US 6492389

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

Let me check for any litigation or Federal Circuit activity involving this patent.

Patent Analysis: US 6,492,389 B1

Verification of the Number

The identifier US 6,492,389 resolves to a single granted US patent — "Small molecule inhibitors of BCL-2 proteins." I found no evidence of a similarly numbered patent being conflated in the results. Note that the number must not be confused with US 10,807,977 B2 (a later, unrelated Bcl-2 degradation compound patent that cites '389 as prior art).

Bibliographic Data

Source: Google Patents (https://patents.google.com/patent/US6492389/en) and FreePatentsOnline (https://www.freepatentsonline.com/[6492389](/patent/6492389).html).

Abstract (verbatim)

"Small molecule inhibitors of Bcl-2 function are used to induce apoptosis of cells which are subject to Bcl-2, which cells are otherwise subject to Bcl-2 mediated blockage of apoptosis. The compounds are useful for treating cancer, autoimmune disorders and viral infection."

Technical Field / Context

The patent sits at the intersection of oncology and apoptosis biology. Bcl-2 is an anti-apoptotic ("death antagonist") protein; its overexpression is associated with a wide range of cancers and with resistance to chemotherapy and γ-irradiation. The inventors used a computer-aided docking screen (DOCK3.5) against a model of the Bcl-2 hydrophobic pocket (built from the homologous Bcl-x_L structure) to identify small-molecule inhibitors, then validated hits using a fluorescence-polarization competition binding assay against a fluorescein-labeled Bak BH3 peptide ("Flu-1193") and DNA-fragmentation apoptosis assays in HL-60 (Bcl-2-transfected) and 697 leukemia cells.

Independent Claim Overview (Plain Language)

The granted claims are method-of-treatment claims, not composition-of-matter claims. Notably, although the specification discloses three generic compound formulas (I, II, and III) and two large compound tables, the issued claims are limited to methods using the formula III compounds. There are three independent claims (1, 11, and 12).

Claim 1 — Inducing apoptosis in Bcl-2–regulated cells
A method of inducing apoptosis in cells of a subject that are regulated by Bcl-2, by administering an effective amount of a compound of formula III. Formula III is a chromene-based scaffold with a large R_1 substituent (e.g., OH, NH₂, heterocycles such as piperidinyl, morpholino, pyrrolidino), R₂/R₄ ester or acyl groups, R₃ as a nitrile/alkenyl/heterocycle, R₅ as H/halogen/methoxy, and R₆–R₈ as ring substituents (with the proviso that at least one of R₆–R₈ must be Cl, Br, or F when the others are hydrogen). It also covers pharmaceutically acceptable salts where the compound has an NH₂ or COOH group.

Claim 11 — Reversing Bcl-2–mediated apoptosis blockage in cancer cells
A method of reversing Bcl-2–mediated blockage of apoptosis in cancer cells by contacting those cells with a formula III compound. This is essentially the in vitro/cell-contact counterpart to claim 1.

Claim 12 — Treating Bcl-2–expressing cancer in a subject
A method of treating a subject with a cancer characterized by cancer cells that express Bcl-2, by administering an effective amount of a formula III compound. Claim 13 depends on this and recites specific cancer types (prostate, colorectal, gastric, non-small-cell lung, renal, thyroid, neuroblastoma, melanoma, and acute/chronic lymphocytic and non-lymphocytic leukemias).

Representative dependent claims of interest:

• Claim 2 — limits the compound to a dissociation constant of ≤ about 500 μM for the BH1/BH2/BH3 hydrophobic pocket of Bcl-2.
• Claim 6 — limits the compound to HA14-1 or HA14-8 (the two most specifically named species).
• Claims 8–10 — narrow the target cell population to cancer cells, virus-infected cells, or self-reactive lymphocytes, respectively.

Litigation / Docket Check (CAFC 2026)

I specifically searched for Court of Appeals for the Federal Circuit 2026 docket activity and district-court litigation naming US 6,492,389 and found no authoritative results. Consistent with this, the patent's legal status is "Expired – Lifetime" with an anticipated expiration of July 20, 2019, so an active 2026 infringement docket is unlikely. Its ongoing relevance appears to be purely as prior art / citation material — for example, it is cited in later Bcl-2 patent families (e.g., the Abbott/Genentech-family WO 2012/071374 applications and US 10,807,977 B2).

Uncertainty Notes

• No CAFC 2026 docket exists for this patent as far as I can determine. If the underlying query refers to a 2026 case, it may concern a different patent number, or the '389 patent only as cited prior art. I cannot confirm any pending appeal.
• The claim text available through secondary databases (FreePatentsOnline, Justia) is truncated at the chemical-substituent markup; my claim descriptions above are based on the specification's parallel disclosure of formula III and the visible claim text. The precise wording of claims 11 and 12 mirrors claim 1's formula III definition, but I have not verified every substituent listing character-for-character.
• The specification describes compounds HA11-1 through HA11-73 (formula I) and HA14-1 through HA14-13 (formula III) as screened hits, but only the formula III methods were claimed — a notable scope reduction from the disclosed invention.

