US 6194191

I'll research this patent across USPTO sources and litigation dockets.

Let me check for litigation and any CAFC/Federal Circuit proceedings involving this specific patent.

Let me verify the claim text and check for PTAB/IPR and any litigation record for this patent.

US Patent 6,194,191 — Analyst Summary

Sourcing note: I worked from the Google Patents full-text record for US6194191 (fetched 2026-09-24; the authoritative text supplied), cross-checked against uspto.report's full-text/claims record and the EPO/patent-family record (WO 98/22588 / EP 0968284, family ID 21858843). I could not retrieve any 2026 Federal Circuit docket or PTAB proceeding naming this patent; see "Litigation / CAFC" below.

1. Bibliographic data

A minor discrepancy worth flagging: Google Patents and uspto.report both give the filing date as 1997-11-20, but one secondary source (patents-review.com, discussing a later continuation) states "08/975,519, filed Nov. 29, 1997." The 1997-11-20 date is consistent with the PCT/EPO family record (WO 97/21504 filed 1997-11-20) and should be treated as correct.

2. Abstract (as issued)

The present invention addresses the need to improve the yields of viral vectors when grown in cell culture systems. In particular, it has been demonstrated that for adenovirus, the use of low-medium perfusion rates in an attached cell culture system provides for improved yields. In other embodiments, the inventors have shown that there is improved Ad-p53 production with cells grown in serum-free conditions, and in particular in serum-free suspension culture. Also important to the increase of yields is the use of detergent lysis. Combination of these aspects of the invention permits purification of virus by a single chromatography step that results in purified virus of the same quality as preparations from double CsCl banding using an ultracentrifuge.

3. Plain-language overview of the independent claims

There are six independent claims: 1, 30, 61, 71, 78 and 86 (plus claims 88–89, which depend jointly on claims 1, 30 or 86). All are process claims for making adenovirus preparations.

Claim 1 — baseline production method. Grow host cells in medium → feed them by perfusion or fed-batch → infect with adenovirus → lyse the cells to release virus, where the lysis is achieved by autolysis of the infected cells → purify the virus from the lysate. (Claims 2–29 add: one or more chromatography steps, preferably a single ion-exchange/anion-exchange step at pH ~7.0–10.0 using DEAE, TMAE, QAE, PEI, Toyopearl Super Q 650M, MonoQ, Source Q or Fractogel TMAE; glucose held at ~0.7–1.7 g/L; diafiltration; an adenoviral vector with a promoter (SV40 IE, RSV LTR, β-actin, CMV IE, adenovirus major late, polyoma F9-1, tyrosinase) driving a therapeutic gene (a long list culminating in p53); replication-incompetent / E1A-E1B-deleted virus; 293 host cells; Benzonase® or Pulmozyme® treatment; tangential-flow membrane concentration with a 100–300K NMWC regenerated-cellulose or polyethersulfone membrane; serum-free media and serum-weaning; suspension or anchorage-dependent culture.)

Claim 30 — glucose-controlled feeding variant. Grow host cells in glucose-containing medium → feed by perfusion or fed-batch at a rate that keeps glucose below 2.0 g/L (claim 31 narrows to ~0.7–1.7 g/L) → infect with adenovirus → harvest and lyse to produce the lysate. Dependent claims 43–60 then add specific ex situ lysis (hypotonic/hypertonic, freeze-thaw, sonication, impinging jet, microfluidization, detergent) or in situ detergent lysis (Thesit®, NP-40®, Tween-20®, Brij-58®, Triton X-100® or octyl glucoside), nuclease treatment, single-step ion-exchange chromatography, diafiltration and TFF concentration.

Claim 61 — chromatography without CsCl. Grow host cells → feed by perfusion or fed-batch → infect → lyse by one of a recited set of mechanical/chemical means (hypotonic, hypertonic, impinging jet, microfluidization, solid shear, detergent, liquid shear, high-pressure extrusion, autolysis or sonication) to make a crude lysate → purify by one or more chromatography steps, expressly without cesium chloride density-gradient centrifugation. (Claims 62–70 narrow the lysis mode, e.g. 1% (w/v) detergent.)

Claim 71 — serum-free + defined recovery. Grow host cells in serum-free medium → infect → harvest and lyse → purify by chromatography without CsCl density gradient, where the purification is a single chromatography step, and the recovery of purified adenovirus is 70% ± 10% of the starting PFU. (Claims 72–77 add anion exchange, nucleic-acid reduction, and concentrate/diafiltrate/buffer-exchange steps.)

Claim 78 — as claim 71, plus nuclease digestion. Same serum-free-less scheme as claim 71 but with an explicit step of treating the lysate with a nuclease to reduce contaminating nucleic acid before the single, CsCl-free chromatography step, again with 70% ± 10% PFU recovery. (Claims 79–85 add anion exchange, further purification, concentration and buffer exchange, and serum-free media.)

Claim 86 — fed/perfused + CsCl-free single column. Grow host cells → feed by perfusion or fed-batch → infect → lyse by one of the recited means → purify by chromatography without CsCl density-gradient centrifugation, the chromatography being a single step. Claims 88 and 89 specify that the nutrient supply in the claim 1 / 30 / 86 embodiments is fed-batch (88) or perfusion (89).

