Invalidity dossier

US 5627052

Methods for the production of proteins with a desired function

Current assignee: BRITISH COLUMBIA FOUNDATION UNIVERSITY OF

Added 9/29/2026, 7:31:24 AM

At a glanceNo PTAB challengesNo litigation on fileBiotechnology

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Patent summary

Title, assignee, inventors, filing/issue dates, abstract, and a plain-language overview of the claims.

✓ Generated

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

Let me try to retrieve the complete claim set and check for any post-issuance proceedings specific to this patent.

Search coverage / confidence statement

  • USPTO PatentCenter and PACER were not directly queried — I did not have direct database access; results are from public web indexes (Google Patents, Espacenet, EveryPatent, Jüsta, Unified Patents) returned by search. Treat bibliographic data as high confidence (multiple concordant sources), and claim text as good but unverified against the official printed patent (the source appears to be OCR with typographical errors).
  • No CAFC 2026 docket involving US 5,627,052 was found. Searching 2026 Federal Circuit dockets/opinion digests returned only unrelated cases (FedEx v. Qualcomm/Roambee, Arendi, Ollnova v. ecobee, Ironburg v. Valve, etc.). This is consistent with the patent's recorded status of Expired – Lifetime (anticipated expiration 2014-05-06), which makes a 2026 appeal involving it improbable. I state this as "not found," not as proof of nonexistence.
  • Minor metadata inconsistency in my sources: the authoritative document provided to me was fetched 2026-09-29, while your prompt states the current date is April 26, 2026. I did not attempt to reconcile this.
  • Patent number interpreted literally as 5,627,052 (not 5,627,053 or similar).

Bibliographic summary — US 5,627,052

Field Value
Title Methods for the production of proteins with a desired function
Patent number US 5,627,052 A (grant)
Application no. US 08/464,261
Inventor John W. Schrader (CA)
Original assignee B.R. Centre Ltd (per Espacenet: "B R CENTRE LTD [CA]")
Assignee changes (recorded 2002-06-19) Assignments from BR Centre Limited → University of British Columbia Foundation; and (listed current assignees) University of British Columbia Foundation and Abgenix Biopharma Inc.
Filing date (this application) 1995-06-05
Priority date 1990-08-02
Continuity (per spec) Continuation of Ser. No. 08/088,601, filed Jul. 6, 1993 (abandoned), which is a continuation of Ser. No. 07/561,984, filed Aug. 2, 1990 (abandoned). Espacenet priority list: US19900561984 (1990-08-02); US19930088601 (1993-07-06).
Issue date 1997-05-06
Legal status Expired – Lifetime (anticipated expiration 2014-05-06)
Classifications C07K16/00, C07K16/18, C07K16/24, C07K16/244 (IL-2), C07K16/28; IPC(1) A61K39/395
Related PCT WO 1992/002551 A1, "Methods for the Production of Proteins with a Desired Function" (University of British Columbia listed)

Abstract (as published): The invention provides a method for producing proteins with a desired function, generally comprising (a) providing a population of antibody-forming cells suspected of containing at least one cell capable of producing an antibody exhibiting a desired function; (b) suspending the population in a medium having an indicator system incorporated therein, the indicator system being capable of indicating the presence and location of a cell which forms antibodies exhibiting the desired function; (c) identifying a cell forming an antibody exhibiting the desired function; (d) isolating the identified antibody-forming cell from the medium; (e) determining the amino acid sequence of the variable region (or a portion thereof) which confers the desired function; and (f) synthesizing a protein with a desired function containing that amino acid sequence. (Source text contains a typo, "coffers" for "confers.")

Note the abstract/summary is narrower than the granted claims in one respect and broader in another: the granted independent claims require the B cells to be non-hybridoma and non-EBV-transformed, a limitation absent from the abstract as printed.


Plain-language overview of the independent claims

The claim set I could retrieve contains four independent claims (1, 2, 6, 7) plus dependent claims 3–5 and 8–10 (my retrieval was truncated at claim 10, so the total claim count is unverified). Source: EveryPatent reproduction of the printed claims; expect OCR artifacts ("progency" = progeny; "transletting" = transfecting; "all indicator system" = an indicator system).

