US 5182258

I'll search for authoritative records on this specific patent number.

Now let me check for any litigation or CAFC docket activity, and retrieve the claim text.

Let me pull the actual granted claim set for US5182258.

Search scope note

I searched for US 5,182,258 specifically (USPTO/Google Patents/PubChem/Justia/FreePatentsOnline, and Federal Circuit 2026 docket material). I found no litigation, IPR, or CAFC appeal involving patent 5,182,258. The 2026 Federal Circuit documents that surfaced (Collision v. Samsung, Implicit, Spero v. Mercedes) are unrelated to this patent number. Note also that the number "5182258" collides with an unrelated Japanese patent/gazette number (JP 5182258, Yoshitomi, solder alloy / JP-A-5182258, 1976) — those are not the U.S. patent and should not be conflated.

US 5,182,258 — bibliographic record

Discrepancy flag: one aggregator (Unified Patents portal) displayed the priority date for US‑5182258‑A as "1989‑03‑19." The authoritative full text and the other databases give 1989‑03‑20. I treat 1989‑03‑20 as correct, but note the inconsistency per your literal-interpretation rule.

Family: priority was subsequently claimed by US 5,283,236 (filed 1992‑10‑26) and US 5,278,142 (filed 1992‑10‑26). PubChem lists the family as US‑5182258‑A and US‑5283236‑A. WO 97/49386 cites "US 5182258 A (ORBON CORP), 26 January 1993, 1–16," indicating the patent carried claims 1–16.

Abstract (as issued)

Compositions and methods for systemic delivery of polypeptides through the eyes are disclosed. The compositions include a systemically active polypeptide at a concentration such that the composition is substantially isotonic with tear fluid. The compositions may include a permeation-enhancing agent to aid systemic absorption of higher molecular weight polypeptides, as well as peptidase inhibitors. Therapeutically effective amounts of the polypeptide compositions can be administered to the eyes where the drug passes into the nasolacrimal duct and becomes absorbed into circulation.

Independent claims — plain-language overview

The full claim set was not retrievable from my searches (the granted text I could access ends in the Detailed Description). Based on the patent's own Summary of Invention, the claim set covers four statutory embodiments — two compositions and two methods:

1. Composition / ocular delivery device (systemic, nasolacrimal). A pharmaceutical composition for systemic delivery by ocular administration and absorption in the nasolacrimal duct, comprising a systemically active polypeptide in a pharmaceutically acceptable vehicle, where the polypeptide concentration is such that the composition is substantially isotonic with tear fluid, optionally with a permeation-enhancing agent to boost nasolacrimal absorption into the systemic circulation.

2. Composition in an ocular delivery device. A composition comprising a systemically active polypeptide in an ocular delivery device (e.g., matrix‑type insert, soft contact lens, capsule‑type device), the device being formulated to release polypeptide into tear fluid at a rate that does not significantly disrupt tear‑fluid tonicity.

3. Method — topical instillation. A method of systemically delivering a polypeptide drug by administering into the eye a therapeutically effective concentration in a pharmaceutically acceptable vehicle, the concentration being less than the amount that causes significant ocular hypertonicity, with an effective amount of a permeation‑enhancing agent co‑administered, so the drug passes into the nasolacrimal duct and is absorbed into systemic circulation.

4. Method — ocular delivery device. A method of systemically delivering a polypeptide by administering a therapeutically effective amount in an ocular delivery device formulated to release the polypeptide into tear fluid without significantly disrupting tear‑fluid tonicity, whereby the drug passes into the nasolacrimal duct and is absorbed systemically.

Dependent-claim structure I could partially confirm (from an EveryPatent rendering of the 5,182,258 claim set — treat with moderate confidence): claims 6–8 depend from claim 1 and narrow the permeation‑enhancing agent to saponin, EDTA, fusidic acid, polyoxyethylene 9‑lauryl ether, polyoxyethylene 20‑stearyl ether, and glycocholate (claim 7 = polyoxyethylene 9‑lauryl ether; claim 8 = polyoxyethylene 20‑stearyl ether); claim 9 depends from claim 3 and specifies the drug is insulin. Claim 3 therefore appears to be a method claim (consistent with the "method of claim 3" dependency). The number of independent claims (likely 3–4) and their exact numbering cannot be stated with high confidence from the sources I retrieved.

Uncertainty statement

• High confidence: title, application number, inventor, assignee, filing date, issue date, priority date, legal status, abstract, and the four disclosed embodiments.
• Moderate confidence: the exact wording and numbering of claims 1–16 and which claims are independent. The claim text I found in aggregators overlaps the closely related continuation US 5,278,142 (which claims the "ocular delivery device" embodiments in claims 1–3), so the two must not be merged. For a filing-grade or litigation-grade quotation of the 5,182,258 claims, pull the grant from USPTO Patent Center / the official PDF rather than a third‑party mirror.
• No CAFC 2026 activity located for this patent; if you have a specific docket number you believe involves it, provide it and I can target that search.

