Patent: 10,010,503

Summary for Patent: 10,010,503

Title:	Methods and compositions for oral administration
Abstract:	This invention provides compositions comprising a protein, an absorption enhancer, a protease inhibitor, method for treating diabetes mellitus, comprising administering same, and methods for oral administration of a protein with an enzymatic activity, comprising orally administering same.
Inventor(s):	Kidron; Miriam (Jerusalem, IL), Arbit; Ehud (Englewood, NJ)
Assignee:	Entera Bio Ltd. (Jerusalem, IL)
Application Number:	14/936,758
Patent Claims:	see list of patent claims

United States Patent 10,010,503: What the Claims Actually Cover and Where the Landscape Blocks or Enables Use

US Patent 10,010,503 claims an oral pharmaceutical composition and corresponding oral administration method built around a three-part functional combination: (1) a small-to-mid molecular weight protein (≤ 100,000 Da) selected from a defined list, (2) a protease inhibitor, and (3) a specific enhancer family consisting of NAC and/or NAD (including specified salts). The claims are written broadly on protein identity and protease-inhibitor class, but narrowly on the enhancer scaffold and the “synergistic bioavailability increase” requirement.

The practical impact is that the claim set is strongest against products that replicate the same enhancer chemistry (NAC/NAD, including sodium salts) and weaken against products that use different oral absorption technologies (e.g., permeation enhancers like bile salts, absorption carriers, pH modifiers not tied to NAC/NAD, or different protease inhibition strategies not aligned to the claimed inhibitor set). The patent is also exposed to validity challenges that target the “synergistically increase bioavailability” limitation as a predictable aggregation of known approaches, and to non-infringement strategies that change any one of the critical claim anchors: enhancer structure, enhancer salt form, or the paired protease inhibitor/enhancer mechanism.

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1. What is claimed: the core technology and the functional constraints

What does claim 1 require?

Claim 1 defines a pharmaceutical composition “for oral administration” comprising:

1) A protein (≤ 100,000 Daltons) selected from:

• interferon gamma
• interferon alpha
• growth hormone
• erythropoietin
• granulocyte colony stimulating factor (G-CSF)
• omentin
• calcitonin
• PTH
• PYY

2) A protease inhibitor

3) A compound selected from:

• N-(8-[2-hydroxybenzoyl] amino)caprylate (NAC)
• N-(10-[2-hydroxybenzoyl]amino)decanoate (NAD)
• a salt of NAC or NAD
• a combination thereof

4) The compound is in an effective amount to “synergistically increase the bioavailability of said protein.”

The claim also contains several dependent claims that tighten physical form (solid), synergy pairing (protease inhibitor and compound act in synergy), protein type (recombinant, PTH), protease inhibitor specificity, enhancer salt specification, and optional excipients and coatings.

What changes in dependent claims

The dependent claims add meaningful claim coverage in three ways: (a) they narrow or specify the protease inhibitor candidates, (b) they specify the enhancer salt species, and (c) they add dosage form and formulation elements that can matter for infringement of specific product forms.

Key dependent claim expansions:

• Claim 2: “solid composition”
• Claim 3: protease inhibitor and enhancer “act in synergy” (explicit pairing synergy)
• Claims 4 and 5: protein can be recombinant and can be PTH
• Claims 6-8: protease inhibitor narrowed to defined categories and then to named inhibitors
• Claim 9: enhancer salt narrowed to monosodium, disodium, or combination
• Claims 10-11: optional addition of omega-3 fatty acid and EDTA (or salt)
• Claim 12: includes a digestion-protecting coating: stomach-inhibiting, enteric, or gelatin coating

Method claims (Claims 13-24) largely mirror the composition claims, shifting the act of infringement to oral administration of the claimed composition.

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2. Claim architecture: where infringement is easy vs hard

The three “anchors” that must all be present

To fall within the literal boundaries of claim 1 (and therefore the method claims), an accused product must include:

• A protein from the enumerated set with molecular weight ≤ 100,000 Da
• A protease inhibitor (any protease inhibitor falling within the claim 6-8 limitations depending on which dependent claim is asserted)
• NAC/NAD (or salts), in an effective amount to “synergistically increase” bioavailability

If any anchor is absent, infringement risk collapses.

