Patent: 10,058,630

Summary for Patent: 10,058,630

Title:	Methods for inhibiting stenosis, obstruction, or calcification of a stented heart valve or bioprosthesis
Abstract:	Methods for inhibiting stenosis, obstruction and/or calcification of a heart valve following implantation in a vessel having a wall are disclosed. In one aspect the method includes providing a bioprosthetic heart valve mounted on an elastical stent; treating the bioprosthetic heart valve with a tissue fixative; coating the stent and the bioprosthetic valve with a coating composition including one or more therapeutic agents; implanting the bioprosthetic valve into the vessel in a diseased natural valve site; eluting the coating composition from the bioprosthetic valve; and inhibiting stenosis, obstruction and/or calcification of the bioprosthetic heart valve by preventing the attachment of stem cells to the bioprosthetic heart valve, the stem cells circulating external and proximate to the bioprosthetic heart valve by activating nitric oxide production (i) in the circulating stem cells, (ii) in an endothelial cell lining covering the bioprosthetic heart valve tissue, (iii) or both.
Inventor(s):	Rajamannan; Nalini M. (Chicago, IL)
Assignee:	CONCIEVALVE, LLC (Minneapolis, MN)
Application Number:	15/601,236
Patent Claims:	see list of patent claims

Executive summary US Patent 10,058,630 claim set is drafted as a combination method that links (1) a bioprosthetic heart valve processing step (tissue fixation and post-fixation coating), (2) a specific coating composition containing a nitric oxide activator plus an anti-proliferative plus an extracellular matrix (ECM) production inhibitor, and (3) the functional mechanism of preventing stem cell attachment to the implanted valve/stent to inhibit post-implant stenosis/obstruction/calcification. Dependent claims narrow stem cell identity, specify broad classes and examples for nitric oxide activators (including multiple statins and unrelated agents), expand anti-proliferative agents to sirolimus-family drugs and paclitaxel, and expand ECM inhibitors to broad categories of farnesyltransferase/palmitoylation pathway inhibitors and anti-osteoporotic agents. The result is a landscape with multiple “likely invalidity vectors” common to combination method claims: overbreadth from genus-style selections and functional language (“inhibiting attachment,” “inhibiting ECM production”), plus substantial overlap with earlier work in (a) NO-releasing/NO-modulating anticalcification approaches, (b) drug-eluting bioprosthetic valves, and (c) anticalcification approaches targeting proliferation and matrix/mineralization pathways.

Below is a claim-by-claim critical construction of the asserted scope, and a structured patent landscape to map likely claim adjacency, infringement risk, and design-around levers for US practice.

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What does US Patent 10,058,630 claim cover: key elements, claim construction, and implied scope?

US 10,058,630 is best treated as a three-part combination method:

1. Device/processing substrate

   • A bioprosthetic heart valve having tissue with one or more cusps.
   • Mounted on an elastical stent for replacement of a natural diseased valve.
   • Treated with a tissue fixative prior to applying a coating composition.
   • Coating after fixation on the stent and/or cusps.
   • The implant is into a diseased natural valve site; the method includes eluting the coating.

2. Therapeutic composition content (mandatory)

   • Coating composition includes:
     • (i) a nitric oxide activator
     • (ii) an anti-proliferative agent
     • (iii) an inhibitor of extracellular protein matrix production
   • The coating is drug-loaded such that it elutes from stent and/or cusps.

3. Mechanism/functional outcome (mandatory functional limitation)

   • Inhibits stenosis/obstruction/calcification by preventing attachment of stem cells circulating external/proximate to the implanted valve/stent.
   • Achieves this by:
     • activating nitric oxide production
     • inhibiting cell proliferation
     • inhibiting extracellular protein matrix production
   • Applied to circulating stem cells and/or endothelial lining covering the valve tissue.

Independent claim 1: critical scope notes

A. “Tissue fixative prior to applying coating” This narrows away from approaches where coating is applied before fixation. In practice, many bioprosthetic valve manufacturing workflows involve fixation (e.g., glutaraldehyde or alternatives). If a challenger proves the prior art uses fixation prior to coating, this limitation may not impart meaningful novelty.

