Details for Patent: 9,278,105

Which drugs does patent 9,278,105 protect, and when does it expire?

Patent 9,278,105 protects MINOCIN and is included in one NDA.

This patent has thirty patent family members in twenty-two countries.

Summary for Patent: 9,278,105

Title:	Tetracycline compositions
Abstract:	The present invention relates to compositions, pharmaceutical compositions, and methods for preparing the same, comprising a tetracycline with improved stability and solubility. Some embodiments include a tetracycline with an excess of a divalent or trivalent cation.
Inventor(s):	David C. Griffith, Serge Boyer, Michael N. Dudley, Scott Hecker
Assignee:	Melinta Subsidiary Corp
Application Number:	US13/654,018
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,278,105
Patent Claim Types: see list of patent claims	Use; Composition; Formulation;

US Patent 9,278,105 Scope, Claims, and U.S. Patent Landscape for Intravenous 7-Dimethylamino-Tetracyclines with Mg Cation Ratios

US Patent 9,278,105 claims a narrow-but-practical U.S. method-of-treatment and reconstitution/administration framework for intravenous (IV) use of 7-dimethylamino-tetracycline antibiotics (covering minocycline, tigecycline, PTK796, and glycylcyclines) formulated with magnesium or other divalent/trivalent metal salts at high metal-to-antibiotic molar ratios, with controlled pH (generally >4 and <7), and controlled osmolality (<500 mOsm/kg) and specific excipient exclusions. The estate is claim-heavy on formulation-operational parameters (metal ratio bands, pH/osmolality cutoffs, absence of designated solubilizers/additives) and includes process-formulation variants (liophile/lyophilized solid reconstitution and dilution steps).

Bottom line: infringement risk concentrates on IV dosing regimens that match the claimed physicochemical envelope (Mg2+/antibiotic ratio >3:1 and often ≥5:1 up to ≥10:1; pH bands; osmolality thresholds) and that follow the claimed preparation rules (and, for claim 34+, reconstituting/diluting a water-soluble solid containing the metal salt). Workarounds typically fall into two lanes: (1) change the metal identity or reduce the molar ratio outside the claimed ranges, or (2) change the formulation/excipient set or physicochemical target values (pH, osmolality), while ensuring stability and manufacturability.

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What do US Patent 9,278,105 claims protect for IV minocycline and tigecycline with magnesium?

US Patent 9,278,105 protects methods of treating bacterial infections using IV-administered aqueous solutions (and, in dependent claim 34+), reconstituted/diluted dosing solutions whose composition is defined by:

1. Active class: “7-dimethylamino-tetracycline antibiotic” including minocycline and glycylcyclines (expressly tigecycline), and PTK796.
2. Metal cation: magnesium cation for claim 1+; divalent or trivalent metal cations for claim 34+ (including Mg2+, Ca2+, Zn2+, Ga3+).
3. High molar ratio:
   • Claim 1: Mg/antibiotic greater than 3:1
   • Dependent escalations: ≥5:1, >8:1, ≥10:1
   • Additional “from 5:1 to 10:1” closure: claims 49–52
4. Aqueous and IV route: composition is an aqueous solution administered IV.
5. pH constraint: pH >4 and <7, with additional dependent bands (e.g., pH <6; pH <5; and pH windows in specific examples: >5.5 and <6.5; >6 and <7).
6. Osmolality constraint: <500 mOsm/kg, with additional cutoffs <400, <350, and specific example-dependent osmolality ranges.
7. Excipients excluded (claim 2–3): multiple classes of additives are excluded, including antioxidants and specific solubilizers/agents (pyridine-containing compounds, gluconate, alcohol/glycerol/PEG, pyrrolidone-containing compounds, water-miscible local anaesthetics, urea, lactose, dehydrating agent; and specific enumerated dehydrating agents like absolute ethanol, ethyl acetate, acetic anhydride).
8. Solution exclusion set is explicit and testable: “does not comprise” language tied to measurable ingredients and categories.

Claim scope structure:

• Independent claim 1 is a direct IV dosing method with a tightly-defined physicochemical envelope and explicit excipient absences.
• Independent claim 34 broadens the operational format by capturing reconstitution/dilution from a “water-soluble solid composition” plus metal salt, still tied to high metal ratio, pH and osmolality limits for the final IV “second solution,” and still supporting a set of metals and antibiotics.

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How do the claim 1 parameters define the infringement envelope (Mg ratio, pH, osmolality, excipient exclusions)?