Sources: Google Patents US5182258A, PubChem US-5182258-A, Justia – Orbon Corporation, uspto.report/patent/grant/5182258, EveryPatent 5182258, EveryPatent 5278142, WO1997049386A1.

I'll search for litigation involving US patent 5182258 across patent litigation databases.

Let me search patent litigation databases specifically.

Litigation Search: US Patent 5,182,258

Patent Identity Confirmation (interpreted literally)

Before reporting on litigation, I confirmed the patent I searched against:

• Patent number: US 5,182,258 (US5182258A)
• Title: "Systemic delivery of polypeptides through the eye"
• Inventor: George C. Y. Chiou
• Assignee: Orbon Corp (assignment recorded Oct. 27, 1989)
• Application: US 07/412,979, filed Sept. 26, 1989
• Priority: March 20, 1989 (CIP of Ser. No. 326,200)
• Granted: Jan. 26, 1993
• Status: Expired – Fee Related (anticipated expiration Jan. 26, 2010)
• Related family: US 5,283,236 and US 5,278,142 (both claiming priority to the '258 application)

Finding: No Known Litigation

I found no record of any litigation involving US Patent 5,182,258. Specifically:

• No district court infringement suits (D. Del., E.D. Tex., N.D. Cal., etc.) naming this patent.
• No Court of Appeals for the Federal Circuit appeals.
• No Patent Trial and Appeal Board proceedings (IPR/PGR/CBM) against the patent.
• No complaints listed against assignee Orbon Corp. involving this patent.

Evidence and Sources Consulted

Important Caveats

1. Interpretation rule honored: Searches for "5182258" returned several unrelated identifiers that must not be conflated with the US patent — e.g., JP 5182258 (a Yoshitomi chemical / a J-GLOBAL solder-alloy patent), a Florida LLC FEI number, and a Chinese environmental-penalty record. None involve US 5,182,258.
2. Database limitation: I could not exhaustively query PACER, Docket Navigator, or Lex Machina (paywalled). My conclusion rests on free/public sources (Google Patents, Unified Patents portal, Justia, CourtListener, PubChem) and web search.
3. Practical context: The patent expired for fee non-payment in 2010 and is assigned to a small entity (Orbon Corp). The absence of litigation is consistent with an expired, low-assertion patent, but "not found" is not the same as "provably never filed."

Bottom Line

No litigation is known for US Patent 5,182,258. If you need a definitive negative, I recommend a targeted PACER/Docket Navigator or Lex Machina query on the exact patent number and on "Orbon Corp" as a party — but on the available public record, there are no plaintiffs, defendants, case numbers, jurisdictions, or outcomes to report.

I'll start by checking the canonical PTAB record and running targeted searches to see whether any AIA trial proceedings exist for this patent outside the ODP ingest.

Let me run a couple more targeted searches to confirm the negative and check for related litigation/appeal history.

PTAB / AIA Trial Review — U.S. Patent No. 5,182,258

Patent: U.S. 5,182,258 — Systemic delivery of polypeptides through the eye
Inventor: George C. Y. Chiou | Original assignee: Orbon Corp.
Application: 07/412,979 | Filed: 1989-09-26 | Priority: 1989-03-20 (CIP of 07/326,200)
Granted: 1993-01-26 | Status on file: Expired – Fee Related; anticipated expiration 2010-01-26
Source of record: https://patents.google.com/patent/[US5182258](/patent/US5182258)/en

Proceedings overview

There are zero AIA trial proceedings on file for U.S. 5,182,258 — the canonical USPTO ODP "PTAB proceedings on file" block returns an empty list, and independent web searches surfaced no IPR, PGR, or CBM proceeding, no institution decision, and no Federal Circuit appeal involving this patent number. The bottom line for a defendant is not "this patent is hardened by surviving IPRs" — it is that the patent is expired and structurally foreclosed from the AIA trial regime, so the absence of PTAB activity tells you nothing about claim strength. Do not read the empty docket as validation; read it as a patent whose term ended before AIA trials existed in usable form.

Because the requested per-proceeding format presupposes at least one proceeding, I am substituting a verified-negative analysis rather than inventing case numbers.

Eligibility screen — why no AIA trial exists or is possible

AIA trials simply could not have reached this patent in any economically rational way. The empty PTAB docket is structural, not evidentiary.

Strategic summary

1. Claim status: everything is untested; nothing is canceled. No IPR or PGR certificate has ever issued against 5,182,258, so there is no claim-level cancellation record. The claims as granted in 1993 — the composition claims (systemically active polypeptide in a pharmaceutically acceptable vehicle, present at a concentration such that the composition is substantially isotonic with tear fluid, plus a permeation-enhancing agent) and the ocular-delivery-device claims — stand as issued and have never been narrowed or amended by any post-grant proceeding. That is not a defensive benefit here: it simply means no one had a reason to attack a patent that ceased to have commercial life in 2010.

2. Estoppel landscape: none, by definition. Section 315(e)(2) estoppel attaches only to a petitioner whose IPR reached final written decision. With no instituted trial, there is no estoppel chain, no privity question, and no defensive-aggregator footprint to trace. The corollary is also true: there is no FWD to cite if you are accused today.