Bottom line: US 6,492,389 is an expired Thomas Jefferson University patent claiming methods of inducing apoptosis, reversing Bcl-2–mediated apoptosis blockade, and treating Bcl-2–expressing cancers using chromene-type small-molecule Bcl-2 inhibitors (formula III; e.g., HA14-1).

I'll search for litigation involving US patent 6492389.

Let me search more targeted litigation databases.

Let me search more specific litigation databases.

Summary of Findings

No litigation, PTAB proceeding, or ITC action involving U.S. Patent No. 6,492,389 was identified in the searches I ran. I was unable to find any plaintiff-versus-defendant case in which this specific patent number appears in the pleadings, docket, or a patent-litigation aggregator.

Because a "no results" answer is only useful if I am transparent about coverage and false positives, here is exactly what I did and did not find.

What I searched

• Unified Patents litigation/portal content (via search indexing of portal.unifiedpatents.com)
• Justia dockets / CourtListener / PACER-derived materials
• Google Patents and FreePatentsOnline records for the patent
• General web searches for litigation, infringement complaints, and the patent number in both formats (6492389 and 6,492,389)

What the patent record itself shows

• Patent: U.S. 6,492,389 B1, "Small molecule inhibitors of BCL-2 proteins"
• Assignee: Thomas Jefferson University
• Inventors: Ziwei Huang, Dongxiang Liu, Xiaobing Han, Zhijia Zhang, Jialun Wang
• Application: US 09/357,229; filed 1999-07-20
• Priority: 1998-07-21 (provisional 60/093,561; and 60/128,100 filed 1999-04-07)
• Granted: 2002-12-10
• Legal status on the record: Expired – Lifetime; anticipated expiration 2019-07-20
• Claims: Directed to methods (inducing apoptosis of Bcl-2-regulated cells, reversing Bcl-2-mediated blockage of apoptosis in cancer cells, and treating Bcl-2-expressing cancers) using chromene compounds, with claim 6 reciting the specific compounds HA14-1 and HA14-8.

This is a method-of-use patent covering the research compound HA14-1, which was sold as a laboratory reagent (e.g., by EMD Biosciences, BioMol, Axxora). I found no evidence that the patent was ever asserted in court, and its full term has now run (it expired in July 2019).

False positives to flag (these are NOT this patent)

Several search hits involved different patents whose numbers end in "389," which must not be conflated with U.S. 6,492,389:

• U.S. 6,233,389 — TiVo/DISH Network litigation (multimedia storage/playback)
• U.S. 6,949,389 — Pictiva Displays v. Samsung litigation (display technology)
• U.S. Reissue/other '389 patents — Freedman stowable seat; ProudLion IP smartwatch cases
• Japanese Patent No. 6492389 — a Pulstec Industrial X-ray diffraction device
• RU 2593231 C2 — an AbbVie Bcl-2 application that merely cites US 6,492,389 as prior art (a citation, not litigation)

None of these have any connection to U.S. 6,492,389.

Caveats

• I cannot rule out the existence of litigation that is not publicly indexed or that predates readily searchable electronic dockets. This patent's enforcement window spans roughly 2002–2019, and older cases may be poorly captured by the sources I could access.
• I did not have direct, authenticated access to PACER or to a subscription litigation database (e.g., Docket Navigator, Lex Machina, RPX Insight); my results come from indexed web sources. A confirmatory check on those paid platforms would be the appropriate next step before stating definitively that no litigation exists.
• I found no PTAB petition (IPR/PGR) challenging U.S. 6,492,389 in the indexed results either, but again this is based on public indexing only.

Bottom line

Based on the sources I could access, there is no known litigation involving U.S. Patent No. 6,492,389. If you need a definitive negative for a filing or opinion, I recommend a direct PACER/Docket Navigator or RPX Insight query, which I was not able to run here.

I'll verify the canonical "no proceedings on file" signal against public sources before concluding.

Let me check the aggregators that track PTAB challenges specifically.

Two more targeted checks — the PTAB petitions portal and any ex parte reexamination history.

AIA Trial Proceedings — US 6,492,389

Canonical source: the structured "PTAB proceedings on file" block in this prompt (USPTO Open Data Portal). That block reports zero AIA trial proceedings for this patent. My independent web checks (PTAB Decisions / PTACTS portal indexing, Unified Patents portal, Google Patents legal-events, FreePatentsOnline) surfaced nothing that contradicts it. Details and coverage caveats below.

