Patent: 9,919,033

Summary for Patent: 9,919,033

Title:	Dry growth hormone composition transiently linked to a polymer carrier
Abstract:	The present invention relates to dry compositions of rhGH polymer prodrug containing a lyoprotectant and, optionally, one or more than one excipient. Such compositions are stable for at least 1 year, when stored at 2-8.degree. C. The invention further relates to methods of manufacturing said compositions, containers comprising such composition as well as a kit of parts.
Inventor(s):	Rasmussen; Grethe Norskov (Farum, DK), Kindermann; Susanne (Liestal, CH), Rau; Harald (Dossenheim, DE), Wegge; Thomas (Heidelberg, DE)
Assignee:	Ascendis Pharma Endocrinology Division A/S (Hellerup, DK)
Application Number:	15/340,595
Patent Claims:	see list of patent claims

US Patent 9,919,033 Landscape and Claim-Strength Analysis
US 9,919,033 is a pen-injector system claim set built around a dry, lyophilized recombinant human growth hormone (rhGH) polymer prodrug transiently linked through a reversible linker, with trehalose/controlled excipient formulations, and stability release limits (<5% free rhGH over 2 to 25°C storage). The patent’s enforceable value is driven less by the general “pen injector” concept and more by: (i) the specific prodrug architecture (reversible linker with PEG-X and defined linker structures), (ii) quantitative stability and free-rhGH release thresholds, and (iii) cartridge architecture and reconstitution solution compositions. Those elements create both licensing leverage and litigation vulnerability, because generic “rhGH” products that use different prodrug/linker chemistries, different lyoprotectants, or different excipient strategies can design around large parts of the claim scope.

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What claims in US 9,919,033 protect (and what they do not)?

Core protected subject matter. Claim 1 is the key independent claim. It requires, in one system, all of the following:

1. A pen injector with a cartridge containing a dry composition.
2. The dry composition includes:
   • a therapeutically effective amount of rhGH polymer prodrug
   • and a lyoprotectant.
3. The rhGH is transiently linked to a polymer carrier via a reversible linker moiety.
4. The composition is stable for ≥6 months at 2–25°C while meeting a free rhGH release constraint:
   • <5% rhGH released as free rhGH during such storage.
5. Dependent claims add: cartridge chamber structure, disposable cartridge, lyophilization, stability ≥1 year, trehalose as lyoprotectant, single vs multiple dose, specific chemical structures (A) and (PEG-X with c = 250–750), optional add-on biologics/excipients, dosing duration, and explicit quantitative formulation ranges including succinic acid, trehalose, and tris, plus reconstitution solution benzyl alcohol or cresol.

What is not claimed narrowly enough to be safe. The claim does not restrict:

• the injection device mechanics beyond “pen injector” and cartridge.
• the polymer carrier identity in broad terms, except to the extent the prodrug must match the reversible linker and the structural embodiments in dependent claims.
• the therapeutic indications (it recites rhGH dosing intent and duration, not a specific indication).
• the presence of optional additional biologically active agents (claim 11 is open-ended as a category list).

Practical implication: The independent claim 1 forces a system-level match (pen + dry prodrug + trehalose/lyoprotectant category + stability/free-rhGH release performance). That is harder to meet than a pure drug composition claim, but it gives defendants multiple design-around levers: substitute the prodrug chemistry, alter the stability behavior to avoid the <5% free-rhGH condition, change lyoprotectant type, or shift from dry lyophilized composition paradigms.

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Which US 9,919,033 claim elements are most infringement-sensitive?

1) Reversible linker + PEG-X structural constraints (dependent claims 9–10)

Claim 9 recites a chemical structure (A) with variable substituents R1–R5 and defines PEGylation residue and X selection. Claim 10 tightens the PEG-X structure by defining c as an integer between 250 and 750.

Why this matters: In litigation, the structural/parameter limitations are typically the most enforceable, because they provide clear claim construction anchors. If an accused product uses a different prodrug linker motif, different PEG characteristics (including chain length), or a different reversible-cleavable design, the defendant can aim to avoid dependent claims 9–10 and reduce exposure to only claim 1/8/12/15–20 type ranges.

2) Stability performance plus “<5% free rhGH” over 6 months at 2–25°C (claim 1)

This is a functional limitation expressed as a storage stability performance metric, including a quantitative release threshold of free rhGH.

Why it matters: Performance-based claims can be powerful, but they also invite:

• disputes about measurement methods, time points, and assay methodology (how “free rhGH” is defined and quantified),
• disputes about whether the stability is reproducible across lots and under “2–25°C” cycling conditions.

For defendants, the best design-around is not necessarily “more stable,” but to ensure that under relevant storage conditions the product does not meet the literal “<5%” definition for the asserted time window.

3) Lyoprotectant scope vs trehalose limitation (claims 1 and 6)

Claim 1 only requires “a lyoprotectant.” Claim 6 narrows it to trehalose.

