Patent: 10,576,160

Summary for Patent: 10,576,160

Title:	Nucleophilic catalysts for oxime linkage
Abstract:	The invention relates to materials and methods of conjugating a water soluble polymer to an oxidized carbohydrate moiety of a therapeutic protein comprising contacting the oxidized carbohydrate moiety with an activated water soluble polymer under conditions that allow conjugation. More specifically, the present invention relates to the aforementioned materials and methods wherein the water soluble polymer contains an active aminooxy group and wherein an oxime or hydrazone linkage is formed between the oxidized carbohydrate moiety and the active aminooxy group on the water soluble polymer, and wherein the conjugation is carried out in the presence of a nucleophilic catalyst.
Inventor(s):	Siekmann; Juergen (Vienna, AT), Haider; Stefan (Prinzersdorf, AT), Rottensteiner; Hanspeter (Vienna, AT), Turecek; Peter (Klosterneuburg, AT)
Assignee:	Baxalta Incorporated (Bannockburn, IL) Baxalta GmbH (Zug, CH)
Application Number:	15/644,129
Patent Claims:	see list of patent claims

Executive summary: U.S. Patent 10,576,160 is an oxidation-then-conjugation process patent centered on (i) oxidizing carbohydrate residues on a therapeutic protein (typically FVIII and FIX family members) using NaIO4 or Pb(OAc)4, (ii) preparing an “activated” PSA bearing an aminooxy reactive group by oxime-formation with an aminooxy linker using an oxidized PSA substrate, and (iii) executing oxime ligation between the oxidized carbohydrate and the aminooxy-PSA under catalytic m-toluidine. Claims 1 and 14 are the core independent method claims; dependent claims then narrow to specific time-temperature-light-stirring windows, specific PSA aminooxy linkers (3-oxa-pentane-1,5-dioxyamine; 3,6,9-trioxa-undecane-1,11-dioxyamine; 3,6,9,12,15-pentaoxa-heptadecane-1,17-dioxyamine), purification mode (anion exchange chromatography), and a detailed FVIII/FIX-oriented operational recipe. The patent’s scope is broad on “therapeutic protein” selection but operationally tight on the chemistry and catalysis package: activated aminooxy PSA + oxidized carbohydrate + oxime linkage + m-toluidine-catalyzed conjugation + specified low-temperature handling and defined purification/oxidation variables. A key licensing or freedom-to-operate (FTO) pivot is whether a competitor uses an oxime-forming catalyst other than m-toluidine, avoids PSA with an active aminooxy group prepared via the claimed oxime-on-PSA activation step, changes the oxidant away from NaIO4/Pb(OAc)4, or uses alternative oxime ligation stopping/quenching chemistry or purification routes.

U.S. Patent 10,576,160 claim scope: oxime-connecting PSA to oxidized therapeutic protein carbohydrates with m-toluidine?

The patent’s claims are process-chemistry methods, not product claims. Claim 1 (broad platform) and claim 14 (FVIII-specific variant) both require the same chemical identity core: an oxime linkage formed between an oxidized carbohydrate moiety on a therapeutic protein and an “activated” PSA containing an aminooxy group, with m-toluidine catalyzing oxime linkage formation.

What is actually claimed in method steps?

Claim 1 structural logic

1. Activate PSA: incubate oxidized PSA with an aminooxy linker that contains an active aminooxy group to form a stable oxime linkage between oxidized PSA and the activated aminooxy linker; incubation conditions are time 1 min to 24 h and temperature 2°C to 10°C with or without light and stirring.
2. Purify activated PSA: purification by chromatography, filtration, dialysis, precipitation, or combinations at 2°C to 8°C.
3. Oxidize therapeutic-protein carbohydrate: oxidize carbohydrate moiety using a buffer with oxidizing agent NaIO4 or Pb(OAc)4.
4. Conjugate by oxime ligation: contact the oxidized carbohydrate moiety with the activated aminooxy-PSA under conditions allowing conjugation; oxime linkage formation is catalyzed by m-toluidine.

Claim 14 structural logic is the same chemistry pack as Claim 1, but explicitly sets therapeutic protein = FVIII and oxidant = NaIO4, while retaining m-toluidine catalysis.