B. “Nitric oxide activator” is drafted as a broad class of agents Claim 1 requires an NO activator included in the coating. Dependent claim 3 enumerates many “NO-linked” compounds that are not all NO donors in the strict sense; some are pleiotropic agents that may influence endothelial NO synthase (eNOS) activity or NO bioavailability. This breadth increases the odds that earlier art uses one of the listed statins or other NO-modulators in valve coatings or anticalcification contexts.

C. “Anti-proliferative agent” This is a typical class in drug-eluting devices. If earlier valve coatings included antiproliferatives such as sirolimus-family or paclitaxel, the novelty may shift only to the specific combination with the other two categories and the “stem cell attachment prevention” functional mechanism.

D. “Inhibitor of extracellular protein matrix production” This is the most expansive functional anchor. The later dependent claims make it even broader, spanning:

• inhibitors targeting farnesylation/palmitoylation (protein lipidation affecting signaling)
• anti-osteoporotic agents including bisphosphonates and denosumab (mineralization/osteogenic pathways) This breadth is fertile for invalidity arguments based on lack of enablement and/or lack of written description when the patent specification does not map each enumerated agent to the asserted “ECM production” endpoint. Even when enabled, breadth increases the chance that earlier references disclose similar ECM inhibition in anticalcification or anti-mineralization valve strategies.

E. “Preventing attachment of stem cells… by activating NO production, inhibiting proliferation, and inhibiting ECM production” This is a multi-step functional limitation. It can be used as an infringement hook if accused products claim to reduce calcification via suppression of progenitor/stem cell adhesion. But it also creates a litigation vulnerability: challengers can argue that prior art approaches that reduce calcification did so through other mechanisms (e.g., reduced immune response, reduced microcalcification nucleation) not necessarily via “stem cell attachment prevention.” If courts treat this as an intended-use/functional outcome, it may be harder to enforce without strong evidence of the asserted mechanism under the claimed conditions.

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Which dependent claims narrow or expand scope the most: a claim-by-claim critical analysis?

Claim 2: specific stem cell types

Adds: stem cells selected from cKit positive stem cells, SCA1 cells, COP cells, mesenchymal stem cells.
Effect: narrows the stem cell population. That narrowing may reduce infringement surface for defendants whose product is shown to act on other progenitors or endothelial responses not tied to these markers.
Critical view: these markers are commonly used in preclinical progenitor biology. If earlier valve calcification literature implicates mesenchymal progenitors or endothelial progenitors, this limitation may still be met.

Claims 3-5: nitric oxide activator breadth and dosing specificity

Claim 3 lists a very wide slate, including:

• multiple statins (atorvastatin, rosuvastatin, pravastatin, mevastatin, fluvastatin, simvastatin, lovastatin)
• L-arginine, citrulline, NADPH
• acetylcholine, histamine, bradykinin, adenosine triphosphate, thrombin, insulin, glucocorticoids, salicylates
• L-NMMA/L-NAME (notably these are NOS inhibitors, which complicates “activator” semantics)
• nitroglycerine/isborbides/amyl nitrite/nicorandil
• tetrahydrobiopterin
• ezetimibe
• PCSK9 inhibitor

Claim 4 adds oral administration of eNOS nitric oxide activators.
Claim 5 specifies oral dosage ranges for several drugs and includes ezetimibe.

Effect on infringement landscape

• If the accused therapy is a local coating-eluting system, claim 4/5 suggests additional oral dosing is part of the method. That can reduce infringement exposure unless a combined regimen is used.
• If the method is alleged as “coating composition” plus systemic oral NO activators, defendants can argue that their product is not paired with oral dosing in the claimed ranges.

Critical litigation vulnerability

• Including NOS inhibitors (e.g., L-NMMA/L-NAME) under “nitric oxide activator” can create a claim construction fight and strengthen arguments around indefiniteness or lack of clear coverage. Many patent systems treat such internal inconsistencies as a scope-clarification issue that can cut either way, but it also signals that the patent’s “activator” concept may be functionally broad, not chemically consistent.

Claim 6: ECM inhibitor tied to bone formation inhibition in osteoblasts

Effect: narrows ECM inhibition to bone formation via osteoblasts from stem cells.
Critical view: calcification of bioprosthetic valves is often discussed in terms of osteogenic differentiation and mineralization. If prior art anticalcification hinges on osteogenic pathway suppression, claim 6 is likely satisfied. If the prior art uses anti-inflammatory immune modulation without explicit osteoblast pathway suppression, this limitation may differentiate.

