US 5292509

I'll search for this specific patent number across the requested sources.

Now let me check for any litigation or CAFC 2026 docket activity involving this patent.

Coverage note

I searched for the exact string 5292509 / 5,292,509 across Google Patents, Unified Patents, Justia, EPO Global Patent Index, and general litigation/docket sources (PACER-derived dockets, Docket Alarm, UniCourt, CourtListener). I found no district-court case and no Federal Circuit docket (2026 or otherwise) naming U.S. Patent 5,292,509. Two important caveats: (a) I could not query PACER or the CAFC CM/ECF docket directly, so my "no litigation" finding is based on indexed web sources, not a native docket pull; and (b) the patent expired in 2011, which makes live infringement litigation unlikely. Treat the litigation portion of this report as "no evidence found," not "confirmed none."

Everything below is grounded in the Google Patents record and the patent's own full text. I did not substitute any similar patent number (e.g., 5,292,549, 5,292,593, 5,292,509-adjacent) — all statements are for 5,292,509 only.

Bibliographic data — US 5,292,509

Assignee history (as recorded): Google Patents lists the original assignee as St Louis University. A 2004-12-02 reassignment entry records an assignment from Bethesda Eye Institute to Hageman, Gregory S. (effective 2004-11-16). Separately, the EPO search report for EP 0756636 lists the PCT sibling WO 9116070 A1 as belonging to BETHESDA EYE INST, cross-referenced to US 5,292,509 (Hageman). These sources are not mutually consistent about the original owner — see uncertainties below.

Abstract (verbatim)

"A method for selectively and completely disinserting the ocular vitreous body, epiretinal membranes and/or fibrocellular membranes from the neural retina, ciliary epithelium and posterior lens surface of the mammalian eye as an adjunct to vitrectomy comprises administering to the eye an effective amount of a protease-free glycosaminoglycanase enzyme, such as chondroitinase ABC, adapted to disrupt and/or degrade chondroitin sulfate glycosaminoglycan/proteoglycan localized specifically to sites of vitreoretinal adhesion and thereby permit complete disinsertion of the vitreous body and/or epiretinal membranes."

The independent claim — plain-language overview

Claim 1 (the only independent claim) covers a method of treating a mammalian eye with three required elements in combination:

1. Purpose/context: selectively and completely disinserting the ocular vitreous body, epiretinal membranes, or fibrocellular membranes from the neural retina, ciliary epithelium, and posterior lens surface, as an adjunct to vitrectomy — i.e., the enzyme is an adjunct to, not a replacement for, surgical vitrectomy.
2. Step: administering to the eye an effective amount of an enzyme.
3. Functional limitation on the enzyme: the enzyme must disrupt or degrade chondroitin sulfate proteoglycan localized specifically to sites of vitreoretinal adhesion, thereby permitting complete disinsertion.

The inventive core is the third element: the functional definition of the enzyme by its target (chondroitin sulfate proteoglycan at adhesion sites). The claim does not name a specific enzyme. Note that the claim is a method-of-treatment claim — its novelty rested on the discovery that chondroitin sulfate proteoglycan mediates vitreoretinal adhesion, which is what the specification characterizes as "the first recognition of the presence of a specific chemical moiety in regions of vitreoretinal adhesions."

Dependent claims (2–9), in plain language:

• Claim 2 (dep. 1): the enzyme is a protease-free glycosaminoglycanase. This is the key narrowing — the specification and Example 7 emphasize that protease contamination caused severe toxicity.
• Claim 3 (dep. 2): the enzyme is one of protease-free chondroitinase ABC, chondroitinase AC, chondroitinase B, chondroitin 4-sulfatase, chondroitin 6-sulfatase, hyaluronidase, or β-glucuronidase.
• Claim 4 (dep. 1): effective amount is ~1 to 10,000 units.
• Claim 5 (dep. 1): effective amount is ~50 to 1,000 units.
• Claim 6 (dep. 1): administration by intravitreal, subvitreal, sublenticular, or posterior chamber route.
• Claim 7 (dep. 1): enzyme is delivered as a pharmacologically acceptable buffered solution.
• Claim 8 (dep. 7): the buffer is sodium acetate.
• Claim 9 (dep. 3): the enzyme is specifically chondroitinase ABC — the commercial embodiment (Seikagaku Kogyo, Tokyo; isolated from Proteus vulgaris).

Supporting experimental data in the specification (context for the claims)

• 25 U chondroitinase ABC / 1 hr → partial disinsertion; 100, 150, 240 U / 1 hr → complete.
• 10, 20, 50 U / 1 hr → not complete (posterior vitreous and anterior hyaloid detached, but vitreous base remained); 100 U → complete in one of two monkeys.
• 200 U: 10 min → no disinsertion; 15 min → partial; 20/30/45 min → complete.
• 75 U / 2 hr → complete.
• 20 U of protease-containing chondroitinase ABC → lens dislocation, massive orbital edema, retinal detachment — the toxicity contrast that motivates the "protease-free" limitations of claims 2 and 3.
• 40 U β-glucuronidase / 30 min → partial; 40 U heparitinase I & II / 30 min → partial; cathepsins A, B, D (25 U each, 90 min) → no disinsertion.

Prior art on the face of the patent: US 4,174,389 (Cope), US 4,524,065 (Bio-Specifics N.V.), US 4,696,816 (Brown); non-patent citations: Thomson, Am. J. Ophthalmol. 107:99 (1989) and Winkler et al., Arch. Ophthalmol. 103(11):1743–1746 (1985). Discussed in the specification: Moorhead et al. (Retina 5:98–100, 1985; Arch. Ophthalmol. 101:265–274, 1983), Shehab et al. (Invest. Ophthalmol. Vis. Sci. Suppl. 27:317, 1986), Yamagata et al. (Chem. Abstracts 68:84511g, 1968).

This patent is cited as prior art or background in a substantial downstream family, including US 5,495,536; US 5,716,617; US 5,855,883; US 5,888,798 (all American Cyanamid, Proteus vulgaris chondroitinases I/II); US 5,722,428 (Washington University); and AU 772884 B2 / the Ista hyaluronidase family.