Proceedings overview

Total AIA trial proceedings on file: 0. Breakdown: 0 active, 0 with claims invalidated, 0 with claims sustained, 0 settled, 0 with institution denied.

The bottom-line defensive posture is unusual and worth stating precisely: the patent was never subjected to an IPR, PGR, or CBM at any point in its ~17-year enforceable life, and it expired on 2019-07-20 without ever being asserted. That is not the same as "hardened" — no panel has ever construed these claims, so there is no IPR-driven estoppel, no FWD disposition, and no claim-level validity ruling. For a defendant today, the practical posture is dominated not by PTAB history but by expiry: claims 1–13 lapsed for failure to maintain/term end, so there is no injunctive or damages exposure for post-expiration conduct, and § 315(e) estoppel is entirely inapplicable because no petition exists to trigger it.

Proceedings

(None to list. There is no proceeding number to report, and I will not manufacture one. The remainder of this section explains what the empty set means and how I tested it.)

No IPR / PGR / CBM on file

• Type: N/A
• Filed: N/A
• Status: No proceeding (USPTO ODP returns no AIA trials; corroborated by web search — see coverage note)
• Judge panel: N/A
• Petition grounds: N/A
• Institution decision: N/A
• Final Written Decision: N/A — no claim of US 6,492,389 has ever been canceled, amended, or confirmed in an AIA trial
• Settlement / termination: N/A
• Appeal: No FWD exists, so no Board decision could have been appealed to the Federal Circuit on the merits of this patent
• Defensive value: Because there is no FWD, there is no § 315(e)(2) estoppel against anyone, and no claim has been judicially or administratively construed. A defendant retains the full § 282 invalidity toolkit in district court, untrammeled by any prior PTAB record.

Why the empty set is expected here (statutory and practical filters)

Three structural reasons explain the null result, and they should be understood before treating it as merely an artifact:

1. PGR is statutorily unavailable. Post-grant review under § 321 applies only to patents whose claims have an effective filing date on or after 2013-03-16. US 6,492,389 claims priority to 1998-07-21 and was filed 1999-07-20 — it is squarely pre-AIA, so PGR was never an option.
2. CBM is now unavailable. Transitional CBM review (§ 18 of the AIA) sunset for new petitions on 2020-09-16, and in any event was limited to "covered business method" patents, which these apoptosis method-of-treatment claims are not.
3. IPR was available 2012-09-16 → 2019-07-20 but was never used. For an IPR to make commercial sense, someone must be practicing or about to practice the claimed methods. This patent covers a research reagent (HA14-1, sold by EMD Biosciences, BioMol, Axxora, etc.) rather than a marketed therapeutic, and its owner — Thomas Jefferson University, an academic institution — is not known to have asserted it. No competitor had a reason to spend $300K+ on a petition.

Strategic summary

Claim status. Every claim — independent claims 1, 11, and 12, plus dependents 2–10 and 13 — is UNTESTED. No claim is canceled; no claim is board-confirmed. The claim set stood exactly as granted on 2002-12-10 and was never narrowed by any post-grant process. If someone is quoting claims to you, note the distinction the earlier sections drew: the § 102/§ 103 merits of the formula III genus, and of the species claims to HA14-1 and HA14-8 (claim 6), have never been adjudicated by any tribunal, PTAB or otherwise.

Estoppel landscape. § 315(e)(2) estoppel is a non-issue: it bars only a petitioner, real party in interest, or privy from re-litigating grounds that were raised or reasonably could have been raised in an instituted IPR. With zero petitions, no party is estopped from any ground. All § 102 and § 103 defenses remain on the table for a defendant in district court — including, notably, the extensive post-1999 third-party literature on HA14-1 and the chromene Bcl-2 chemotype, and the possibility of § 112 written-description/enablement attacks on the broad "formula III" genus (the specification names only HA14-1 through HA14-13 and relies heavily on a docking-model rationale). Nothing in the file history has been tested adversarially on any of these theories.

Pattern signals. There are none to read. No repeat petitioner, no patent-owner appeal activity, no defensive aggregator involvement. I found no Unified Patents proceeding or portfolio record specific to US 6,492,389. The patent's ongoing citation life is as prior art and background literature — it is cited in later Bcl-2 families (e.g., the AbbVie/Abbott-family WO 2012/071374 material, RU 2593231 C2, US 9,872,861, US 10,807,977 B2), and the HA14-1 chemotype recurs in later filings. That citation traffic is scientific, not adversarial.

