Patent: 9,175,068

Summary for Patent: 9,175,068

Title:	Method to produce a highly concentrated immunoglobulin preparation for subcutaneous use
Abstract:	The present invention relates to a new and improved method for preparing a highly concentrated immunoglobulin composition from pooled plasma for subcutaneous injection. A composition comprising 20% or more immunoglobulin suitable for subcutaneous use is also described.
Inventor(s):	Teschner; Wolfgang (Vienna, AT), Butterweck; Harald Arno (Vienna, AT), Pljevljakovic; Azra (Vienna, AT), Bauer; Theresa Friederike (Vienna, AT), Koelbl; Bernhard (Achau, AT), Schwarz; Hans-Peter (Vienna, AT), Nikolic; Nebojsa (Vienna, AT), Poelsler; Gerhard (Vienna, AT), Kindermann; Johanna (Maria Enzersdorf, AT)
Assignee:	Baxalta Incorporated (Bannockburn, IL) Baxalta GmbH (Glattpark (Opfikon), CH)
Application Number:	13/949,565
Patent Claims:	see list of patent claims

What Is the Claim Scope of US 9,175,068 and How Likely Is It to Block Competitors?

US 9,175,068 claims a two-stage ultrafiltration / diafiltration (UF/DF) process to make a concentrated IgG composition with tightly defined process parameters. The core inventive thread is procedural: use a low NMWCO membrane (≤100 kDa) for initial concentration and diafiltration, then perform a second concentration step with the same low NMWCO cutoff in a second UF system having reduced membrane surface area, after a defined post-wash regime, and combine concentrates.

High-level claim architecture

The independent claim (claim 1) is a method with steps that must all be satisfied in order. Claims 2 to 12 are parameter ranges (NMWCO and membrane area ratio). Claims 13 to 24 add an optional second post-wash and pooling step, with dependency tied to the NMWCO selections.

Claim 1 required elements (all must be met):

1. Feed and purity condition: “a first solution comprising IgG” with at least 95% of protein in the first solution being IgG.
2. Stage 1 concentration (UF): Concentrate to 2% to 10% (w/v) IgG using a first UF/DF system with a first ultrafiltration membrane NMWCO ≤ 100 kDa.
3. Stage 1 diafiltration (UF/DF): Diafilter the concentrate against a buffer (still using the first membrane/system) to form first IgG diafiltrate.
4. Stage 1 final concentration (UF): Concentrate diafiltrate to >20% (w/v) using the first membrane to form a second IgG concentrate.
5. Membrane post-wash regime: Wash the first ultrafiltration membrane by re-circulating post-wash buffer volume ≥ 2× dead volume of the first UF system; this yields a first IgG post-wash solution.
6. Transfer into a second UF system with reduced area: Transfer the first IgG post-wash solution into a second UF system with a second membrane NMWCO ≤ 100 kDa where second membrane surface area < first membrane surface area.
7. Second concentration of post-wash: Concentrate the transferred post-wash solution to >20% (w/v) in the second UF system, yielding a third IgG concentrate.
8. Pooling: Combine the third IgG concentrate with the second IgG concentrate to form the final concentrated IgG composition.

Claims 2–4 narrow NMWCO thresholds for both membranes:

• Claim 2: ≤80 kDa
• Claim 3: ≤60 kDa
• Claim 4: ≤50 kDa

Claims 5–8 require same NMWCO across first and second membranes:

• Claim 5: same NMWCO (general)
• Claim 6: same with ≤80 kDa
• Claim 7: same with ≤60 kDa
• Claim 8: same with ≤50 kDa

Claims 9–12 enforce membrane area ratio:

• Claim 9: second membrane surface area ≤ 1/10 of first
• Claim 10: same with ≤80 kDa
• Claim 11: same with ≤60 kDa
• Claim 12: same with ≤50 kDa

Claims 13–24 add a second post-wash for the second membrane:

• Claim 13: adds steps (I) and (J) for washing the second membrane, forming a “second IgG post-wash solution,” and combining it with the final product.
• Claims 14–16: tie that add-on to NMWCO ≤80/≤60/≤50 kDa.
• Claims 17–20: tie that add-on to “same NMWCO” selections.
• Claims 21–24: tie that add-on to the “area ≤ 1/10” selection.

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Where Does the Claim Draw the Line? (Key Limitations That Drive Infringement Risk)

1) The purity gate: “at least 95% of protein is IgG”

This is a material limitation. Many downstream IgG processes handle mixed protein feeds or earlier fractions. If a competitor starts with material below the purity threshold, it can argue non-infringement on claim 1’s explicit condition.

Practical implication: most process development work that starts after protein A may meet purity thresholds, but the claim requires the condition be met for the “first solution” used in step (A). If the competitor uses a different intermediate, it must track whether the “first solution” qualifies.