Uncertainties and data conflicts (flagged explicitly)

1. Date discrepancies between databases. Google Patents (and the patent's own text) give priority 1990-04-16, filing 1992-06-05, issue 1994-03-08. Unified Patents' record shows 1990-04-15, 1992-06-04, 1994-03-07 — a uniform one-day offset, most likely a timezone/normalization artifact rather than a real difference. I treated the Google Patents/patent-face dates as authoritative, per the instruction to prefer the provided full text.
2. Assignee conflict. "St Louis University" (Google Patents), the 2004 assignment recording Bethesda Eye Institute → Hageman, and the EPO citation of the sibling WO 9116070 A1 to "Bethesda Eye Institute" cannot all be reconciled from the sources I retrieved. I cannot state with confidence which entity was the original applicant of record.
3. Claim/specification mismatch on dose. Claim 5 recites "approximately 50 and 1000 units," while the specification's preferred range is "approximately 100 and 1000 units." This is a real textual discrepancy in the record, not an OCR artifact I can dismiss. If claim 5 was amended during prosecution, the amendment history would explain it — I did not retrieve the file wrapper.
4. Figure callout anomaly. The Granted-Description text refers to "a monkey following treatment with chondroitinase ABC and vitrectomy (FIGS. 4A-8)" where "4A-B" is clearly intended, and later says other studies appear in "FIGS. 9-11" in a sentence where the cited figures are 11–13. These read as OCR/encoding errors in the retrieved text, but I am flagging them rather than silently correcting them.
5. Litigation/docket negative result. No CAFC or district-court docket referencing 5,292,509 surfaced in 2026 or any year. Because I could not query PACER/CM-ECF natively, this should be read as "no indexed evidence found." The 2011 expiry makes active enforcement litigation improbable but does not foreclose historical or declaratory-judgment activity that simply isn't web-indexed.
6. No PTAB activity found. I saw no IPR/PGR/CBM record for this patent in the retrieved results. This is a weaker negative than the litigation point because I did not query the PTAB docket directly.

I'll research litigation involving US Patent 5,292,509 using the sources you specified.

Bottom line

I found no litigation involving U.S. Patent No. 5,292,509 in any source I was able to reach. Based on the searches performed, there are no known infringement suits, declaratory judgment actions, IPRs/PGRs, or Federal Circuit appeals involving this patent. I am reporting that as "none found," not as a certified negative — see the caveats below.

What I searched (and what came back)

Cases identified

None. Because no case was found, there are no entries for plaintiff, defendant, jurisdiction, case number, filing date, or outcome. I am deliberately not inventing or inferring any docket to fill these fields.

Exclusion of similar numbers (per your instruction)

Several near-identical or overlapping identifiers surfaced and are not this patent; I did not treat them as US 5,292,509:

• JP5292509B2 — a Japanese patent on a "Portable electronic device, display control method, and display control program." Entirely unrelated subject matter.
• US5292513, US5292543, US5292637, etc. — adjacent-number patents appearing only in a 1994 patent-abstracts compilation.
• Family members of the same invention in other jurisdictions: WO1991016070A1, EP0528875A4/A1, JP3571715B2, AU653338B2 (titled "Enzymatic disinsertion of vitreous body"), CA2080700C, SG50581A1, ZA912770B. These are foreign counterparts, not U.S. litigation.

Why "no litigation" is plausible here

Three structural factors make the absence credible rather than merely an artifact of a failed search:

1. Claim type. All nine claims are method-of-treatment claims (administering a protease-free glycosaminoglycanase to disinsert the vitreous as an adjunct to vitrectomy). This is not a drug-product or formulation claim, so the usual Hatch-Waxman/ANDA enforcement pattern would not apply.
2. Expiry. The patent expired March 8, 2011 (Google Patents lists anticipated expiration; Unified Patents lists 2011-03-07). Any pre-expiry assertion window closed more than a decade ago.
3. No commercialized covered product found in the record. The specification points to chondroitinase ABC from Seikagaku Kogyo (isolated from Proteus vulgaris), and the later citing art (e.g., the American Cyanamid chondroitinase I/II family) builds on the disclosure rather than being sued over it. That citing activity is evidence of technological influence, not of litigation.

Important caveats

• Absence of evidence ≠ evidence of absence. My searches did not fully render the Unified Patents litigation caselist, PACER, Docket Alarm, RPX Insight, or CAFC dockets. A suit filed before 2011, or a state-court/settlement dispute never docketed publicly, could exist without surfacing in these results.
• Do not treat this as a freedom-to-operate or validity clearance. A null litigation result says nothing about the patent's validity, enforceability, or scope — only that no assertion was located.
• The patent's prosecution history includes a continuation of Ser. No. 509,367 (filed Apr. 16, 1990, now abandoned) and a later assignment from Bethesda Eye Institute to Gregory S. Hageman (recorded 2004). Ownership history is documented in the Assignment records, but that is chain-of-title activity, not litigation.

Recommended next steps for a definitive answer

If you need this certified for a diligence or FTO opinion, run these directly:

1. Unified Patents litigation portal — search the exact patent number in the case list at portal.unifiedpatents.com/litigation/caselist.
2. PACER — Docket Alarm or Bloomberg Law "Patent Litigation" search restricted to 5292509; also query by parties (St. Louis University, Bethesda Eye Institute, Hageman).
3. USPTO PTAB — ptacts.uspto.gov search for any IPR/PGR/CBM naming US 5,292,509 as the challenged patent.
4. CAFC — cafc.uscourts.gov opinion/order search for 5292509.
5. Delaware/state court dockets where St. Louis University or Bethesda Eye Institute has historically filed, if pre-2011 enforcement is a concern.

Summary: No litigation involving U.S. Patent 5,292,509 was located. Plaintiff, defendant, jurisdiction, case number, filing date, and outcome are all "none found."

I'll verify the "no proceedings" default against the live record before writing anything up.

Let me check for any litigation, reexam, or appeal activity tied to the patent or its family before concluding.

Proceedings overview

Total AIA trial proceedings on file: 0. Breakdown: 0 active, 0 claims invalidated, 0 claims sustained, 0 settled, 0 institution denials. The USPTO Open Data Portal returns no AIA trial proceedings for US 5292509, and independent web searches (PTAB dockets, USPTO PTAB E2E/PTAB Decisions, CAFC/CourtListener references, and third-party patent trackers) surfaced no IPR, PGR, or CBM involving this patent — I found nothing to flag, and I am not inventing a proceeding number to fill the section. The bottom-line defensive posture is therefore not "the patent has survived two IPRs and is hardened" and not "claims 1–5 have been canceled." It is a third, stronger posture for a defendant: the patent is expired and its enforcement window closed on 2011-03-08, roughly 18 months before the AIA trial regime even existed — any demand letter citing US 5292509 today has no live claim to assert, regardless of PTAB history.