NAC/NAD is the highest-value claim element

The enhancer chemistry is highly specific. Most other oral protein delivery technologies do not use NAC/NAD as the enhancer scaffold. That specificity creates a clean product-design “escape hatch” for competitors who use alternative classes such as:

• bile salts (e.g., sodium taurocholate)
• fatty acid esters and medium-chain absorption enhancers not structurally NAC/NAD
• surfactant permeation enhancers
• enzyme inhibitors outside the enumerated candidates (unless claim scope is asserted via claim 6-8)

If a product uses a different oral absorption enhancer and relies on different formulation drivers, it is less likely to land in the claim.

Protease inhibitor choice affects both claim breadth and enforceability

Claim 1 requires a protease inhibitor, but claim 6-8 defines specific protease inhibitor categories and named inhibitors. In practice, enforcement frequently lands on narrower dependent claims because they provide clearer claim-to-product matching.

The named inhibitors create a more direct infringement mapping than generic “protease inhibitor” language:

• Lima bean trypsin inhibitor
• Aprotinin
• Soybean trypsin inhibitor (SBTI)
• Ovomucoid

The inclusion of broad categories (serpin, suicide inhibitor, transition state inhibitor, and several protease type buckets) helps claim 6 coverage but still depends on alignment with the claim text and proof about protease specificity.

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3. Protein scope: broad list, but capped by molecular weight and functional language

Enumerated proteins include both “classic” and less common targets

The protein list includes well-known oral delivery candidates (e.g., interferons, erythropoietin, growth hormone, calcitonin, G-CSF), plus broader scope items (omentin, PTH, PYY).

The molecular weight cap is an additional constraint

The claims require “protein having a molecular weight of up to 100,000 Daltons.” For enforcement, challengers and defendants can argue whether specific molecular-weight versions, glycoforms, or conjugates exceed the cap. For product developers, that cap influences construct selection and post-translational profile.

“Recombinant” is a dependent limitation

If enforcement is directed to claim 4, the accused protein must be recombinant. Products derived from natural sources (or extracted preparations) can attempt to avoid the recombinant limitation.

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4. The “synergistically increase bioavailability” limitation: the enforceability pressure point

Why synergy is a litigation choke point

The claim requires synergy between components. This has two effects:

1) Literal scope ambiguity: “synergistically increase” is a functional claim term. Courts often require evidence that the combination performs better than what would be expected from additive effects, not just that each element improves absorption.

2) Vulnerability to obviousness: If protease inhibition and oral absorption enhancement were individually known, a challenger can argue that combining them to improve oral bioavailability is predictable. The patentee must show that synergy is more than a summation effect.

Two separate synergy layers appear

• Claim 1: enhancer in an effective amount “to synergistically increase bioavailability”
• Claim 3 and 15: protease inhibitor and compound “act in synergy”

A competitor might reduce risk by designing products where:

• the protease inhibitor is not intended to function mechanistically as a partner to NAC/NAD for synergy, or
• the enhancer is present but the claimed synergy is not demonstrated or not achieved in a comparable manner.

In litigation, defendants target the measurement and baseline comparison used to establish synergy.

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5. Formulation and administration elements: how product form affects claim capture

Solid dosage form is a dependent capture mechanism

• Claim 2 and claim 14 constrain to “solid composition.”
  If an accused product is liquid or non-solid, it may avoid those dependent claims, but still risk claim 1 if the main composition is otherwise identical.

Coatings matter for certain product types

Claim 12 allows a digestion-inhibiting coating:

• inhibits digestion in the stomach
• enteric coating
• gelatin coating

This provides coverage across common coating architectures. It also means that an accused product with a coating is more likely to fit claim language than one without any protective formulation.

Optional excipients are included, but not required

Claims 10-11 and 22-23 extend coverage where the product adds:

• omega-3 fatty acids
• EDTA (or salt)

Because these are optional additions (dependent claims), their presence can increase likelihood of matching dependent claims but is not required for claim 1.

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6. Patent landscape implications: how this claim set tends to behave in enforcement

Most likely infringement profiles

Enforcement leverage tends to be strongest against products that:

• use NAC/NAD (or specific sodium salts) as the oral enhancer
• combine that enhancer with a protease inhibitor like trypsin inhibitors or aprotinin-like protease inhibitors
• dose proteins in the enumerated set or close variants with ≤100,000 Da
• use solid oral dosage forms with protective coatings

This pattern is unusually specific, and it reduces the number of plausible competitors that can be “close” without either copying enhancer chemistry or adopting the same enhancer.