Where the claim boundaries sit (chemical “gotchas”)

• The claim requires PSA is “containing an active aminooxy group” prepared by a specific oxime linkage formation on PSA via oxidation of PSA followed by aminooxy-linker oxime formation.
• Oxime formation on the therapeutic protein side requires oxidized carbohydrate moiety prepared with NaIO4 or Pb(OAc)4.
• m-toluidine is a required catalyst for oxime linkage formation (not merely optional).

If any one of these elements is missing, a literal infringement argument weakens because the independent claims are conjunctive.

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What do claims 1 and 14 require, element-by-element, for infringement?

Below is an element map for Claim 1 and Claim 14, translated into a practical infringement checklist.

Claim 1: element checklist

1. A method of conjugating PSA containing an active aminooxy group to an oxidized carbohydrate moiety of a therapeutic protein.
2. Oxidized carbohydrate moiety is generated by incubating with buffer containing NaIO4 or Pb(OAc)4.
3. Activated PSA is generated by:
   • incubating an oxidized PSA with an aminooxy linker having an active aminooxy group to form a stable oxime linkage between oxidized PSA and the aminooxy linker,
   • incubation time 1 min to 24 h,
   • temperature 2°C to 10°C,
   • with/without light; with/without stirring.
4. Purify activated PSA by one of: chromatography/filtration/dialysis/precipitation (or combinations) at 2°C to 8°C.
5. Oxime linkage between oxidized carbohydrate and aminooxy-PSA is formed.
6. m-toluidine catalyzes the oxime linkage formation.

Claim 14: added narrowing but same chemistry core

• Same as Claim 1 with:
  • Therapeutic protein has biological activity of FVIII.
  • Carbohydrate oxidation uses NaIO4 (not Pb(OAc)4).
• m-toluidine catalysis remains required.

How broad is “therapeutic protein” under the claims?

Claim 5 lists a very large class (coagulation factors, cytokines, growth factors, interferons, antibodies and fragments, enzymes, hormones, binding proteins, etc.), plus a “protein in Table 1” catch-all. This broad listing makes the platform claim potentially cover many PSA-conjugated biologics, but infringement still hinges on whether the accused process includes the specified oxime-PSA activation and m-toluidine-catalyzed oxime ligation sequence.

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How strong is the patent estate for oxime-based PSA conjugation under U.S. Patent 10,576,160?

High-level strength drivers

• The independent claims are chemistry-specific and include a required catalyst (m-toluidine).
• They also specify how activated aminooxy PSA is made (oxime linkage between oxidized PSA and aminooxy linker under low temperature and defined time range) and how it is purified (low temperature 2°C-8°C, purification method categories).
• The oxidation chemistry is specified (NaIO4 or Pb(OAc)4).
• Dependent claims then narrow to particular operational recipes (4°C for 1 hour, anion exchange chromatography at 4°C, oxidation with NaIO4, defined linkers and aminooxy linker structures).

Primary vulnerability drivers

• The claim includes a “method comprising contacting… under conditions that allow conjugation” formulation. If a competitor uses substantially the same chemical steps but changes certain operational parameters that fall outside dependent claim ranges, they may still be within independent claim scope if those parameters are not limiting.
• The dependent claims include broad ranges in several places (times from minutes to hours; temps from 2°C to 37°C in some dependent method recipes). This reduces the practical value of the narrower dependent claims as design-around levers.

In practice, the strongest separation strategy is catalyst and chemistry identity, not minor temperature/time changes.

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Which aspects are most likely to be targeted in Paragraph IV generic-or-biosimilar style challenges?

This patent is process-based for PSA conjugation. Traditional Paragraph IV (small molecules/generics) frameworks do not map cleanly, but the same strategic logic applies: design a pathway to market while avoiding infringement of manufacturing or conjugation claims.

Most plausible “avoidance” points for competitors

1. Catalyst switch: Use an oxime-forming catalyst other than m-toluidine (or run the process without any catalyst arguably within the claim).
2. Different PSA activation scheme: Use a PSA bearing aminooxy functionality via a different synthetic route that does not meet the claimed “incubating oxidized PSA with aminooxy linker under conditions forming a stable oxime linkage between oxidized PSA and aminooxy linker” step.
3. Different carbohydrate oxidant: Use periodic-acid analogs or other oxidation systems that do not fall under NaIO4 or Pb(OAc)4.
4. Different oxime ligation target chemistry: Use hydrazone formation, different electrophile formation, or different conjugation linkages altogether. (Even if the final linkage is “oxime,” the claim requires specific catalyst and process architecture.)
5. Purification conditions/sequence: Claim 1 requires purification at 2°C-8°C using one of the listed methods. A process purifying activated PSA outside these temperature limits may be a non-literal avoidance.

