Patent: 10,717,958

Summary for Patent: 10,717,958

Title:	Method for producing a product (e.g. polypeptide) in a continuous cell culture fermentation process
Abstract:	A method for improving productivity in microbial fermentations and mammalian cell culture bioreactors.
Inventor(s):	Laustsen; Mads (Gentofte, DK)
Assignee:	CMC BIOLOGICS A/S (Soborg, DK)
Application Number:	16/400,201
Patent Claims:	see list of patent claims

United States Patent 10,717,958 Landscape Analysis: Chemostat Series Bioreactors, In-Line Separation, and High Cell Density Production Claims

Executive summary: U.S. Patent 10,717,958 claims a chemostat fermentation workflow using two bioreactors in series: a growth bioreactor and an induction/production bioreactor, with in-process impurity removal via separation devices and parallel harvesting modules to remove product, impurities, and medium while replenishing medium. The claims are heavily process- and apparatus-structured (multiple outlets/inlets, specific flow-rate relationships, and membrane cutoff parameters) and include a high cell density constraint (≥5 million cells/mL, with dependent claim narrowing to ≥10 million cells/mL). The claim set also broadly recites product class (biopolymers and biologics, including antibodies, growth factors, enzymes, and cytokines), which materially affects infringement scope and invalidity risk because the core novelty appears anchored in bioreactor architecture + chemostat operation + in-line purification/havesting logic, not in product identity.

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What is US Patent 10,717,958 claiming in a chemostat bioreactor series system?

Core independent claim (Claim 1) in plain technical structure: The method produces a product selected from:

• Biopolymer expressed by a cell/microorganism
• Intracellular product
• Extracellular product
• Periplasmatic product

using a chemostat fermentation process with two bioreactors in series:

First bioreactor (growth)

• (i) Optional first outlet: impurity/medium removal using a separation device that removes impurities below product size, while retaining product
• (ii) Second outlet: a product harvest module removing product + impurities + medium
• (iii) Inlet: medium addition (nutrient replenishment + equilibrating removed medium)

Second bioreactor (induction/production)

• (iv) Third outlet: separation device removing impurities below product size and medium while retaining product
• (v) Fourth outlet: product harvest module removing product + impurities + medium
• (vi) Inlet: medium addition
• (vii) Inlet for cells/microorganisms + medium from first bioreactor (series operation)

Process steps

• (a) Grow (and optionally ferment) expression/production cells in first bioreactor in suitable medium and conditions, with:
  • impurity and medium removal via separation device
  • harvest via product harvest module
  • new medium added to replenish nutrients and equilibrate the removed fraction
• (b) Transport the harvested fraction (product/impurities/medium) to the second bioreactor, which already contains cells grown in the first bioreactor, then:
  • induction of production in second bioreactor
  • continue impurity removal (separation device) and product/impurity/medium harvesting (harvest module)
  • add new medium to replenish nutrients and equilibrate removed fraction
• (c) Isolate product from harvested medium
• High cell density limitation: cell density reaches ≥5 million cells per mL medium during fermentation

Claim architecture implication: The independent claim reads like a combined fermentation + continuous clarification/harvest scheme. It is not merely “chemostat fermentation.” It demands (1) two reactors in series, (2) outlet-by-outlet functional separation and harvesting, and (3) a specific mass-balance logic (nutrient replenishment + equilibration after removal).

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Which dependent claims materially narrow scope (cell density, volume, and flow-rate ratios)?

High cell density

• Claim 1: ≥5 million cells/mL
• Claim 10: ≥10 million cells/mL

Risk/strength lever: Cell density thresholds are objective, but also operationally common in modern bioprocessing. The limiting issue is whether competitors’ chemostat/continuous systems hit those thresholds under claim conditions.

Bioreactor size

• Claim 11: each bioreactor has volume of at least 50 L

Infringement effect: This narrows to commercial-scale continuous systems.

Flow-rate relationship (strong specificity)

• Claim 12: second bioreactor impurity separation occurs at a first flow rate; harvest at a second flow rate
• ratio first flow rate : second flow rate = 1:1 to 9:1

Infringement effect: This is a measurable process parameter that can be tested and modeled. It also restricts design-around strategies: swapping split ratios or changing operational fractions may avoid the literal ratio requirement.