3. The real defense is expiry, and it lives outside the PTAB. The patent record shows Expired – Fee Related with an anticipated expiration of 2010-01-26 — the end of the 17-years-from-grant term (greater-of-17/20 rule for pre-URAA patents in force on 1995-06-08; 20 years from the 1989-09-26 filing would have been earlier). A defendant's dispositive point is therefore not invalidity but unenforceability of an expired right: no injunctive exposure, and any § 286 six-year damages lookback closed no later than 2016-01-26. Note carefully that lapse/expiry is not a merits adjudication of validity — you should not represent to a court that the claims have been "held invalid."

4. Family check is warranted. The record shows related continuations/divisions from the same 07/412,979 lineage — U.S. 5,283,236 and U.S. 5,278,142 (both naming Chiou, both from applications filed 1992-10-26 and issuing in early 1994). Those are subject to the same term math and are likewise long expired, but if a demand letter cites a "family" of Chiou eye-delivery patents, verify each one's maintenance-fee and expiry status individually rather than assuming symmetry.

5. Pattern signals: none. No repeat petitioner, no Unified Patents or other aggregator involvement, no patent-owner appeal activity, no PTAB trial history whatsoever. This is a 1980s-era academic/startup pharma patent that never entered the modern assertion economy.

Recommended next steps

If you are a defendant or recipient of a demand citing 5,182,258:

• Verify expiry first, before spending money on prior art. Pull Maintenance Fee Events and the Patent Term Adjustment/Term extension tab in USPTO Patent Center (https://patentcenter.uspto.gov/) for the patent itself and for U.S. 5,283,236 and U.S. 5,278,142. If all three show expired status, the demand is facially deficient and the response is a dated expiry letter, not an invalidity position.
• Do not cite a PTAB Final Written Decision — there is none. There is no decision to link to on PTAB E2E (https://ptacts.uspto.gov/ptabweb/) and nothing on CourtListener or the Federal Circuit docket. Any letter or brief asserting that "the PTAB invalidated these claims" would be sanctionable, and any representation that claims were sustained would be equally unsupported — the merits were never reached.
• If the demand instead cites a different, later-issuing member of this family (the specification's permeation-enhancer and nasolacrimal-absorption disclosure has been cited as prior art by later ophthalmic-formulation patents), treat it as a different patent and re-run this analysis from scratch.

Trial-stage milestones: none to track. There is no institution decision deadline, no oral hearing date, and no statutory one-year FWD deadline, because no petition has ever been filed.

Caveat on search scope: the ODP block is authoritative and negative; my corroborating searches covered PTAB decisions, PTAB E2E, and general web/patent aggregators. I did not run an exhaustive district-court docket sweep, so I cannot affirmatively rule out 1990s-era infringement litigation involving Orbon Corp. Identifier collisions are also heavy here — "5182258" also resolves to a Japanese solder-alloy patent (JP 5182258), a Florida LLC FEI number, and U.S. Trademark Registration 5,182,258 ("OPEN CHAIR," Satellite Healthcare) — so cross-check any hit before relying on it.

If you have a docket number or demand letter in hand, provide it and I will confirm whether it implicates this patent or a family member, and whether any non-PTAB post-grant vehicle (e.g., an ex parte reexamination) was ever requested.

I'll research this patent's ownership record across the available sources.

US 5,182,258 — Ownership & Assignment Reconstruction

"Systemic delivery of polypeptides through the eye" · Appl. 07/412,979 (filed 1989-09-26) · Granted 1993-01-26 · Priority 1989-03-20 (CIP of Ser. No. 07/326,200)

Source-access caveat (read first): The USPTO Assignment Center is a JavaScript-driven search application that could not be queried directly in this session. The recorded-assignment data below is taken from Google Patents' legal-events/assignment rendering of this patent's file (https://patents.google.com/patent/US5182258A/en, fetched 2026-09-26). That rendering exposes the assignment date, conveyor, assignee, correspondent and conveyance type, but it does not expose the reel/frame number. I have therefore not invented reel/frame values. Every reel/frame placeholder below is marked as unretrieved, and the record should be verified at https://assignmentcenter.uspto.gov/ by searching patent number 5182258.

Inventors

• Chiou's Texas A&M affiliation is confirmed by his own contemporaneous publication on this exact work: Chiou, Chuang & Chang, "Reduction of Blood Glucose Concentration With Insulin Eye Drops," Diabetes Care 11(9):750–751 (Oct. 1988), byline "Institute of Ocular Pharmacology, Department of Medical Pharmacology and Toxicology, Texas A&M University College of Medicine, College Station, TX 77843." The spec's working examples (rabbit insulin/enkephalin/TRH/LHRH/glucagon studies) match that lab's output.
• Pattern note — inverted from the classic warning sign. The brief flags "all inventors departing the original assignee within 12 months of filing" as a fire-sale precursor. Here the opposite is true: the sole inventor founded the assignee. Chiou founded Orbon in 1988, one year before this application was filed, and later founded two more ophthalmic start-ups (Univision, 1996; MacuClear, 2006) — per a Taiwanese biotech-industry profile of him (IBMI / Taiwan-healthcare news feature; cite.com.tw author biography). This is inventor-owned-startup behaviour, not abandonment-of-employer behaviour.
• Public-record note worth flagging for title risk: the patent was not assigned to Texas A&M despite the inventor's faculty appointment and the university's lab being the situs of the work. Whether A&M had an obligation to assign (Bayh-Dole / institutional IP policy) is outside what I can verify — I have found no A&M assignment, lien, or later nunc-pro-tunc record.

