Patent: 7,144,861

Summary for Patent: 7,144,861

Title:	Stabilized teriparatide solutions
Abstract:	A stabilized pharmaceutical composition in the form of a solution for parenteral administration of a parathyroid hormone is described wherein the therapeutically active ingredient is stabilized with a buffer and a polyol. Preferred preparations contain in an aqueous solution human PTH(1 34), mannitol, an acetate or tartrate buffering agent and m-cresol or benzyl alcohol as a preservative.
Inventor(s):	Chang; Chin-Ming (Fishers, IN), Havel; Henry A. (Indianapolis, IN)
Assignee:	Eli Lilly and Company (Indianapolis, IN)
Application Number:	10/055,509
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,144,861
Patent Claims:	see list of patent claims

United States Patent 7,144,861 (US7144861): Critical claim analysis and US patent landscape

What does US7144861 claim?

US7144861 centers on a sterile, ready-to-administer aqueous parenteral formulation of human parathyroid hormone (PTH 1-34), stabilized to avoid freeze-drying and reconstitution. The core claim pattern is:

• Active: human parathyroid hormone (1-34) in ~100 to 500 µg/mL
• Buffer: acetate (or acetate/tartrate in vial claim) maintaining pH 3 to 6
• Stabilizer: one or more selected among a defined excipient set (sugars/polyols)
• Preservative: parenterally acceptable preservative, with dependent coverage specifying m-cresol or benzyl alcohol and concentration ranges
• Product form: sterile aqueous solution, not reconstituted from powder (sealed vial claim)

This is a classic “formulation-first” protection strategy: broad on stabilizer identity (within a list), broad on buffer system (in the vial claim), and narrow enough on key numeric ranges to define patentable boundaries.

Claim scope snapshot

Claim	Product or method	PTH (1-34)	Buffer	Stabilizer	Preservative	Key limits
1	Aqueous solution	100 to 500 µg/mL	Acetate buffer; pH 3 to 6	From listed stabilizer group	Parenterally acceptable preservative	Sterile and ready for parenteral use
2	Solution	—	—	—	m-cresol or benzyl alcohol	Depends on claim 1
3	Solution	—	—	—	m-cresol; 0.3% to 1.0% w/w	Depends on claim 2
4	Solution	—	—	Mannitol; 3% to 10% w/w	—	Depends on claim 1-3
5	Solution	—	Buffer; 2 mM to 100 mM	—	—	Depends on claim 1-4/5
6	Solution	—	Acetic acid + sodium acetate	—	—	Depends on claim 5
7	Solution	250 µg/mL	—	—	—	Depends on claim 1-6
8	Solution (explicit composition)	0.25 mg/mL (250 µg/mL)	Acetic acid 0.52 mg/mL + sodium acetate 0.12 mg/mL	Mannitol 50 mg/mL (5% w/w)	m-cresol 2.5 mg/mL (0.25% w/v approx; claim language uses mg per mL)	“Mixed per 1 ml of water”
9	Method to prepare sterile ready-to-administer solution	100 to 500 µg/mL	Acetate buffer; pH >3 to <7	Listed stabilizers	Parenterally acceptable preservative	Sterilize without freeze-drying/reconstitution
10	Method	—	Buffer 2 mM to 100 mM	Mannitol 3% to 10% w/w	m-cresol 0.3% to 1.0% w/w	Depends on claim 9
11	Method (explicit composition)	0.25 mg/mL	Acetic acid 0.52 mg/mL + sodium acetate 0.12 mg/mL	Mannitol 50 mg/mL	m-cresol 2.5 mg/mL	Depends on claim 10
12	Sealed vial (no reconstitution)	100 to 500 µg/mL	Acetate or tartrate; pH 3 to 6	Listed stabilizers	Parenterally acceptable preservative	“Not reconstituted…from a powder”
13	Vial	—	—	Mannitol	—	Depends on claim 12
14	Vial numeric ranges	250 µg/mL	—	Mannitol 1% to 20% w/w	Preservative 0.1% to 2% w/w	Wider stabilizer range than solution claims
15	Vial narrowed	—	—	Mannitol 3% to 10% w/w	m-cresol or benzyl alcohol	Depends on claim 14

Does US7144861 attempt to own “the formulation,” or only “ready-to-administer convenience”?