Proceedings

None on file

• Type: N/A — no Inter Partes Review, Post-Grant Review, or Covered Business Method review has ever been instituted, petitioned, or terminated on US 5292509.
• Filed: N/A
• Status: N/A. For completeness on the prosecution side, the patent's own legal events (per the Google Patents file wrapper at https://patents.google.com/patent/US5292509/en) show only maintenance-fee payments (4-year on 1997-08-26, 8-year on 2001-08-23, 12-year on 2005-09-07) and a 2004 assignment from Bethesda Eye Institute to Gregory S. Hageman (reel/frame 015409/0040, effective 2004-11-16). No reexamination certificate, no reissue, no statutory disclaimer, and no certificate of correction appears — so there is no Office-side narrowing, only the untouched original claims 1–9.
• Judge panel: None — no panel ever convened.
• Petition grounds: N/A
• Institution decision: N/A
• Final Written Decision: None issued. No claim of US 5292509 has ever been canceled, confirmed, or construed by the Board. Claims 1–9 stand exactly as granted on 1994-03-08 — for whatever that is worth given the patent is expired.
• Settlement / termination: N/A
• Appeal: None. No Federal Circuit appeal from any PTAB decision on this patent exists, because no PTAB decision exists. (The '509 has appeared in Federal Circuit-adjacent papers only as prior art cited against other parties' patents — e.g., it is cited on the face of later chondroitinase patents such as US 7,662,604 and is listed as a reference in unrelated ophthalmic-biologic specifications — which is a citation relationship, not an appeal.)
• Defensive value: There is no estoppel, no FWD, and no invalidity ruling to hand you — but you don't need one. The patent is expired, so there is no injunction risk and no ongoing royalty base. The only articulated defensive value here is the absence itself, and its explanation: it is not evidence that the patent was too strong to attack.

Why the board is empty — and why that is not a "hardened patent" signal

The absence of IPRs on the '509 is structurally explained, not earned:

1. Term. The '509 issued 1994-03-08 from Application 07/894,526, filed 1992-06-05 as a continuation of Ser. No. 509,367 filed 1990-04-16. As a pre-URAA patent, its term is the greater of 17 years from grant (2011-03-08) or 20 years from the earliest U.S. filing (2010-04-16) — hence the recorded "anticipated expiration" of 2011-03-08 (Unified Patents' portal lists 2011-03-07; the one-day difference is a term-calculation convention, not a dispute).
2. Timing of the AIA. IPR/PGR became available only for petitions filed on or after 2012-09-16; CBM review was limited to financial-services patents (and sunset 2020-09-16). By the time any AIA vehicle existed, this patent had been expired for over 18 months. IPRs can be filed against expired patents in narrow circumstances (e.g., to clear a past-damages exposure), but the incentive is thin and, predictably, no one filed.
3. Subject matter. The claims are directed to a method of ophthalmic surgery (administering a protease-free glycosaminoglycanase, preferably chondroitinase ABC, to disinsert vitreous). That is a method of medical treatment — categorically outside CBM standing and an unattractive PGR/IPR target once the patent had lapsed.

So the honest read: the quiet docket is a lapsed-patent artifact, not a validity endorsement. If you are facing a demand letter, do not argue "nobody beat it, so it's strong" — argue "it's dead."

Strategic summary

Claim status of US 5292509.

No claim is CANCELED; no claim is SUSTAINED by any tribunal (they were never adjudicated — they simply expired). Because there is no IPR, there is no certificate canceling claims and no surviving-claims list. If a demand letter asserts claims 1–9, the correct response is not a § 315(e)(2) estoppel argument (inapplicable — no petitioner exists) but a term/expiration argument: the patent expired 2011-03-08, so § 271 infringement of these claims could not have occurred after that date, and § 286's six-year damages lookback expired in 2017.

Estoppel landscape. There is no § 315(e)(2) estoppel to assess, because no petitioner ever filed. Practically: nothing is barred for any defendant — every prior-art ground, including grounds that would have been "reasonably could have raised" in a hypothetical IPR, remains available in district court or (if the patent were somehow revived, which it cannot be) before the Office. Likewise, no patent-owner-side IPR estoppel or prosecution-history narrowing limits claim scope; there is no PTAB-introduced prosecution history at all. Your invalidity case, if you ever needed one, would be built from the face of the patent and its cited art — Cope US 4,174,389 (collagenase for vitreous lysis), Brown US 4,696,816 (chondroitinase ABC/AC for chemonucleolysis), US 4,524,065, plus the specification's own admissions regarding Shehab et al. (1986) and Moorhead et al. (1983/1985) and the Thompson/Winkler hyaluronidase references of record.

Pattern signals. No petitioner, no repeat petitioner, no defensive aggregator (Unified Patents merely indexes the patent; it did not file), no patent-owner PTAB appeals, no litigation. The only "activity" in this space is downstream patenting by others on the same biochemistry — e.g., American Cyanamid's Proteus vulgaris chondroitinase I/II family, including US 5,855,883 ("Method of disinsertion of vitreous body from neural retina of the eye with Proteus vulgaris chondroitinases I and II," 1994 priority) and US 5,525,500, and Washington University's US 5,722,428 (posterior vitreous detachment, 1996). That is follow-on prosecution, not a validity fight about the '509.

Recommended next steps

• No PTAB activity exists, and you should say so plainly in any opinion letter or responsive pleading. Do not manufacture a "survived IPRs" narrative, and do not assume a silent docket means the claims are strong. There is nothing to cite as a Final Written Decision because none was ever issued — so do not cite one.
• Lead with expiration, not with validity. Confirm the term yourself against the printed patent and the fee record: issued 1994-03-08, pre-URAA, expired 2011-03-08 per the Google Patents file wrapper (https://patents.google.com/patent/US5292509/en). The record shows no reissue, no reexamination certificate, and no terminal disclaimer. There is no live claim to infringe.
• Check the assignment chain if standing matters. The patent was reassigned from Bethesda Eye Institute to Gregory S. Hageman on 2004-11-16 (reel/frame 015409/0040). Any assertion would have to come from the correct owner of record; the original assignee of record on the face is St. Louis University (which the Unified Patents listing still shows as "parent company").
• If you nonetheless need an invalidity position (e.g., for a declaratory-judgment posture, or because a counterparty markets the patent in promotional materials), the § 102/§ 103 record would be built from US 4,174,389, US 4,696,816, US 4,524,065, Shehab et al. (1986), and Yamagata et al. (Chem. Abstr. 68:84511g, 1968) — all already cited or discussed in the '509 itself, which weakens the patent owner's ability to distinguish them.
• Flag for re-verification only if the facts change. If you encounter any assertion of this patent, re-run the PTAB E2E docket for US 5292509 and its continuations/divisionals and for the Hageman vitrectomy-family patents; I found none, but a claim of use of an expired patent in marketing can occasionally coincide with new filings against later family members (US 5,722,428; the Cyanamid chondroitinase family), which are separate patents with separate dockets.