Original assignee

Orbon Corporation ("ORBON Corp"), assignee of record on the issued patent.

• What it is: a privately held ophthalmic drug-development company founded by the inventor in 1988 — i.e., a genuine operating R&D concern, not a licensing vehicle. Its stated field is ocular/systemic peptide drug delivery, consistent with the patent.
• Product embodying the claims: no evidence of a commercialised product. The claim set covers peptide eyedrop formulations and ocular delivery devices; the underlying science was published extensively (insulin eyedrops, glucagon eyedrops, enkephalin, TRH, LHRH, calcitonin), and Orbon is attributed a small portfolio that includes WO9924019A1 (stabilized dry pharmaceutical compositions) and WO0130337A2 (ophthalmic formulation of dopamine antagonists), but I found no marketed drug, NDA/ANDA, or revenue-bearing product tied to this patent family.
• Current status: no evidence of dissolution, bankruptcy, or acquisition in the sources retrieved. Google Patents lists the current assignee as the same entity — ORBON Corp C/O THOMAS L BARTON HOLTZMANN WISE & SHEPARD — i.e., no post-1989 ownership change is reflected anywhere in the record. Legal status is Expired – Fee Related with an "anticipated expiration" of 2010-01-26.
• Ambiguity I will not paper over: a GoodIP assignee page for "ORBON CORP" aggregates 12 filings including 1999–2001 applications by inventors Richeal, Hemmes, Senatori, McKinnon, Chen, Loong-Lim — names with no connection to the Texas A&M ophthalmic-pharmacology group. GoodIP appears to be merging name variants, and I could not confirm whether those later filings belong to the same Orbon Corporation or to an unrelated entity using the same name. Treat the 12-patent aggregate as unverified.

Assignment timeline

One (1) recorded assignment exists for US 5,182,258. There is no post-issuance chain: no re-assignment, no security interest, no merger, no change of name, no release, no correction.

• 1989-10-27 (executed and recorded same date) — Reel unretrieved / Frame unretrieved
  • Conveyance: Assignment of Assignors' Interest
  • Assignor: George C. Y. Chiou (sole inventor)
  • Assignee: Orbon Corporation, c/o Thomas L. Barton, Holtzmann, Wise & Shepard
  • Correspondent: Thomas L. Barton, Holtzmann, Wise & Shepard (assignee's address of record is the firm's c/o address). ⚠️ This is the only appearance of this correspondent in the chain. A single appearance is not a recurrence finding, and I could not retrieve the other reel/frame entries needed to test whether Barton recurs on the sibling patents (US 5,278,142 / US 5,283,236) — flagging as unverified, not as a pattern.
  • Context: original inventor-to-company assignment — the founder-inventor conveying his rights to the start-up he had just formed (Orbon, founded 1988). Not a fire-sale, not a securitisation, not a transfer to an asserter.

Related-family note (same assignee, not a separate recorded assignment to this patent): two divisionals of 07/412,979 — US 5,283,236 (Appl. 07/966,706) and US 5,278,142 (Appl. 07/966,877) — were both filed 1992-10-26, roughly three months before the parent issued. Both are cited in later art as belonging to ORBON CORP (e.g., the search report of WO1997049386A1 lists "US 5182258 A (ORBON CORP)" and "US 5283236 A (ORBON CORP)"). No assignment away from Orbon on either is reflected in the sources retrieved.

Litigation cross-check: I found no infringement suit naming US 5,182,258, and no assertion by Orbon against any party. Searches for the patent number returned only false positives (a Florida LLC's FEI number, a Chinese listed-company shareholder share count, and an unrelated Japanese Patent No. 5182258 for a solder alloy). No RPX/Unified Patents asserter-directory hit for Orbon.

Timeline diagram

timeline
    title Ownership of US 5182258
    1988 : Orbon founded by inventor Chiou
    1989 : Parent CIP filed Mar 20
         : This application filed Sep 26
         : Inventor assigns rights to Orbon Oct 27
    1992 : Two divisionals filed Oct 26
    1993 : Patent US 5182258 issues Jan 26
    2010 : Recorded term end Jan 26

NPE / troll-pattern signals

Verdict

Insufficient data — the literal test in the rubric is met: the file contains only the original assignment (inventor → Orbon, 1989-10-27) and no later links.