Mg molar ratio thresholds

Key numeric levers in claim 1:

• Mg2+/7-dimethylamino-tetracycline > 3:1 (core)
• Dependent tightening options:
  • ≥5:1 (claim 6)
  • >8:1 (claim 7)
  • ≥10:1 (claim 8)
• Additional “range-limiting” closure for narrower metal bands:
  • 5:1 to 10:1 (claim 49) and 5:1 (claim 50) plus parallel range closure for claim 34 (claims 51–52).

Practical inference: the patent is most enforceable where formulations run at excess Mg relative to the antibiotic to manage solubility/stability and maintain osmolality/pH targets.

pH and osmolality boundaries

Claim 1:

• pH >4 and <7
• osmolality <500 mOsmol/kg

Dependent pH controls:

• pH <6 (claim 4)
• pH <5 (claim 5)

Dependent example pH windows are explicit for tigecycline compositions:

• pH >5.5 and <6.5 (claims 20–25, 20–23 in pH 5.5–6.5; 24–25 expand to >6.0 and <7.0 variants)
• For tigecycline: multiple salts (MgSO4 or MgCl2) with Mg/tigecycline ratios of 5:1 and 12:1.

Antioxidant/pyridine/gluconate and other “does not comprise” carve-outs

Claim 2 and 3 list specific categories and named compounds that are absent:

• Claim 2 excludes: antioxidant; pyridine-containing compound; gluconate; alcohol; glycerol; PEG; pyrrolidone-containing compound; water-miscible local anesthetic; urea; lactose; dehydrating agent.
• Claim 3 excludes: nicotinamide; procaine; and dehydrating agents among: ethyl acetate, acetic anhydride, absolute ethanol, and mixtures.

Operational significance: even if a competitor matches Mg ratio and pH/osmolality, using one of these excluded excipients can avoid literal coverage if the formulation “does not comprise” those ingredients in the final composition.

Volume ceilings

The patent adds dose-volume limitations:

• less than 1000 mL (claim 53)
• less than 500 mL (claim 54)
• less than 200 mL (claim 55)
• less than 110 mL (claim 56)

Parallel constraints in claim 34 for the second solution (claims 57–60).

These are generally aligned with infusion practice, but they give another factual lever for infringement defenses and design-around.

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What is the technical variation captured by dependent claims 11–18 and 20–33 (MgSO4 vs MgCl2 vs NaOH and acetate buffers)?

The patent makes metal identity and base/buffer chemistry part of the claim set.

Metal salt identity (claim 11–13)

Claim 1 includes magnesium cation; dependent claims specify:

• magnesium sulfate (claim 11)
• magnesium acetate (claim 12)
• magnesium chloride (claim 13)

Buffer and base composition (claim 14–17)

• buffer (claim 14), specifically acetate buffer (claim 15)
• base (claim 16), specifically NaOH (claim 17)

Specific example-style compositions for tigecycline (claims 20–25)

Tigecycline is explicitly tied to compositions containing 5 mg/mL tigecycline:

• With MgSO4 + NaOH, Mg:tigecycline 5:1; pH >5.5 and <6.5 (claim 20)
• With MgSO4 + NaOH, Mg:tigecycline 12:1; pH >5.5 and <6.5 (claim 21)
• With MgCl2 + NaOH, Mg:tigecycline 5:1; pH >5.5 and <6.5 (claim 22)
• With MgCl2 + NaOH, Mg:tigecycline 12:1; pH >5.5 and <6.5 (claim 23)
• With MgSO4 + NaOH, Mg:tigecycline 5:1; pH >6.0 and <7.0 (claim 24)
• With MgSO4 + NaOH, Mg:tigecycline 12:1; pH >6.0 and <7.0 (claim 25)

Specific example-style compositions for minocycline (claims 28–33)

Minocycline concentration and salts:

• at least 5 mg/mL (claim 28)
• at least 10 mg/mL (claim 29)
• Example embodiments with 10 mg/mL minocycline:
  • 10 mg/mL + MgCl2 + NaOH, Mg:minocycline 5:1, pH >4.5 and <5.5 (claim 30)
  • 10 mg/mL + MgSO4 + sodium acetate, Mg:minocycline 5:1, pH >4.5 and <5.5, osmolality >275 and <375 mOsm/kg (claim 31)
  • 10 mg/mL + Mg(CH3O2)2, Mg:minocycline 5:1, pH >4.5 and <5.5 (claim 32)
  • 10 mg/mL + MgSO4 + NaOH, Mg:minocycline 5:1, pH >4.5 and <5.5, osmolality >150 and <250 mOsm/kg (claim 33)

Enforcement mechanics: these nested dependent claims create multiple “anchor points” that are easier to map onto formulation records, stability lots, and IV preparation SOPs during litigation discovery.