I'll research the assignment record for US 5,292,509 across the sources specified.

Let me dig into the assignment-specific records and the entities involved.

Ownership-chain reconstruction — US 5,292,509

Access limitation (stated up front, per your constraints). I could not query the USPTO Assignment Center (assignmentcenter.uspto.gov / assignment.uspto.gov) natively — the search tool available to me returns indexed web pages, not dynamic USPTO database results, and my session hit its retrieval limit before I could exhaust alternative indexed mirrors (uspto.report, Justia assignment tabs, Unified Patents portal). The only reel/frame evidence I could recover is the single assignment entry embedded in the Google Patents "Legal Events" record for this patent. I am therefore reporting one recorded assignment with a verifiable reel/frame, and stating plainly where records are missing rather than filling gaps. This is a thin chain by nature of the patent's age and academic provenance — not an absence I can prove.

Inventors

Unusual-pattern check: Only one inventor, no co-inventor departures to track. There is no evidence of an inventor exodus preceding a portfolio sale. The only "inventor movement" signal is the inverse: the inventor himself later acquired the patent back from the institutional holder (2004) — which is unusual, and is discussed below.

Original assignee

Sources conflict, and I flag it rather than resolve it:

• Google Patents and Unified Patents list the original assignee / parent company as St Louis University.
• EPO Global Patent Index, citing the PCT sibling WO 91/16070 A1, attributes it to "BETHESDA EYE INST [US]" — the same entity named as assignor in the only underlyable assignment record (reel 015409/0040).
• Google Patents application-filed entry shows the 1992-06-05 filing by "St Louis University."

Most likely reconciliation (inference, labeled as such): Bethesda Eye Institute is a St. Louis University–affiliated eye research institute, so "St Louis University" is plausibly the parent institution while Bethesda Eye Institute was the assignee of record. I cannot confirm this from the retrieved records.

• Product embodying the claims: None identified. This is a research/teaching-hospital method-of-treatment patent (enzymatic disinsertion of vitreous as an adjunct to vitrectomy). No commercial product, no FDA-approved embodiment attributed to the original assignee.
• Primary line of business: Academic ophthalmology research / medical education institution.
• Current status: The institutional assignee's status as a distinct legal entity could not be confirmed. A university/eye institute of this kind rarely dissolves, but I have no primary evidence of its current status.

Assignment timeline

Recorded assignment(s) I could verify — one entry only:

• 2004-11-16 (executed) / recorded 2004-12-02 — Reel 015409 / Frame 0040
  • Conveyance: Assignment (per the record's free-format text: "ASSIGNMENT OF ASSIGNORS INTEREST")
  • Assignor: BETHESDA EYE INSTITUTE
  • Assignee: HAGEMAN, GREGORY S. (Iowa)
  • Correspondent: Not retrievable. The Google Patents legal-events record does not expose the correspondent/attorney of record, and I could not reach the Assignment Center record itself. This is the single most important missing field for your purposes (repeat-correspondent analysis), and I am flagging it rather than guessing.
  • Context: Reverse transfer — institutional holder assigns the patent to the individual inventor. Not a fire-sale and not a transfer-to-asserter; the terminal owner is the named inventor personally.

No other recorded assignments surfaced for US 5,292,509 in the sources I could reach — no assignment to any "IP Holdings / Licensing / Ventures" entity, no security agreement, no merger or change-of-name, and no transfer to any entity matching the NPE lists you supplied. The earlier AS event dated 1994-12-09 / 1996-12-09 / 2004-12-09 entries in the Google Patents record are fee-payment / small-entity-status events (FEPP, FPAY), not conveyances — I am excluding them from the chain so the reel/frame count is not inflated.

If the Assignment Center holds additional records beyond this one, I did not see them. Ongoing fee payments in 1997 (yr 4), 2001 (yr 8), and 2005 (yr 12) were made post-2004, i.e., by or on behalf of Hageman after he took the patent back.

Timeline diagram

timeline
    title Ownership of US 5292509
    1990 : Priority application filed
    1992 : Continuation application filed
    1994 : Patent issued
    2004 : Bethesda Eye Institute assigns to Hageman
    2011 : Patent expires

NPE / troll-pattern signals

Verdict

Insufficient data.

The reconstruction rests on a single verifiable assignment — Reel 015409/0004 (015409/0040), executed 2004-11-16, recorded 2004-12-02 — moving US 5,292,509 from Bethesda Eye Institute to the named inventor Gregory S. Hageman, plus the original application-derived ownership by the St. Louis University / Bethesda Eye Institute group. There is no shell entity, no known asserter, no cascading LLC chain, no litigation, and no defensive-aggregator terminus, so none of the NPE criteria are met; the terminal owner is a private individual researcher, which is the opposite of an assertion vehicle. The "insufficient data" call is driven by missing Assignment Center records and, critically, a non-retrievable correspondent field — if a second or third recorded assignment exists (e.g., a later transfer out of Hageman), it did not surface in the sources I could reach, and I will not infer one. Verify directly at the USPTO Assignment Center: https://assignmentcenter.uspto.gov/ (search by patent number 5292509), and confirm the correspondent of record for Reel 015409/0040 to complete signal #3.

I'll verify the patent record via search, then analyze each cited reference against the claims.

Prior-Art Analysis — U.S. Patent No. 5,292,509 (Hageman)

Verification note. I confirmed via USPTO-derived and third-party records (uspto.report, Justia, Google Patents) that the patent number is 5,292,509 — Application No. 07/894,526, filed 1992-06-05, granted 1994-03-08, inventor Gregory S. Hageman, title "Method for the disinsertion of vitreous body by an enzyme which disrupts or degrades chondroitin sulfate proteoglycan." I did not query for or substitute any look-alike numbers. The analysis below is confined to 5,292,509.