There is no evidence of any NPE pattern: the sole recorded conveyance is the founder-inventor assigning to his own 1988-vintage ophthalmic drug-development company, the current assignee of record is still Orbon, and I found no assertion, no litigation, no bankruptcy, and no aggregator in the chain. The one soft flag worth carrying forward is the c/o Thomas L. Barton, Holtzmann, Wise & Shepard correspondence address on the 1989 record — combined with the fact that Orbon's owner also spawned later entities (Univision 1996, MacuClear 2006), a portfolio-migration question (did the family ever move, and to whom?) remains open and cannot be closed without the reel/frame data. Verify at the USPTO Assignment Center:

• Assignment Center: https://assignmentcenter.uspto.gov/ — search patent 5182258
• Google Patents legal events: https://patents.google.com/patent/US5182258A/en#legal-events
• USPTO Patent Center: https://patentcenter.uspto.gov/ (appl. 07/412,979) for the full assignment abstract and reel/frame

Do not treat the c/o law-firm address, or the Richeal/Hemmes/Senatori "Orbon Corp" filings aggregated by GoodIP, as evidence of shell-entity or NPE activity — both are unverified and, on the present record, unsupported.

I'll search for US patent 5,182,258 in the USPTO database and identify the prior-art references cited against it.

Note on dates: The task prompt says "Current Date: April 26, 2026," but my operating date is 2026-09-27. I'll flag this inconsistency but proceed with the search.

Now let me pin down the complete list of cited references and the actual claims of the '258 patent.

Tool-limit note

I ran out of search budget mid-task, so some identification details below could not be independently verified and are flagged as such. I have not filled gaps with guesses.

1. Scope and source limitations (read first)

• USPTO full-text / PatentCenter / PAIR was not successfully loaded in this session. My citation data comes from PubChem's patent record for US-5182258-A (which itemizes the search-report citations), Google Patents US5182258A, uspto.report/patent/grant/5182258, everypatent.com/comp/pat5182258.html, and the divisional US 5,278,142 text (FreePatentsOnline/everypatent), whose specification is substantially identical.
• The full text supplied in the prompt omits the claims section. PubChem lists only "170 items" under citations without rendering them all. I therefore reconstructed the claim scope from secondary sources and flag where I am uncertain.
• Date inconsistency (flagged per instructions): the task header says "Current Date: April 26, 2026," while my operating date is 2026-09-27. This does not affect the analysis, but I note it rather than silently reconcile it.

2. Patent identity — confirmed, with a literal-reading warning

Do not auto-correct / do not conflate. Searches for "5182258" continue to surface a Japanese patent 5182258 (a Yoshitomi solder-alloy / J-GLOBAL record, application 2009-200350, publication 2009-297789). It is unrelated to the US patent and its cited references (lead-free solder art) must not be folded into this analysis.

Minor discrepancy flagged: the Unified Patents portal record listed the '258 priority date as 1989-03-19, whereas Google Patents, PubChem, and the '142 specification all state 1989-03-20. One-day discrepancy in a secondary source; the primary record supports 1989-03-20.

3. Claim scope of the '258 patent (partial reconstruction)

The supplied full text has no claims. From everypatent's copy of US 5,182,258 I recovered fragments of claims 3, 6, 7, 8, and 9, which are method claims:

• Claim 1 — a method (claim 6 depends from it and recites "the method of claim 1 wherein the permeation-enhancing agent is at least one agent selected from the group consisting of saponin, EDTA, fusidic acid, polyoxyethylene 9-lauryl ether, polyoxyethylene 20-stearyl ether, and glycocholate").
• Claim 3 — a method wherein the drug is insulin (claim 9 depends from it).
• Claims 7–8 — wherein the enhancer is polyoxyethylene 9-lauryl ether / polyoxyethylene 20-stearyl ether.

The related divisional US 5,278,142 carries the device/composition claims (claim 1: composition with "tonicity equivalent to the tonicity of 0.5% to 1.8% sodium chloride solution"; claim 2: method using an ocular delivery device; claim 3: co-administering a permeation enhancer). The "0.5%–1.8% NaCl" isotonicity limitation is the family's core numerical limitation.

⚠️ I could not recover the verbatim text of claim 1 of the '258. Any §102 mapping to "claim 1" below is therefore provisional.

4. Prior-art references cited in US 5,182,258

PubChem's record for US-5182258-A lists the following as search-report citations (its "SEA" tag).

A. Patent documents

B. Non-patent literature (NPL)

(Refs. 20–24 appear in the specification's own background discussion and are documents of record in the file; refs. 6–19 are the ones PubChem tags as search-report citations.)

5. §102 analysis (pre-AIA 35 U.S.C. §102 governs — 1989 filing)

Framework. This application was filed 1989-09-26 (CIP parent 1989-03-20), so pre-AIA §102 applies.

• §102(b) statutory-bar critical date: publications/patents more than one year before the effective filing date → before 1988-09-26 (or before 1988-03-20 for subject matter carried over from Ser. No. 07/326,200).
• §102(e): a US patent granted on an application filed before the applicant's invention date is prior art as of its filing date — this is how US 4,959,217 could qualify even though it appears to issue around 1990.
• §102(a): an inventor's own 1989 publications are not §102(a) art against him (his own work is not "by others" and cannot predate his own invention), and 1989 publications are also outside the §102(b) one-year window. This is why ref. 10 (Chiou 1989 J. Ocul. Pharmacol. 5(1):81–91) is probably not available as prior art at all.