Claim 7: anti-proliferative agent examples

Includes paclitaxel, sirolimus, biolimus, everolimus.
This overlaps with drug-eluting stents/valves prior art. The added value of claim 7 depends on the combination with NO activator and ECM inhibitor categories.

Claims 8-11: ECM inhibitor via farnesyltransferase/palmitoylation pathway inhibitors with dosing and ezetimibe combination

Claim 8: ECM inhibitor selected from anti-farnesyltransferase inhibitor and/or anti-palmitoylation inhibitor.
Claim 9: enumerates many inhibitors and categories (lonafarnib, tipifarnib, SCH66336, STI571, multiple classes of signaling/maturation inhibitors, protein palmitoylation inhibitors, tunicamycin, cerulenin).
Claim 10: further includes administering oral dosage of the inhibitor(s).
Claim 11: specifies an example: lonafarnib at 115 mg/m2 with 115–150 mg/m2 range plus ezetimibe 10 mg.

Effect: these dependent claims look like they incorporate oncology drug dosing logic and systemic regimens. That can sharply reduce practical infringement if real-world usage does not include those systemic agents at those doses.
Critical view: the scope is broad in selection but narrow in dosing when claim 11 is asserted. In litigation, claim 11 tends to be easier for defendants to differentiate on regimen and dosing, but broader claims 8-10 can still capture “any farnesyl/palmitoylation ECM inhibitor” if delivered or used as claimed.

Claim 12: ECM inhibitor via anti-osteoporotic agents

Includes bisphosphonates, denosumab, calcitonin, teriparatide, raloxifene.
Effect: this is a large genus overlapping heavily with earlier anticalcification strategies. Bisphosphonates and denosumab have extensive literature in vascular calcification and bone mineralization. If earlier valve patents use these agents to limit calcification, claim 12 risks being anticipated or obvious.

Claims 13-16: PCSK9 inhibitor dosing by injection

Claim 13: administering an effective amount by IM or SC injection.
Claim 14-15: initial dose 0.25–1.5 mg/kg and narrower 0.5–1 mg/kg.
Claim 16: alirocumab 75–150 mg every 2–4 weeks or evolocumab 140 mg every 2 weeks or monthly.

Effect: strongly regimen-specific. If an accused product uses PCSK9 inhibitors, it must be in claimed dosing forms and schedules, and must be combined with the device coating and the other class components. If not, claims 13-16 are less likely to be directly infringed, but they broaden the potential “indirect infringement” narrative if a strategy pairs device therapy with PCSK9 treatment.

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What patents are most likely to overlap: likely prior art adjacency and competitive technology themes

Because the claim text is highly structured around device coating + NO activation + anti-proliferation + ECM/anticalcification, the most relevant prior art typically falls into four buckets. This patent’s originality depends on whether it combines these buckets in a novel way and with defensible evidence tied to “stem cell attachment prevention.”

1) Bioprosthetic valve coatings for anticalcification and anti-stenosis

High-overlap themes

• Polymer coatings on valve cusps and/or stents
• Drug-eluting or controlled-release systems using antiproliferatives
• Approaches targeting endothelial coverage and reducing progenitor adhesion
• Surface modification for reducing calcification nucleation

Landscape risk for US 10,058,630 If earlier valve patents disclose a coating with an antiproliferative agent and an NO donor or NO modulation, they may read on broad portions of claim 1. The key differentiation becomes the specific trio: NO activator + antiproliferative + ECM production inhibitor, plus the specific functional “stem cell attachment prevention.”

2) Nitric oxide donor/releaser coatings in vascular/valve contexts

High-overlap themes

• NO-releasing coatings to reduce thrombosis and restenosis
• NO modulation to reduce smooth muscle proliferation and ECM production
• NO-linked eNOS activation concepts (statins are common in NO bioavailability biology)

Landscape risk Claim 3’s inclusion of common statins and many NO bioavailability modulators raises the chance that prior art exists combining statins with anticalcification or antiproliferative therapy in cardiovascular implants. Claim 1 uses “activating nitric oxide production” as a functional requirement. Earlier references that show reduced calcification via NO availability could be used against claim 1, even if they do not explicitly name “stem cell attachment.”

