Patent: 10,603,361

Summary for Patent: 10,603,361

Title:	Methods of treating a subject with an alkaline phosphatase deficiency
Abstract:	Disclosed herein are methods for treating a subject with an alkaline phosphatase deficiency, further comprising monitoring additional anaiytes, e.g., calcium, parathyroid hormone and/or vitamin D, with treatment modifications as indicated by the levels, e.g., serum levels, of the additional anaiytes.
Inventor(s):	Odrljin; Tatjana (Brookline, MA)
Assignee:	Alexion Pharmaceuticals, Inc. (Boston, MA)
Application Number:	15/544,063
Patent Claims:	see list of patent claims

Comprehensive claim-by-claim and landscape analysis for US Patent 10,603,361 (asfotase alfa, calcium homeostasis methods in hypophosphatasia)

Executive summary

US Patent 10,603,361 claims a diagnostic-and-treatment algorithm for maintaining serum calcium homeostasis in an alkaline phosphatase deficiency subject treated with asfotase alfa (SEQ ID NO: 1). The core claim structure is a conditioned method: (i) identify hypocalcemia by serum calcium thresholds, (ii) administer a therapeutic agent to raise serum calcium to ≥8.5 mg/dL, and (iii) in an overcorrection scenario, administer a second agent to lower serum calcium to ≤10.5 mg/dL. Dependent claims expand across hypophosphatasia, ALP isoforms and engineered/fusion/chimeric ALPs, and a broad supportive regimen including calcium, vitamin D/vitamers analogs, PTH/PTH analogs, calcimimetics (cinacalcet), bisphosphonates, prednisone, IV fluids, and diuretics, plus nutrition cofactors (vitamin K, vitamin B, multivitamins).

The claim set is broad on therapeutic categories and delivery settings, but it is narrow on the “anchor”: the subject is treated with asfotase alfa comprising the specific SEQ ID NO: 1, and serum calcium thresholds are integral to steps. Strategically, the enforceable scope is most likely to land on clinical management protocols used in hypophosphatasia patients on asfotase alfa, rather than on the asfotase alfa product itself. For generic or biosimilar competitors, the principal risk is method-infringement exposure from calcium-management practices that match the thresholds and the add-on selection logic.

Critical limitation for enforceability: without prosecution history, specification support mapping, and knowing whether related patents (same family) are narrower or broader, claim construction and validity outcomes cannot be assessed to a litigation-ready degree.

What does US 10,603,361 claim and where are the infringement pressure points?

Answer (featured-snippet style): It claims a method for maintaining calcium homeostasis in hypophosphatasia subjects treated with asfotase alfa (SEQ ID NO: 1) using serum calcium thresholds (initial <8.5 mg/dL; rescue to ≥8.5 mg/dL; upper correction >10.5 mg/dL followed by lowering to ≤10.5 mg/dL) and selected calcium-modulating agents.

Claim 1 is the independent “algorithm” anchor

Claim 1 elements (must all be present for infringement):

1. A subject treated with an alkaline phosphatase for an alkaline phosphatase deficiency.
2. The alkaline phosphatase is asfotase alfa comprising amino acid sequence SEQ ID NO: 1.
3. The subject is determined to have serum calcium <8.5 mg/dL.
4. Administer a therapeutic agent that increases serum calcium to ≥8.5 mg/dL.

Infringement pressure points

• The claim is not just “treat hypocalcemia.” It requires:
  • asfotase alfa with SEQ ID NO: 1, and
  • a serum calcium threshold trigger <8.5 mg/dL, and
  • a goal ≥8.5 mg/dL after the therapeutic agent.

This makes it a practice-based claim tied to post-treatment monitoring and titration.

Claims 2-3 narrow or expand the deficiency and ALP embodiment

• Claim 2: explicitly ties ALP deficiency to hypophosphatasia.
• Claim 3: expands ALP form categories to tissue non-specific ALP, placental, intestinal, engineered ALP, fusion proteins, and chimeric ALPs.

Key tension

• Claim 3 reads as though it expands beyond asfotase alfa, but it is written “wherein the alkaline phosphatase is a tissue non-specific alkaline phosphatase…” while the parent claim 1 already requires asfotase alfa comprising SEQ ID NO: 1. As drafted, Claim 3 likely depends on the same anchor limitation (SEQ ID NO: 1). In practice, a court would construe whether Claim 3 is consistent with SEQ ID NO: 1 or whether it creates ambiguity about scope.

Claim 4 adds an “overcorrection” management branch

• Claim 4: if after administration serum calcium becomes >10.5 mg/dL, the method further includes an additional therapeutic agent to reduce to ≤10.5 mg/dL.

Enforcement significance

• This is a two-stage management protocol. Many real-world regimens involve monitoring and adjustment, but the specific numeric boundary at 10.5 mg/dL is what differentiates the claim.
• Method-infringement risk rises where clinicians follow protocols that aim for normal calcium ranges and adjust meds in a predictable way after hypercalcemia.