Recommended next steps

• No PTAB record to link. I have nothing to point you to at PTAB E2E or CourtListener for this patent — there is no institution decision and no FWD to quote, and I will not invent a Paper number. The absence is itself the finding, and here it is a weak signal rather than the usual "well-asserted patents attract IPRs" inference: this patent was never commercialized or asserted, so non-challenge reflects lack of economic motive, not proven strength.
• Confirm the negative independently before relying on it in a filing. The ODP ingest is canonical but can lag; a direct check of the PTAB E2E / PTACTS portal search by patent number (6,492,389) is the confirmatory step. My corroborating web searches (below) returned no AIA trial, but public indexing of PTAB petitions is imperfect for the 2012–2019 window.
• Do not plan an IPR now. The patent expired 2019-07-20 and its legal status is "Expired – Lifetime." There is no live infringement exposure to defend, and filing an IPR against an expired patent raises real questions about whether a petitioner can show the requisite concrete dispute over claims that can no longer be infringed. If a demand letter has reached you citing this patent, the correct first response is a term/expiry check, not a petition.
• If you nonetheless need a validity ruling on the record, the only Office-side vehicle that remains available to any third party without standing is ex parte reexamination under § 302 — but note that it typically requires a substantial new question of patentability and will not produce a PTAB-style claim-by-claim cancel/sustain disposition. Where the real dispute is a later, live patent in the same Bcl-2 space, direct your IPR budget there.
• Flag the false positives hard. During the search I encountered several near-miss identifiers that must not be confused with this patent, and I want them on the record so they do not get cited into a brief as "PTAB activity":
  • US 8,726,389 — was the subject of IPR2023-00633 (Sophos v. Webroot/OpenText), a completely different patent (network security). Different number, different art, different parties.
  • JP 6492389 — a Pulstec Industrial X-ray diffraction apparatus (Japanese patent).
  • RU 2593231 C2 — an AbbVie application that merely cites US 6,492,389 as prior art; a citation is not a proceeding.
  • US 6,233,389, US 6,949,389 — unrelated '389 patents from litigation aggregator results.

Coverage caveat. I had no authenticated access to PACER, Docket Navigator, Lex Machina, or RPX Insight, and public indexing of PTAB petitions is incomplete for pre-2020 filings. I cannot rule out a sparsely-indexed or sealed proceeding, but nothing in the ODP structured data or in any indexed source supports one. I found no IPR, PGR, CBM, no reissue, and no reexamination certificate for this patent.

Bottom line for a defendant: US 6,492,389 has no AIA trial history whatsoever — no petition, no institution decision, no final written decision, no settlement, no appeal. Its claims 1–13 are untested and now expired. There is no PTAB outcome to lean on, but there is also no PTAB outcome to fear, and no estoppel constraining any invalidity ground you might raise in another forum.

Sources consulted: USPTO Open Data Portal structured block (canonical, supplied in prompt); Google Patents — https://patents.google.com/patent/US6492389/en; FreePatentsOnline — https://www.freepatentsonline.com/6492389.html; USPTO PTAB E2E/PTACTS portal — https://ptacts.uspto.gov/ptacts; Unified Patents portal — https://portal.unifiedpatents.com/.

I'll research the assignment record for this patent using the available tools.

Assignment & Ownership Analysis — US 6,492,389 B1

Access note (read first): I attempted to pull the assignment record directly from USPTO Assignment Center (https://assignmentcenter.uspto.gov/) and its predecessor index (https://assignment.uspto.gov/patent/index.html). Those endpoints did not return record-level data in this session (no reel/frame, no correspondent text). What follows is reconstructed from the Google Patents legal-events tab, which mirrors the Assignment Center's event list but not the reel/frame metadata. I could not retrieve the reel/frame numbers, and I will not guess them. The single assignment event that exists is confirmed by Google Patents; its reel/frame and recorded correspondent remain unverified here.

Inventors

Departure pattern: Not present. The commonly flagged red flag — all inventors leaving the original assignee within 12 months of filing — does not appear here. The same core group (Huang, Wang, Zhang, plus new inventors Shan and Lu) filed and took a further patent (US 6,713,280, "Enhancement of peptide cellular uptake") out of Thomas Jefferson University with a 1999 priority date, and the HA14-1 discovery was published in PNAS in June 2000 with Jefferson as the affiliation. This is the signature of a stable, institution-anchored academic group, not a pre-fire-sale exodus. (Caveat: I could not date-stamp each inventor's departure; the inference rests on the 1999–2000 co-filing and publication record.)

Original assignee

Thomas Jefferson University (Philadelphia, PA) — a nonprofit academic medical center (now part of the Jefferson Health system). The patent was filed 1999-07-20 and issued to Jefferson on 2002-12-10.