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How does independent claim 34 expand coverage to lyophilized solids and reconstitution/dilution steps?

Claim 34 changes the formulation workflow:

• Reconstitute a water-soluble solid composition in a pharmaceutically acceptable diluent to form a first solution.
• Dilute the reconstituted solution with a diluent to form a second solution.
• Administer the second solution IV as a therapeutically effective amount.

Composition is defined as:

• water-soluble solid contains:
  • a 7-dimethylamino-tetracycline antibiotic (or salt thereof), and
  • a salt comprising a divalent or trivalent metal cation
• final second solution has:
  • metal-to-antibiotic molar ratio >3:1
  • pH >4 and <7
  • osmolality <500 mOsmol/kg

Dependent claim 38 specifies the solid is a lyophile (lyophilized form).

Dependent claim 43 enumerates metal cation salts:

• magnesium chloride, magnesium bromide, magnesium sulfate, calcium chloride, calcium bromide, zinc chloride, gallium chloride, magnesium malate, magnesium citrate, magnesium acetate, zinc acetate.

Claim 44 adds excipient absence restrictions for the water-soluble solid:

• does not comprise antioxidant, pyridine-containing compound, nicotinamide, or gluconate.

Claim 39–42 further narrow metal identity and include:

• magnesium sulfate (39)
• calcium chloride (40)
• sodium acetate (41)
• NaOH (42)

Claim 45–48 provide antibiotic selection dependencies mirroring claim 1:

• minocycline, PTK796, and glycylcycline (tigecycline).

Key distinction vs claim 1: claim 34 is designed to cover a broader supply-chain configuration (solid-to-solution workflow) while maintaining the same physicochemical constraints on the administered second solution.

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What does the claim set imply about patent “coverage zones” for Mg ratio design-around and excipient substitutions?

Design-around lever 1: move Mg ratio outside the claimed bands

Because the core claim is >3:1 and dependent claims expand to ≥5:1, >8:1, ≥10:1, the easiest literal-avoidance is to formulate so the final solution has Mg2+/antibiotic ≤3:1 (or to use a metal salt identity not covered by a specific claim tier), or to avoid a specified ratio band such as 5:1 to 10:1 where that dependent claim is asserted.

Design-around lever 2: adjust pH and osmolality

• If the final solution pH is moved to ≤4 or ≥7, it falls outside claim 1’s core pH requirement.
• If osmolality is tuned to be ≥500 mOsm/kg, it breaks the osmolality requirement.
• The dependent pH cutoffs (pH <5 or <6) provide additional ways to avoid specific narrowing dependent claims.

Design-around lever 3: excipient category exclusions

Claim 2–3 and claim 44 target formulation ingredient categories. If a competitor uses an excluded ingredient class (antioxidants, gluconate, certain solubilizers, alcohol/glycerol/PEG, pyrrolidones, urea, lactose, specific dehydrating agents), the literal “does not comprise” condition is not met, blocking those claims.

Design-around lever 4: avoid the “second solution” preparation format

If a competitor uses a direct liquid drug product rather than a water-soluble solid that is reconstituted then diluted, claim 34’s workflow may be avoided. That said, claim 1 can still read on the administered solution if its composition matches the aqueous Mg ratio/pH/osmolality and excipient absences.

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Which claim elements are most likely to be litigated: measurable physicochemical cutoffs or formulation ingredient lists?

The most litigated elements are those that can be tied to:

• analytical measurements (pH, osmolality)
• compositional assays (metal salt identity, concentration, molar ratio)
• formulation “presence/absence” (does not comprise excluded excipients)

Specific numeric cutoffs:

• 3:1 Mg ratio

• <500 mOsm/kg (and subcuts <400, <350)
• pH >4 and <7 (and <6; <5)
• dose volume ceilings

These become direct exhibits in infringement analysis because they can be measured from:

• finalized drug product and stability formulations
• compounding/reconstitution SOPs and validation reports
• internal formulation development datasets and batch records (for solid-to-solution processes, claim 34)

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How would a U.S. generic or IV branded competitor face Orange Book and Paragraph IV risk for this patent?