Commercial significance. Independent claims 61, 71, 78 and 86 reflect the patent's core contribution: replacing the non-scalable double-CsCl ultracentrifugation purification with a single ion-exchange column while retaining equivalent purity (A260/A280 ≈ 1.26–1.27, particle/PFU ≈ 36) and ~60–70% recovery — versus the 23% recovery reported by Huyghe et al. (1996) using a two-column ion-exchange/metal-chelate process. The specification also reports the ATCC deposit of the serum-free suspension-adapted IT293SF 293 cell line (deposited 1997-11-17) and details the AdCMVp53 (INGN 201 / Advexin) manufacturing process.

4. Litigation and CAFC check — important caveats

• No 2026 Federal Circuit docket, appeal, or PTAB (IPR/PGR) proceeding naming US 6,194,191 was found in the searches I ran. I cannot confirm one exists, and I am not asserting that none exists — only that my searches did not surface one.
• The Google Patents record carries a "Family has litigation / First worldwide family litigation filed" flag linking to Darts-IP family 21858843, indicating the family (Introgen/Crucell adenoviral-vector production patents, including US 6,726,907, US 7,510,875 and US 9,428,768) has been litigated somewhere in the world. I was not able to retrieve the case caption, court, or docket number for any such action.
• The patent expired 2017-11-20 (20 years from the 1997-11-20 filing date), so any 2026 enforcement activity would necessarily concern past damages, not ongoing infringement.

5. Stated uncertainties

1. Claim text provenance. The claim wording above comes from a third-party full-text source (uspto.report), which simultaneously notes that a Certificate of Correction exists for this grant. A certificate of correction can alter claim text. I could not independently verify the printed claims against the official USPTO patent image in this session, so the exact scope of claim 1 (in particular the "autolysis of infected cells" limitation) should be confirmed against the granted patent PDF / USPTO PatentCenter.
2. Filing-date discrepancy (1997-11-20 vs. 1997-11-29) is noted above; 1997-11-20 is the better-supported date.
3. Assignee history is per assignment records: Introgen Therapeutics → Crucell Holland B.V. (2009) → currently listed as Janssen Vaccines and Prevention BV. Google Patents itself cautions that assignee data "may be inaccurate."
4. Patent number interpreted literally as US 6,194,191; no other number was substituted.

Grounding URLs: https://patents.google.com/patent/US6194191/en · https://uspto.report/patent/grant/6194191 · https://data.epo.org/gpi/EP0968284A2.pdf · https://patents.justia.com/patent/20100105124 (discussing co-owned US 6,194,191) · https://patentimages.storage.googleapis.com/d8/31/05/074b97406ffa97/US7510875.pdf (lists US 6,194,191 in its references)

I'll search for litigation involving US 6,194,191 across patent litigation databases.

Let me search more specifically for litigation tied to this patent and its owner.

Bottom line

I could not confirm any litigation asserting or challenging US 6,194,191 ("Method for the production and purification of adenoviral vectors," Introgen Therapeutics/now Janssen Vaccines and Prevention BV, app. 08/975,519, filed 1997‑11‑20, granted 2001‑02‑27, expired 2017‑11‑20). I am explicitly flagging that as an absence of found evidence, not as a verified negative — my searches did not return the PACER/CAFC docket-level records that would definitively resolve it.

What I actually found

1. Google Patents carries a litigation flag, but no case data. The authoritative page states:

"Family has litigation / First worldwide family litigation filed" — with a link to Darts‑ip family ID 21858843.

Source: https://patents.google.com/patent/US6194191/en

This indicates some member of the worldwide family (not necessarily US 6,194,191 itself) has been involved in a proceeding captured by Darts‑ip, and that the first such filing is recorded. Google Patents does not expose the parties, forum, or case number here. This is the single strongest lead, and it is unverified — I could not open the Darts‑ip record (licensed dataset, paywalled).

2. No litigation listed on third‑party patent trackers. PatentLeaderboard's page for the patent (https://www.patentleaderboard.com/patent/[6194191](/patent/6194191)) shows only bibliographic and estimated‑value data ($3,803,000) with no litigation entries.

3. Owner's own SEC risk disclosures describe threats, not suits, and not against '191. Introgen's Forms 10‑Q discuss third‑party IP risk around its p53/adenoviral p53 portfolio — Schering‑Plough/Canji US and European patents, a Transgene replication‑deficient adenoviral vector patent, a Schering‑Plough EPO opposition to an Introgen combination‑therapy patent (maintained as amended, Feb 2006), and an unidentified third party attempting to provoke a PTO interference on an Introgen adenoviral p53 patent. None of these is pleaded as litigation over US 6,194,191 specifically, and none identifies a case number.
(example filing: http://business.custercountychief.com/custercountychief/action/getedgarpdf?accesscode=95013407005192)

4. Assignment history relevant to who could have sued. USPTO assignment records (via the Google Patents legal‑events timeline) show Introgen → Crucell Holland B.V. (2009‑09‑24); current assignee is Janssen Vaccines and Prevention BV. Any enforcement of '191 would most plausibly have been by Introgen (1997–2009) or Crucell (2009–2017).

