Patent: 10,046,058

Summary for Patent: 10,046,058

Title:	Use of hydrophobic organic acids to increase hydrophobicity of proteins and protein conjugates
Abstract:	Examples may include a microsphere. The microsphere may include a biodegradable polymer. Furthermore, the microsphere may include a protein mixture selected from the group consisting of a protein-polyethylene glycol conjugate, the protein-polyethylene glycol conjugate and the hydrophobic anion of the organic acid, a protein and the hydrophobic anion of the organic acid, and combinations thereof. Examples may also include a method of making the microspheres. The method may further include reacting a polyethylene glycol with a protein to form a protein-PEG conjugate. In addition, the method may include protonating an amino group on the protein-PEG conjugate with a hydrophobic organic acid to form the protein-PEG conjugate salt. Furthermore, the method may include mixing the protein-PEG conjugate salt in an organic solvent with a biodegradable polymer. The method may also include emulsifying the mixture. Additionally, the method may include hardening the emulsified mixture into the controlled-release microspheres.
Inventor(s):	Rosendahl; Mary S. (Broomfield, CO), Mantripragada; Sankaram B. (Windsor, CO), Gomez; Eliana B. (Boulder, CO)
Assignee:	REZOLUTE, INC. (Louisville, CO)
Application Number:	14/954,591
Patent Claims:	see list of patent claims

Executive summary

US Patent 10,046,058 is directed to controlled-release microspheres that embed protein–polyethylene glycol (protein-PEG) conjugate salts formed by protonating protein or protein-PEG conjugates with hydrophobic anions of specific organic acids (including pamoic acid, docusate hydrogen, and furoic acid), followed by microsphere formation using biodegradable polymers (notably PLA, PLGA, and PLGA copolymers). The independent claim 1 is structured to cover (i) polymer selection, (ii) protein/PEG salt selection, (iii) salt anion chemistry, and (iv) a key process limitation: adding the organic acid in a water-immiscible solvent “without the presence of water” to form a water-immiscible solution prior to microsphere formation.

From an IP-defense standpoint, the claim set has strengths in its specific chemical anion identity (pamoate/docusate/furoate variants), salt formation “without water” during protonation, and microsphere-hardening via polymer emulsification. The most plausible invalidity or design-around pressure points are (1) prior art overlap in forming PEG-protein salts with hydrophobic counterions for depot delivery, (2) obviousness of using standard PLA/PLGA microsphere platforms with known protein-PEG chemistries, and (3) whether the “without the presence of water” limitation is supported broadly and distinguishable over common salt-formation workflows that may use residual moisture.

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What does US Patent 10,046,058 claim for protein-PEG hydrophobic salt microspheres?

Core invention in claim 1 US 10,046,058 claims a microsphere comprising:

• Biodegradable polymer selected from:
  • polylactide (PLA)
  • polyglycolide (PGA)
  • poly(d,l-lactide-co-glycolide) (PLGA)
  • polycaprolactone (PCL)
  • polyorthoester
  • polyester-polyether copolymer
  • polylactide-PEG copolymer
• Protein mixture including one of:
  • protein–PEG conjugate + hydrophobic anion of an organic acid
  • hydrophobic anion + protein
  • combinations
• Hydrophobic organic acid anion comprises:
  • pamoic acid (pamoate anion)
  • docusate hydrogen (docusate anion)
  • furoic acid (furoate anion)
• Process limitation:
  • microsphere is formed by adding the organic acid to:
    • the protein–PEG conjugate, or
    • the protein in a water-immiscible solvent in an organic phase
  • the addition occurs without the presence of water
  • thereby forming a water-immiscible solution, which is then used in microsphere formation

Claim structure implications The claim is not a generic depot claim; it is a chemical-process-constrained microsphere claim. The dependency chain in claims 2–9 and 10–16 adds narrower coverage across:

• specific therapeutic proteins (examples: hGH, GLP-1, insulin, parathyroid hormone/enfuvirtide/octreotide)
• PEG architecture (methoxy-PEG; monoPEGylated conjugate)
• anion identity (pamoate; ratio ranges)
• polymer specifics (PLGA; PLGA molecular weight window)
• process parameters (salt molar ratio; logP threshold; additional protonation step)

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How do claims 2–16 narrow scope for specific proteins, PEG forms, and anion chemistries?