• Products embodying the claims? No. Jefferson itself never commercialized a Bcl-2 inhibitor. The flagship compound HA14-1 was commercialized only as a laboratory research reagent by third-party suppliers (EMD Biosciences / Calbiochem, BioMol, Axxora). Jefferson's monetization model was academic licensing, not product sales — consistent with a university holding.
• Primary line of business: higher education, biomedical research, and healthcare delivery.
• Current status: Operating (no bankruptcy, no dissolution, no acquisition of the university). The patent itself, however, is Expired – Lifetime as of 2019-07-20.

Assignment timeline

One assignment is recorded in the chain. Google Patents legal events show a single inventor→university conveyance recorded shortly after filing:

• 1999-07-20 (executed) / 1999-08-12 (recorded) — Reel unverified (not returned by Assignment Center in this session); frame unverified
  • Conveyance: Assignment of assignors' interest
  • Assignor: HUANG, ZIWEI; LIU, DONGXIANG; HAN, XIAOBING; ZHANG, ZHIJIA; WANG, JIALUN (all five named inventors)
  • Assignee: THOMAS JEFFERSON UNIVERSITY
  • Correspondent: Not captured in the record text I could access. During prosecution the agent of record was Drinker Biddle & Reath LLP (the firm's pre-2020 name; the Chinese bibliographic record for this patent lists 代理机构 "Drinker Biddle & Reath LLP"). See the flag in the notes below.
  • Context: Standard employee/inventor-to-institution assignment — the routine obligation-to-assign conveyance every university requires before filing. Not a sale, not a securitization, not a transfer to an asserter.

No post-issuance assignments are recorded. Specifically, I found no assignment to any LLC, holding company, assertion vehicle, or defensive aggregator. Google Patents' legal-events tab for this patent lists only the filing event, the 1999 inventor assignment, the 2002 grant, and the 2019 anticipated expiration — no subsequent reassignment entries.

Flag — internal inconsistency in the earlier section: the previously generated summary listed the attorney/agent as "Faegre Drinker Biddle & Reath LLP." "Faegre Drinker" is the merged firm name that did not exist until 2020. A 1999–2002 assignment/prosecution record would name Drinker Biddle & Reath LLP only. The earlier entry is anachronistic and should be corrected; it does not affect ownership.

Timeline diagram

timeline
    title Ownership of US 6492389
    1998 : Priority date from provisional filing
    1999 : Non-provisional filed 20 July
         : All five inventors assign rights to Thomas Jefferson
    2002 : Patent issued 10 December
    2019 : Patent term expires 20 July

NPE / troll-pattern signals

Verdict

Insufficient data — applying your definition literally ("no records, or only the original assignment"). The chain contains exactly one assignment: the 1999-08-12 inventor-to-institution conveyance to Thomas Jefferson University (executed 1999-07-20, per the Google Patents legal-events record). There are zero post-issuance transfers, so there is no NPE chain to score, and none of the eight troll-pattern signals is present.

Substantively: this reads as an original-assignee-retains-title academic holding, not an NPE situation. Thomas Jefferson University has owned US 6,492,389 continuously since 1999; the patent expired 2019-07-20; the asserted research compound HA14-1 was never commercially exploited by the owner, only sold as a reagent by third parties. Any 2026 relevance is as cited prior art, not as an asserted asset.

Verification links:

• USPTO Assignment Center: https://assignmentcenter.uspto.gov/ (search patent number 6492389)
• Legacy Assignment Search: https://assignment.uspto.gov/patent/index.html
• Google Patents legal events: https://patents.google.com/patent/US6492389/en

Residual uncertainty to close on a paid/authenticated source: the reel/frame of the single 1999 assignment and the name of the recording correspondent were not obtainable here. Someone with PACER-equivalent access to Assignment Center (or a Docket Navigator / Lex Machina / RPX query) should pull the 1999-08-12 record to confirm the reel/frame and correspondent before this is certified as a complete negative for post-issuance transfers.

I'll research the prior art cited on the face of US 6,492,389 and in its prosecution history.

Let me get the actual front-page citations for the patent.

Let me find the exact citation lists attached to this patent record.

Important scope note before the analysis

I was not able to retrieve the actual front‑page "References Cited" block of US 6,492,389 from an authoritative source in the searches I ran. The Google Patents text dump supplied in the task omits that section entirely, and FreePatentsOnline/Justia renderings I reached returned the specification but not a clean U.S.-patent / foreign-patent / other-publications table. So I will not present a fabricated list of citations. Instead I do three things:

1. State what is verifiable about the record;
2. Set out the references that are demonstrably tied to this patent (they appear in its own specification, which is where the great majority of a chemistry patent's cited art normally sits) and map them to the claims;
3. Tell you exactly where the definitive PTO‑892 "References Cited" list must be pulled from, and flag that I could not do so here.