The patent does both, but the balance shifts by claim type:

1. Product claims (1-8, 12-15) define a specific aqueous formulation scaffold with numeric ranges.
2. Method claims (9-11) add a process limitation: sterilize without freeze-drying or reconstitution prior to patient use.

From a validity/obviousness standpoint, the strongest patentable angle is the combination of:

• aqueous, sterile, ready-to-administer delivery (not a lyophilized kit),
• PTH 1-34 at defined µg/mL levels,
• acidic buffer window (pH ~3-6),
• specified stabilizer class (sugars/polyols) and numeric ranges, and
• preservative identity and concentration (in dependent claims).

The method claims are vulnerable if the underlying step is routinely taught for such peptides: “admixture then sterile processing” may be considered obvious unless the patent ties sterilization to stability outcomes and the formulation parameters are truly non-trivial.

Claim-by-claim critical analysis: likely strengths and likely attack surfaces

Claim 1: “Aqueous pharmaceutical solution” with broad stabilizer list, narrow pH window

Strengths

• The stabilizer is restricted to a known list (glucose, trehalose, raffinose, sucrose, mannitol, sorbitol, inositol, glycerine, propylene glycol, mixtures). That is narrower than “any stabilizer.”
• The buffer is restricted to acetate and pH 3-6, which helps differentiate from neutral pH peptide formulations.
• The active is restricted to PTH (1-34) and a numeric concentration range (100-500 µg/mL).

Attack surfaces

• The stabilizer list reads like standard peptide excipients; an examiner or challenger can argue routine selection.
• The buffer range and pH may be considered a predictable formulation optimization axis for peptides.
• “Parenterally acceptable preservative” in claim 1 is broad and can be used to map prior art without committing to m-cresol or benzyl alcohol.

Claim 2-3: Preservative narrowed to m-cresol or benzyl alcohol, then to m-cresol concentration

Strengths

• Claim 3 supplies a numeric range (0.3% to 1.0% w/w m-cresol). This improves claim specificity and can matter in obviousness and enablement disputes.

Attack surfaces

• If prior art already discloses sterile aqueous peptide solutions with m-cresol in that range, claim 3 becomes a “known range” issue.
• If prior art uses benzyl alcohol, claim 2 stays broad enough to capture it, but claim 3 does not.

Claim 4: Mannitol at 3-10% w/w

Strengths

• Mannitol is singled out with an explicit numeric range.
• Mannitol is a common bulking/cryoprotectant-like excipient; in aqueous systems it can still impact stability and viscosity and protect against aggregation.

Attack surfaces

• Because mannitol is ubiquitous in peptide formulations, an opponent can argue that selecting mannitol within 3-10% is a routine optimization rather than a non-obvious invention.
• If prior art already uses mannitol in that range with PTH 1-34 at similar pH, this claim risks obviousness.

Claim 5-6: Buffer concentration 2 mM to 100 mM, and explicit acetic acid/sodium acetate components

Strengths

• Adds numeric buffer concentration control plus explicit formulation components.
• Helps distinguish from phosphate-buffered peptide solutions and from generic acetate buffer descriptions.

Attack surfaces

• Buffer concentration ranges are often treated as routine parameter tuning if prior art shows stability across a similar window.
• If acetate buffer is already known for PTH formulations, these limitations may not add enough differentiation.

Claim 7: PTH fixed at 250 µg/mL

Strengths

• The numeric fixation is helpful for distinguishing from generic “range” prior art.

Attack surfaces

• If prior art includes the same or effectively identical concentration in a comparable buffered stabilizer-preserved solution, this becomes a copycat range issue.

Claim 8: Explicit per-mL recipe (composition lock-in)

Strengths

• This is the most defensible claim format because it is anchored to a precise composition:
  • PTH (1-34): 0.25 mg/mL
  • Mannitol: 50 mg/mL
  • m-cresol: 2.5 mg/mL
  • Acetic acid: 0.52 mg/mL
  • Sodium acetate: 0.12 mg/mL
• It can be used to argue direct infringement only when accused products match those quantities or their equivalents.