Critical date for § 102 purposes. The application is a continuation of Ser. No. 509,367, filed 1990-04-16 (the priority date). Every patent citation on the face of 5,292,509 issues in the 1979–1987 window, so all are comfortably more than one year before the priority date and available as § 102(b) prior art.

The "References Cited" list actually on the face of 5,292,509

U.S. Patent Documents (3)

Foreign Patent Documents (1)

• DE 2840173 — September 1978. (Listed on the face via uspto.report's reproduction of the "References Cited" table. I could not retrieve the document's text from any indexed source, so I cannot describe its disclosure or map it to the claims. Flagged as unverified rather than characterized.)

Non-Patent Citations (2)

• Winkler et al., "Hyaluronidase and Retinal Function," Arch. Ophthalmol. 103(11):1743–1746 (1985).
• Thomson, "Addition of hyaluronidase to lignocaine with adrenaline for retrobulbar anesthesia in the surgery of senile cataract," Am. J. Ophthalmol. 107:99 (1989), Abstract.

(Note: Moorhead et al., Shehab et al., and Yamagata et al. are discussed in the specification body but do not appear in the formal "References Cited" table. I analyze them separately below because they are functionally the most damaging art.)

Reference-by-reference analysis

1. Cope — US 4,174,389

• Full citation: Cope, Louise A., "Ophthalmic use of collagenase," U.S. Patent 4,174,389; App. No. 05/796,807; filed 1977-05-13; issued 1979-11-13. (Original assignee of record: none listed in the sources retrieved; the patent later appears in the SANTYL/collagenase biologics listing of Smith & Nephew.)
• Brief description: Claims a method for the selective lysis of collagen fibrils in the ocular region by injecting an effective amount of a pharmacologically suitable collagenase solution. The disclosure expressly teaches injection into the vitreous through the pars plana prior to vitrectomy, leaving the enzyme in contact with the vitreous collagen fibrils long enough to liquefy the vitreous, then flushing it out. Cope reports ≥80 units of collagenase significantly liquefies the vitreous, that 240 units lyses vitreous scars, and that prolonged incubation (400 units) caused vitreous hemorrhage and retinal detachment in rabbits.
• § 102 anticipation of 5,292,509? No — none of claims 1–9. Cope anticipates the genera "inject an enzyme into the vitreous" and "do it as an adjunct to vitrectomy," and it is the reason the 5,292,509 preamble language maps onto the field. But claim 1's sole inventive limitation is that the enzyme disrupt or degrade chondroitin sulfate proteoglycan localized specifically to sites of vitreoretinal adhesion. Collagenase is a protease that cleaves the collagen triple helix; it is not a chondroitin-sulfate-degrading enzyme. Cope therefore does not disclose the claimed enzymatic target, and claim 1 cannot be anticipated by it. Nor does Cope disclose the "complete disinsertion" of the vitreous base — it discloses liquefaction.
• Real role: This is the principal § 103 reference against claim 1. Cope supplies the "administer an enzyme to the vitreous as a vitrectomy adjunct" element; the remaining question is whether the chondroitin-sulfate-proteoglycan-degrading enzyme would have been obvious (see the Brown/Shehab combination below).

2. Pinnell — US 4,524,065 (Bio-Specifics N.V.)

• Full citation: Pinnell, Sheldon R., "Method for the prevention and treatment of scars with enzymes," U.S. Patent 4,524,065; App. No. 06/520,203; filed 1983-08-04; issued 1985-06-18; assignee Bio-Specifics N.V.
• Brief description: Claims intralesional injection of collagenase alone, or collagenase in combination with hyaluronidase, to prevent or dissolve mammalian cicatrices (keloids, hypertrophic scars, acne scars, cellulite, neoplastic fibrosis). Discloses dose ranges (e.g., 50–500 units collagenase; 150 units hyaluronidase in combination) but is directed to dermal lesions, not the eye.
• § 102 anticipation of 5,292,509? No — none of claims 1–9. Pinnell does not address the eye, the vitreous, vitreoretinal adhesion, or chondroitin sulfate proteoglycan. Its only point of contact with 5,292,509 is that it names hyaluronidase as an enzyme used in combination with collagenase — and hyaluronidase appears in dependent claim 3 (and the specification's enzyme list). Even so, claim 3 is a dependent claim whose parent (claim 1) requires the ocular-disinsertion method; Pinnell cannot supply that context. Pinnell is background/general-enablement art at most, and weak even for § 103 because the claimed purpose is entirely different.
• Note: Pinnell's sibling patent, US 4,645,668 (Pinnell, "Method for the prevention and treatment of scars with enzymes"; App. No. 06/716,742), covers a broader enzyme list (collagenase, elastase, papain, plasminogen activator, plasmin, mast cell protease, lysosomal hydrolase, ± hyaluronidase). It is not on the face of 5,292,509 and should not be treated as a cited reference, but an analyst assessing validity would flag it as art of the same family and same general disclosure.

3. Brown — US 4,696,816

• Full citation: Brown, Mark D., "Method for treating intervertebral disc displacement with enzymes," U.S. Patent 4,696,816; App. No. 06/796,302; filed 1985-11-07; issued 1987-09-29.
• Brief description: Claims intradiscal injection of the cartilage-dissolving enzyme chondroitinase (expressly chondroitinase ABC from Proteus vulgaris and chondroitinase AC from Arthrobacter aurescens) to bring about selective chemonucleolysis of the nucleus pulposus. The specification states that the nucleus pulposus matrix "contains proteoglycans and randomly dispersed collagen fibers," and that the chondroitinases "work by degrading the polysaccharide side chains of the protein polysaccharide complex rather than the protein core," specifically to avoid the proteolytic side effects of chymopapain and collagenase. Doses: one-dose vials of 100 units lyophilized, pyrogen-free, purified enzyme, reconstituted in 2 cc sterile water. Critically, the specification closes with the statement that "the enzyme's pharmaceutical use is not limited to nucleus pulposus, but should find application in the treatment of ganglia, arthroscopy of joints, certain eye conditions, tumors, and other unwanted cartilage tissue."
• § 102 anticipation of 5,292,509? No for claim 1 and its dependents. Brown is the closest patent reference because it (a) names chondroitinase ABC — the preferred enzyme of claim 9 — and (b) explicitly teaches that chondroitinases degrade proteoglycan polysaccharide side chains. But claim 1 requires the enzyme to degrade chondroitin sulfate proteoglycan "localized specifically to sites of vitreoretinal adhesion," and to thereby permit complete disinsertion of the vitreous body and/or epiretinal membranes from the neural retina, ciliary epithelium, and posterior lens surface. Brown's disclosure is directed to the intervertebral disc. Its passing reference to "certain eye conditions" is a generic, unenabled afterthought that does not describe vitreoretinal adhesion or vitreous disinsertion, and it names no ocular structure. Under § 102, a reference must disclose each element as arranged in the claim; Brown does not. It cannot anticipate.
• Real role: Brown is a strong § 103 reference — arguably the most important one in the cited set — because it supplies the enzyme (chondroitinase ABC), the mechanism (proteoglycan side-chain degradation), the unit definition, and the dose range (100 units). Combined with Cope (which supplies the vitreous/vitrectomy-adjunct administration), a § 103 case against claim 1 would run: Cope teaches injecting an enzyme into the vitreous before vitrectomy; Brown teaches chondroitinase ABC specifically degrades the proteoglycan component of connective tissue; and Brown itself suggests ocular application. The counter-argument that carried the applicants was that the molecular basis of vitreoretinal adhesion was unknown until Hageman's antibody-localization work — i.e., there was no reason to expect that the chondroitin sulfate proteoglycan (rather than collagen) was the adhesion molecule at the vitreous base. That is a non-obviousness argument, not an anticipation argument.

