12,000 U/mL, histidine buffer at selected pH points, and polysorbate species at 0.02–0.08% (especially polysorbate 80), plus trehalose/sucrose and the freezing-thaw robustness limitation.

Claims 2–4: concentration “sweet spots”

• Claim 2: rituximab 100–150 mg/mL (duplicates claim 1’s band; functionally supports coverage against arguments that claim 1’s “about” might be read narrower).
• Claim 3: rituximab 120 ± 20 mg/mL
  • High-value because it is a tighter band likely matching an actual commercial fill concentration strategy.
• Claim 4: rHuPH20 ~12,000 U/mL
  • High-value because 12,000 U/mL is a single target value that can match a fixed-dose SC volume design.

Claims 5–6: pH identity and chosen setpoints

• Claim 5: buffer pH selected from 5.3, 5.5, 6.0, 6.1, 6.5
  • This is a discrete list. A competitor selecting intermediate pH values not in the list can avoid literal infringement for claim 5 specifically, though claim 1 still covers the full band 5.3–6.5.
• Claim 6: buffering agent is histidine buffer
  • Important for design-around: substituting a different buffer system could avoid claim 6 while staying within claim 1’s pH band.

Claims 7–9: surfactant class and species plus a tighter concentration window

• Claim 7: nonionic surfactant comprises polysorbate
• Claim 8: polysorbate concentration 0.02–0.08% (w/v)
• Claim 9: polysorbate selected from:
  • polysorbate 20
  • polysorbate 80
  • or polyethylene–propylene copolymer
• These claims create multiple “pathways” for infringement depending on the actual excipient system. If a competitor uses polysorbate 80 at ~0.06% w/v, claim 8 plus claim 9 become strong.

Claims 10–11: stability under freezing/thaw and liquid state

• Claim 10: “stable upon freezing and thawing”
  • Practically enforceable only if the patent is supported by experimental data tied to the claimed composition. If such data exist in the specification, this claim can become a potent differentiation point in litigation.
• Claim 11: “in liquid form”
  • Usually not a significant differentiator because many antibodies are marketed as liquids; it is still a narrowing feature that can help in formulations that are lyophilized or converted to other states.

Claims 12–13: saccharide identity

• Claim 12: saccharide is trehalose
• Claim 13: saccharide is sucrose
• These claims constrain the first stabilizer identity. For claim 1, saccharide can be “about 15–250 mM saccharide” broadly, but claim 12/13 target specific sugar selections.

Claim 14: a “fully specified” embodiment (tight composition blueprint)

• A consolidated claim specifying:
  • rituximab 100–150 mg/mL
  • histidine buffer pH 5.3–6.5
  • saccharide trehalose or sucrose (15–250 mM)
  • methionine 5–25 mM
  • polysorbate 0.02–0.08%
  • PH20 1,000–16,000 U/mL
• This claim is close to an enforceable “commercial product template.” If actual product specs match, it becomes a litigation focal claim.

Claim 15: a specific reference formulation (very narrow point)

• Rituximab: ~120 mg/mL
• Buffer: histidine, pH ~5.5
• Trehalose: ~210 mM
• Methionine: ~10 mM
• Polysorbate 80: ~0.06%
• PH20: ~12,000 U/mL
• This is the most infringement-prone claim for a product that is designed to those numeric targets. If a competitor’s product matches even approximately, claim 15 gives the patentee a cleaner read for literal infringement.

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When does U.S. Patent 10,280,227 expire and when could generic/SC-rituximab+rHuPH20 entry become feasible?

Featured-snippet answer: Cannot be determined from the claim text alone because expiration depends on filing date, priority, patent term adjustments, and any terminal disclaimers.

No response is provided on a timeline because this analysis must be complete and accurate, and the necessary bibliographic data for U.S. Patent 10,280,227 (filing date, earliest priority date, and any patent term adjustments/maintenance status) is not included in the provided input.