For the specific point you asked about — "each patent citation for 6492389" — I must be explicit: I could not verify that US 6,492,389 has any U.S. patent documents on its face. Its cited art that I can document is overwhelmingly non‑patent literature (journal articles), which is consistent with a 1998-priority, first-in-class academic filing. Any claim that a specific U.S. patent appears on its face would be unverified.

1. Record verification (US 6,492,389 literally)

The identifier resolves to one patent. I found no confusable "6,492,389." (Different patents ending in 389 — e.g., US 6,233,389 TiVo, US 6,949,389 displays — are unrelated and must not be conflated.)

Critically for a § 102 analysis: the granted claims are method-of-use claims only (inducing apoptosis, claim 1; reversing Bcl‑2‑mediated apoptosis blockage, claim 11; treating Bcl‑2‑expressing cancer, claim 12, with claim 13 reciting tumor types). There are no compound per se claims — a fact that itself signals the chromene scaffold was old in the art.

2. Cited references I can document, with § 102 mapping

The following are reproduced from the patent's own specification/description (the body text the task supplied). In USPTO practice, references discussed in the specification are commonly carried onto the front page as "Other Publications." I mark each with the claim(s) it could potentially bear on under 35 U.S.C. § 102 and state my anticipation conclusion.

A. Bcl‑2/Bcl‑x_L structure and BH3‑pocket art (target and mechanism)

B. Bcl‑2 as a therapeutic target / "inhibit Bcl‑2 to kill tumors" art (potentially the closest § 102 art)

C. Chemistry-of-the-scaffold art (the real § 102 hazard — and why no compound claims issued)

The species of formula III are 2‑amino‑4H‑chromene‑3‑carboxylates/carbonitriles. The specification admits they are pre-existing, commercially available compounds:

"The compounds of Table II are available from Maybridge Chemical Company."

and, for formula I, that the screen used "the 150,000 compounds contained in the Available Chemicals Dictionary (Molecular Design Limited)."

3. Bottom-line § 102 assessment

• No reference I can document anticipates any of the granted claims (1–13). Every candidate either (a) discloses the Bcl‑2pocket/biology without the formula III compounds (A1–A6, B1–B8), or (b) discloses the chromene compounds without the therapeutic method steps (C1–C2).
• The closest § 102 art is the Bcl‑2‑inhibition therapeutic concept (B1, B2), and it fails only because claims 1/11/12 are expressly limited to compounds of formula III. Had those claims been drafted to cover inhibition of Bcl‑2 generally, B1/B2 would have been serious § 102(b) art. This is almost certainly why the issued claims are method-of-use claims restricted to formula III.
• The real novelty problem for this family was § 102 on the compounds — the spec's own admission that HA14‑1 et seq. and the RCL_/ACD hits were commercially available is the reason there are no compound claims.
• The two provisionals (60/093,561; 60/128,100) are the applicant's own priority documents, not § 102 prior art.

4. What I could not verify — and the exact next step

1. I could not retrieve the front-page "References Cited" list of US 6,492,389. Consequently I cannot confirm or deny the presence of any U.S. patent document, foreign patent document (e.g., WO 00/04901, whose publication date I have not independently verified), or examiner-cited article. My § 102 mapping above is built from the specification text only.
2. Some database hits that look like citations of '389 are actually forward citations (later patents citing '389 as prior art), not prior art to '389. Confirmed examples: US 2010/0197686 A1 ("Therapeutic compounds"); US 9,872,861 (referenced-cited list); US 10,807,977 B2; and RU 2593231 C2's search report. These say nothing about '389's own novelty.
3. To answer your question definitively, pull the PTO‑892 / "List of References Cited by Examiner" from USPTO PatentCenter → Application 09/357,229 → Image File Wrapper, or the EPO Global Dossier for that application. Those documents segregate examiner-cited from applicant-submitted references and will give the exact, verifiable list — including any U.S. patent documents — that I was unable to obtain here.

Caveat stated plainly: because I could not access the authoritative citation list, treat the tables above as documented-in-specification art rather than as a certified restatement of the patent's face. If the IFW shows an examiner-cited U.S. patent or foreign document not appearing in the specification, that reference would need to be added and re-mapped to claims 1–13.

I'll reconstruct the prior-art landscape relevant to this patent's claims, since the analysis must rest on concrete references rather than general reasoning.

Let me gather the specific pre-1998 chemistry and biology references needed to build §103 combinations.

Obviousness Analysis — U.S. Patent No. 6,492,389 B1 under 35 U.S.C. § 103

0. Threshold note on "the Prior Art section of this page"

No discrete "Prior Art" section was included in the material supplied in this task. The message contains (a) the full Google Patents text of US 6,492,389, (b) the previously generated summary and litigation sections, and (c) a "Prior art keywords" field on the Google Patents record (group; ococh; cooch; bcl; alkyl — merely keyword tags, not references). To avoid fabricating a reference list, I reconstructed the operative prior art from the patent's own Background/Detailed Description citations plus live searches run for this task. Every reference below is dated, and I flag explicitly which candidate references are post-priority and therefore unusable as §103 art against this patent's 21 July 1998 priority date.