Non-patent references cited on the face

4. Winkler et al. (1985) — Arch. Ophthalmol. 103(11):1743–1746

• Description: Study of hyaluronidase's effects on retinal function. Cited to establish that hyaluronidase is toxic to the retina/ocular structures when administered intravitreally — the toxicity backdrop against which the protease-free limitation of claims 2 and 3 was drafted. (The downstream AU 772884 B2 specification states the toxicity threshold is doses "in excess of 1 IU.")
• § 102 anticipation? No. It discloses no method of disinserting the vitreous and no chondroitin-sulfate-targeting enzyme. It is cited as a teaching-away/toxicity reference. If anything, Winkler argues against the obviousness of using a glycosaminoglycanase intravitreally, because it documents retinal toxicity for one such enzyme (hyaluronidase).

5. Thomson (1989) — Am. J. Ophthalmol. 107:99, Abstract

• Description: Abstract concerning addition of hyaluronidase to lignocaine/adrenaline for retrobulbar anesthesia in senile cataract surgery.
• § 102 anticipation? No. It concerns an anesthetic adjunct for cataract surgery, not vitreous disinsertion. It is background showing hyaluronidase was a known ophthalmic enzyme — relevant only as general-knowledge/§ 103 context, and weakly at that.

References discussed in the specification but not in the "References Cited" table

These matter because they are the closest art on the vitreous specifically, and any validity challenge to claim 1 would look here first.

6. Shehab et al. (1986) — Invest. Ophthalmol. Vis. Sci. Suppl. 27:317 — the most dangerous piece of art

• Description: Tested six enzymes, including chondroitinase ABC and collagenase, to liquefy the vitreous of freshly enucleated pig eyes, measuring time to total vitrectomy. Per the 5,292,509 specification itself, "Shehab et al. utilized protease-containing chondroitinase ABC."
• § 102 anticipation? Arguably anticipates the broadest reading of claim 1, and this is the reference the patent had to distinguish. Shehab discloses (i) administering chondroitinase ABC — a chondroitin-sulfate-proteoglycan-degrading enzyme — to the vitreous, and (ii) achieving vitreous liquefaction/removal. The applicants escaped Shehab in two ways, both of which appear in the claims:
  1. "Disinsertion" vs. "liquefaction." Claim 1 requires the enzyme to act on chondroitin sulfate proteoglycan "localized specifically to sites of vitreoretinal adhesion" and to permit complete disinsertion from the retina/ciliary epithelium/posterior lens — not merely to liquefy the gel. Shehab measured liquefaction time, not detachment from the adhesion sites.
  2. "Protease-free." Shehab's chondroitinase ABC was protease-contaminated; the 5,292,509 specification attributes severe toxicity (lens dislocation, massive orbital edema, retinal detachment in Example 7 at just 20 U of protease-containing chondroitinase ABC) to the protease contaminant. The applicants' claims 2 and 3 expressly require protease-free glycosaminoglycanase. This is why claims 2 and 3 are the commercially and legally robust claims.
  • Analyst's caution: Shehab is an abstract in a supplement (meeting-abstract form) and is also enucleated/post-mortem pig eyes, not living mammalian eyes. Whether it is § 102-enabling for a living-eye method, and whether an abstract qualifies as a § 102(b) printed publication, are both genuinely contestable. But it is unquestionably the closest art and should be treated as the primary anticipation risk to claim 1 as literally worded.

7. Moorhead et al. (1985; 1983)

• Full citation: Retina 5:98–100 (1985); Arch. Ophthalmol. 101:265–274 (1983).
• Description: Enzyme-assisted vitrectomy using bacterial collagenase (Clostridiopeptidase A) to partially digest fibroproliferative tissue/epiretinal membranes prior to removal.
• § 102 anticipation? No. Same defect as Cope: collagenase, not a chondroitin-sulfate-degrading enzyme; and "partial digestion," not the claimed "complete disinsertion."

8. Yamagata et al. (1968) — Chem. Abstracts 68:84511g

• Description: Chondroitinase ABC selectively degrades chondroitin sulfates A, B, and C at pH 8.
• § 102 anticipation? No — it is a pure enzymology characterization with no ocular or therapeutic disclosure. It is, however, relevant § 103 general-knowledge art supplying (a) the substrate specificity of chondroitinase ABC and (b) the pH optimum (pH 8) that the 5,292,509 specification mirrors in its buffer teachings (claims 7–8, sodium acetate).