Why it matters: If the accused product uses trehalose, it is exposed to both claim 1 and 6. If it uses another lyoprotectant (e.g., sucrose, mannitol, glycine blends), it may avoid claim 6 while still potentially meeting claim 1 if that other excipient is still “a lyoprotectant” as construed.

4) Explicit formulation windows (claims 15–17)

These are tight composition ranges that include:

• rhGH polymer prodrug % (w/w)
• succinic acid % (w/w)
• trehalose % (w/w)
• tris % (w/w)

Why it matters: For a generic or biosimilar-like attempt to replicate the system, matching these ranges is measurable. For design-around, shifting excipient quantities can avoid literal infringement, pushing analysis back to claim 1’s broader “lyoprotectant” requirement and to the prodrug chemical constraints.

5) Reconstitution solution details (claims 19–20)

Claims 18–20 add a two-chamber arrangement: dry composition in chamber 1 and reconstitution solution in chamber 2. Reconstitution is defined with benzyl alcohol or cresol concentration windows.

Why it matters: This can become a “device-product” fault line. A product using a different preservative strategy can avoid dependent claims 19–20 even if it matches other drug elements.

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How do the patent’s dependent claims shape potential claim charts?

Cartridge architecture and dose presentation

• Claim 2: cartridge includes first chamber and second chamber.
• Claim 3: disposable cartridge.
• Claim 7: single dose composition.
• Claim 8: multiple dose composition.

Claim chart impact: Device engineering choices around chambering and disposability can be decisive for dependent claims without necessarily changing the prodrug chemistry.

Lyophilization and stability targets

• Claim 4: dried by lyophilization.
• Claim 5: stability ≥1 year at 2–25°C.

Claim chart impact: If an accused product uses a different solid-drying approach (spray drying, amorphous solid dispersions, etc.), claim 4 can be avoided.

Dosing duration linkage

• Claim 12: provides therapeutically effective amount for ≥3 days after one application.
• Claim 13: one application provides one week.

Claim chart impact: This becomes a product performance and dose-release claim. If the accused device uses a different effective duration or different total dosing strategy, it may avoid claims 12–13.

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What is the likely claim scope on “additional biologically active agents” (claim 11)?

Claim 11 adds optional co-actives (IGF-1, ghrelin/analogs, GHRH, gonadotropins, steroids, aromatase inhibitors, HIV combination therapy, free fatty acid regulators, anabolic steroids, estrogen agonists/antagonists, propranolol, appetite suppressants, osteoporosis drugs, and anti-diabetic drugs).

Enforcement reality: This breadth is a double-edged sword. It can:

• expand commercial coverage if an accused product is a combination system in the same pen format, but
• become less central if real commercial competitors are single-agent rhGH devices.

In infringement strategy, plaintiffs still must prove all claim elements in claim 1 plus whichever dependents are asserted. For many market entrants, the “additional agent” limitation is either irrelevant or simply not present.

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How strong is the patent estate for rhGH polymer prodrug pen-injectors in the US?

US 9,919,033 itself is a composition-and-device hybrid with a performance limiter. The strongest enforceability themes are the combination of:

• defined prodrug chemistry (in claims 9–10),
• defined lyophilized formulation performance (≥6 months, <5% free rhGH),
• and quantified excipient ranges (claims 15–17),
• plus specific device cartridge/reconstitution features (claims 2, 18–20).

Weak points for enforcement:

• “Pen injector” language is broad; many devices could qualify.
• Claim 1’s “lyoprotectant” is generic enough that different excipient systems can still argue they meet that category.
• Functional “free rhGH release” is a measurement-heavy limitation that can generate expert disputes.

Commercial implication: The patent is best used as a leverage tool against products that intentionally mirror the same prodrug linker approach and stability/lyophilized formulation targets. It is less likely to block entrants that choose different prodrug linkers or different stability/excipient design spaces.

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When does US 9,919,033 lose exclusivity?

No exclusivity timing can be calculated from claim text alone. Determining expiration requires the patent’s filing date, USPTO docket history, and any filed terminal disclaimer or PTA/term adjustments. Those data are not present in the provided material, so a correct expiration timeline cannot be produced.

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What is the Orange Book status of this patent?

Orange Book listings apply to FDA-approved small-molecule drugs or certain biologics licensed under BLA but listed for reference products with exclusivities. US device-plus-prodrug patents are often tied to biologics products, and Orange Book status depends on whether the referenced product is listed with the patent.

No product identity, FDA reference number, NDA/BLA, or Orange Book listing data is included in the provided content, so the Orange Book status cannot be determined accurately here.

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Which companies are challenging the patent via Paragraph IV (or similar)?

Paragraph IV challenges target FDA-approved NDA/ANDA drug patents. A rhGH polymer prodrug pen system could be implicated either by ANDA-like generics (if applicable) or by other pathways, but the Paragraph IV framework depends on the FDA submission type and whether this patent is listed for the relevant product.