False positives I excluded (different patents — same "'419"/"'191" shorthand)

Per the strict rule to interpret identifiers literally, note that these are not US 6,194,191:

Caveats and recommended verification steps

• I could not directly query the Unified Patents litigation caselist (https://portal.unifiedpatents.com/litigation/caselist), PACER, or the CAFC docket by patent number in this session; those are the sources most likely to surface a case I missed.
• Because the patent expired 2017‑11‑20, any infringement action would necessarily predate that.
• To close this out, I'd recommend: (a) pulling Darts‑ip family 21858843 for the specific jurisdiction/parties; (b) a PACER "patent" docket search for "6,194,191"; and (c) a check of MDL/ITC Section 337 dockets for Crucell/Janssen adenovirus‑vector disputes.

I do not know with high confidence that this patent was ever litigated, and I will not assert a case name, number, or outcome that I could not ground in a retrieved source.

I'll verify the canonical "no proceedings" finding against public sources before writing up.

Proceedings overview

Zero AIA trial proceedings — no IPR, PGR, or CBM petition has ever been filed against US 6,194,191, per the canonical USPTO Open Data Portal ("PTAB proceedings on file") block, which returns an empty set as of the most recent ingest. The breakdown is therefore: 0 active, 0 claims invalidated, 0 claims sustained, 0 settled, 0 institution denials. For a defendant, this means the patent's claims are entirely untested at the PTAB — there is no FWD to hand you a canceled claim, and equally, no PTAB record that the patent owner has ever had to defend. That cuts both ways: no claim of '191 has been killed, but the patent has also never been pressure-tested by a well-funded petitioner, so its validity is unadjudicated rather than "hardened."

Critical practical point: because the patent expired 2017-11-20 (anticipated expiration, per the Google Patents legal-status timeline) and its priority runs to 1996-11-20, the AIA trial menu is largely closed anyway —

• PGR: unavailable. The patent's effective filing date predates 2013-03-16.
• CBM: unavailable. It would fail the § 18(d)(1) "financial product or service" eligibility test on its face (a viral-vector manufacturing method), and the CBM program sunset on 2020-09-16.
• IPR: technically still filable against an expired patent, but the only rational petitioner posture — a defendant served with an infringement complaint (§ 315(b)) — presupposes a live assertion that the 2017 expiry now forecloses.

Proceedings

None to report. There is no IPR#########, PGR#########, or CBM######### number to list. To be explicit about what I checked and what I did not find:

False positives observed (do not treat these as proceedings against '191): search hits referencing "6194191" resolve to (a) prior-art lists in other patents (e.g., US 7,510,875; US 10,570,416; US 11,326,182; EP 1,407,006; EP 3,323,895), and (b) — repeating an exact finding from the litigation section — Edward S. Weil, attorney registration no. 6,194,191, in N.D. Ill. 1:07-cv-04946 (Apple/AT&T Mobility), which is a bar number, not a patent. Source: https://docs.justia.com/cases/federal/district-courts/illinois/ilndce/1:2007cv04946/[212324/128](https://assignmentcenter.uspto.gov/search/patent/reelFrameDetail?reelFrame=212324-0128)

Adjacent adversarial activity — European, not PTAB, not '191, but instructive: the family's adenovirus-purification technology has been attacked by third parties at the EPO, just not the US '191 patent:

• T 0238/11 (Boards of Appeal, 3.3.08, decision 2015-04-08) — opposition to Crucell Holland B.V.'s EP 1 869 171 ("Virus purification using ultrafiltration"); opponent Gabriele Ahrens; patent maintained in amended form on a 20-claim main request after the proprietor dropped claims 21–24 in the face of a lack of inventive step. https://www.epo.org/boards-of-appeal/decisions/pdf/t110238eu1.pdf
• T 1203/19 (Boards of Appeal, 3.3.08, decision 2022-04-26) — appeal from revocation of EP 2 428 229 ("Oncolytic adenoviruses for treating cancer"). https://legacy.epo.org/boards-of-appeal/decisions/pdf/t191203eu1.pdf

The takeaway is that the technology area attracts opponents; the US '191 patent specifically never attracted an AIA petitioner.

Strategic summary

Claim status of 6,194,191. Every claim is UNTESTED. Not one claim is CANCELED and not one is SUSTAINED by the PTAB — there is no final written decision, so there is no claim-level disposition to report, and I will not manufacture one. The patent issued 2001-02-27 with a claim set directed to an adenovirus production/purification method (growing host cells at low perfusion rate, infection, harvest and detergent lysis to crude lysate, concentration, buffer exchange/diafiltration, nuclease reduction of contaminating nucleic acid, and a single ion-exchange chromatography isolation step — as summarized in the specification's summary-of-the-invention passages on Google Patents; I have not verified verbatim claim text or the exact claim count in this session, so I am not quoting claim numbers). All of that subject matter stands unadjudicated at the Board.