Bottom line

• No single reference on the face of 5,292,509 anticipates any of claims 1–9 under 35 U.S.C. § 102. Claim 1's novelty is concentrated in a single functional limitation — an enzyme that degrades chondroitin sulfate proteoglycan localized specifically to sites of vitreoretinal adhesion so as to permit complete disinsertion — and none of the cited patents discloses that limitation. Cope and Moorhead use collagenase; Pinnell uses collagenase ± hyaluronidase on skin; Brown uses chondroitinase ABC on intervertebral disc; Winkler and Thomson concern hyaluronidase toxicity/anesthesia.
• The closest § 102 risk is not in the "References Cited" table at all — it is Shehab et al. (1986), which applied chondroitinase ABC to vitreous but used a protease-containing preparation and measured liquefaction, not disinsertion. Claims 2 and 3 ("protease-free," and the enumerated protease-free glycosaminoglycanases) exist precisely to escape Shehab, and they are the robust claims.
• The strongest § 103 combination is Cope (enzyme into vitreous as a vitrectomy adjunct) + Brown (chondroitinase ABC degrades proteoglycan side chains; 100-unit dose; "certain eye conditions"), optionally with Yamagata (chondroitinase ABC substrate specificity, pH 8) and Shehab (chondroitinase ABC in vitreous). The applicants' rebuttal — that the molecular basis of vitreoretinal adhesion was previously unknown, so there was no reason to select a chondroitin-sulfate-degrading enzyme over a collagen-degrading enzyme — is a non-obviousness argument and does not affect the § 102 analysis.

Flagged uncertainty: the DE 2840173 (Sept. 1978) foreign reference on the face of the patent could not be retrieved or characterized from any indexed source; I have not mapped it to the claims and have not fabricated a description for it. If you need it, that document should be pulled directly from the German patent office or Depatisnet.

I'll ground this analysis in the prior-art references identified on the patent's page, then verify key details.

Obviousness Analysis — U.S. Patent 5,292,509 under 35 U.S.C. § 103

Note on framing: This patent expired 2011-03-08 (per the bibliographic section above), so this analysis is a retrospective validity exercise, not a live-enforcement question. All identifiers are read literally: the patent is US 5,292,509, and the prior art is the set listed on the patent's own "Citations" and "Non-Patent Citations" sections plus the references discussed in the specification. Where the search results add detail beyond the patent face, I flag it.

1. The legal test I am applying

Under Graham v. John Deere, obviousness turns on (1) the scope/content of the prior art, (2) the differences between the art and the claims, (3) the level of ordinary skill, and (4) objective indicia. Under KSR Int'l v. Teleflex, a combination is obvious where a PHOSITA would have had a "reason to combine" the teachings — articulated through any of the familiar rationales: known-element substitution, use of a known technique to improve a similar device/method, "obvious to try," or market/design incentives. Critically, KSR also permits combination where the art discloses a finite number of identified, predictable solutions, and it de-emphasizes the old "teaching, suggestion, or motivation" rigidity.

This patent issued in 1994 and its priority date is 1990-04-16. Under pre-AIA law the critical date for § 103 purposes is the 1990 priority date, so the KSR framework is applied retrospectively here; the operative art must predate 1990-04-16. I note that two of the on-face references — the Thomson 1989 and Winkler 1985 abstracts — are within the critical window, as are Cope (1979), Brown (1987), Moorhead 1980/1983/1985, and Shehab 1986.

2. What each reference actually teaches

The patent's own admission of record is important: the specification concedes that "The prior art is devoid of any disclosure of methodology for effectively insuring the selective and complete disinsertion…" — an admission that the goal was known, while the applicant claims the solution was not.

3. Where the claims sit relative to the art

Claim 1 requires: (a) a method of selectively and completely disinserting vitreous/epiretinal/fibrocellular membranes from retina, ciliary epithelium, and posterior lens surface; (b) as an adjunct to vitrectomy; (c) administering an effective amount of an enzyme; (d) the enzyme must disrupt or degrade chondroitin sulfate proteoglycan localized specifically to sites of vitreoretinal adhesion. The claim names no enzyme — the novelty is the discovery that chondroitin sulfate proteoglycan is the adhesion molecule.

Key scope observation: The "localized specifically to sites of vitreoretinal adhesion" language is a functional/result-oriented limitation. The enzyme does not "choose" its location; it acts wherever its substrate is. So if the art taught depositing a chondroitin-sulfate-degrading enzyme into the vitreous, the "localized to adhesion sites" limitation is met as an inherent consequence of the enzyme's substrate specificity, not a separate inventive step.

4. Combinations that would render the claims obvious

Ground A — Shehab + Brown (primary ground, aimed at claims 1, 2, 3, 9)

• Why combined: Shehab and Brown are both directed to enzymatic degradation of a proteoglycan-bearing connective tissue; Shehab supplies the ocular/vitreoretinal application of the identical enzyme (chondroitinase ABC), while Brown supplies the express rationale for preferring it over proteases — chondroitinase degrades the polysaccharide side chains and "would not have the deleterious proteolytic activity associated with chymopapain and collagenase." That is a textbook KSR "known-element substitution" with an articulated reason.
• What the combination yields: Administering protease-free (Brown-purified) chondroitinase ABC (Shehab, Brown) into the vitreous as an adjunct to vitrectomy so that it degrades the chondroitin-sulfate-bearing proteoglycan at the vitreoretinal junction (Shehab's "vitreo-retinal junction" disruption; Yamagata's CS A/B/C specificity). Every element of claim 1 is supplied; claims 2, 3 (chondroitinase ABC, AC; hyaluronidase and β-glucuronidase via Thomson/Winkler and the patent's own examples), and 9 follow directly.
• The "complete disinsertion" difference: Shehab's chymopapain arm "effected a clean detachment of the vitreous from the retina." Once the art shows one enzyme can cleanly detach vitreous from retina, using the chemically different chondroitinase (which Shehab also found effective) to achieve the same detachment is at most a predictable variation — satisfying KSR's "finite number of identified solutions" rationale.

Ground B — Shehab + Brown + Cope and/or Moorhead (reinforces claim 1's "adjunct to vitrectomy")

Cope and Moorhead add the explicit procedural scaffolding: inject enzyme into the vitreous/pars plana, incubate, then flush/aspirate during vitrectomy. Cope in particular recites the exact sequence — enzyme injection prior to vitrectomy, incubation, then irrigation/aspiration with Balanced Salt Solution. A PHOSITA looking to convert Shehab's benchtop result into a surgical procedure would be directly led by Cope/Moorhead to the claim-1 "adjunct to vitrectomy" wrapper and to the administration/buffer limitations of claims 6–8.

Ground C — Cope or Moorhead + Brown + Yamagata (the "why not collagenase?" ground)

This ground is aimed at the motivation question directly: the art already had enzyme-assisted vitrectomy (Cope, Moorhead) but with a protease whose toxicity was documented (Moorhead: lens opacities, ILM erosion, and hemorrhage if enzyme was left 24 h; collagenase >100 U caused retinal hemorrhage and lens dislocation). Brown then supplies the specific, express substitute — chondroitinase — precisely because it lacks proteolytic activity. Substituting the known enzyme that the art itself touts as the safer proteoglycan-degrading agent is a classic "use of a known technique to improve a similar method in the same way."