Claim 1 — "Find the rare antibody-making cell, read its variable-region sequence, rebuild the protein."

  1. Take B cells (or their antibody-forming progeny) from a warm-blooded animal; the cells must be non-hybridoma and not EBV-transformed — i.e., primary cells, not immortalized fusion or EBV lines.
  2. Suspend them in a medium containing an indicator system that reveals where a cell making an antibody with the desired function sits.
  3. Identify that cell.
  4. Isolate it from the medium.
  5. Determine the amino acid sequence of the variable region (or the functional portion) of its antibody.
  6. Synthesize an antibody/antibody variable region/portion having that sequence.

Claim 2 — Same discovery workflow, but recombinant instead of synthetic.
Same steps (a)–(e) as claim 1 (again requiring non-hybridoma, non-EBV B cells), then (f) put the DNA encoding that variable region into a vector that directs expression and secretion of the antibody or variable-region protein; (g) transfect a host cell; (h) grow it; (i) isolate the product.

Claim 6 — Full RNA-to-recombinant-protein pipeline.
Same discovery steps, then (e) recover RNA from the isolated cell; (f) make cDNA; (g) amplify the cDNA of the functional variable region; (h) insert amplified cDNA into an expression/secretion vector; (i) transfect a host cell; (j) grow the host; (k) isolate the product from the host cell.

Claim 7 — Another independent method claim (text truncated in my retrieval; I cannot state its full scope with confidence). Given the pattern of the specification and claim 6, it corresponds to the alternative RNA-amplification route (amplify RNA, then generate cDNA, then express) or the DNA-recovery route. Flagging this as unverified.

Dependent claims recovered:

  • Claims 3, 4, 5 — Add-on molecular-biology routes to claims 1 or 2: (3) recover RNA → cDNA → amplify; (4) amplify RNA → generate cDNA; (5) recover DNA → amplify the variable-region DNA.
  • Claim 8 — Medium is a gelified layer or a liquid layer.
  • Claim 9 — Medium is a nutrient medium.
  • Claim 10 — (truncated) — appears to further define the medium/indicator system.

Note that dependent claims 8–10 refer to claim 8 in a chain and, per the retrieved text, claim 8 depends on "claims 1, 2, 6, or 7."


Substantive characterization (from the specification)

The patent's core insight is a "plaque-assay-guided single-cell cloning" approach that bypasses hybridoma technology entirely:

  1. Functional, not just binding, screening. The "indicator system" is engineered to report the biological function the antibody performs (neutralization, growth-factor mimicry, complement-mediated lysis, enzymatic cleavage), not merely antigen binding. Disclosed indicator systems include: indicator-cell layers that die or survive depending on antibody activity; virus/cell systems (vaccinia + baby rabbit kidney cells; HIV-1 + human T-cell lines); antigen-coated erythrocytes with complement and enhancing anti-immunoglobulin serum (Jerne-type hemolytic plaques); mixtures of two cell types (HLA types, blood groups, tumor vs. normal); and substrate-based systems (gelatin/collagenase, plasminogen/skim-milk casein clearance, fluorogenic amide-4-methylcoumarin peptide substrates, aerolysin precursor activation).
  2. Single-cell picking and confirmation. Positive cells are retrieved with a micromanipulator and micropipette and re-tested in a fresh indicator system to confirm the activity and rule out cross-reactivity against the indicator components.
  3. Sequence rescue from one cell. RNA or DNA from the single isolated cell is processed (oligo-dT capture, reverse transcription, PCR with degenerate sense and constant-region antisense primers), cloned into a vector (exemplified by pUC12 and the p587L expression vector reconstituting a murine IL-3 leader), and expressed (COS-7 example), with affinity purification.
  4. Claimed applications (in the description, not the claims): producing antibodies mimicking cytokines/growth factors (IL-1α, IL-1β, IL-2 through IL-7, IFN-α, IFN-γ, G-CSFs/M-CSF/GM-CSF, TNF-α, TGF-β, EPO, EGF, PDGF, kit ligand), neutralizing pathogens (HIV-1 example), discriminating HLA/blood-group/tumor antigens, and catalytic antibodies (including transition-state-analog immunization).
  5. Commercial significance — this is the foundational "single B-cell cloning" patent family (Schrader/UBC, later linked to Abgenix), frequently cited in later antibody patents as background for isolating and cloning cognate heavy/light chain variable regions from single B cells (e.g., cited alongside WO 92/02551 and Babcook et al., PNAS 93:7843–48 (1996)).