Key legal point — anticipation vs. obviousness. Every reference above is drawn from one of four buckets: (i) ocular delivery devices (refs. 1, 5, 19, 20, 21), (ii) mucosal/nasal polypeptide delivery with enhancers (refs. 3, 11, 13, 18, 24), (iii) ocular pharmacokinetics/peptidases/barriers (refs. 14–16, 22, 17), or (iv) injectable insulin background (ref. 23). None of them, on its face, discloses the full combination claimed: a systemically active polypeptide administered into the eye at a concentration substantially isotonic with tear fluid (the family's 0.5%–1.8% NaCl equivalent), optionally with a permeation enhancer, absorbed via the nasolacrimal duct into systemic circulation. That combination is a §103-type combination of teachings, not a §102 anticipation. Accordingly:

6. Ranking of most relevant prior art

1. Chiou & Chuang, J. Ocul. Pharmacol. 4(2):165–177 (1988) — same inventor, same ocular systemic-delivery concept; the single most dangerous §102(b) reference if its public-availability date precedes the critical date.
2. Christie & Hanzal, J. Clin. Invest. 10:787–793 (1931) — the only true ocular-polypeptide-delivery prior art of record; anticipated the concept but with rabbit data the patent distinguishes.
3. Aungst et al., Pharm. Res. 5(5):305–308 (1988) + EP 0 115 627 + Hirai 1981 — collectively supply the "permeation enhancer for polypeptide mucosal absorption" element (claims 6–8).
4. Ueno 1983 / Saettone 1984 / Park 1984 / US 4,093,709 — supply the ocular-device element relevant to the divisional '142 claims.

7. What remains unverified (do not treat as established)

• Verbatim claim 1 of US 5,182,258, and the complete claim set (likely ≥9 method claims). The prompt's full text omits claims.
• Titles/dates/inventors for US 4,186,184, US 4,959,217, and WO 87/03473 — examined but not confirmed; I have deliberately not supplied descriptions.
• Exact publication dates for Chiou 1988 (J. Ocul. Pharmacol. 4(2); Life Sci. 43(6)) — the pivotal §102(b) fact.
• Assignee/applicant of EP 0 115 627.
• Anything from PACER/PatentCenter, Docket Navigator, or Lex Machina — not accessed (consistent with the earlier litigation section, which also relied on free/public sources only).

No contradictions with the previously generated litigation section were found — patent number, title, inventor, assignee, filing/priority/grant dates, and expired status all reconcile. The only discrepancies identified are external (the unrelated JP 5182258 solder-alloy patent; and the 1989-03-19 vs. 1989-03-20 priority-date variance on the Unified Patents portal).

Recommended next step for a definitive §102 record: pull the '258 file wrapper via USPTO PatentCenter to obtain the Form PTO-1449 / PTO-892 listing exactly which references the examiner applied and against which claims, plus the verbatim claim set (columns 8–12 of the printed patent).

I'll gather prior-art references relevant to ocular/systemic polypeptide delivery, building on the bibliography already established.

Let me pull the cited prior-art patents and the key pre-1988 references.

Let me retrieve the issued claims and additional prior-art references cited on the face of the patent.

Obviousness Analysis — US 5,182,258 under 35 U.S.C. § 103(a)

Patent: US 5,182,258 A — Systemic delivery of polypeptides through the eye (Chiou; Orbon Corp)
Filing: 1989‑09‑26 (CIP of Ser. No. 326,200, filed 1989‑03‑20) — pre‑AIA §103 governs
Grant: 1993‑01‑26

Scope dependency (honored, not repeated): the earlier sections established the bibliographic record, the absence of litigation/PTAB/CAFC activity, and — critically — that the exact issued claim text could not be verified and that the '258 claim numbering must not be merged with '142/'236. That caveat governs this analysis: I analyze the four disclosed statutory embodiments and the claim groups the prior section partially confirmed, and I flag where a limitation-level mapping is provisional.

1. A confirmed contradiction-resolver for the earlier caveat

The earlier section warned that aggregator claim text for '258 might actually be '142 text. My search confirms the warning was well-founded: FreePatentsOnline's rendering of US 5,278,142 gives claim 1 as the device-composition, claim 2 as the device-method, and claim 3 as "The method of claim 2 further comprising coadministering an effective amount of a permeation-enhancing agent." That is a different dependency architecture from the '258 rendering the earlier section described (claim 3 = method; claim 9 = insulin; claims 6–8 = enhancer species depending from claim 1). So the two patents must be analyzed separately, and any §103 mapping below is keyed to the four embodiments in the '258 specification rather than to a mirrored claim set.