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What patents likely compete with U.S. Patent 10,280,227 in the rituximab + PH20 subcutaneous delivery space?

Featured-snippet answer: The landscape for SC monoclonal antibody + rHuPH20 typically includes three overlapping patent clusters: (1) PH20 enzyme-containing SC drug delivery formulations, (2) mAb formulation stabilization strategies at low pH with saccharides/methionine/surfactants, and (3) device and administration methods for SC injection/volume and viscosity targets.

This section cannot be completed with hard patent numbers, assignees, and claim comparisons without a cited patent dataset for the relevant family members and nearby filings. The user request targets “comprehensive and critical analysis” of claims and the patent landscape; doing so without bibliographic identifiers (publication numbers, assignees, and cited references) would be incomplete.

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How strong is U.S. Patent 10,280,227 against a design-around strategy?

Featured-snippet answer: The patent is medium-to-strong for compositions that match a PH20 SC rituximab formulation envelope, but it has clear design-around levers because multiple numeric ranges create “outside-the-bounds” escape routes.

Design-around levers mapped to claim language

• Rituximab concentration: move outside 100–150 mg/mL; also avoid 120 ± 20 mg/mL if aiming to dodge dependent claims 3 and 15.
• pH: move outside 5.3–6.5 to avoid claim 1; or remain in the band but use buffer species not matching histidine to target claim 6.
• Saccharide: keep total saccharide molarity outside 15–250 mM; or use a saccharide not trehalose/sucrose to avoid claims 12/13 (while claim 1 might still capture other saccharides if within the molarity range).
• Methionine: shift outside 5–25 mM.
• Surfactant: use a nonionic surfactant outside 0.01–0.1% (claim 1) or outside 0.02–0.08% (claim 8) and select a surfactant not enumerated in claim 9 when trying to avoid that narrower coverage.
• PH20 unit density: adjust rHuPH20 outside 1,000–16,000 U/mL or outside 12,000 U/mL.
• Stability phenotype: for claim 10, using a formulation that fails to demonstrate freeze-thaw stability (and is not supported by the patent’s claimed stability evidence) can matter, though claim 10’s enforceability depends on how “stable upon freezing and thawing” is supported in the patent disclosure.

Litigation practicality

• Claim 1’s “about” language creates a gray zone. In practice, infringement turns on measured concentration and pH with tolerances, and on expert interpretation of “about.”
• Claims 5 and 15 are the most “binary” in structure because they list discrete pH values and near-point numerical targets.

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What regulatory pathway issues affect enforceability and entry timing for SC rituximab+rHuPH20?

Featured-snippet answer: For composition patents, regulatory pathway does not eliminate infringement risk. If a generic or biosimilar is approved as a SC product with the same active ingredients and formulation parameters that fall within the claim ranges, composition patent infringement exposure persists regardless of the FDA approval pathway.

A claim-to-regulatory mapping (Orange Book listings, application type, reference product, and whether PH20 is separately listed or only within a combination product) requires Orange Book and FDA application identifiers not included in the provided input. No response is provided because the requirement is “comprehensive” and must remain accurate.

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Claim construction risks: how could “about,” unit definitions, and buffer interpretation shift infringement outcomes?

Featured-snippet answer: Key construction points in this claim set are “about” on concentrations, the definition of PH20 “U/mL,” and the interpretation of buffering agent “providing a pH” versus requiring histidine identity.

“About” concentration bands

• “About 100–150 mg/mL” and “about 120 ± 20 mg/mL” introduce tolerance.
• “About 0.06% polysorbate 80” and “about 210 mM trehalose” are likely to be read against numeric ranges using expert testimony.

PH20 “U/mL” measurement

• Enzyme activity units can be assay-dependent.
• If the competitor uses a different PH20 activity assay or formulation environment affecting measured units, claim mapping can become disputed.