Where dependent claims matter

Dependent claims 2, 3, 4, 8, 15 specify concrete “recipe” conditions that may be easier for challengers to argue are not met. But those dependent claims only matter if the independent claim is already met; the major infringement pivot remains independent claim chemistry and m-toluidine catalysis.

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What formulations are protected by this patent: PSA-Protein conjugates for FVIII/FIX and beyond?

The patent protects the conjugation process, not a formulation composition like a sterile liquid or freeze-dried powder.

What “drug product” types are indirectly covered?

• PSA-conjugated biologics (glycoproteins, enzymes, antibodies/fragments) where carbohydrate residues are oxidized and conjugated through an oxime linkage to PSA carrying an aminooxy group.
• The claim is method-based, so the product is evidence of process, but claim text does not require a particular final dosage form.

How the claim text links to common PSA platforms

The specified chemistry aligns with known PSA conjugation strategies:

• oxidize carbohydrates (NaIO4 or lead tetraacetate),
• form an oxime bond via aminooxy functionality,
• stabilize the PSA activation step with an oxime between PSA and an aminooxy linker,
• catalyze oxime formation with an amine catalyst (m-toluidine explicitly required).

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What patents likely overlap or compete with U.S. Patent 10,576,160 in the PSA-oxime conjugation space?

This question requires cross-referencing the patent’s bibliographic metadata (filing date, assignee, related family members, and patent citations). That information is not included in the prompt. Without at least the assignee and priority data, a complete overlap map across the U.S. patent landscape cannot be produced accurately, and a risk-graded answer would be incomplete.

No further landscape conclusions are provided.

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What is the Orange Book status of U.S. Patent 10,576,160 and does it govern market exclusivity?

A process patent for conjugation does not map automatically to Orange Book listings (which are tied to approved drug applications for small molecules with patents listed in Orange Book). No indication is given here of a specific FDA application, listed NDA/BLA, or Orange Book entry tying this patent to a specific product.

No Orange Book status analysis is provided.

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What generic entry risks exist for PSA-conjugated biologics tied to this patent?

The question depends on identifying the relevant approved product(s) that use the conjugation chemistry covered by this patent, then mapping exclusivities and potential biosimilar pathways. The prompt provides no linked product name, BLA/NDA, marketing authorization, or regulatory pathway status.

No generic-entry risk quantification is provided.

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How does U.S. Patent 10,576,160 compare with other oxime-linked carbohydrate conjugation patents?

A meaningful comparison requires identifying competitor patents (and their claim elements), typically through citation analysis and claim charting against known oxime bioconjugation IP. Without the patent’s assignee and citation network, a reliable comparison cannot be completed.

No comparative patent analysis is provided.

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Key claim submodules: PSA aminooxy linker structures and why they matter for design-around

Dependent claim 12 lists PSA aminooxy linkers with explicit polyether dioxyamine structures:

• 3-oxa-pentane-1,5-dioxyamine
• 3,6,9-trioxa-undecane-1,11-dioxyamine
• 3,6,9,12,15-pentaoxa-heptadecane-1,17-dioxyamine

The claim further ties these to a PSA oxidized to form a terminal aldehyde group at the non-reducing end of the PSA.

Practical implication

Even if a competitor uses an aminooxy-PSA, they can seek non-infringement by:

• using a different aminooxy linker chemistry not matching these listed structures (though Claim 1 does not limit to these linkers; it only requires “an aminooxy linker comprising an active aminooxy group,” so linker substitution alone may not avoid Claim 1),
• altering PSA oxidation end-group formation away from the “terminal aldehyde group at the non-reducing end” concept (again, this may or may not be limiting depending on how “oxidized PSA” is interpreted under claim construction).

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Detailed operational recipe in dependent claims 7 and 8: what would an accused process likely match?

These dependent claims provide a quasi-standard operating window. They are likely to capture real-world manufacturing runs if the patent arose from a specific process.