Attack surfaces

• If a competitor’s product differs slightly (for example different m-cresol concentration, different acetate ratio, or different stabilizer), claim 8 may not read on it.
• If the patent’s enablement depends on a narrow composition, a challenger can argue the broader claims lack support.

Claim 9-11: Method without freeze-drying/reconstitution

Strengths

• The method includes a non-lyophilized workflow limitation: sterilizing without freeze-drying or reconstitution prior to patient use.
• This can separate it from kit-based prior art (powder plus reconstitution step).

Attack surfaces

• The patent can be attacked by arguing that “not freeze-drying” is a product-form difference, not a method step with functional transformation.
• If prior art teaches sterile filtration and aseptic filling of aqueous peptide formulations, then the method may be considered obvious given the composition is obvious.

Claim 12: Sealed vial with “not reconstituted from a powder” and acetate/tartrate buffer flexibility

Strengths

• Vial form aligns with commercial fill-finish reality and can capture distribution and packaging use.
• The buffer system is expanded from acetate to acetate or tartrate, which increases coverage.

Attack surfaces

• The “not reconstituted from powder” limitation may not distinguish much if the accused product is already a ready-to-use aqueous vial.
• Tartrate buffer allowance increases breadth but also increases obviousness risk because it widens the design space.

Claim 13-15: Mannitol-focused vial plus preservative options and expanded stabilizer range

Strengths

• Claim 14 gives broader mannitol range (1% to 20% w/w) and preservative range (0.1% to 2% w/w), improving coverage against formulation variations.
• Claim 15 narrows back to 3-10% mannitol and m-cresol or benzyl alcohol, aligning with earlier solution claims.

Attack surfaces

• Broad ranges are vulnerable if prior art covers stability across the same ranges or if the patent lacks evidence that stability holds throughout the entire breadth.
• If competitors use different stabilizers outside the list, these claims do not cover them.

Core legal theme: “Parameter selection” versus “unexpected stability”

The claims are built on selecting:

• pH (3-6),
• acetate/tartrate buffer type,
• buffer concentration (2-100 mM),
• stabilizer from a conventional group with numeric percentages,
• preservative identity (m-cresol or benzyl alcohol) and concentration bands,
• final peptide concentration (100-500 µg/mL),
• and a non-lyophilized, sterile, ready-to-administer dosage form.

A challenger’s best line is that peptide formulation for injectable use is a well-understood optimization problem and that each axis is within predictable engineering ranges for stabilizing peptides in acidic solution with polyols and preservatives.

US7144861’s survival posture therefore depends on whether the patent record supports:

• non-obviousness via stability advantages (aggregation suppression, potency retention, reduced degradation) versus conventional choices,
• and whether claimed ranges are critical rather than convenient.

Patent landscape implications in the US (high-level map of risk)

Without reproducing the full US family file for US7144861 and without enumerating all specific citing/counter-citing documents, the landscape can still be mapped by claim elements that typically define novelty challenges for peptide formulations in the US.

Likely prior-art clusters that collide with US7144861

1. Ready-to-use aqueous peptide injections (sterile, fill-finish)
   These collide directly with claim 9 and claim 12’s “not reconstituted from a powder” concept.

2. Acidic buffer peptide stabilizer formulations (pH ~3-6)
   Acetate and tartrate buffers in acidic windows are common for peptide stability and reduce deamidation pathways relative to neutral conditions.

3. Polyol/sugar stabilization packages
   Mannitol, sorbitol, trehalose, sucrose, and glycerin appear across many peptide patents as stabilizers or viscosity/tonicity components.

4. Preservative selection for multi-dose stability
   m-cresol and benzyl alcohol are standard preservatives. Numeric ranges like 0.1% to 1% often appear in prior art for injectable peptides.

5. PTH 1-34 specific formulation teaching
   If earlier patents disclose PTH (1-34) in acetate buffer with mannitol and m-cresol, US7144861 becomes a narrower “range and recipe” improvement rather than a foundational invention.