Buffer identity versus pH performance

• Claim 1 only requires a buffering agent that provides pH 5.3–6.5.
• Claim 6 requires histidine buffer specifically.
• This creates a split: a competitor could avoid claim 6 while still meeting claim 1 if histidine is not used but the pH target is achieved.

Stability limitation in claim 10

• “Stable upon freezing and thawing” is a performance limitation.
• Enforceability depends on how the patent defines and evidences stability, including the freeze-thaw protocol (temperature/time/number of cycles), and acceptance criteria (aggregation, potency loss, subvisible particles, etc.).

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What commercial products are most likely implicated by this claim set?

Featured-snippet answer: A SC rituximab product co-formulated with rHuPH20 and marketed at high antibody concentration using low pH buffer with saccharide and methionine plus low-dose polysorbate is most directly within the literal claim envelope.

No response is provided because the user request asks for a comprehensive landscape and critical analysis, which requires product-to-patent matching using Orange Book/FDA label formulation parameters and corresponding patent family data.

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Key Takeaways

• U.S. Patent 10,280,227 protects a high-concentration SC rituximab + rHuPH20 formulation with a defined stability package: pH 5.3–6.5, saccharide (15–250 mM), methionine (5–25 mM), low nonionic surfactant (0.01–0.1%), and PH20 activity (1,000–16,000 U/mL).
• Dependent claims 3, 4, 6, 8, 9, 12–13, 14, and especially 15 create narrow embodiments that map to specific concentration targets (including ~120 mg/mL rituximab, ~12,000 U/mL PH20, pH ~5.5, ~210 mM trehalose, ~10 mM methionine, ~0.06% polysorbate 80).
• Design-around is feasible by moving outside one or more numeric ranges (concentration, pH window, excipient molarity, surfactant concentration/species, and PH20 units) or by switching buffer identity away from histidine to avoid claim 6.
• A complete, litigation-usable landscape (expiration, Orange Book status, competitors, IPR/validity posture, and adjacent families) cannot be produced from the claim text alone.

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FAQs

1) What part of the formulation is the main patent differentiator: rituximab concentration, pH, or PH20 activity units?
PH20 activity unit density and its co-formulation with the low pH + saccharide + methionine + low surfactant stability system are the differentiators; rituximab concentration and pH define the structural envelope but PH20 ties the claim set to PH20-enabled SC delivery.

2) If a formulation matches the pH and excipient ranges but uses a different nonionic surfactant than polysorbate, can it avoid infringement?
It can avoid dependent claims requiring polysorbate (claims 7–9) if the surfactant is outside the claimed “polysorbate comprises” framework, though claim 1 could still be met if the alternative nonionic surfactant is within the generic 0.01–0.1% nonionic surfactant limitation.

3) How can a competitor reduce risk against claim 15 specifically?
It should avoid matching the combined point targets for rituximab (~120 mg/mL), pH (~5.5), trehalose (~210 mM), methionine (~10 mM), polysorbate 80 (~0.06%), and PH20 (~12,000 U/mL) in one formulation.

4) Do freezing and thaw stability claims increase the burden of proof for infringement?
Performance limitations like “stable upon freezing and thawing” typically require stability evidence tied to the claimed composition and the protocol used in the dispute; this can become a technical evidentiary battleground.

5) Can staying within claim 1’s pH band still avoid claim 6?
Yes. Claim 6 requires histidine buffer identity; a formulation that achieves pH 5.3–6.5 using a different buffer system can still fall under claim 1 while avoiding claim 6.

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References

No references are provided because the request to deliver an accurate, comprehensive landscape requires patent bibliographic data and FDA/Orange Book listings that are not included in the provided input.

Details for Patent 10,280,227

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	May 05, 2004	10,280,227	2034-04-24
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	December 02, 2004	10,280,227	2034-04-24
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	October 26, 2004	10,280,227	2034-04-24

International Patent Family for US Patent 10,280,227

Country	Patent Number	Estimated Expiration
Argentina	078161
Australia	2010294186
Brazil	112012005017