Explicit uncertainties

  1. Claim 7's full text and the total number of claims were not retrievable from the source I could access; claim numbering above is based on a truncated secondary reproduction, not the official USPTO copy.
  2. Assignee history beyond the recorded 2002-06-19 assignments (e.g., whether Abgenix's interest later passed to Amgen) is not confirmed by my search results; I have no authoritative record on that chain.
  3. No litigation, IPR, PGR, reissue, or reexamination record for US 5,627,052 was surfaced in searches. Absence of results is not affirmative proof of absence, but is consistent with a patent that expired in 2014.
  4. No CAFC 2026 docket referencing US 5,627,052 was found; the 2026 Federal Circuit materials returned by search concern unrelated patents.

Generated 9/29/2026, 12:43:36 PM

Cases on file (0)

Specific litigation cases in our database that name US patent 5627052. The free-form analysis below may also discuss cases beyond this list.

No cases on file mention this patent. Upload a CSV or add a case manually in Admin → Manage litigation cases.

Litigation summary

Past and pending lawsuits — plaintiffs, defendants, jurisdictions, outcomes, and notable rulings.

✓ Generated

I'll research litigation involving US patent 5627052. Let me run several targeted searches.

Let me search more specifically on litigation databases and the patent's assignees.

Litigation Search Report — U.S. Patent No. 5,627,052

Patent identified literally as: US 5,627,052 (US5627052A) — "Methods for the production of proteins with a desired function" (inventor John W. Schrader). Filing date 1995-06-05 (continuation; priority 1990-08-02), granted 1997-05-06, anticipated expiration 2014-05-06, status: Expired – Lifetime. Assignee chain: B.R. Centre Ltd → University of British Columbia → Abgenix Biopharma Inc. (2002 assignments).

Bottom line

I found no litigation (district court, ITC, CAFC appeal, PTAB/IPR, or interference proceeding) involving U.S. Patent No. 5,627,052.

Every "hit" my searches returned for the string "5627052" was one of the following — not litigation:

  1. Prior-art citations to US 5,627,052 in the reference lists / specifications of other patents. The recurring Justia format lines ("5627052 | May 6, 1997 | Schrader") are entries in the "Patent History"/citations tables of unrelated patents — e.g., US 7,521,048 (TRAIL receptor-2, Amgen), US 10,323,084 (anti-amyloid beta antibodies), and US 10,150,996 (immune-cell genome quantification). These are citation lists, not case dockets.
  2. Foreign/granted patent specifications citing US 5,627,052 as background art — e.g., EP 2,892,909; EP 3,943,508; EP 3,800,200; EP 2,262,831; CN 101589062B; KR 101790802B1; RU 2595409C2; EA030827B1. These are reference lists only.
  3. The patent's own Google Patents / Espacenet bibliographic pages (assignments and legal-status events, not suits).

Note on similarly numbered patents (excluded per your instruction)

My searches surfaced several different patents whose numbers resemble "5627052." These are NOT U.S. 5,627,052 and I am explicitly not attributing their litigation to it:

  • U.S. 7,594,052 — asserted in Network System Technologies, LLC v. Samsung Electronics Co., Ltd., No. 2:22-cv-00481 (E.D. Tex.) and NST v. Qualcomm Inc., No. 1:22-cv-01331 (W.D. Tex.) (IPR), among others.
  • U.S. 8,893,052 — asserted in Pantech v. OnePlus (E.D. Tex., jury verdict Mar. 2024).
  • U.S. 5,265,562 — at issue in the Kruse Technology v. Daimler/Mercedes-Benz litigation (C.D. Cal., SACV 10-1066 JVS).
  • The Sofamor Danek "'562 patent" (spinal implant) in the Sofamor Danek v. DePuy-Motech preliminary-injunction appeal.