Estoppel landscape — there is none. § 315(e)(2) estoppel attaches only to a petitioner that obtained an FWD, or whose IPR was instituted and then terminated by settlement. Since no IPR was ever instituted, no party is estopped, and no prior-art ground has been "used up." Conversely, a defendant cannot borrow anyone else's invalidity work product from a PTAB record; there is no IPR file history to mine for admissions, no patent-owner preliminary response narrowing arguments, and no Board construction of the key claim terms ("low perfusion rate," "reducing the concentration of contaminating nucleic acids," "consisting essentially of a single chromatography step"). Validity would have to be litigated from scratch in district court — if there were any live theory, which the 2017-11-20 expiry largely forecloses.

Pattern signals. No repeat petitioner, no serial IPR filer, no defensive aggregator. The strongest structural signal is absence: well-commercialized, long-lived patents often draw IPRs, especially in gene-therapy manufacturing where Crucell/Janssen, Merck, and GSK all operate. '191 survived an 18-year enforceable life (2001–2017) without a single AIA challenge. Two plausible explanations, both worth weighing: (i) it was licensed rather than litigated (the technology reads on widely used industrial Ad purification workflows, and a license is cheaper than an IPR for a practice-the-prior-art manufacturer), or (ii) the earliest-priority 1996 art position made § 102/§ 103 challenges unattractive. I cannot confirm which from retrieved sources.

One cross-reference correction / supplement to the prior litigation section. That section reported no confirmed litigation. The reference list of US 7,510,875 (a continuation of '191 via 6,726,907) discloses: "Complaint Avenue Pharmaceuticals Products, Inc. and Aventis Pharma, S.A., Plaintiff, v. Introgen Therapeutics, Inc., Defendant. Civil Action No. 01-451 from the U.S. District Court for the District of Delaware, Jun. 29, 2001, dismissed with prejudice Jul. 2, 2001." https://patentimages.storage.googleapis.com/d8/31/05/074b97406ffa97/US7510875.pdf — That is a real, dated D. Del. action naming Introgen as defendant in the same portfolio family, dismissed with prejudice just three days after filing (consistent with a settlement or consent dismissal). It does not name US 6,194,191 as the asserted patent, so it does not contradict the litigation section's bottom line — but it is a concrete case-number lead that section did not have, and it should be checked against PACER for the asserted patents. Also note the Google Patents flag "Family has litigation / First worldwide family litigation filed" (Darts-ip family 21858843) remains unverified; Aventis v. Introgen, D. Del. 01-451 is a plausible candidate for that flag.

Recommended next steps

If you are a defendant being (or about to be) asserted against:

1. Check the expiry first. The patent expired 2017-11-20 and the record shows "Expired – Lifetime." Any demand letter citing '191 for ongoing activity is legally hollow; damages for past infringement would be time-barred under § 286 absent tolling. This is a threshold response, not an IPR strategy.
2. You cannot file an IPR on these facts and win anything useful. PGR and CBM are unavailable (pre-AIA priority; non-financial subject matter; CBM sunset 2020-09-16). An IPR on an expired patent is possible in the abstract, but you would be spending $300k+ to cancel claims in a patent that cannot be enforced — and you would be racing the § 315(b) one-year clock only if a complaint had actually been served.
3. There is no FWD to link to and no disposition to quote. If someone tells you "claims 1–5 of '191 were canceled in IPR," that is false. The correct citation is: no AIA trial proceeding exists on US 6,194,191, verified against the USPTO Open Data Portal. Point them to the PTAB E2E / Decisions portals: https://ptab.uspto.gov and https://www.uspto.gov/patents/patent-trial-and-appeal-board/decisions (bulk data via https://developer.uspto.gov/ptab-api/swagger).
4. Run the family check I could not complete. The continuation chain — 6,726,907 → 7,510,875 → 7,445,930 (plus 7,125,706, per the family table at https://data.epo.org/gpi/EP0968284A2.pdf) — is where any PTAB fight would more plausibly have occurred, since those claims were enforced later and cover the product/byproduct aspects. Query each number at https://portal.unifiedpatents.com/litigation/caselist and CourtListener (https://www.courtlistener.com/?q=%226%2C194%2C191%22) before advising.
5. Treat the Darts-ip flag as a to-do, not a fact. Pull Darts-ip family 21858843, and check D. Del. Civil Action No. 01-451 (Aventis v. Introgen) for the asserted patent numbers.

Confidence statement. I am highly confident there is no PTAB proceeding on US 6,194,191 — the structured ODP block is empty and two independent web passes surfaced no petition, institution decision, FWD, or appeal, only art citations and the attorney-registration-number false positive. I am not asserting a verified negative for the family (6,726,907, 7,510,875, 7,445,930, 7,125,706); my family query was truncated and I did not complete it. I found no CAFC appeal because there was no FWD to appeal; the only appellate decisions I located in this space are European (T 0238/11 and T 1203/19) and concern different patents owned by Crucell.

I'll research the assignment chain for US 6,194,191, focusing on the recorded transfers and the parties involved.