Claim 7 (multi-step with quenching)

• Step 1 pH adjust of therapeutic protein solution to 5.0-8.0.
• Step 2 oxidation with oxidant to final 10 µM to 1000 µM; 0.1 min to 5 h; 2°C to 37°C.
• Step 3 contact with activated PSA excess 1-fold to 300-fold molar excess; 0.5 h to 24 h; 2°C to 37°C.
• Step 4 add nucleophilic catalyst 1 mM to 50 mM; 0.1 min to 30 min; 2°C to 37°C.
• Step 5 conjugation 0.5 h to 24 h; 2°C to 37°C.
• Step 6 quench with one of specified agents to 1 mM to 100 mM; 5 min to 120 min; 2°C to 37°C.

Claim 8 (specific example with 22°C and defined concentrations)

• FVIII-family functional recipe with:
  • pH 6.0 at ~1 mg/mL protein,
  • oxidant NaIO4 to ~400 µM, 10 min at 22°C, no light, stirring,
  • PSA ~50-fold molar excess, 15 min at 22°C, no light, stirring,
  • m-toluidine to 10 mM, 15 min at 22°C, no light, stirring,
  • conjugation 2 h at 22°C, no light, stirring,
  • quench with L-cysteine to 10 mM for 60 min at 22°C, no light, stirring.

Why claim 8 is commercially relevant

It locks in:

• m-toluidine identity (as the nucleophilic catalyst),
• NaIO4 as the carbohydrate oxidant,
• L-cysteine quench,
• and specific concentration and timepoints.

A manufacturing deviation that keeps the same catalyst identity but changes one concentration/time may still fall under independent claim 1 if those parameters are not limiting there.

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Timeline and expiration analysis for U.S. Patent 10,576,160

A full expiration timeline requires the patent’s filing date, priority date, and whether any PTA (patent term adjustment) or terminal disclaimers apply. None of those bibliographic fields are present in the prompt. A quantified expiration and exclusivity timeline cannot be produced accurately.

No timeline analysis is provided.

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Key Takeaways

• U.S. Patent 10,576,160 is anchored on oxime-based PSA bioconjugation where m-toluidine catalyzes oxime bond formation between an oxidized carbohydrate moiety (from NaIO4 or Pb(OAc)4) and activated PSA bearing an aminooxy group.
• The independent claims require both:
  1. an activated PSA preparation step that forms a stable oxime linkage between oxidized PSA and an aminooxy linker at 2°C-10°C, and
  2. m-toluidine-catalyzed oxime ligation to the oxidized therapeutic-protein carbohydrate.
• Dependent claims strengthen patent coverage around specific operational “recipes,” including FVIII-focused embodiments (claim 14 and claim 15) and concrete processing parameters (claims 2, 3, 8).
• For competitive design-around, the most meaningful levers are catalyst identity (m-toluidine), oxidant identity (NaIO4/Pb(OAc)4), and whether activated aminooxy PSA is made via the claimed PSA-oxime activation sequence.

FAQs

1. If a competitor uses an aminooxy-PSA but omits m-toluidine, does this patent still apply?
   The independent claims require m-toluidine catalysis of oxime linkage formation.

2. Does using NaIO4 instead of Pb(OAc)4 automatically keep all claims in play?
   Claim 1 allows either NaIO4 or Pb(OAc)4, while claim 14 and the FVIII recipe depend on NaIO4.

3. Can purification method changes avoid infringement?
   Claim 1 limits purification temperature (2°C-8°C) and method categories; moving outside those constraints is an FTO lever.

4. Are the listed PSA aminooxy linkers the only allowable ones under the broadest independent claim?
   Claim 12 limits certain embodiments, but Claim 1 requires only an aminooxy linker with an active aminooxy group, not specifically those three.

5. Do quenching agents matter if the conjugation chemistry matches the independent claims?
   Quenching details appear in dependent claims; the independent claims still hinge on oxime formation mechanics and m-toluidine catalysis.

References

1. U.S. Patent 10,576,160 (claims provided in prompt).

Details for Patent 10,576,160

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	January 15, 1974	10,576,160	2037-07-07
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	December 27, 1984	10,576,160	2037-07-07
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 15, 1985	10,576,160	2037-07-07
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 16, 1990	10,576,160	2037-07-07
Bel-mar Laboratories, Inc.	CHORIONIC GONADOTROPIN	chorionic gonadotropin	Injection	017054	March 26, 1974	10,576,160	2037-07-07