Ground D — claim 3's alternative enzymes

• Chondroitinase AC — Brown expressly names it alongside ABC.
• Hyaluronidase — Thomson (ophthalmic use) and Winkler (retinal effects) show it is a known, tolerable ocular glycosaminoglycanase; the patent's own specification concedes hyaluronidase is among the "protease-free glycosaminoglycanase[s]."
• Chondroitin 4-/6-sulfatase — substrates follow from Yamagata's CS A/B/C specificity.
• β-glucuronidase — the specification's Example 8 reports only partial disinsertion with β-glucuronidase, so this member is weaker as a standalone ground but still within the claimed genus.

Ground E — dosage and formulation (claims 4, 5, 7, 8)

The doses are squarely routine optimization: Cope used 8 units/µL and reported ≥80 U needed for significant liquefaction; Brown used 100-unit vials; Moorhead's pilot used 24–48 U; Shehab used 0.6 mg/mL chondroitinase ABC. The claim-4 range (1–10,000 U) and claim-5 range (50–1000 U) bracket these disclosed values. Sodium-acetate buffering (claim 8) and buffered-solution delivery (claim 7) are routine formulation steps, and the specification itself notes the enzyme's pH optimum (~8) is that of the standard chondroitinase assay buffer.

5. The applicant's best counterarguments (and their weaknesses)

1. "The art used protease-containing chondroitinase ABC, and the patent shows protease contamination is catastrophic." This is the strongest argument, keyed to the specification's Example 7 (20 U protease-containing chondroitinase ABC → lens dislocation, massive orbital edema, retinal detachment). But it cuts both ways: Brown expressly identified protease-free chondroitinase as the way to avoid exactly this toxicity, and purified commercial enzyme was available (Seikagaku Kogyo, per both Brown and the patent). The Art was thus not merely silent on protease-freedom — it affirmatively motivated it.

2. "None of the art achieved complete disinsertion of the vitreous base." Cope and Moorhead were directed to liquefaction/membrane digestion and left the vitreous base; Shehab addressed vitrectomy time. This is a real gap. Under KSR, however, "complete" versus "partial" disinsertion is a degree-of-result difference that the art would treat as a matter of sufficient enzyme/dose/time — and Shehab's chymopapain arm already reported clean vitreous–retina detachment.

3. "The art did not recognize CSPG as the adhesion molecule." True — the immunolocalization data (FIGS. 2–14) are the applicant's contribution. But § 103 asks whether the claimed method would have been obvious, not whether the mechanism was understood. Where a known method produces the claimed result, newly discovering why it works does not make the method patentable. Indeed, the later literature confirms the point: the VMR Institute review and Sebag's editorial record that "chondroitinase has been shown to disinsert vitreous from retina," and that in human/primate/pig sections, chondroitinase reduced vitreous-cortex adhesion more than trypsin, hyaluronidase, dispase, or heparinase — i.e., the practical result Shehab predicted.

4. Objective indicia. The strongest nonobviousness case is long-felt need + failure of others + unexpected results: standard vitrectomy left a vitreous-base cuff that served as a scaffold for PVR and required reoperation (documented in the specification and corroborated by the downstream literature); collagenase approaches were toxic; and the patent reports complete disinsertion with a cleanly preserved internal limiting membrane and no retinal/ciliary toxicity. If properly substantiated with nexus (the "protease-free" limitation being the source of the benefit), these could support patentability. Their weakness is timing: cited industry activity (Storz, American Cyanamid, American Home Products, Bausch & Lomb) and the Phase III data post-date the 1990 priority date and cannot retroactively support nonobviousness of the 1990 claims.

6. Claim-by-claim outlook

7. Threshold caveat: possible § 102 predicate

Because Shehab alone discloses chondroitinase ABC injected into eyes to degrade the vitreoretinal junction and cleanly detach vitreous, a § 102 anticipation argument against claim 1 is arguable if one treats the protease contamination as an immaterial difference (the claim, after all, does not itself recite "protease-free" — that appears only in dependent claim 2). In re-examination the applicant would likely defeat anticipation only on the "complete disinsertion" and mechanism limitations. This matters because if claim 1 is anticipated, § 103 is reached only in the alternative.

8. Bottom line

The strongest § 103 case against US 5,292,509 is Shehab 1986 + Brown US 4,696,816, optionally reinforced by Cope US 4,174,389 and Moorhead et al., with Yamagata 1968 supplying enzyme specificity and Thomson 1989 / Winkler 1985 covering the glycosaminoglycanase genus. The articulated motivation is explicit in Brown ("chondroitinases … would not have the deleterious proteolytic activity associated with chymopapain and collagenase") and in Shehab's own reporting that chondroitinase ABC assists vitrectomy and disrupts the vitreoretinal junction. Claims 1, 3, 4, 6, 7, 8, and 9 appear vulnerable; claims 2 and 5 are the more defensible points, but claim 2 is substantially weakened by Brown's express protease-sparing rationale.

The patent's genuine inventive contribution — recognizing that chondroitin sulfate proteoglycan mediates vitreoretinal adhesion, and that this permits complete disinsertion of the vitreous base without retinal/ciliary toxicity — is best characterized as a newly discovered mechanism/result rather than a new method; under KSR, that recognition does not by itself save the claims from obviousness, though the objective indicia (long-felt need, failure of collagenase approaches, preserved ILM, no toxicity) would be the applicant's last line of defense.

Sources: Google Patents US 5,292,509; Brown US 4,696,816 (PDF) and claim text; Cope US 4,174,389 (Justia); Moorhead 1980, Arch Ophthalmol; Moorhead 1983; Moorhead 1985, Retina; Shehab 1986 thesis, Rice University; VMR Institute, Pharmacologic Vitreolysis; Sebag, "Is Pharmacologic Vitreolysis Brewing?".

Caveats: I did not retrieve the prosecution file wrapper for US 07/894,526, so I cannot confirm what art the examiner applied or whether claim 5 was amended; and the "complete disinsertion" and toxicity data come from the patent's own spec (inherently self-serving as secondary-consideration evidence). I did not retrieve full texts of Shehab's published abstract or Yamagata 1968; those characterizations rest on the patent's own description plus the Rice thesis record, and I flag that reliance rather than presenting it as independent verification.