United States Patent 11,497,737: Scope, Claim-by-Claim Boundaries, and Landscape Implications

United States Patent 11,497,737 is directed to a commercial batch of a pharmaceutical composition that contains rapamycin-loaded nanoparticles made with albumin plus a non-nanoparticle portion that also contains albumin and rapamycin. The patent’s core novelty is the controlled albumin aggregation state inside the nanoparticles (polymeric albumin other than oligomeric albumin vs oligomeric albumin vs monomeric/dimeric/oligomeric distributions), coupled to extensive product-specification claims covering particle size, polydispersity, impurity levels, morphology, and fill-finish/unit dosage conformance.

The independent claim 1 is structured as a composition and testing-defined characterization claim: the albumin aggregation state in the nanoparticles is defined by a specific workflow (separate nanoparticles from non-nanoparticle portion, dissolve nanoparticles, size-exclusion chromatography). Dependent claims then narrow those ranges and add operationally meaningful controls (solvent residuals, particle metrics, seco-rapamycin impurity, sterile content, amorphous form, zeta potential, and device-level unit dosing tolerance).

What does Claim 1 actually require for infringement?

Claim 1 is a commercial-batch claim with a two-phase composition requirement and a distribution requirement that is tied to a measurement method.

A. Two-part composition: nanoparticle + non-nanoparticle portion

A litigable composition must include:

Nanoparticles comprising rapamycin and albumin
Non-nanoparticle portion comprising albumin and rapamycin

This is not a simple “particles in solution” claim. It requires that after the batch is formed, there is measurable material in both:

the nanoparticle fraction, and
the remaining (non-nanoparticle) fraction

In practice, the claim forces the accused product to have a partitioning behavior for rapamycin and albumin that produces a detectable non-nanoparticle pool alongside the nanoparticle pool.

B. Aggregation-state window inside the nanoparticles

The key distribution requirement is:

42% to about 60% of the albumin in the nanoparticles must be in the form of polymeric albumin other than oligomeric albumin.

And the claim defines how to determine that percentage:

separate nanoparticles from the non-nanoparticle portion
dissolve the nanoparticles
subject dissolved nanoparticles to size-exclusion chromatography

This makes analytical method and fractionation elements central to claim construction and infringement testing:

The accused party must match the claimed percentage as measured using the claimed workflow (or an equivalent argued during litigation).

C. “Commercial batch” implies product-in-practice

“Commercial batch” makes the claim read on manufactured product lots, not only lab-scale preparations. This matters for enforcement strategy because the patent is anchored to QC-realistic release criteria (particle sizes, residual solvents, dose tolerance, sterility).

How do Claims 2-5 constrain albumin aggregation state?

These claims tighten Claim 1 by specifying oligomeric/monomeric/dimeric/polymeric fractions either inside nanoparticles (Claims 2-3) and/or across the whole composition and in the non-nanoparticle fraction (Claims 4-5).

Claim 2 (nanoparticle oligomeric albumin cap)

about 1% to about 4.5% of the albumin in the nanoparticles is oligomeric albumin
determined by the Claim 1 separation/dissolution/SEC workflow

Practical effect: Even if a product meets the polymeric-albumin window (Claim 1), it must also keep oligomeric albumin low in the nanoparticle fraction.

Claim 3 (nanoparticle monomeric/dimeric bounds)

monomeric albumin in nanoparticles: about 25% to about 50%
dimeric albumin in nanoparticles: about 5% to about 16%
same separation/dissolution/SEC method

Practical effect: These bounds create a multi-parameter “triangle” with Claim 1 and Claim 2. A product that shifts albumin distribution among monomeric/dimeric/oligomeric/polymeric forms can miss the combined constraint set.

Claim 4 (whole composition albumin distribution)

Requires the total albumin composition distribution by SEC after applying the SEC determination step to “the composition”:

monomeric albumin: about 80% to about 95%
dimeric albumin: about 4% to about 15%
oligomeric albumin: about 0.3% to about 3%
polymeric albumin other than oligomeric: about 2% to about 7%

Practical effect: Claim 4 ties the global albumin state to the micro-state inside nanoparticles. It reduces design-around by enforcing batch-level albumin aggregation profile.

Claim 5 (non-nanoparticle portion albumin distribution)

Requires the non-nanoparticle portion distribution:

non-nanoparticle monomeric: about 80% to about 95%
non-nanoparticle dimeric: about 4% to about 14%
non-nanoparticle oligomeric: about 0.5% to about 4%
non-nanoparticle polymeric other than oligomeric: about 0.5% to about 3%

Practical effect: This creates a strong internal consistency check across fractions. It also gives the patentee an enforcement handle even if an accused party argues about nanoparticle size-only differences: the claim set tests distribution in a specific fraction.

Is this a “particle product spec” patent or a “composition structure” patent?

It is both, but the balance is explicit: Claim 1 defines the fractionation-based aggregation chemistry, and the remaining claims layer in a broad set of commercial QC specifications that can be used in both infringement and validity/obviousness argument framing.

What are the key particle-size and colloidal-stability claim hooks?