2. Legal framework

Pre‑AIA §103(a); Graham v. John Deere Co., 383 U.S. 1 (1966) (scope/content of prior art; differences; PHOSITA level; secondary considerations); KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007) (a claimed combination is obvious where the improvement is the predictable use of prior-art elements according to their established functions; "obvious to try" is enough where there is a finite number of identified, predictable solutions; market pressure or a design incentive to solve a known problem supplies the motivation). Also In re Schreiber / Rapoport line: preamble "intended use" language does not add patentable weight to an apparatus/composition claim — directly relevant to the "for systemic delivery by ocular administration and absorption in the nasolacrimal duct" preamble.

3. The prior-art universe (from the face of the patent + the background admissions)

Specification admissions that operate as prior art. The '258 background itself states that "much of the drug so administered is not absorbed by the eye … and enters the systemic circulation via the nasolacrimal system," and that "the nasolacrimal duct drains tears and other substances from the eye and is lined with absorptive mucosa." Under In re Fout-type reasoning, an applicant's own characterization of the art is usable against the claims.

⚠ Flag on the Chiou 1988 self-citations. Four of the most on-point references are the inventor's own 1988 papers. Because the CIP was filed 1989‑09‑26 and priority runs to 1989‑03‑20, these publications are less than one year before the critical date, so they are §102(a)/§103 art (swear-behind-eligible under Rule 131) rather than §102(b) art. This materially weakens their independent use but does not remove them from a §103 combination. This is the single most important procedural caveat in this memo and I could not verify from available sources whether a Rule 131 affidavit was filed.

4. Level of ordinary skill

A Ph.D. or M.S. in pharmaceutics, pharmaceutical chemistry, or pharmacology with ~2–5 years' experience in ophthalmic formulation/ocular drug delivery, or an M.D. in endocrinology/ophthalmology with formulation exposure. Such a person would know: (a) tear turnover and nasolacrimal drainage limit ocular residence time; (b) ophthalmic solutions are conventionally rendered isotonic with tear fluid (≈0.9% NaCl equivalent; tolerated range ≈0.5–1.8% NaCl); (c) absorption enhancers and peptidase inhibitors are standard mucosal-absorption tools. The '258 claims' own 0.5–1.8% NaCl-equivalent framing (carried in the sibling '142) is exactly the conventional ophthalmic range, underscoring that the isotonicity limitation reflects routine formulation, not invention.

5. Combination analyses

Combination A — Composition claims (polypeptide + vehicle + isotonic; and + enhancer)

Primary: Christie & Hanzal (1931) + Chiou & Chuang (1988), J. Ocul. Pharmacol. 4(2):165‑177.
Secondary: McClure (1975); Hirai 1978/1981; Aungst (1988); Lee (1985/1987).

• Christie & Hanzal supply the ocular → systemic → hypoglycemic result for insulin.
• Chiou & Chuang (1988) supply the generalization to a MW 300–3500 polypeptide class, delivered in PBS (isotonic), with the explicit conclusion that ocular instillation is a workable systemic route.
• McClure supplies the mechanism (nasolacrimal drainage to absorptive nasal mucosa), which is also the specification's own admitted understanding.
• The "substantially isotonic with tear fluid" limitation is a classic result-effective variable recognized in the prior art and optimized by routine experimentation: isotonicity is a standing requirement of every ophthalmic vehicle (EP 0115627; US 4,186,184; standard formularies). The claims' own broad 0.5–1.8% NaCl tolerance cuts against narrow criticality.
• The enhancer element is met by Hirai 1978: saponin, sodium glycocholate, BL‑9 at 1% for insulin — the very species recited in the '258 dependent claims (per the earlier section's partial reading: saponin, EDTA, fusidic acid, BL‑9, POE‑20‑stearyl ether, glycocholate; and see Table 3 of the '258, which reports glycocholate ≈2×, BL‑9 ≥3×, EDTA 3×, fusidic acid ≈4× enhancement). Aungst 1988 confirms the enhancer set works for insulin across several mucosal sites, i.e., the enhancer effect is a membrane-level, site-independent property.

Motivation (KSR rationales):

1. Known problem + known solution. The patent's own background recites the problem (injections painful, non‑sterile, variable absorption per Galloway 1981, poor compliance). Chiou 1988 explicitly frames the ocular route as the solution.
2. The references point to the same physiological tissue. The nasolacrimal duct terminates at the nasal mucosa; locating insulin at the nasal mucosa is precisely what Hirai does. A POSITA reading McClure and Hirai together would have had an explicit reason to expect an ocularly instilled peptide to encounter the same mucosa Hirai was already enhancing. This is the strongest single motivation in the record.
3. Finite, predictable candidate set. Hirai 1978 enumerates a small closed list of enhancers (saponin, glycocholate, BL‑9) — KSR "obvious to try" with predictable results.
4. Use-language preamble carries no weight. Under Schreiber, "for systemic delivery by ocular administration and absorption in the nasolacrimal duct" is an intended use, not a structural limitation.

Combination B — "Ocular delivery device" composition claims

Primary: Ueno (1983) + Saettone (1984) + WO 87/03473/US 4,959,217.
Secondary: Park (1984); Chiou 1988.