No FDA submission identifiers, ANDA/ANDA case list, or litigation docket is provided, so the identities of challengers cannot be stated without risking error.

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What litigation risk does US 9,919,033 face in generic or biosimilar design-around scenarios?

Design-around cluster 1: substitute the reversible linker chemistry

If an accused product uses a polymer prodrug but not the same reversible linker architecture (or does not match the dependent structural formulae of claims 9–10), it may avoid the specific chemical constraints that appear likely to anchor claim construction.

Design-around cluster 2: alter storage stability profile and free-rhGH release

Even if the prodrug is similar, if the product’s stability does not keep “less than 5%” free rhGH over 6 months at 2–25°C under the relevant tested conditions, claim 1 can be avoided.

Design-around cluster 3: change lyoprotectant strategy

Use of non-trehalose lyoprotectants can target avoidance of claim 6 and may challenge whether “lyoprotectant” is met (claim 1’s breadth), depending on construction.

Design-around cluster 4: shift excipient concentrations outside claims 15–17

Moving succinic acid, trehalose, or tris out of the specified ranges can avoid dependent claims 15–17, reducing exposure.

Design-around cluster 5: revise reconstitution chemistry or device chambering

Changing benzyl alcohol/cresol concentrations or chamber configuration avoids claims 19–20 and claim 18.

Litigation posture likely to work best for defendants: Attack the claim element that is easiest to show differs, typically the prodrug chemistry (if distinct) or the performance metric (<5% free rhGH) with assay methodology.

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How does US 9,919,033 compare with other rhGH long-acting polymer prodrug and device patents?

A true competitive comparison requires identification of:

• the patent family members (continuations, divisionals),
• the assignee and inventor set,
• overlapping prior art,
• and any competing prodrug linker platforms (e.g., different polymer conjugates, albumin-binding moieties, Fc fusions, PEGylation strategies).

None of that metadata is available in the provided text. A comparison would be speculative, so it cannot be produced here.

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Key takeaways

• US 9,919,033 is a system claim where infringement likely hinges on matching both the rhGH polymer prodrug chemistry (reversible linker; dependent structural formulae) and the product performance limits (≥6 months at 2–25°C with <5% free rhGH release).
• The patent’s commercial coverage is highest against products that use the same prodrug linker design and similar lyophilized formulation/excipient strategy (trehalose and quantified succinic acid/trehalose/tris ranges).
• Defenses and design-arounds concentrate on: different reversible linker architectures, different storage/free-rhGH behavior, alternate lyoprotectants, excipient concentrations outside the claimed windows, and different reconstitution preservative and cartridge chamber designs.
• Exact exclusivity timing, Orange Book status, and litigation/Paragraph IV challenge mapping cannot be derived from the claim text alone.

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FAQs

1) Can a product that is still a pen injector avoid infringement by using a different lyoprotectant than trehalose?
It can avoid claim 6 if trehalose is not used, but claim 1 still requires “a lyoprotectant” generally, so avoidance depends on whether the alternative excipient qualifies under claim construction and whether the stability/free-rhGH performance limitations are met.

2) What is the most litigated limiter in claim 1: “reversible linker” or “<5% free rhGH”?
In practice, both. “Reversible linker” supports chemistry-based noninfringement arguments; “<5% free rhGH” is a measurement-driven performance limiter that invites assay and stability-design disputes.

3) If an accused product matches the prodrug but differs in excipient percentages, which claims are most at risk?
The independent claim 1 can still be at risk if the system meets stability and performance limits. Dependent formulation-window claims 15–17 can be avoided by moving succinic acid/trehalose/tris amounts outside the stated ranges.

4) Does using lyophilization always matter?
For dependent claim 4, yes. Claim 1 can still apply if lyophilization is not required there, but dependent coverage depends on whether the accused process matches the drying method limitation.

5) Are the benzyl alcohol and cresol reconstitution limits likely to block infringement?
They can block dependent claims 19–20 when preservative chemistry or concentration differs. They are less likely to eliminate exposure to claim 1 unless the differences also affect stability/free-rhGH release and the prodrug system.

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References (APA)

No external sources were provided in the prompt, and no patent bibliographic data (filing date, assignee, family, or FDA linkage) is included to cite accurately.

Details for Patent 9,919,033

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Llc	ZOSTAVAX	zoster vaccine live	For Injection	125123	May 25, 2006	9,919,033	2036-11-01
Ascendis Pharma Endocrinology Division A/s	SKYTROFA	lonapegsomatropin-tcgd	For Injection	761177	August 25, 2021	9,919,033	2036-11-01

International Patent Family for US Patent 9,919,033

Country	Patent Number	Estimated Expiration
South Africa	201204334
World Intellectual Property Organization (WIPO)	2011073234
United States of America	9511122