Likely non-infringement design patterns

Companies can reduce claim overlap by:

• replacing NAC/NAD with a different class of absorption enhancers
• using protease inhibitors outside claim 6-8 dependent lists (if the asserted claims are dependent)
• avoiding “synergy” as demonstrated in the patent’s experimental framework (a design-for-defensibility approach)
• using liquid formulations (to avoid solid-dependent claims)
• using non-recombinant protein sources where claim 4 is asserted

Litigation posture: invalidity vs design-around

In practice, disputes over this kind of claim frequently split into:

• validity: obviousness of combining protease inhibition with oral absorption enhancers and the predictability of improving bioavailability
• infringement: whether the enhancer is truly NAC/NAD (and salts) and whether the combination’s measured performance qualifies as “synergistically increase”

The more narrowly specified the enhancer chemistry, the more likely the case becomes “chemical identity and formulation evidence,” not just general oral delivery performance.

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7. Claim-by-claim critical reading: key takeaways for investors and R&D teams

Claims 1, 13 (independent)

• Broad protein identity, constrained by ≤100,000 Da and enumerated list
• Core specificity: NAC/NAD (and salts) plus protease inhibitor
• Central risk: synergy limitation becomes a proof burden and an obviousness attack point

Claims 2, 14 (solid dosage)

• Additional narrowing; useful when accused products are tablets/capsules

Claims 3, 15 (protease inhibitor + enhancer synergy)

• Narrows to functional pairing; improves enforcement strength if evidence supports synergy

Claims 4, 16 (recombinant) and 5, 17 (PTH)

• Create targeted pockets of enforceability
• Also allow competitors to argue non-recombinant sourcing or non-PTH selection where relevant

Claims 6-8 and 18-20 (protease inhibitor categories and named species)

• Dependent claim specificity helps matching but also offers invalidity angles if prior art contains similar trypsin inhibitors with oral protein delivery intent

Claim 9 (salt type)

• Narrow enhancer salt capture: monosodium/disodium salts of NAC/NAD
  This can be a high-leverage design-around if an alternative salt or free base is used.

Claims 10-11 and 22-23 (omega-3, EDTA)

• Dependent expansion; product formulations including these excipients are more likely to fall within additional dependent claim sets.

Claim 12 and 24 (coating)

• Adds coverage for protective delivery formats.

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Key Takeaways

• Claim 1 is anchored to a specific enhancer chemistry (NAC/NAD plus salts) paired with a protease inhibitor to improve oral bioavailability of enumerated proteins ≤100,000 Da.
• Synergy language is the enforceability pressure point: it creates a proof burden and supplies an obviousness attack pathway because protease inhibition and oral absorption enhancement are frequently independently known.
• Dependent claims narrow the “where” and “what”: solid dosage forms, recombinant proteins, PTH-only coverage, specific protease inhibitor species/categories, NAC/NAD sodium salt forms, and added excipients/coatings.
• Design-around is most feasible by changing enhancer chemistry or salt form and by avoiding the paired-protease/enhancer synergy evidence framework used to support the patent’s functional claim term.

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FAQs

1. What is the single most important element to avoid infringement?
   The enhancer scaffold: NAC/NAD (and claimed salts).

2. Can a product avoid the patent by changing the protein target?
   Yes, if the protein is not in the enumerated list or does not meet the ≤100,000 Da constraint, the claim 1 composition basis fails.

3. Do omega-3 fatty acids or EDTA need to be present for infringement?
   No. They appear in dependent claims (10-11, 22-23), so they increase match probability only if asserted.

4. How do protease inhibitors affect claim strength?
   Protease inhibitor selection determines whether the accused product fits dependent claims 6-8 (and method equivalents), which often provide clearer infringement mapping.

5. Why is the “synergistically increase bioavailability” term central in disputes?
   It is functional and can become a litigation proof requirement and a validity vulnerability under obviousness arguments that the combination is predictable.

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References

[1] United States Patent 10,010,503 (claims as provided).

Details for Patent 10,010,503

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bayer Healthcare Pharmaceuticals Inc.	TRASYLOL	aprotinin	Injection	020304	December 29, 1993		2035-11-10