Which protein targets are covered

US 10,046,058 explicitly lists:

• Claim 2: human growth hormone
• Claim 3: GLP-1
• Claim 4: microspheres also include insulin–PEG conjugate
• Claim 5: protein includes at least one of:
  • insulin
  • parathyroid hormone (and fragments)
  • enfuvirtide
  • octreotide

Interpretation: Coverage is broad across protein therapeutics but still limited to proteins that fall within claim recitations and “protein mixture” permutations.

Which PEG forms are covered

• Claim 6: PEG is methoxy polyethylene glycol.
• Claim 9: PEG conjugate is monoPEGylated.

Interpretation: These dependencies can help enforce narrower claims against competitors using different PEG forms (e.g., multi-PEGylation) but do not constrain claim 1 if not used as fallback.

Which anion chemistries are covered

• Claim 7: hydrophobic anion is pamoate anion (from pamoic acid).
• Claim 8: anion:protein-PEG conjugate molar ratio 1:1 to 11:1.
• Claim 14: ratio 3:1 to 8:1.
• Claim 15: hydrophobic anion has logP > 1.
• Claim 16: further protonating at least one amino group on the protein or protein-PEG conjugate.

Interpretation: Claim 1 already anchors to the acid identity set. Claims 7/8/14/15/16 further constrain enforceability to specific formulations and salt levels.

Which polymer specifics are covered

• Claim 10: polymer comprises poly(d,l-lactide-co-glycolide) (PLGA).
• Claim 11: biodegradable polymer molecular weight 7,000–17,000 Da.

Interpretation: Competitors using substantially different PLGA grade or molecular weight can attempt to avoid dependent claim 11 and related scope, but claim 1 still covers other polymer classes.

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What is the key process limitation: “addition without the presence of water,” and why does it matter?

Claim 1 process anchor The microsphere formation requires:

• adding the organic acid to protein-PEG conjugate or protein in a water-immiscible solvent in an organic phase
• with the addition occurring without the presence of water
• to form a water-immiscible solution

Claim 12 reinforces the manufacturing logic Claim 12 provides a broader method view:

• provide aqueous protein solution with pH buffer
• react PEG with protein to form protein-PEG conjugate
• then protonate an amino group using the hydrophobic organic acid in a water-immiscible solvent in an organic phase without the presence of water to form a protein-PEG conjugate salt
• mix salt with polymer, emulsify into aqueous solution, harden to form microspheres

Enforcement consequence This “without water” element can operate as a distinguishing feature if prior art salt formation uses:

• aqueous acid addition
• solvent systems containing appreciable water
• or salt formation steps that are not decoupled from hydration

At the same time, it can be attacked as:

• a definitional/trace-moisture argument (what counts as “presence of water”)
• an obvious process-control step if prior art already teaches drying/anhydrous salt formation for moisture-sensitive proteins

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What prior art categories are most likely to overlap US 10,046,058?

Because the patent is not a single-novel composition but a combination of known elements (depot microspheres + PEG-protein chemistry + specific hydrophobic counterions + salt formation in organic phase), the most relevant invalidity landscape typically clusters into four buckets:

1) Microsphere depot platforms using PLA/PLGA

Prior art is dense on protein/peptide encapsulation and release using PLA/PLGA. Claim 1’s novelty, if any, likely relies on the salt chemistry and water-immiscible, “no water” protonation step, not polymer selection.

2) PEGylated proteins and depot formulation

PEG-protein conjugates are widely used to alter pharmacokinetics. Claim 1 ties PEGylation to depot microspheres but focuses on protein-PEG conjugate salts with hydrophobic anions.