2) The two UF concentration endpoints: 2%–10% then >20%

The method requires:

• first UF concentration to 2% to 10% (w/v); then
• final concentration to >20% (w/v) after diafiltration;
• then again concentration to >20% (w/v) for the post-wash solution in the second system.

This makes the claim sensitive to:

• whether the first target concentration is within 2%–10%; and
• whether the second-stage post-wash is concentrated beyond 20% (w/v).

3) Membrane cutoff is capped at ≤100 kDa for both membranes

The claim’s novelty does not require a specific brand or material, but it requires:

• NMWCO of the first membrane: ≤100 kDa
• NMWCO of the second membrane: ≤100 kDa
• optional narrower thresholds in dependent claims.

If a competitor uses a membrane with higher nominal cutoff (for instance 300 kDa / 500 kDa), it falls outside claim 1. If it uses ≤100 kDa but different cutoff, it can still fall into dependent claims depending on the exact threshold.

4) The “two-system” + reduced surface area transfer is central

Step (F) and claim 9 onwards are the structural “hook”:

• post-wash solution goes from the first system to a second system with lower membrane area.
• claim 9 quantifies it as “no more than a tenth.”

If a competitor instead performs post-wash in the same membrane module and only then pools, it may avoid the step (F) transfer + second system concentration architecture.

If a competitor uses a second UF system but does not reduce surface area (or reduces it less than required in a dependent claim), it may still infringe claim 1 (surface area merely “lower”), but not claims 9–12.

5) The post-wash requirement is quantitatively defined

Claim 1 requires:

• recirculate post-wash buffer with volume ≥ 2× dead volume of the first UF system.

This is a crisp technical constraint. Competitors who employ lower wash volumes, different wash mechanics, or wash in a way that does not match the defined “volume equal to at least two times the dead volume” could design around.

Claims 13–24 extend this concept to the second membrane, which can increase specificity but also increases the design space for competitors (they may avoid the second wash step altogether).

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How Strong Is the Claim Against Design-Arounds? (Critical Landscape Logic Without Speculation)

Likely high-risk zones

A product developer that:

• uses protein A polish material where IgG is ≥95% of protein,
• runs UF to 2%–10%, then UF/DF diafiltration,
• concentrates to >20%,
• performs a substantial membrane post-wash with ≥2× dead volume,
• then transfers the post-wash filtrate to a second smaller-area UF module with NMWCO ≤100 kDa
• and again concentrates above 20%, then pools

is operating close to the literal boundaries. The claim is drafted to be process-specific enough that “close” behavior can still avoid infringement if any quantitative boundary is missed.

Likely low-risk zones

Design-arounds tend to cluster in three places:

1. Avoid the purity gate
   If “first solution” is a fraction where IgG is less than 95% of protein, literal infringement on claim 1 is harder.

2. Avoid the second system with reduced area Using the same module for post-wash processing can avoid step (F)’s architecture.

3. Avoid the quantitative post-wash regime Using post-wash volumes below 2× dead volume can avoid step (E) as written. Dependent claims add another post-wash on the second system (claims 13–24), giving another possible carve-out: omit or change that second post-wash handling.

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Dependent Claims as a Patchwork of Tightening Constraints

Dependent claims do not change the process order or the core architecture. They tighten:

• Membrane NMWCO: ≤80/≤60/≤50 and “same NMWCO for both”
• Surface area ratio: second membrane ≤1/10 first
• Second post-wash step: adds (I) and (J) to wash and pool additional IgG

This structure matters for enforcement:

• If a competitor practices the core process in claim 1 but uses NMWCO in the 60–100 kDa window, they can still infringe claim 1 but not claims 2–4.
• If they use NMWCO within the selected thresholds but do not reduce membrane area to ≤1/10, they still risk claim 1 but not claim 9–12.
• If they omit second post-wash pooling, they risk claim 1 (and possibly claims 2–12 depending on membrane parameters), but not claims 13–24.

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Enforcement Reality: What Matters in Claim Construction

“Dead volume” and module-specific sizing

Claim 1 references “dead volume of the first ultra-/diafiltration system.” Dead volume is often equipment-defined and may differ with configuration. In practice, disputes can emerge if:

• a process engineer defines dead volume differently, or
• the competitor uses a different system geometry or recirculation path such that the effective volume differs.

Claim language is still equipment-linked and quantitative, so exact compliance is a must for a risk-managed approach.

“At least 95% of protein… is IgG”

This is a test condition. The claim does not state a test method. But a literal infringement analysis will still hinge on analytical confirmation of the IgG fraction in the “first solution.” That moves the analysis from “what was intended” to “what the material actually was.”

Concentrations are in w/v and include strict thresholds

• Step (A): 2% to 10% (w/v)
• Steps (C) and (G): greater than 20% (w/v)

If a competitor concentrates to exactly 20% (w/v) and not greater, it can argue the “greater than” boundary is not met. If it concentrates to 20.5%, it is met. This is straightforward but operationally significant.