Claims 7-10 and 21 address particle size distribution and colloidal properties.

Size and distribution

Claim 7: volume weighted mean particle size about 200 nm or less
Claim 8: Z-average particle size about 200 nm or less
Claim 9: polydispersity index less than 0.3
Claim 10: span of particle size distribution ((Dv95 − Dv5)/Dv50) about 0.8 to about 1.2

Practical effect: Design-around by “making particles bigger” or broader is constrained by multiple overlapping size metrics.

Surface charge

Claim 21: zeta potential about −25 mV to about −50 mV

Practical effect: A product with a different albumin conformational state or surface chemistry that shifts zeta potential can avoid these dependent claims, but not necessarily Claim 1 unless the aggregation-state and SEC fraction requirements still match.

What composition ratios and composition states are claimed?

Rapamycin/albumin loading

Claim 11: nanoparticles about 25% to about 45% albumin by weight and about 55% to about 75% rapamycin by weight
Claim 27: 90% or more of the rapamycin in the composition is in the nanoparticles

Practical effect: This captures high encapsulation/association efficiency, not low-loading suspensions.

Concentrations

Claim 13: albumin concentration about 1 mg/mL to about 100 mg/mL
Claim 14: albumin concentration about 30 mg/mL to about 100 mg/mL
Claim 15: rapamycin concentration about 1 mg/mL to about 50 mg/mL

Osmolality

Claim 16: osmolality about 280 mOsm/kg to about 400 mOsm/kg

Suspension vs dried

Claim 12: nanoparticle composition is a nanoparticle suspension
Claims 17-18: nanoparticles have been resuspended from a dried composition and composition is a dried composition

Practical effect: The claims cover at least two manufacturing and product states: suspension and dried/rehydrated. That matters for any competitor platform using different fill formats.

What impurity and residual solvent constraints are in the claims?

These are direct constraints that can be measured by routine analytical chemistry and can be used as “release spec” criteria.

Claim 6: seco-rapamycin less than 3% by weight of (seco-rapamycin + rapamycin)
Claim 19: tert-butanol residual less than 250 ppm
Claim 20: chloroform residual less than 60 ppm

Practical effect: Products that avoid these residuals by changing process chemistry may still fall under Claim 1, but they can potentially avoid narrower dependent claims (19-20) and associated enforcement narratives.

What morphology, crystallinity, and amorphous-state claims exist?

The patent includes specific solid-state characterization gates.

General non-spherical and non-smooth particle morphology

Claim 24: at least 20% non-spherical nanoparticles by cryo-TEM
Claim 25: at least 20% with non-smooth surface by cryo-TEM

Amorphous morphology of nanoparticles and rapamycin

Claim 22: nanoparticles have amorphous morphology as determined after separation, lyophilization, and X-ray diffraction crystallinity measurement
Claim 23: rapamycin in nanoparticles has amorphous morphology as determined by any of:
- Raman spectroscopy
- polarized light microscopy
- DSC
- mDSC
- FTIR
- NMR

Practical effect: These claims are strong for enforcing a “state-of-matter” position: not only particle size, but amorphous form and morphology.

What other operational constraints appear in the dependent claim set?

Albumin source

Claim 26: albumin is human albumin

Sterility

Claim 28: nanoparticle composition is sterile

Excipients: caprylic acid derivative / tryptophan derivative

Claim 29: composition comprises a caprylic acid derivative and/or a tryptophan derivative

Unit-dose vial tolerance

Claim 30: composition contained in multiple vials with unit dosage labeling; rapamycin amount in each vial is within 10% of label amount

Practical effect: Claim 30 targets commercial distribution quality, not only formulation chemistry.

Where is the “scope leverage” in this claim set?

The scope is anchored by Claim 1 and then broadened by many dependent claims that look like QC release criteria. That structure produces a landscape effect:

If an accused product matches Claim 1’s SEC-defined polymeric albumin-in-nanoparticle window, the patent is already on target.
Dependent claims then allow the patentee to confirm matching through additional measurable attributes (particle size, zeta potential, impurity profiles, amorphous state, morphology, sterility, unit dosing).

The combined structure means multiple independent analytical axes can be used to show infringement. That reduces the probability of an accused product “accidentally” falling outside because of a single parameter.

How to read this as a patent landscape for competitors

1) Design-around paths that are partially blocked

Competitors attempting to avoid the patent likely focus on:

changing the albumin aggregation distribution inside nanoparticles (SEC-defined),
reducing the polymeric albumin other than oligomeric fraction below 42% or above 60%, or
altering the oligomeric albumin fraction so it falls outside 1% to 4.5% (for dependent Claim 2),
changing the monomeric/dimeric composition inside nanoparticles (Claim 3),
changing the encapsulation partitioning so less than 90% of rapamycin is in nanoparticles (Claim 27),
altering particle size/polydispersity/PSD span (Claims 7-10),
altering amorphous state or particle morphology metrics (Claims 22-25).

However, because Claim 1 only fixes one explicit polymeric fraction window plus the existence of both nanoparticle and non-nanoparticle phases, a competitor must ensure the whole SEC-based fractionation workflow outcome falls outside those windows. Adjusting one colloidal property may not help if the albumin aggregation distribution still matches.