3) Hydrophobic counterions and salt formation to modulate solubility

Pamoate salts are well-established in pharmaceuticals for hydrophobicity and controlled solubility. The patent’s inclusion of:

• pamoic acid (pamoate)
• docusate hydrogen (docusate)
• furoic acid (furoate) suggests an argument that specific hydrophobic anions improve encapsulation efficiency and/or release control.

4) Non-aqueous or anhydrous salt formation

The “without water” requirement can be compared against prior art workflows that:

• use organic-phase acid addition
• use controlled water content
• dry inputs to anhydrous conditions

Practical litigation read-across For validity challenges, claim drafters commonly meet trouble where prior art exists for:

• making salts of proteins/PEG-proteins with hydrophobic acids
• then encapsulating using standard PLGA microsphere methods
• without a clear teaching that the “without water” constraint is non-obvious and yields a distinct technical effect

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How strong is the patent estate likely to be across US exclusivity and enforcement?

Claim 1 strength vectors

• Specific anion identity set (pamoic/docusate/furoic)
• Specific process constraint (no water during protonation in organic phase)
• Explicit coupling of salt to microsphere formation (salt increases solubility in organic phase; salt mixed with biodegradable polymer; emulsify and harden)

Claim 1 risk vectors

• Standard depot microencapsulation is prior art.
• PEG-protein depot claims are prior art.
• Pamoate-type salts are known in general pharmaceutical practice.
• The “without water” limitation may be argued as an optimization or a typical solvent-drying control.

Dependent claims as fallback If claim 1 faces invalidity, dependent claims 2–16 create a ladder:

• Specific protein targets can survive if prior art is general and not tied to those proteins in combination with the anion/salt process.
• Ratio windows and logP thresholds can distinguish formulation designs.
• PLGA molecular weight window narrows to specific polymer grades.

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What generic entry risks exist for biosimilars and generics of covered proteins under this patent?

Key point US 10,046,058 is a formulation and method-of-making patent on controlled-release microspheres, not on the protein drug entity itself (hGH, GLP-1, insulin, etc.) or on biologic sequences. That shifts the entry risk to any competitor that:

1. makes microsphere formulations,
2. using the covered salt chemistry (protein-PEG conjugate salt with specified hydrophobic anions), and
3. uses the covered preparation workflow (including the “without water” step).

Biosimilar/biologic risk

• For biosimilars of proteins, risk concentrates on drug product form (microspheres) rather than the active ingredient per se.
• If a biosimilar competitor uses a different delivery system (e.g., solution, implant, different depot chemistry) or different counterions, it can reduce exposure.

Generic risk

• Small-molecule generics face less relevance because the patent is for protein-PEG microspheres.
• The main threat is “follow-on” or “next-entry” depot product using the same protein-PEG salt approach.

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How does the manufacturing process map to design-around options?

Most direct design-around levers

1. Use different hydrophobic anions

   • If the competitor avoids pamoate/docusate/furoate anions (or their equivalents that do not meet claim definitions), they can exit claim 1.

2. Change salt formation conditions

   • If protonation is done with non-zero water presence, or via an aqueous step that still yields a salt but does not meet “without presence of water,” the process element can be attacked.

3. Change PEG architecture

   • Avoid methoxy-PEG or avoid monoPEGylated conjugates if relying on dependent claims.

4. Change PLGA grade

   • If claim 11 is targeted, using PLGA molecular weights outside 7,000–17,000 Da can reduce dependent claim exposure.

Secondary design-around levers

• Adjust anion:protein-PEG ratios outside 1:1–11:1 or 3:1–8:1 to avoid dependent claims 8 and 14.
• Ensure anion logP does not satisfy logP>1 if feasible, to avoid claim 15.
• Avoid additional protonation of amino groups beyond baseline conditions for claim 16.

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What would an Orange Book status search likely show for a patent like this?

If the covered products are FDA-approved protein drug products delivered as depot microspheres, the patent would typically appear in the Orange Book as a drug product patent (and/or method-of-use patent) if the patent was timely listed for the applicable NDA/BLA-to-RLD. The claim set is formulation/method oriented, which most commonly maps to:

• drug product patents (formulation, delivery system)
• potentially method-of-manufacture patents listed only in certain circumstances

However, without the FDA listing record for US 10,046,058, a precise Orange Book status cannot be stated here.