3) Anti-proliferative and drug-eluting technologies on heart valves

High-overlap themes

• Sirolimus everolimus family drug release in cardiovascular implants
• Paclitaxel antiproliferative use in restenosis settings
• Controlled release from stents and coatings

Landscape risk If earlier bioprosthetic valve patents combine a rapamycin-family drug with anticalcification or anti-stenosis performance, claim 7 becomes vulnerable, and claim 1 becomes vulnerable once the other two composition components are found or are obvious.

4) ECM/inhibitors: farnesyltransferase/palmitoylation inhibitors or anti-osteoporotic agents in calcification

High-overlap themes

• Bisphosphonates as inhibitors of mineralization and osteogenic signaling
• Denosumab and calcitonin pathway modulation in mineralization
• Protein lipidation inhibitors in signaling modulation, sometimes tied to proliferation or differentiation

Landscape risk Claim 12 is the biggest overlap generator because anti-osteoporotic drug classes have strong vascular calcification and mineralization literature. If earlier valve or vascular implant patents already use bisphosphonates/denosumab to reduce calcification and improve mechanical integrity, claim 1’s “ECM production inhibition” requirement may be anticipated on the basis that calcification is a kind of ECM/mineralization process.

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How strong is the patent estate implied by this claim set: key enforceability risks?

1) Breadth + genus selections increase anticipation/obviousness odds

The “nitric oxide activator” claim 3 includes multiple drug classes and mechanistic agents, plus statins and PCSK9 inhibitors. The ECM inhibitor claim 12 includes broad anti-osteoporotic drug classes. Courts commonly treat broad selection lists as inviting prior art combinations that match at least some members.

2) Functional mechanism (“preventing attachment of stem cells”) invites mechanism-evidence disputes

Even if a coating reduces calcification, proving it specifically prevents stem cell attachment could be difficult if prior art used different endpoints (e.g., reduced calcium deposition, reduced osteogenic markers, reduced inflammation). On infringement, if the mechanism is treated as limiting, defendants may argue lack of correspondence.

3) Systemic administration dependent claims create regimen carve-outs

Claims 4-5 (oral NO activators), 10-11 (oral ECM inhibitors), and 13-16 (PCSK9 injection) can be used as defenses if accused products deploy only local coating without systemic drugs. This can reduce direct infringement but also allows a design-around: avoid pairing device coating with the claimed systemic regimen.

4) “Nitric oxide activator” labeling includes agents that can inhibit NOS

In claim 3, inclusion of L-NMMA and L-NAME (NOS inhibitors) conflicts with “activator” semantics. That creates a claim-construction fault line. Depending on how a court interprets the claim language, it can either broaden coverage via functional definition or narrow it via consistent usage. Either way, it increases litigation friction.

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What generic entry risks exist for US 10,058,630: will coatings be treated as patent-surfaced products?

A critical point: this patent is a method claim tied to a coated bioprosthetic valve and elution/administration regimens. Generic “entry” risk is less about generic small molecules alone, more about whether a competitor can deploy:

• a bioprosthetic valve with elastical stent,
• treated with tissue fixative prior to coating,
• with a coating composition that includes the three required categories,
• and uses or includes the stem-cell-attachment-prevention mechanism.

Practical generic/biosimilar analogue

Bioprosthetic valves are not “generic drugs” in the usual way. Competitors can still be blocked by method patents and device patent claims if their manufacturing and treatment regimens replicate the steps, including coating composition content and elution.

Where risk is highest

• If competitors use NO-modulating statins or other NO pathway agents in valve coatings.
• If they add antiproliferatives like sirolimus/everolimus family.
• If they also use bisphosphonates/denosumab or other ECM/mineralization inhibitors in the same coating system or as paired therapy.
• If they document reduced calcification with progenitor/stem-cell adhesion evidence aligned to the “attachment prevention” mechanism.

Where risk is lowest

• Competitors that avoid the triple-composition requirement (omit one class).
• Competitors that keep systemic drugs out of the regimen.
• Competitors that argue their ECM inhibition acts via immune suppression or mineral nucleation reduction rather than “ECM protein matrix production inhibition” as construed.

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Which patent infringement pathways are most plausible: direct vs induced vs contributory

Direct infringement is most plausible when a manufacturer markets a valve and a regimen that matches:

• coating composition with nitric oxide activator + anti-proliferative + ECM inhibitor,
• tissue fixation prior to coating,
• implantation workflow,
• stem-cell attachment prevention mechanism as a functional limitation,
• and any required systemic oral/injection steps if asserted claims 4-5, 10-11, and 13-16.