Let me pull the assignment-record details and the current corporate status of the assignees.

Let me verify the bankruptcy asset-sale specifics and look for the recorded assignment details (reel/frame, correspondent).

Assignment record — US 6,194,191

Sourcing caveat up front (read before the timeline). The USPTO Patent Assignment Center (https://assignmentcenter.uspto.gov/) was not directly queryable in this session, so I could not extract reel/frame numbers, execution dates, or the correspondent of record for any link in this chain. Everything below is reconstructed from the Google Patents legal‑events timeline on the authoritative page (https://patents.google.com/patent/US6194191/en), the bankruptcy docket/opinion for the original assignee (W.D. Tex. Bankr. No. 08‑12442; In re Introgen Therapeutics, Inc., 429 B.R. 570 (Bankr. W.D. Tex. 2010)), and SEC/press filings. I am not inventing reel/frame or correspondent fields. Where the task asks for a reel/frame and I did not retrieve one, I say so. The corresponding Assignment Center searches ("6194191" as the property number) should be run to fill these three fields.

Inventors

Four named inventors, all apparently employees of the original applicant, Introgen Therapeutics, Inc. (Houston, TX) at filing — the application is a US national‑stage/family member of PCT WO 98/22588 (Introgen Therapeutics Inc.; Cho Toohyon; Zhang Shuyuan; Thwin Capucine; Wu Zheng), filed 1996‑11‑20 priority / 1997‑11‑20 US filing:

Unusual patterns / flags

• Not all four inventors appear on the recorded 1998 assignment. The Google Patents legal event for 1998‑05‑26 names only THWIN, Capucine; WU, Zheng; ZHANG, Shuyuan as assignors. Toohyon Cho is absent. This can mean (a) Cho assigned by a separate instrument not captured in this event, (b) Cho was a non‑employee/institutional inventor, or (c) a data gap in the Google Patents feed. I could not resolve it without the Assignment Center record — treat as unclear, not as a finding of a defect.
• I found no evidence that the inventors departed Introgen within 12 months of filing (which would precede a portfolio fire‑sale). The fire‑sale in fact came ~11 years later, driven by Introgen's product failure, not inventor attrition.

Original assignee

Introgen Therapeutics, Inc. (Houston/Austin, TX) — named on the face of the issued patent as original assignee.

• Line of business: clinical‑stage gene therapy. Its lead program was ADVEXIN® / INGN 201, a replication‑incompetent adenoviral vector delivering wild‑type p53, plus a contract manufacturing/services arm (Introgen Technical Services, "ITS"). The '191 claims are a manufacturing/purification process, so the patent is a process asset supporting the firm's clinical‑grade adenoviral vector production, not a product‑per‑se.
• Did they ship a product embodying the claims? No approved product. ADVEXIN never obtained FDA approval (FDA refused to file the BLA in 2008); the described purification method was used to make clinical material.
• Current status: Failed / liquidated. Voluntary Chapter 11 filed December 2008; assets sold piecemeal through 2009 (manufacturing assets to Vivante GMP Solutions; the "Crucell Patents" to Crucell Holland B.V.; the remainder to Pope Investments II, LLC). Reported as Chapter 7 / ceased operation December 2009; liquidating plan confirmed 2010. Entities associated with former principals were later reconstituted (p53, Inc. → MultiVir) — not successors to '191.

Assignment timeline

Only three assignment‑type legal events are exposed for this patent, plus a current‑assignee (succession) field. No reel/frame numbers, execution dates, or correspondents were retrievable in this session — that gap is a limitation of the sources I could reach, not a claim that the fields are missing from USPTO records.

• 1998‑05‑26 (recorded) — Reel/Frame: not retrieved

  • Conveyance: Assignment of assignors' interest (recorded at issuance stage)
  • Assignor: Capucine Thwin; Zheng Wu; Shuyuan Zhang (Toohyon Cho not listed — flag)
  • Assignee: Introgen Therapeutics, Inc.
  • Correspondent: not exposed in retrieved sources
  • Context: Initial inventor → employer assignment of rights in the application. Not a fire‑sale or asserter transfer.

• 2003‑03‑19 (recorded) — Reel/Frame: not retrieved

  • Conveyance: Assignment of assignors' interest
  • Assignor: Lucetta Caston; Deborah Wilson
  • Assignee: INTROGEN THERAPEUCTICS, INC. (sic — "THERAPEUCTICS" is the literal spelling in the Google Patents event; a known data‑quality typo for "THERAPEUTICS")
  • Correspondent: not exposed in retrieved sources
  • Context: Appears to be a confirmatory/corrective internal assignment, but the assignors are not the named inventors — anomalous. Likely a family/related‑application assignment bundled into this record, or an assignment of some residual interest. Unclear; verify in Assignment Center.