2) The patent supports enforcement built around routine QC tests

Many dependent claims correspond to:

SEC fraction profiling of albumin species,
DLS particle metrics (Z-average, PDI, PSD span),
zeta potential,
cryo-TEM morphology thresholds,
amorphous/crystallinity checks (XRD, Raman, DSC, FTIR, NMR),
solvent/impurity specs (sec-rapamycin, tert-butanol, chloroform),
sterility and unit dose conformance.

That makes this patent landscape-friendly for litigants because it can be tested with typical analytical toolkits used in manufacturing.

3) Landscape position: narrow on “what” and wide on “how-to-manufacture outcomes”

The core chemical identity is fixed:

rapamycin,
albumin,
albumin aggregation states inside nanoparticles and in the non-nanoparticle fraction,
plus nanoparticles with defined particle-size and amorphous properties.

Yet the claims do not primarily recite a specific manufacturing step sequence. Instead, they recite resultant product characterization, which can broaden potential infringement coverage across different processes that converge on similar product attributes.

Claims risk matrix (where infringement is most likely to be concentrated)

Claim cluster	What it locks down	Litigation “first-pass” test signals
1 + 2 + 3	Albumin aggregation distributions in nanoparticle fraction via SEC	SEC of nanoparticle fraction after separation and dissolution
4 + 5	Whole composition and non-nanoparticle fraction aggregation distributions	SEC across total and non-nanoparticle fraction
7-10	DLS size, PDI, PSD span	DLS metrics meeting hard thresholds
21	Zeta potential window	Electrophoretic mobility measurements
6, 19, 20	Impurity and residual solvents	Standard impurity/residual assays
22-25, 23	Amorphous state and morphology by XRD/Raman/DSC/cryo-TEM	Solid-state assays plus cryo-TEM scoring
11, 27	Albumin/rapamycin loading and rapamycin partition	Weight fraction and association efficiency
28, 30	Sterility and unit dose tolerance	Sterility test and vial label conformance

What is missing for a full “patent landscape” map vs other US patents?

A complete multi-patent landscape requires:

bibliographic details of 11,497,737’s patent family (publication numbers, priority dates, assignee, related continuations),
prosecution history events (claims allowed, office actions),
and identification of citing/cited documents in USPTO/Google Patents.

Those data are not provided here; the analysis above is limited to the claim text scope you supplied.

Key Takeaways

Claim 1 is the scope anchor: it requires a batch with rapamycin + albumin nanoparticles plus a non-nanoparticle albumin/rapamycin portion, and it mandates a SEC-measured aggregation window where 42% to about 60% of nanoparticle albumin is polymeric albumin other than oligomeric albumin after a defined separation/dissolution workflow.
The dependent claims create a multi-constraint product fingerprint spanning nanoparticle albumin species distributions (Claims 2-5), rapamycin partitioning (Claim 27), particle-size metrics (Claims 7-10), zeta potential (Claim 21), impurities/residual solvents (Claims 6, 19-20), amorphous state and morphology (Claims 22-25), and commercialization specs (Claims 28, 30).
For competitors, the highest-risk infringement path is matching SEC-defined albumin aggregation state inside nanoparticles. If that aligns, downstream mismatches (size, charge, morphology) may only avoid certain dependent claims, not Claim 1.

FAQs

1) Does the patent require that all rapamycin is in nanoparticles?
No. Claim 1 requires rapamycin is present in nanoparticles and also in the non-nanoparticle portion. A stricter requirement appears in Claim 27, which requires 90% or more of rapamycin in the composition be in the nanoparticles.

2) What analytical method is central to the key albumin aggregation limitations?
Claim 1 defines determination of albumin fraction via size-exclusion chromatography after separating nanoparticles from the non-nanoparticle portion and dissolving nanoparticles.

3) Are particle-size limits standalone enough to avoid infringement?
They can avoid dependent claim coverage (Claims 7-10), but avoiding Claim 1 requires escaping the SEC-based polymeric/oligomeric albumin distribution in the nanoparticle fraction and/or the required presence of both nanoparticle and non-nanoparticle portions.

4) Does the patent cover both suspension and dried formulations?
Yes. Claim 12 covers a nanoparticle suspension, while Claims 17-18 cover nanoparticles resuspended from a dried composition and compositions that are dried.

5) Are impurity and residual solvent thresholds included as enforceable limits?
Yes. Seco-rapamycin is limited in Claim 6, and residual tert-butanol and chloroform are limited in Claims 19 and 20.

References

[1] United States Patent 11,497,737 (claim text provided).

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Aadi Sub	FYARRO	sirolimus	POWDER;INTRAVENOUS	213312-001	Nov 22, 2021		RX	Yes	Yes	11,497,737	⤷ Start Trial	Y				⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	120318	⤷ Start Trial
Australia	2020375810	⤷ Start Trial
Brazil	112022007710	⤷ Start Trial
Canada	3158764	⤷ Start Trial
China	115003284	⤷ Start Trial
European Patent Office	4051241	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 11,497,737