Induced/contributory becomes plausible if:

• the manufacturer supplies a coated valve and relies on standard-of-care systemic drugs (statins, PCSK9 inhibitors, bisphosphonates, etc.) in ranges that match dependent claims.
• or if patient labeling and clinical protocols specify these systemic agents in ways that map onto the dependent method steps.

The breadth of included agents increases the chance that standard cardiovascular regimens overlap with parts of the claim set, but induced infringement usually depends on deliberate encouragement and knowledge of the patent.

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How could competitors design around US 10,058,630: high-probability levers

1. Remove one required category

   • Keep NO modulation but drop antiproliferative or ECM inhibitor.
   • Keep antiproliferative and ECM inhibitor but use NO pathway via a different non-“activator” approach not falling within the claimed category (hard given claim 3’s breadth).

2. Change the ECM inhibitor strategy

   • Use an immune-modulating anticalcification approach (anti-inflammatory, anti-fibrotic) that is not framed as “inhibitor of extracellular protein matrix production.”
   • Avoid bisphosphonates/denosumab if claim 12 is asserted.

3. Avoid systemic dosing steps

   • If claims 4-5 and 10-11 and 13-16 are central, using local coating only (no matching oral/injection components) can be a strong mitigation.

4. Dispute stem cell attachment mechanism

   • Use coatings designed to reduce calcification via endothelial integrity and thromboresistance rather than preventing stem cell attachment, then argue mechanism divergence.
   • In enforcement, lack of stem-cell-attachment data can undercut infringement of functional limitations.

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Key Takeaways

• US 10,058,630 is a combination method claim centered on a coated, tissue-fixed bioprosthetic valve using a three-component functional composition: NO activation, antiproliferation, and ECM production inhibition to prevent stem cell attachment and reduce valve stenosis/obstruction/calcification.
• Independent claim 1 is broad enough to be challenged by prior art that separately discloses NO-modulating anticalcification coatings, antiproliferative valve coatings, and ECM/mineralization suppression, with the litigation hinge being whether the prior art also supports the claimed “stem cell attachment prevention” mechanism.
• Dependent claims materially narrow by specifying stem cell types and systemic dosing routes and ranges, creating defense opportunities if competitors use only local coatings or do not pair systemic regimens at claimed doses.
• The patent’s practical strongest infringement posture typically requires showing: the coating contains all three functional classes in combination and elutes from the valve/stent, and the clinical/protocol regimen matches any asserted dependent systemic steps.

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FAQs

1. Can a competitor infringe US 10,058,630 with local valve coating only, without oral or injectable co-therapy?
   Yes for independent claim 1, if the coating contains all required composition categories and the method includes the claimed implantation/elution steps. Dependent claims 4-5, 10-11, and 13-16 generally require specific systemic administration.

2. What is the biggest vulnerability of claim 3’s “nitric oxide activator” list in litigation?
   It includes agents that can act as NOS inhibitors (e.g., L-NMMA, L-NAME), which can be used to pressure claim construction and undermine a consistent “activator” interpretation.

3. How can defendants attack “ECM production inhibition” coverage?
   By showing their ECM/calcification reduction mechanism does not match the construed “extracellular protein matrix production” concept, or that the agents used are not actually “inhibitors” of the claimed process under the claimed conditions.

4. Does claim 2’s stem-cell marker limitation reduce enforcement risk?
   It can. If a competitor’s data or the record supports action on different progenitor populations, claim 2 may not read. Independent claim 1 does not require the markers.

5. What coating-and-regimen combinations are most likely to trigger infringement risk from this claim set?
   Coatings combining NO pathway modulators (including statin-like agents), antiproliferative drugs (sirolimus/everolimus/paclitaxel-like), and ECM/mineralization inhibitors (bisphosphonates/denosumab-like or protein lipidation inhibitors), paired with systemic regimens only where dependent claims are asserted.

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References

[No references were provided in the prompt.]

Details for Patent 10,058,630

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	March 13, 1924	10,058,630	2037-05-22
Amgen Inc.	PROLIA	denosumab	Injection	125320	June 01, 2010	10,058,630	2037-05-22
Amgen Inc.	XGEVA	denosumab	Injection	125320	November 18, 2010	10,058,630	2037-05-22