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What patent-expiration and exclusivity questions drive filings, and what is typically the decision logic?

For competitors, the decision logic is usually:

• Patent filing date and term determine the hard cut for exclusivity.
• Family members can extend practical blocking positions even after one number expires.
• Patent type matters: drug product and method-of-use patents can block generics differently than manufacturing-only patents.

For this patent’s claim set, the effective blocking position would apply if a generic/biosimilar candidate replicates:

• the specific microsphere chemistry and
• the specific non-aqueous salt-forming process.

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How could patent litigation likely frame validity and infringement arguments?

Infringement theory

Plaintiff would argue that the accused product:

• uses biodegradable polymer of a covered class (including PLGA)
• uses protein-PEG conjugate salt with one of the covered hydrophobic anions (pamoate/docusate/furoate)
• is produced via a process where the anion is added in an organic phase without water present, forming a water-immiscible solution
• is emulsified/hardened to form the microspheres

Validity theory

Defendants would likely argue:

• claim 1 is an obvious combination of known depot microsphere formulations with known PEG-protein chemistry and known pamoate-type hydrophobic counterions
• the “without presence of water” limitation is inherent or obvious as an anhydrous process control
• dependent claims are not novel over formulations using PLGA and standard PEG-protein salts

Evidence that would matter

• process documentation for production steps (water content, solvent systems, timing)
• characterization of anion identity and salt formation chemistry
• polymer grade and MW
• PEG architecture and degree of PEGylation

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Patent landscape map: what to search for around US 10,046,058

A comprehensive landscape around this patent typically focuses on:

1. continuations/divisionals of US 10,046,058 (same assignee and priority)
2. related anion salt patents covering pamoate/docusate/furoate with PEG-proteins
3. PLGA microsphere patents for protein-PEG depot systems
4. process patents on non-aqueous protein-PEG salt formation

Assignee and priority mapping are required to do this rigorously; without those bibliographic and family data, a complete landscape cannot be generated from the claim text alone.

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Key takeaways

• US 10,046,058 protects protein-PEG conjugate salts using hydrophobic anions from pamoic acid, docusate hydrogen, and furoic acid, embedded in biodegradable polymer microspheres.
• The independent claim 1 is constrained by a process limitation: the organic-acid addition occurs in an organic phase without water present, forming a water-immiscible solution.
• Enforcement risk for competitors is highest when their depot product uses the same anion set and replicates the non-aqueous salt formation step.
• The dependent claims build fallback positions using specific proteins (hGH, GLP-1, insulin, PTH fragments, enfuvirtide, octreotide), PEG architecture (methoxy-PEG, monoPEGylated), ratio windows, and PLGA grade.

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FAQs

1. Does US 10,046,058 cover the protein drug alone or only the controlled-release microsphere product?
   It is drafted on microspheres and microsphere manufacturing methods, not the free protein entity.

2. What single claim element most supports differentiation from standard PLGA protein microspheres?
   The salt-forming step requiring addition of the organic acid in an organic phase “without presence of water.”

3. Can a competitor avoid the patent by changing from pamoic acid to another hydrophobic acid?
   Yes, if the anion is not within the claim’s enumerated acid set (pamoic/docusate/furoic and mixtures) and does not fall within a captured equivalency argument.

4. If a competitor uses PLGA but with molecular weight outside 7,000–17,000 Da, is it automatically outside the patent?
   That avoids dependent claim 11, but claim 1 can still be implicated if other elements are met.

5. How do anion:protein-PEG molar ratios affect infringement risk?
   They primarily affect exposure under dependent claims (1:1 to 11:1; 3:1 to 8:1), not necessarily claim 1.

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References

(No sources were provided in the prompt beyond the claim text. No external citation can be generated without bibliographic, prosecution, or FDA listing records for US 10,046,058.)

Details for Patent 10,046,058

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		2035-11-30