Claim construction basis: The granted claims are method-of-use claims (inducing apoptosis, reversing Bcl-2–mediated apoptosis blockade, treating Bcl-2–expressing cancer) practiced with compounds of formula III. The compounds themselves are not claimed as compositions. That distinction drives the entire obviousness analysis: the novelty question reduces to (1) whether the formula III compounds were known or obvious, and (2) whether the new use was obvious.

1. The reference set

⚠️ References that are NOT prior art (do not use in a §103 rejection)

2. What the claims require (element breakdown)

The claim elements therefore map almost one-to-one onto the patent's own Background section — i.e., onto admitted prior art.

3. The §103 combinations

Combination A — The structure-based-design route (R1 + R2 + R3 + R4 + R5)

The strongest prima facie case, because it is the patent's own disclosed method.

The combination: Muchmore (R1) teaches the BH1/BH2/BH3 hydrophobic cleft and states it "may represent the binding site for other Bcl-2 family members." Sattler (R2) confirms a BH3 peptide (Bak, the exact 16-mer used by the inventors) binds that cleft with a solved complex structure. Yin (R3) validates the pocket as functionally essential (pocket mutants kill anti-apoptotic activity). Meng (R4) supplies the routine docking algorithm (DOCK3.5). R5 supplies a large catalog of pre-existing, synthetically accessible small molecules — including the 2-amino-4H-chromene class (R6).

Motivation to combine: Express and unambiguous. R1 is not merely a structure — it is a statement of purpose ("may represent the binding site"). Once R2 resolved the bound-peptide conformation, the POSA had both a defined binding site and a template ligand. Applying a known docking algorithm (R4, already used in the art for receptor-ligand screening) to a known target structure (R1/R2) with a known compound catalog (R5) involves no new principle — it is the predictable use of known tools for their known purposes. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007) (predictable variation; "obvious to try" where the prior art gives a finite number of identified, predictable solutions with a reasonable expectation of success).

Reasonable expectation of success: Moderate-to-high. Peptide BH3 mimetics were known to work at the pocket (R2); the remaining problem was converting a peptide to a small molecule, and computational screening of a 150,000-compound catalog was the standard, art-recognized way to do it. That the patent reports only modest potency (K_D 7 µM for HA12-16, 15 µM for HA02, IC₅₀ ~9 µM for HA14-1) supports rather than defeats obviousness — routine optimization, not a new principle.

Defeating this combination requires the patentee to show that the POSA would not have expected any small molecule to bind the pocket (i.e., that the field regarded it as undruggable). That is the core non-obviousness argument (see §5).

Combination B — Known chromene chemistry + known Bcl-2 target (R6 + R1/R2/R3)

Even without the docking route, R6 establishes that 2-amino-4H-chromene-3-carboxylates/carbonitriles are a long-established, readily varied scaffold. R1–R3 define the Bcl-2 pocket. If a pre-1998 reference (verification needed — see caveat) disclosed any antiproliferative or cytotoxic activity for the 2-amino-4H-chromene class, the "select and use" rationale would be strong: a POSA seeking a small-molecule Bcl-2 ligand would look to a privileged cytotoxic heterocyclic scaffold. Caveat: the specific chromene antitumor disclosures I located (MX-58151) are 2004 and cannot be used. There may be pre-1998 chromene-cytotoxicity art (candidate: the Lilly compound LY290181-type 2-amino-4H-chromene tubulin inhibitors, and earlier benzopyran pharmacology), but I could not verify a pre-July-1998 publication in the sources retrieved, so I do not rely on it.

Combination C — Therapeutic-objective art (R7 + R8 + R9) → claims 8–13

Independent of how the molecule works, R7 shows Bcl-2 inhibition was already a clinically pursued cancer strategy (antisense in NHL), and R8 documents Bcl-2 overexpression in exactly the cancer types recited in claim 13. R9 documents the viral and autoimmune settings recited in claims 9–10. A POSA with an available Bcl-2–inhibiting small molecule would have had every motivation to administer it in these indications; the claims recite no more than the known diseases for which Bcl-2 is a known driver. These dependent claims would fall even if an independent claim survived.

Combination D — Claims 2 and 6 (affinity threshold; species election)

• Claim 2 recites a result-effective variable (binding affinity for a defined pocket). Selecting compounds by measured affinity is routine optimization and, under In re Kollman / In re Boesch, a recitation of a property obtained by routine testing does not confer patentability. R4 supplies the screening methodology.
• Claim 6 (HA14-1 / HA14-8) claims specific catalog compounds. Once the genus is obvious, a species that is commercially available and already in the screened library is obvious to select. In re Petering / In re Baird analysis favors the examiner here; there is no evidence of a newly discovered unexpected property for those two species beyond the genus-level property already asserted.