• 2009‑09‑24 (recorded) — Reel/Frame: not retrieved

  • Conveyance: Assignment
  • Assignor: Introgen Therapeutics, Inc.
  • Assignee: Crucell Holland B.V. (Leiden, NL)
  • Correspondent: not exposed in retrieved sources
  • Context: Bankruptcy fire‑sale. The W.D. Tex. Bankruptcy Court approved the sale of certain assets to Crucell on 2009‑04‑23; Crucell purchased eight patent families (the "Crucell Patents") for $425,000, with Introgen retaining a 35% share of all net license revenues, royalties and proceeds from Crucell's licensing of those patents, in perpetuity. The '191 family is a member of those divested Introgen manufacturing‑patent families. (Source: In re Introgen Therapeutics, Inc., 429 B.R. 570; https://www2.txwb.uscourts.gov/opinions/opdf/08-12442-cag_Introgen%20Therapeutics,%20Inc.%20and%20Introgen%20Technical%20Services,%20Inc._2010-04-29%2023;05;02.pdf)

• Current assignee field (no separate recorded assignment event): Janssen Vaccines and Prevention B.V. — reflects corporate succession / change of name, not a new arm's‑length purchase: Johnson & Johnson acquired Crucell (18% stake Sept 2009; full buyout completed 2011), and Crucell Holland B.V. was renamed Janssen Vaccines & Prevention B.V. in 2014. No distinct assignment reel is exposed in the legal‑events timeline for this step.

Note: The Assignment Center may hold more recorded instruments (releases, security interests, name‑change records) than the Google Patents legal‑event feed surfaces. Run the Assignment Center query by patent number to confirm completeness.

Timeline diagram

timeline
    title Ownership of US 6194191
    1996 : Priority application filed
    1997 : US application 08 975 519 filed
    1998 : Inventors assign rights to Introgen
    2001 : Patent issued 27 Feb
    2008 : Introgen files Chapter 11
    2009 : Court approves sale to Crucell
         : Assignment recorded 24 Sep
    2011 : Johnson and Johnson acquires Crucell
    2014 : Crucell renamed Janssen Vaccines
    2017 : Patent expires 20 Nov

NPE / troll‑pattern signals

1. Shell‑entity transfer — not present. Every named owner is an operating company: Introgen Therapeutics, Inc. → Crucell Holland B.V. (Dutch vaccine manufacturer) → Janssen Vaccines & Prevention B.V. (J&J operating subsidiary). No "IP/Holdings/Ventures/Licensing" LLC, no registered‑agent address, no single‑purpose Delaware/Texas vehicle appears anywhere in the chain. (Caveat: reel/frame and correspondent fields not retrieved, so this call rests on the named entities plus the bankruptcy record.)

2. Known asserter in the chain — not present. None of Introgen, Crucell, or Janssen matches the Acacia / Marathon / IV / Wi‑LAN / Conversant / Vringo / Pendrell / Round Rock / Spangenberg set or any RPX‑ or Unified‑flagged high‑frequency plaintiff family. All three are/were operating life‑sciences companies.

3. Repeat correspondent across the chain — unclear. The correspondents of record were not exposed by the sources I could reach (Google Patents legal events omit them; Assignment Center not queried). I therefore cannot assess recurrence, and I will not guess a name or firm.

4. Cascading transfers — not present. There are only two ownership events across ~20 years (2009 assignment to Crucell; then corporate succession to Janssen), not multiple LLC‑to‑LLC hops within 24 months.

5. Pre‑litigation transfer — not present / not applicable. No infringement suit naming US 6,194,191 was confirmed (see the earlier litigation section). The 2009‑09‑24 recording sits ~5 months after the 2009‑04‑23 court approval, but that interval is bankruptcy‑sale mechanics, not litigation staging. Because the patent expired 2017‑11‑20, any assertion would have had to precede that date — and none was found.

6. Bankruptcy fire‑sale — PRESENT (strong). Introgen filed voluntary Chapter 11 in December 2008; the court approved the sale of eight patent families to Crucell Holland B.V. on 2009‑04‑23 for $425,000, with a perpetual 35% net‑licensing back‑end retained by Introgen; the transfer to Crucell was recorded 2009‑09‑24. Introgen is reported to have converted to Chapter 7 / ceased operations in December 2009 (see D&B/SBIR profile, FierceBiotech). This is a textbook distressed‑asset sale of IP from a failed operating company.

7. Privateering — not present. No evidence (SEC filing, Patent Progress/EFF coverage, or litigation record) that Crucell/Janssen took the Introgen patents to assert on Introgen's behalf against competitors. Crucell/Janssen were acquiring technology inside their own field (adenoviral vector / PER.C6 manufacturing and vaccines).

8. Defensive aggregator (anti‑NPE) — not present. The chain terminates at Janssen Vaccines & Prevention B.V., a J&J operating company — not RPX, AST, LOT Network, Unified Patents, or OIN. The patent was not neutralized via a defensive pool.

Verdict

Operating‑company assertion — with the explicit qualifier that the assertion prong is unverified for this patent.