Claims 5-8 cover PTH-low and vitamin D-low scenarios plus routes

• Claim 5: combine with calcium or vitamin D when parathyroid hormone is statistically low.
• Claim 6: add vitamin D or a functional analog when vitamin D is statistically low.
• Claims 7-8: further specify vitamin D administration and routes (oral, intramuscular, IV).

Critical claim-language issue

• “Statistically significant low” introduces an evidentiary/statistical component. For infringement analysis, a defendant could argue that their clinical determinations were not made using statistical thresholds or comparable methodology. That said, in patent litigation, courts often treat “statistically significant” as a functional limitation tied to observable laboratory findings; whether it’s a strong barrier depends on claim construction and specification support.

Claims 9-12 specify dosage range and agent categories

• Claim 9: ALP dosage range 2–9 mg/kg/week (or comparable daily dosage).
• Claim 10: therapeutic agent may be calcium gluconate or calcium chloride.
• Claim 11: therapeutic agent may be vitamin D or functional vitamin D analog.
• Claim 12: therapeutic agent may be PTH or functional PTH analog.

These add clearer categories and, for Claim 9, a dosing envelope that could exclude regimens outside the claimed range.

Claims 13-18 add hypercalcemia management options

• Claim 13: calcimimetic in the context of reducing calcium after overshoot.
• Claim 14: cinacalcet.
• Claim 15: bisphosphonate.
• Claim 16: prednisone.
• Claim 17: intravenous fluid.
• Claim 18: diuretic.

This is broad enough to capture multiple clinical responses to post-ALP therapy calcium dynamics.

Claims 19-22 add nutritional cofactors and multivitamins

• Claim 19: vitamin K.
• Claim 20: vitamin B (grouping ambiguous).
• Claim 21: multivitamin.
• Claim 22: tighter serum calcium trigger: 7.0 mg/dL or lower to 0.5 mg/dL or lower.

Practical impact

• Claim 22 narrows the definition of “low calcium” for a dependent variant, potentially aligning with more severe hypocalcemic cohorts.

What is the patent landscape around US 10,603,361: who else likely holds method claims for asfotase alfa calcium management?

A full landscape requires identifying (1) the patent family of US 10,603,361, (2) all related continuations/divisionals, and (3) other patents in the asfotase alfa portfolio that cite or are cited by this filing, including Orange Book and non-Orange Book method patents.

However, the supplied information includes only claim text, not bibliographic details. Without filing date, priority date, assignee, related family members, and without external record access, it is not possible to produce a complete, accurate, litigation-grade landscape with named competitors and expiration dates.

Accordingly, no landscape map, “how many patents cover it,” or “who is challenging it” can be responsibly stated from the information provided.

How strong are the claims for enforceability (novelty, obviousness, and claim construction risk)?

Answer: Strength is likely highest on the numeric-trigger logic tied to asfotase alfa SEQ ID NO: 1 and on the specific step of raising serum calcium to ≥8.5 mg/dL from a baseline <8.5 mg/dL. Weakness exposure rises from breadth of “therapeutic agent” categories, the possible inconsistency between Claim 3’s ALP variants and the SEQ ID limitation, and from the “statistically significant” limitation.

Where claim scope is tightest

• Asfotase alfa anchored to SEQ ID NO: 1 is a strong tether that excludes generic “ALP for ALP deficiency” methods.
• The serum calcium thresholds (<8.5 mg/dL trigger and ≥8.5 mg/dL target) are relatively specific for method claims.
• Claim 4 adds a second numeric threshold branch (>10.5 mg/dL overshoot then ≤10.5 mg/dL correction).

Where claim scope is most vulnerable

• Therapeutic agent breadth: calcium gluconate/chloride, vitamin D/analogs, PTH/analogs, calcimimetics (cinacalcet), bisphosphonates, prednisone, IV fluids, diuretics. Many of these are standard hyper/hypocalcemia management tools generally known in endocrine practice.
• “Functional analogs”: broad definitional language can be attacked as indefinite or as failing to provide enablement for the full breadth.
• “Statistically significant low”: introduces a measurement/statistics concept that may create enablement and definiteness disputes depending on the specification and claim construction.

Claim 3 internal consistency risk

Claim 3 appears to conflict with the independent claim’s asfotase alfa SEQ ID requirement by allowing other ALP embodiments. If a court reads Claim 3 literally as overriding or expanding beyond SEQ ID NO: 1, the claim set could be challenged. If instead Claim 3 is treated as specifying additional ALP types that include (or are coextensive with) asfotase alfa, then the breadth is restrained.

What generic or biosimilar entry risks exist for asfotase alfa tied to this method?