Separation device options (moderate breadth with specific technical sub-variants)

• Claim 13: separation device in second bioreactor can be:
  • impurity filter unit, or
  • gravitational separation, or
  • centrifugal separation
• Claim 14–17: membrane filter variants
  • Claim 14: membrane filter
  • Claim 15: nominal MW cutoff (NMWC) of at least 1000 NMWC
  • Claim 16: NMWC pore size 2,000–15,000 NMWC
  • Claim 17: NMWC pore size ≤ 80% of product MW

Design-around lever: Membrane selection and cutoff selection can be a clear non-infringement route if the device does not meet the NMWC constraints, or if separation is implemented via a different mechanism not encompassed by the claim terms.

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What patents protect the concept of two chemostats in series with in-line separation and harvest?

Critical point: You provided only the claim set text, not the patent’s bibliographic data (assignee, filing date, priority, or jurisdictional family) or the specification’s described novelty. Without that, the landscape cannot be completed without risking incorrect identification of:

• priority/filing timing,
• claim interpretation anchors,
• and the real “closest prior art” categories used during prosecution.

Given the constraint, the only defensible analysis is claim-driven. The landscape likely clusters around four prior-art buckets relevant to a validity challenge:

1. Chemostat fermentation with continuous medium feed and product/biomass withdrawal
2. Two-stage (growth then induction) bioreactor processing, including fed-batch or continuous induction models
3. In-line or at-line clarification/separation using membranes/centrifugation to remove impurities smaller than product
4. Continuous or semi-continuous downstream harvesting logic in a bioreactor loop

However, producing a numbered list of specific earlier U.S. patents, with claims and dates, would require the actual patent’s assignee and priority to avoid fabricating a landscape.

No complete and accurate landscape can be produced from the provided inputs.

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How broad is the claim coverage across biologics, antibodies, and enzymes?

Claim 5 enumerates a wide range of proteins and biologics (examples include EPO, G-CSF, insulin, Tenecteplase, interferons, coagulation factors, and multiple monoclonal antibodies such as Trastuzumab, Infliximab, Rituximab). The claim text also includes “biopolymer is a polypeptide or protein” (Claim 4) and supports products expressed by a range of cells and microorganisms (Claim 3).

Coverage effect:

• The claim is product-agnostic in the independent claim except for the broad “biopolymer/intracellular/extracellular/periplasmatic” categories.
• Dependent claims then sweep in specific production hosts (E. coli, Bacillus, yeast, filamentous fungi, mammalian cell lines, hybridomas) and specific protein classes.

Infringement implication: A competitor using the same process architecture for any qualifying protein class risks falling within the claim if they also satisfy the chemostat + series two-reactor + separation/harvest + cell density constraints.

Validity implication: Breadth across product types can increase invalidity risk if prior art discloses the same process for any protein product class. But novelty likely rests on the process architecture and separation/harvest scheme, not on protein identity.

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What would an infringement analysis hinge on for a competitor using continuous processing?

Claim 1 infringement hinges on all of the following conjunctive elements:

1. Chemostat fermentation process (continuous feed/removal logic)
2. Two bioreactors in series:
   • first for growth
   • second for induction/production
3. Outlet/inlet structure:
   • optional separation outlet in first bioreactor
   • harvest module outlet in first bioreactor
   • separation outlet + harvest module + medium inlet in second bioreactor
   • inlet transferring cells/microorganisms + medium from first to second
4. Functional separation logic:
   • separation device retains product while removing impurities with size below product
5. Harshest “mass balance” elements:
   • impurity removal during production and during growth
   • product/impurity/medium harvested via harvest module
   • new medium added to replenish nutrients and equilibrate removal
6. Cell density threshold: ≥5 million cells/mL

Dependent claim 12 adds:

• quantifiable flow split ratio (1:1 to 9:1) between the separation and harvest modules in the second bioreactor.

Dependent claim 14–17 add membrane/cutoff constraints:

• NMWC and cutoff relative to product MW.

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When does the patent lose exclusivity under U.S. patent term rules?

Not answerable from the provided inputs. Patent term end dates require:

• filing date,
• earliest effective non-provisional priority date,
• provisional status,
• and any PTA/PTA caps.

Without the patent’s bibliographic record, giving a “loss of exclusivity” date would be error-prone.

No complete and accurate response can be produced.

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What is the Orange Book status of US Patent 10,717,958?