Where US7144861 may still defend against obviousness

• Non-lyophilized route combined with a defined acid-buffered stabilization package for PTH (1-34) is a product differentiation argument.
• Claim 8’s explicit recipe can preserve defensibility for direct infringement cases.
• Dependent claims (3, 4, 5-6, 10-11, 14-15) narrow to numeric ranges, which can defeat a single prior-art reference that only partially overlaps.

Business consequences: how competitors can design around US7144861

US7144861’s structure shows the typical “design-around” pressure points:

1. Change stabilizer identity
   The stabilizer is restricted to a fixed list. Using a stabilizer outside the listed group (for example certain amino acids, surfactants, or alternative excipients) can avoid independent claim 1 and all dependent stabilizer-specific claims (4, 13-15).

2. Change pH outside 3-6 (solution) or the acetate pH constraint in method claims
   Even modest shifts could avoid claim 1 and claim 12 if outside the defined windows.

3. Change preservative away from m-cresol and benzyl alcohol
   Claim 2-3 and claim 15 can be avoided by selecting other parenteral preservatives.

4. Change the numeric concentrations
   Claims 3, 4, 5, 10, 14, and claim 8’s exact per-mL recipe are range- and amount-sensitive.

5. Move away from “not reconstituted from powder”
   If a competitor uses a lyophilized form requiring reconstitution, claim 12’s “not reconstituted” limitation may avoid.

Key Takeaways

• US7144861 is a formulation and dosage form patent focused on a sterile, ready-to-administer aqueous PTH (1-34) product using acidic acetate/tartrate buffering, a specified stabilizer class (including mannitol), and standard preservatives (m-cresol or benzyl alcohol) with defined concentration ranges.
• The strongest novelty posture is the combination of aqueous sterile ready-to-use presentation with a controlled pH/buffer-stabilizer-preservative system for PTH (1-34), reinforced by numeric restrictions.
• The core obviousness risk is that most formulation elements (acidic pH, mannitol/polyols, acetate buffers, m-cresol/benzyl alcohol preservatives) are common across peptide injectables, so the patent’s defensibility depends on whether the record shows criticality or unexpected stability gains tied to the specific claimed ranges.
• Competitors can likely design around by changing stabilizer identity (outside the list), shifting buffer/pH, using a different preservative, or moving outside the numeric constraints, with the explicit per-mL recipe in claim 8 offering the most infringement-resilient scope.

FAQs

1) What is the central invention in US7144861?

It is a sterile, ready-to-administer aqueous formulation of human PTH (1-34) using an acetate (or acetate/tartrate for vial) buffer system at pH 3 to 6, with a stabilizer selected from a defined list and a parenteral preservative, avoiding freeze-drying and reconstitution in the method claims.

2) Which claim provides the tightest product match?

Claim 8 is the tightest because it specifies an explicit per-1 mL composition: 0.25 mg/mL PTH (1-34), 50 mg/mL mannitol, 2.5 mg/mL m-cresol, and specific acetic acid/sodium acetate amounts.

3) Where is the patent most vulnerable to obviousness?

Claims that rely on broadly conventional excipient categories and preservatives (stabilizer list and “parenterally acceptable preservative”) are vulnerable unless the patent record demonstrates that the selected ranges and combinations produce non-predictable stability advantages for PTH (1-34).

4) Can a competitor avoid US7144861 by using a different buffer salt?

Yes, in part. The solution claims require acetate and pH 3-6, while the vial claim allows acetate or tartrate. Using a different buffer system or pH outside the claim windows can reduce coverage.

5) How do the method claims differ from the product claims?

Method claims add a functional workflow: sterilizing without freeze-drying or reconstitution prior to patient use. Product claims focus on the formulation and packaged sterile state.

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References

[1] United States Patent 7,144,861. “Aqueous pharmaceutical solution of parathyroid hormone (1-34).” Claims text as provided in prompt.

Details for Patent 7,144,861

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Takeda Pharmaceuticals U.s.a., Inc.	NATPARA	parathyroid hormone	For Injection	125511	January 23, 2015		2022-01-23