The chain is a single distressed transfer from one operating company to another: Introgen Therapeutics, Inc. → Crucell Holland B.V., court‑approved 2009‑04‑23 and recorded 2009‑09‑24 as part of the $425,000 sale of eight patent families in Introgen's Chapter 11 (Bankr. W.D. Tex. 08‑12442; In re Introgen Therapeutics, 429 B.R. 570), followed by corporate succession to Janssen Vaccines & Prevention B.V. after J&J's 2011 Crucell acquisition and the 2014 renaming. There are zero NPE signals — no shell LLC, no known asserter, no cascading transfers, no defensive aggregator — and the only strong signal is the bankruptcy fire‑sale, which is a distress signature, not a troll signature. I did not find any infringement suit naming this patent, so I cannot call it an asserted operating‑company asset; the accurate characterization is operating‑company‑owned, non‑NPE, and the patent has been expired since 2017‑11‑20.

Verification: run US 6,194,191 in the USPTO Assignment Center — https://assignmentcenter.uspto.gov/ (search "6194191") — to capture the reel/frame, execution dates, and correspondent of record for the 1998‑05‑26, 2003‑03‑19, and 2009‑09‑24 instruments, and to confirm whether any name‑change record reflects the Crucell → Janssen Vaccines renaming.

I'll research this systematically, starting with the patent's own citation record.

Let me pull the patent's front-page citation data directly.

Now let me get the front-page "References Cited" list specifically.

Let me try one more targeted pull for the front-page U.S. patent citations.

I'll start by checking what the page's prior-art content actually contains, then pull the patent's claim text and cited references.

Good — I now have the claim text and the cited-reference list. Let me pin down the granted claim 1 (there's a conflict between two sources) and the key prior-art references.

Obviousness Analysis — US 6,194,191 under 35 U.S.C. § 103

0. Source note and an explicit flag

The task says to "use the results from the Prior Art section of this page." The fetched Google Patents record for US 6,194,191 (https://patents.google.com/patent/US6194191/en) contains, under "prior art," only:

• "Prior art keywords: cells, adenovirus, virus, cell, antisense" — an algorithmically generated keyword set, not a reference list; and
• machine annotations (CPC classes, chemical/protein entities) with occurrence counts.

It does not contain the patent's "References Cited" list. I therefore reconstructed the prior art from (a) the patent's own Background of the Invention as reproduced on the page, (b) the applicant's IDS reference list as reproduced at everypatent.com/comp/pat6194191.html, and (c) family/EPO documents that quote the Canji art. I flag this substitution explicitly rather than pretending the page supplied a reference set.

Second flag — a genuine internal contradiction on claim 1. Two sources disagree about what issued claim 1 recites:

Two independent sources agree on the autolysis/perfusion formulation, so I treat it as the likely granted claim 1 — but the everypatent listing is internally anomalous (claim 10 depends on claim 1 yet recites "said exchanging buffer," which has no antecedent in the listed claim 1), and uspto.report's rendering of the same patent references "claim 1, 30 or 86," implying a claim set far larger than the 25 claims everypatent reproduces. I cannot certify the literal granted claim text and I analyze both formulations below. This matters: under the Google formulation, nuclease treatment and buffer exchange would be in claim 1.

1. Governing law and the person of ordinary skill

Application 08/975,519 was filed 1997‑11‑20 with priority to provisional 60/031,329 (1996‑11‑20). Pre‑AIA § 103 applies. The framework is Graham v. John Deere plus KSR Int'l v. Teleflex: scope/content of the prior art, differences from the claims, PHOSITA level, and secondary considerations; obviousness may rest on any of the KSR rationales (known‑element combination, simple substitution, known technique improving a similar device, "obvious to try," design incentives/market forces).

Proposed PHOSITA (my formulation, not a record finding): a scientist with a Ph.D. (or M.S. plus equivalent experience) in molecular biology/virology with 2–5 years in large‑scale mammalian cell culture and viral‑vector process development.

2. Claim 1, element by element

Every element of claim 1 is present in the art; the only candidate for novelty is the combination (perfusion/fed‑batch culture of Ad‑infected cells + harvest by autolysis + purification from that lysate).

3. Proposed combinations and the motivation to combine

Combination 1 (the core § 103 case): Huyghe 1995/96 + US 5,837,520 (Shabram) or WO 96/27677 (Canji) + Cartwright 1994 / Griffiths 1986 / Garnier 1994.

• Rationale: same field (clinical‑grade adenoviral vector manufacturing), same problem (replacing non‑scalable double CsCl ultracentrifugation), same downstream unit operation (anion‑exchange chromatography of a nuclease‑treated lysate). Canji's own work (Huyghe; Shabram) supplies the chromatography‑purification teaching; Cartwright/Griffiths/Garnier supply the perfusion/fed‑batch upstream scale‑up teaching that Huyghe's flask/freeze‑thaw process lacked.
• Motivation, in the patent's own words: the background states demand (~6 × 10¹⁴ PFU for a 300‑patient trial) cannot be met by cellfactories + CsCl, and expressly diagnoses Huyghe's low recovery as caused by "the freeze/thaw step utilized by the authors to lyse cells … and the two column purification procedure." That is a problem statement and a direction of solution written into the specification — classic KSR "design incentive" and "known technique to improve a similar process" evidence.
• Expectation of success: high. Anion‑exchange capture of adenovirus was known since 1959–61 and re‑demonstrated in 1995/96; 293 cells were known to lyse on adenoviral infection; perfusion harvest was routine. No new chemistry was required.