The claim set is a method-of-treatment and preparation/administration patent with a strong formulation footprint. In U.S. practice, the risk profile for a generic is driven by:

• whether the patent is listed in the Orange Book for a specific NDA/ANDA product
• whether the generic’s proposed label and intended use are aligned with “method of treating a bacterial infection”
• whether the generic’s IV formulation matches the claimed physicochemical envelope and excipient absence restrictions

If the patent is Orange Book-listed for the relevant antibiotic product, a Paragraph IV notice would typically target that listing; infringement then turns on product composition and method-of-use mapping.

Operational point: even when an ANDA is for the active drug, infringement can arise due to differences in formulation/excipient set and metal salt chemistry used to achieve IV stability and solubility.

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How strong is the patent estate for this technology space (what makes the claims enforceable vs easy to avoid)?

Strength factors (high enforceability)

• Numeric physicochemical constraints that can be measured.
• Metal-to-antibiotic ratio that narrows the formulation.
• Explicit excipient exclusions that create binary tests.
• Specific antibiotic coverage (minocycline, tigecycline) and explicit metal salt examples (MgSO4, MgCl2, acetate, NaOH).

Avoidance pathways (lower enforceability if competitors redesign)

• Many IV formulations can adjust pH/osmolality and metal ratio with formulation development.
• The excipient “does not comprise” lists provide clear carve-outs, though competitors must replace those functional roles.
• The claim 34 workflow can be avoided with alternate drug product formats (if a competitor does not use a water-soluble solid reconstitution/dilution pipeline), though claim 1 remains a fallback.

Net: the estate is strongest against close formulation copies and against “same chemistry” IV presentations that keep pH/osmolality and metal ratio targets for solubility/stability.

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Key takeaways

• US Patent 9,278,105 is built around an IV formulation and administration method for 7-dimethylamino-tetracyclines using high metal (Mg) molar ratios and tight pH/osmolality limits, plus explicit excipient exclusions.
• Claim 1 covers aqueous IV administration with Mg2+/antibiotic >3:1 and pH >4 and <7 and osmolality <500 mOsm/kg, excluding multiple solubilizers/additives.
• Claim 34 covers a reconstitution then dilution workflow from a water-soluble solid (including lyophilized forms), with the same physicochemical limits on the final administered second solution, and expanded metal cation identities.
• Patent risk concentrates on competitors whose IV formulations match:
  • Mg2+/antibiotic ratio (including ≥5:1 and ≥10:1 tiers),
  • pH (including dependent <6 and <5 tiers),
  • osmolality (<400, <350 tiers),
  • and excipient “does not comprise” exclusions.

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FAQs

1. Can a competitor avoid US 9,278,105 by switching from magnesium sulfate to magnesium chloride?
   Literal avoidance depends on which dependent claims are asserted; both MgSO4 and MgCl2 are explicitly contemplated in example-like dependent claims, but changing salt alone may not avoid claim 1 or 34 if the metal-to-antibiotic ratio, pH, osmolality, and excipient exclusions still match.

2. If a formulation uses Mg2+/antibiotic >3:1 but pH is 7.0, does it still infringe?
   No literal coverage under claim 1’s core pH requirement if the pH is not “less than 7” (and dependent claims may further narrow pH bands).

3. Does claim 34 require the solid to be lyophilized?
   No. Lyophile is a dependent limitation (claim 38). Claim 34 covers water-soluble solid generally, with the lyophilized constraint only attaching when asserted with claim 38.

4. Can excipient substitution defeat infringement despite matching Mg ratio and pH/osmolality?
   Yes. The claims contain multiple “does not comprise” limitations for antioxidants, pyridine compounds, gluconate, alcohol/glycerol/PEG, pyrrolidones, urea, lactose, and specific dehydrating agents.

5. What is the most direct analytical test to assess infringement risk?
   Measuring the final administered solution’s (i) molar ratio of divalent/trivalent metal to antibiotic, (ii) pH, (iii) osmolality, and verifying the presence/absence of excluded excipients.

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References (APA)

1. US Patent 9,278,105. United States Patent and Trademark Office.

Drugs Protected by US Patent 9,278,105

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Rempex	MINOCIN	minocycline hydrochloride	INJECTABLE;INJECTION	050444-001	Approved Prior to Jan 1, 1982		RX	Yes	Yes						METHOD OF TREATING BACTERIAL INFECTIONS

International Family Members for US Patent 9,278,105

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2011252919
Brazil	112012028524
Canada	2799079
Chile	2012003168
China	102970992
Colombia	6650346
Denmark	2568987