Ueno expressly discloses matrix‑type, capsule‑type (Ocusert®) and silicone‑rubber ocular devices for controlled release; Saettone discloses polymeric inserts controlling ophthalmic bioavailability; WO 87/03473 discloses sustained/delayed release of macromolecules. The sole twist in the '258 device claims is the rate limitation ("release … such that the concentration in tear fluid does not significantly disrupt tonicity") — which is nothing more than the inherent consequence of using an isotonic loading concentration in a known device, i.e., the predictable use of a prior-art element for its established function. Motivation: sustained release directly addresses the known short ocular residence time (Saettone; Lee 1987) and the known hypertonicity problem that the specification itself attributes to concentrated drops.

Combination C — Method claims (topical instillation; concentration below "significant ocular hypertonicity")

Primary: Chiou & Chuang 1988 + Christie & Hanzal 1931.
Secondary: Hirai 1978/1981; Aungst 1988; Diabetes Care 11:750‑751 (insulin eyedrops lowering blood glucose).

The method steps are "administer a therapeutically effective concentration into the eye … in a pharmaceutically acceptable vehicle," plus a co‑administered enhancer. Every step is disclosed: instillation (Christie; Chiou), vehicle (PBS, Chiou), effective concentration below hypertonicity (routine — the patent itself concedes >10% w/v is hypertonic, converting the limitation into "use less than ~10%"), and enhancer co‑administration (Hirai). Where the claimed method is limited to insulin (per the earlier section's reading of claim 9), it is squarely met by Christie (insulin, ocular, systemic glucose effect) and by Chiou's own Diabetes Care 1988 abstract on insulin eyedrops.

Combination D — Peptidase-inhibitor-dependent claims (if any)

Lee 1986 (enkephalins hydrolyzed in cornea) + Hirai 1981 (bile salts inhibit proteolytic enzymes) + Aungst 1988 (aprotinin as an absorption promoter for insulin) + the '258-cited peptidase inhibitors (Leu‑Leu, bestatin, thiorphan, puromycin, captopril, bacitracin, PMSF, pepstatin A, aprotinin). Any such claim is an obvious combination of a known problem (ocular peptidases) with known inhibitors of the same class. Notably, the '258 results themselves show Leu‑Leu did not improve insulin absorption — so this element also fails the "unexpected results" test in the applicant's own data.

6. Secondary considerations (Graham prong 4)

7. Where the §103 case is weakest / what could defeat it

1. Claim text is unverified. Without the certified claims I cannot map the "isotonic"/"hypertonicity" and enhancer limitations to specific claim numbers, or confirm which claims are independent. Any validity opinion must be re‑run against the granted text.
2. The best references are the inventor's own. A Rule 131 swear‑behind (or proven earlier invention) on the four 1988 Chiou papers would remove the most damaging art. I could not determine whether the file wrapper contains such an affidavit. If those papers are removed, Combinations A and C lose their most direct "polypeptide class through the eye" teaching and would rest on Christie (1931, insulin only, conjunctiva only) + McClure (mechanism) — a weaker but still colorable case.
3. Christie is dated and conjunctival‑specific; a POSITA could argue it does not fairly teach the nasolacrimal route (that teaching comes from McClure, a different drug class).
4. CAFC/PTAB precedent is unavailable — no controlling or persuasive decision construing these limitations exists (consistent with the prior section's finding of no litigation).
5. Unverified face citations. US 4,093,709 and US 4,186,184 are listed as cited documents but I did not verify their titles/content in this session; Combination B should be re‑grounded on their actual disclosures before being relied upon. WO 87/03473 A1 is the better‑grounded device reference (its US counterpart US 4,959,217 is confirmed as "Delayed/sustained release of macromolecules," Syntex, filed 1986‑05‑22).

8. Bottom line

Yes — a strong prima facie §103(a) case exists against every disclosed embodiment, and it rests on KSR‑compliant rationales rather than on hindsight:

• Composition claims: obvious over Christie & Hanzal (1931) + Chiou & Chuang (1988, J. Ocul. Pharmacol. 4:165‑177) + McClure (1975), with the isotonicity limitation supplied as a conventional, result‑effective ophthalmic formulation parameter; and obvious over that trio further in view of Hirai (1978) and/or Aungst (1988) for the enhancer element.
• Device claims: obvious over Ueno (1983) + Saettone (1984) + WO 87/03473 in view of the ocular‑systemic teaching of Christie/Chiou.
• Method claims: obvious over Chiou & Chuang (1988) + Christie & Hanzal (1931), further in view of Hirai (1978) and Aungst (1988).

The single most powerful fact for the obviousness challenger is the route identity of the target tissue: the references themselves explain that ocularly instilled drug reaches the nasal mucosa via the nasolacrimal duct, while a separate body of art (Hirai) teaches exactly how to enhance insulin absorption at that nasal mucosa. Combining an ocular vehicle with a nasal enhancer is the predictable use of a known element for its established function.

Confidence: high on the reference teachings and the KSR rationales; moderate on limitation‑by‑limitation claim mapping (granted claim text unverified); unknown whether a Rule 131 affidavit neutralizes the Chiou 1988 self‑art.