Answer: The patent is a method-of-treatment patent, so biosimilar or generic entry risk focuses less on product labeling and more on whether clinicians perform calcium-management protocols that match the claimed threshold steps while prescribing a biologic that includes SEQ ID NO: 1.

Product vs. practice

• A biosimilar entrant would still need to have an accused product. But if the accused product is asfotase alfa or a biosimilar with the same sequence identity and recognized interchangeability, the main litigation risk becomes method practice.
• A “generic” of asfotase alfa is not a small-molecule generic scenario; entry would be via biologics pathway or interchanged biologic development, depending on regulatory posture.

Commercial risk pathway

• If payers or clinical protocols mandate monitoring and calcium rescue targets, method claims can create a predictable exposure.
• If clinical practice is individualized with different thresholds, titration goals, and agent selection not tracking the numeric boundaries, infringement odds decrease.

Regulatory and Orange Book status: what does this patent cover and where would it show up?

This patent is framed as a method of maintaining calcium homeostasis using a biologic therapy (asfotase alfa). Such patents are typically associated with:

• FDA listing frameworks where applicable (for drugs: Orange Book; for biologics: BLA-related listings).
• Potential method-of-use coverage for prescription drug labeling rather than formulation.

But without the patent’s bibliographic data (assignee and reference product) and without the FDA listing record, it is not possible to state Orange Book/BLA listing status. The provided information is insufficient to produce a correct regulatory status answer.

How do the claims compare with standard hypocalcemia and hypercalcemia management in endocrine practice?

Answer: The claimed novelty is the intersection of (1) asfotase alfa treatment with a specific protein sequence, and (2) a threshold-based calcium monitoring and correction algorithm using specific medication classes or examples.

Conventional overlap that may drive obviousness arguments

• Calcium supplementation (calcium chloride/gluconate)
• Vitamin D and analogs
• PTH analogs
• Calcimimetics (cinacalcet) in hypercalcemia contexts
• Bisphosphonates, steroids, IV fluids, diuretics as general hypercalcemia treatments

The differentiator likely relied upon in prosecution

• Numeric serum calcium thresholds tied to decision points.
• Treatment while the subject is being managed on asfotase alfa for hypophosphatasia.

In litigation, this typically translates to: the drug knowledge is old, but the specific “when/what target” protocol in the context of asfotase alfa is the contested layer.

Which parts of the claim set are most likely to be asserted in a dispute?

Answer: Most assertable subsets are the tight threshold steps in Claim 1 and Claim 4, then the downstream dependent claim options that match the expected clinical rescue choices.

Likely high-value dependents:

• Claim 1 (core)
• Claim 4 (overshoot branch)
• Claim 10-12 (calcium/vitamin D/PTH)
• Claim 14-18 (cinacalcet, bisphosphonates, prednisone, IV fluids, diuretics)
• Claim 22 (very low calcium trigger subgroup)

Lower-value dependents (context-dependent):

• Vitamin K/B/multivitamin add-ons (harder to show direct linkage to serum calcium correction steps unless the protocol integrates them as required steps).

Key Takeaways

• US 10,603,361 is a method-of-treatment algorithm anchored to asfotase alfa with SEQ ID NO: 1 and numeric serum calcium thresholds (<8.5 mg/dL trigger; ≥8.5 mg/dL target; >10.5 mg/dL overshoot; ≤10.5 mg/dL correction).
• Claim 4 creates a second-stage hypercalcemia management path, expanding infringement exposure to common hypercalcemia agents (calcimimetics including cinacalcet, bisphosphonates, prednisone, IV fluids, diuretics).
• Breadth of “therapeutic agent” categories increases validity and claim construction risk (obviousness) but also broadens practical reach if the protocol matches the thresholds.
• “Statistically significant low” and potential Claim 3 ALP-variant inconsistency are the main claim-language risk points for enforceability.
• A defensible landscape (assignees, expirations, family members, Orange Book/BLA status, litigation/Paragraph IV equivalents) cannot be constructed from the claim text alone; that part requires bibliographic and record data not provided.

FAQs

1. Does US 10,603,361 require monitoring serum calcium before and after dosing?
2. If calcium is corrected using only dietary changes, does it fall within the “therapeutic agent” limitation?
3. Can a method be infringed when serum calcium is borderline (just above 8.5 mg/dL) at the decision point?
4. How does the presence of “functional analogs” affect claim scope for vitamin D and PTH-related agents?
5. Would a protocol that aims for a normal calcium range different from 10.5 mg/dL avoid Claim 4?

References

No external sources were cited because the prompt did not include patent bibliographic data, related family identifiers, FDA listing identifiers, or any litigation/record documents.

Details for Patent 10,603,361

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	10,603,361	2036-01-28
Alexion Pharmaceuticals, Inc.	STRENSIQ	asfotase alfa	Injection	125513	October 23, 2015	10,603,361	2036-01-28