Not determinable from the provided inputs. Orange Book status requires the listed FDA application(s), dosage form, and the specific listed patents for a given product.

No complete and accurate response can be produced.

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What Paragraph IV, generic entry, or biosimilar challenges should be monitored for this patent?

Not determinable from the provided inputs. A Paragraph IV or biosimilar challenge requires:

• identifying the tied reference product(s),
• matching Orange Book patent listings or BLA/RLD patent listings,
• and then cross-referencing litigation dockets.

Your input does not include:

• the assignee or the technology owner,
• the relevant RLD(s),
• FDA application numbers,
• or any litigation caption.

No complete and accurate response can be produced.

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How does US Patent 10,717,958 compare with typical bioprocess patents (upstream-only vs integrated continuous processing)?

Claim-driven comparison:

Where this claim is different

Most bioprocess patents focus on one slice:

• upstream continuous cultivation mechanics, or
• downstream purification/filtration chemistry, or
• a two-stage expression system concept.

Here, Claim 1 requires a connected loop inside the system:

• impurity separation and harvest modules are described at outlet level in each bioreactor,
• the chemostat logic is applied both during growth and during induction,
• the system includes a specific cell transfer inlet from reactor 1 to reactor 2,
• and the method includes nutrient replenishment and equilibration tied to the removal steps.

Where claim breadth still exists

Claim 1 does not limit:

• to a specific expression system (other than “cells/microorganisms” broadly),
• to specific induction triggers beyond “induction of production,”
• to specific product classes beyond the broad biopolymer/product category,
• to a specific purification downstream method beyond “isolate product from harvested medium.”

Net effect: It is an upstream-focused integrated continuous processing claim, with product breadth that could matter for infringement but less for validity if the core novelty lies in system architecture.

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Key Takeaways

• U.S. Patent 10,717,958 is built around two bioreactors in series operating in a chemostat mode, with in-process impurity separation and harvest module removal, plus medium replenishment and equilibration.
• The claim is structurally detailed and conjunctive, with a key commercial limiter of cell density ≥5 million cells/mL and a scale limiter of ≥50 L per bioreactor (dependent claim).
• The strongest narrowing elements for infringement analysis are:
  • flow-rate ratio in the second bioreactor (Claim 12), and
  • membrane NMWC and cutoff constraints relative to product MW (Claims 14–17).
• The breadth of dependent claims across hosts and biologic protein types increases the potential infringement surface for any qualifying continuous chemostat system meeting the process constraints.
• Exclusivity timing, Orange Book status, and litigation/Paragraph IV/biosimilar risk cannot be determined from the provided information.

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FAQs

1) Does US 10,717,958 require a specific induction chemical or only “induction of production”?

The independent claim recites “induction of production” without specifying the inducer, so the requirement is functional unless narrowed by the specification.

2) Can a competitor avoid infringement by using only centrifugation instead of membrane separation?

Claim 13 permits gravitational or centrifugal separation in the second bioreactor; avoiding infringement is therefore less about the separation mechanism category and more about meeting or failing the exact outlet/inlet and functional/quantitative requirements of the claims.

3) What is the practical evidentiary hook for proving infringement of the flow-rate ratio (Claim 12)?

The relevant operational variables are the “first flow rate” through the separation device and the “second flow rate” through the harvest module, with the ratio required to fall within 1:1 to 9:1.

4) Do the dependent claims tie the membrane cutoff to the product molecular weight?

Yes. Claim 17 limits the membrane cutoff such that the NMWC pore size is a maximum of 80% of the MW of the product (as recited).

5) Are extracellular vs intracellular products treated differently in Claim 1?

Claim 1 covers intracellular, extracellular, and periplasmatic products in the same overall chemostat-series architecture, without requiring different separation logic by product location.

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References

1. (No sources cited. The input includes only the claim text and does not include patent bibliographic data, prosecution history, or any prior-art or litigation references.)

Details for Patent 10,717,958

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	KOATE, KOATE-DVI	antihemophilic factor (human)	For Injection	101130	January 24, 1974		2039-05-01
Takeda Pharmaceuticals U.s.a., Inc.	HEMOFIL M	antihemophilic factor (human)	For Injection	101448	March 14, 2001		2039-05-01
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	November 26, 1997		2039-05-01
Hoffmann-la Roche Inc.	ZENAPAX	daclizumab	Injection	103749	December 10, 1997		2039-05-01