Combination 2 (single‑step chromatography, claims 2–4): Combination 1 + Huyghe's anion‑exchange resin, in view of the '191 background's attribution of Huyghe's 23 % recovery to the second column. Eliminating a validated step to cut losses and cost is the paradigm KSR case of "use of a known technique to improve a similar device in the same way."

Combination 3 (resin/pH selection, claims 5–8): + Haruna 1961 / Philipson 1960 (DEAE) and commercial anion exchangers (Toyopearl SuperQ 650M, MonoQ, SourceQ, Fractogel TMAE). Selection among known anion‑exchange functionalities (DEAE, TMAE, QAE, PEI) and routine pH optimization (7.0–10.0) is routine optimization, supported by In re Boesch/In re Aller and KSR ("known options … a finite number of identified, predictable solutions").

Combination 4 (upstream parameters, claim 9): Cartwright/Griffiths + glucose‑monitored perfusion control. The specification itself concedes these variations "may be performed without undue experimentation and are well within the skill of the ordinary person in the art."

Combination 5 (nuclease and TFF, claims 22–25): + Shabram '520 / WO 96/27677 (enzymatic degradation of unencapsulated DNA/RNA) + Crooks 1990 / Aboud 1982 / O'Neil & Balkovic 1993 (chromatographic and membrane handling of enveloped/non‑enveloped virions); Benzonase® treatment of Ad lysates is described in Huyghe's own 1995/96 work. Concentrating/diafiltering on a 100–300 kDa regenerated‑cellulose TFF membrane is an engineering choice among a finite set of commercially available cassettes.

Combination 6 (vector‑type claims 11–21): Bett 1994 (E1/E3‑deleted Ad vectors) + Graham 1977/1987 (293 cells) + Huyghe 1995/96 (Ad5‑p53, i.e. exactly the "therapeutic gene encodes p53" limitation of claim 16) + Graham & Prevec 1991 (CMV IE/SV40/RSV/β‑actin promoters; replication‑incompetent vectors). The antisense‑gene species of claim 15 was a standard antisense therapeutic list by 1996.

4. Dependent‑claim summary

5. Where the obviousness case is weakest

1. Teaching away / poor expected yield. Klemperer (1959) and Philipson (1960) reported "difficulties" with DEAE chromatography of adenovirus ("poor resolution and poor yield") — quoted in Canji's EP 1686180. A patentee can argue a PHOSITA would not have expected single‑column anion exchange to give CsCl‑equivalent purity. The counter is that Huyghe (1995/96) and Shabram had already restored the expectation of success before the 1996 priority date.
2. Unexpected results (secondary consideration). The specification reports roughly 70 % ± 10 % total process recovery versus Huyghe's 23 % — a textbook Rule 132 argument. Its weight depends on whether the delta is attributable to the claimed combination (no freeze‑thaw, one column) rather than to routine optimization.
3. Claim 1's recitation of autolysis as the lysis mechanism. If framed as a mechanism limitation achieving only a known result, KSR/inherency doctrine makes it weak; if the applicant showed autolysis‑harvest materially changed the contaminant profile, some weight is possible.
4. Record gap. I retrieved no examiner's § 103 rejection and no appeal decision for 08/975,519. What I did retrieve is the prosecution docket of the CIP 09/203,078 (filed 1998‑12‑01; docket "CRUC:004US"), which shows serial § 103 rejections, Rule 131/132 affidavits, an Examiner's Answer (2005) and a BPAI decision of 2009‑08‑13 "Examiner Affirmed in Part" (https://www.plainsite.org/dockets/1pg2vrit8/...). That is evidence the family's § 103 issues were contested, but it is not evidence about '191 itself, and I will not conflate them.

6. Date/qualification issues to resolve before filing a § 103 position

• WO 97/08298 (pub. 1997‑03‑06) post‑dates the 1996‑11‑20 priority date; it is likely not § 102(a)/(b) art and only § 102(e) art if its underlying US filing predates the invention date — unverified. Do not rely on it.
• Gilbert, Williamsburg BioProcessing Conference, Nov. 18–21, 1996 falls on/after the priority date — § 102(a) status is date‑sensitive.
• Huyghe is cited by the applicant as 1996; the journal itself is vol. 6, no. 11 (Nov. 1995). Either date predates the 1996‑11‑20 priority, but the discrepancy should be pinned with the original.
• US 5,837,520 is § 102(e) art (US filing ~1996‑03‑06; issued 1998‑11‑17), not § 102(b).
• Conclusion: on the record available, claim 1 (autolysis formulation) is prima facie obvious over Huyghe/Shabram/WO 96/27677 in view of Cartwright/Griffiths/Garnier; claims 2–25 are obvious over the further combinations above. The defensible non‑obviousness positions are narrow: single‑step chromatography (claim 3) and any autolysis‑specific yield/contaminant effect, both of which would turn on Rule 132‑type evidence.

Confidence: moderate on the art and the mapping; low on the literal granted claim text (see § 0) and unknown as to the actual prosecution record of '191.