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US Patent Landscape: What the Claim Structure Suggests About the Prior Art “Target” (Method-Process Patents)

This patent reads like a targeted refinement of established IgG UF/DF workflows:

• protein A/polish IgG in aqueous buffer,
• UF concentration,
• diafiltration into a final buffer,
• then high-concentration product formulation,
• plus membrane post-wash handling to recover retained IgG and avoid losses,
• with a specific upgrade: process the post-wash with a second, smaller-area UF system.

In such landscapes, prior art typically clusters around:

• UF/DF for mAbs and IgGs,
• tangential flow filtration (TFF) concentration of IgG,
• wash strategies for membrane recovery,
• operational parameters like NMWCO and concentration endpoints,
• staged concentration / pooling approaches.

The claim’s differentiation is the combination of:

• explicit purity requirement (≥95% IgG),
• quantitative wash volume tied to dead volume,
• two-system architecture where the second system has lower membrane area,
• and the combination of high-concentration endpoints (>20% w/v) across stages.

Because the claims are process method claims, not composition claims, they are generally more enforceable when competitors use essentially the same manufacturing logic. If competitors follow a different architecture (for example, single-module post-wash without transfer to a second UF module), this kind of claim can lose reach quickly even if their final product is similar.

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Risk Map for an IgG Manufacturer (How to Spot Literal Match vs. Design-Around)

Literal-match checklist for claim 1

A process likely matches claim 1 if it satisfies all of the following:

• IgG “first solution” has ≥95% of protein as IgG
• Uses UF/DF systems with membrane NMWCO ≤100 kDa for both membranes
• First UF concentrates to 2%–10% (w/v)
• UF/DF diafilters to a “first IgG diafiltrate”
• UF concentrates to >20% (w/v) to produce a “second IgG concentrate”
• Performs a first membrane wash by recirculating post-wash buffer at ≥2× dead volume (first system)
• Transfers that post-wash solution to a second UF system with lower membrane area
• Concentrates transferred post-wash solution to >20% (w/v) to produce “third IgG concentrate”
• Pools third concentrate with second concentrate into final product

Design-around indicators

A competitor’s process is less likely to infringe claim 1 if it breaks any one of these constraints:

• IgG fraction in first solution is <95%
• any membrane uses NMWCO >100 kDa
• post-wash does not use ≥2× dead volume
• post-wash is not processed in a second UF system (or second system area is not “lower”)
• concentration does not exceed >20% (w/v) in the required steps

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Key Takeaways

• US 9,175,068 is a tightly parameterized UF/DF method claim for producing high-concentration IgG using low NMWCO membranes (≤100 kDa) and a two-stage post-wash recovery architecture.
• Claim 1’s enforceable center is procedural: the ≥2× dead volume post-wash plus transfer of post-wash to a second UF system with reduced membrane area, followed by >20% (w/v) concentration and pooling.
• Dependent claims add enforceability “levers” on NMWCO thresholds (≤80/≤60/≤50), same-cutoff pairing, a ≤1/10 membrane area ratio, and an additional second-membrane post-wash pooling step.
• A competitor can reduce infringement exposure by changing one or more quantitative boundaries (IgG purity, NMWCO, post-wash volume, concentration endpoints, or second-system area logic), since the claim is not drafted at a high level of abstraction.

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FAQs

1) Does the patent claim a specific IgG formulation composition?

No. It claims a method for preparing a concentrated IgG composition, with the composition outcome defined by the process steps and pooling, not by specific excipients or antibody specificity.

2) Is the “95% IgG protein” requirement an optional constraint?

No. It is a literal limitation in step (A): the first solution must have at least 95% of protein as IgG.

3) Can a competitor avoid infringement by using a different buffer or excipient?

Buffer selection is not specified in the claim as a critical limiter. The main infringement drivers are membrane NMWCO, concentration targets, post-wash volume vs. dead volume, two-system transfer, and membrane area relationship.

4) What role does the second UF membrane play?

It processes the first IgG post-wash solution in a second UF system with lower membrane surface area, and concentrates it to >20% (w/v) for pooling into the final product.

5) Do dependent claims change the process order?

No. They tighten parameter conditions (NMWCO, membrane area ratio) and add an optional second membrane post-wash pooling step. The core sequence in claim 1 remains the same.

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References

1. United States Patent No. 9,175,068.

Details for Patent 9,175,068

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Takeda Pharmaceuticals U.s.a., Inc.	GAMMAGARD LIQUID	immune globulin infusion (human)	Injection	125105	April 27, 2005		2033-07-24
Octapharma Pharmazeutika Produktionsges.m.b.h.	CUTAQUIG	immune globulin subcutaneous (human)-hipp	Solution	125668	December 12, 2018		2033-07-24

International Patent Family for US Patent 9,175,068

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	2010138736
United States of America	8546548
United States of America	2022153823
United States of America	2019085064