4. Claim-by-claim summary of the prima facie case

5. Counterarguments the patentee would raise (and how they cut)

1. "The pocket is undruggable." Before this work, Bcl-2 inhibition was pursued with antisense oligonucleotides and peptides, not small molecules — arguably evidence the field did not expect success. This is the best non-obviousness argument. But it is evidence of unexpected results, and it must be weighed against the fact that neither R1 nor R2 contained any teaching away from small molecules; R1 in fact invited ligand design. Under KSR, "a patent composed of several elements is not proved obvious merely by demonstrating that each element was known" — but here the method of achieving the goal was itself known (R4).

2. First-in-class / unexpected results. HA14-1 was, by the field's own later accounts, "the first reported small-molecule inhibitor of Bcl-2" (see the ScienceDirect topic page and Sigma datasheet, both post-dating the patent). Unexpected results are a classic secondary consideration — but they attach to the compound, which is not claimed; the claims are to methods. A method claim using a known compound for a newly recognized mechanism is more vulnerable, because the compound's properties are fixed and the "invention" is the discovery of the target — a discovery squarely enabled by R1/R2.

3. Teaching away. I found no reference teaching away from small-molecule Bcl-2 inhibition. Absent teaching away, the obviousness case is not rebutted by the mere existence of an alternative (peptide/antisense) approach.

4. Commercial success / licensing. The patent record shows no litigation and no product commercialization (it expired 2019-07-20 as a research-tool patent); HA14-1 was sold as a laboratory reagent. There is therefore no objective evidence of commercial success to rebut the prima facie case.

5. Post-KSR framing. Under the current standard, the "invention" is the application of a known computational method (R4) to a known target structure (R1/R2) using a known compound library (R5) — the paradigm of predictable, if laborious, engineering. The most likely §103 rejection would be framed as: "It would have been obvious to one of ordinary skill in the art to computationally screen a catalog of commercially available small molecules (R5, R6) against the Bcl-2/Bcl-xL BH3 hydrophobic pocket disclosed by Muchmore (R1) and structurally characterized with the Bak BH3 peptide by Sattler (R2), using the DOCK3.5 algorithm of Meng (R4), because R1 expressly identified that pocket as a ligand-binding site and R3 established it as functionally essential — thereby arriving at the compounds of formula III with a reasonable expectation of success."

6. Uncertainty notes and limits of this analysis

• No "Prior Art section" was supplied, so this is a reconstruction. A formal reexamination/validity opinion would pull the actual front-page "References Cited" and the WO 00/04901 international search report, which were not in the material provided and which I could not retrieve before hitting the tool limit.
• The single most consequential evidentiary gap is whether a pre-July-1998 reference disclosed antiproliferative/cytotoxic activity of 2-amino-4H-chromenes. If one exists, Combination B converts the §103 case from "moderate–strong" to "strong" across all independent claims. I could not verify such a reference (the MX-58151 and HA14-1 "tumor antagonist" characterizations I found are 2004/2006 and thus not prior art).
• I have not verified the actual claim text character-for-character (the FreePatentsOnline/Justia rendering truncates the chemical markup), consistent with the caveat already recorded in the Patent Summary section. The claim-element mapping in §2 is from the specification's parallel formula III disclosure and the visible claim text.
• Do not conflate this patent with the unrelated '389-ending patents already flagged in the Litigation section (U.S. 6,233,389 TiVo; U.S. 6,949,389 Pictiva; JP 6492389; RU 2593231 C2).
• Because the patent expired 2019-07-20, this analysis is retrospective — e.g., for invalidity-contentions in follow-on litigation, IPR-estoppel, or freedom-to-operate literature review — not for a live reexamination.

Bottom line

A reasoned prima facie §103 case exists, and its strongest form is Combination A: Muchmore (1996) + Sattler (1997) + Yin (1994) + Meng/DOCK3.5 (1992) + the MDL catalog / known 2-amino-4H-chromene chemistry. That combination tracks the patent's own admitted method and supplies motivation, a defined target, a routine tool, and pre-existing compounds. Dependent claims 2, 6, 8, and 13 are weaker still, resting on routine optimization, commercial availability of species, and the patent's own admitted Bcl-2 disease associations. The patentee's best rebuttal is unexpected results / first-in-class for small-molecule Bcl-2 inhibition — but that argument attaches to the (unclaimed) compound species, not to the claimed methods, and there is no teaching-away or commercial-success evidence in the record to reinforce it.