None of these is U.S. 5,627,052.

Caveats on completeness

  • I could not query the Unified Patents litigation portal directly; that tool call was not completed, and I hit the search-step limit before exhausting PACER/CAFC/Docket Alarm/Justia-docket sources.
  • U.S. 5,627,052 expired in 2014, which reduces the likelihood of post-2014 infringement suits, but does not by itself rule out older litigation.
  • Searches were conducted against general web sources, not a complete litigation database. A definitive negative would require a direct PACER/CAFC docket search and a Unified Patents / Lex Machina / Docket Navigator query by patent number.

Conclusion: On the evidence available, there is no known litigation involving U.S. Patent No. 5,627,052. The patent's principal commercial significance is as the foundational document behind the "SLAM" (Selected Lymphocyte Antibody Method) technology later associated with Abgenix (acquired by Amgen), and it is widely cited as prior art in antibody-discovery patents — but that citation activity is not litigation. If you need a court-of-record confirmation, the next step is a direct PACER/CAFC docket lookup and a Unified Patents "Litigation" search for patent 5,627,052.

Generated 9/29/2026, 12:43:28 PM

Proceedings on file (0)

All PTAB activity →

AIA trial proceedings (IPR / PGR / CBM) filed at the USPTO Patent Trial and Appeal Board against this patent. Sourced from the USPTO Open Data Portal and refreshed every six hours; each proceeding number deep-links to the PTAB E2E docket.

No PTAB proceedings on file. This patent has not been challenged via IPR, PGR, or CBM. The absence is itself a signal — well-asserted patents eventually attract IPRs. The LLM analysis below may surface filings the ODP feed hasn’t indexed yet.

PTAB challenges

AIA trial proceedings at the USPTO Patent Trial and Appeal Board — IPR, PGR, and CBM. Petitioners, judge panels, claim-level invalidation outcomes from Final Written Decisions, and Federal Circuit appeals. The single most important defensive datapoint after litigation history.

✓ Generated

PTAB / AIA Trial Activity — US 5,627,052 ("Methods for the production of proteins with a desired function")

Analyst note on sourcing: The canonical structured block provided for this patent reports that the USPTO Open Data Portal (ODP) returns no AIA trial proceedings for US 5,627,052 as of the most recent ingest. I ran independent web searches against PTAB-related sources (PTAB E2E/PTACTS document hits, Unified Patents portal, CAFC/Justia cross-references, litigation dockets) to look for older or un-indexed proceedings. I found none. All PTAB hits that surfaced in search were for different patents (see "Pattern signals" below). Accordingly, the finding below is a negative finding, stated plainly rather than padded with invented proceeding numbers.


Proceedings overview

Total AIA trial proceedings on file: 0. Breakdown by status: 0 active / 0 claims invalidated / 0 claims sustained / 0 settled / 0 institution denied — there is nothing to break down. The bottom-line defensive posture: US 5,627,052 has never been challenged at the PTAB, and it is now time-barred as a practical matter — the patent expired on 2014-05-06, so any defendant facing a demand letter today is dealing with a dead patent, not a hardened one. The absence of PTAB activity is not a signal of strength here; it is a signal of age and expiration. No IPR/PGR/CBM has ever been instituted on this patent, and none can meaningfully be filed against its expired claims as an offensive tool.

Supporting bibliographic anchors (from the authoritative full text and the structured record):

  • Patent: US 5,627,052 A; Application No. 08/464,261; filed 1995-06-05; granted/publication 1997-05-06.
  • Priority: 1990-08-02 (earliest US filing 07/561,984); continuation chain via 08/088,601 (filed 1993-07-06, abandoned).
  • Inventor: John W. Schrader. Original assignee: BR Centre Ltd; later assignments recorded to University of British Columbia and Abgenix Biopharma Inc.
  • Statutory expiry: anticipated expiration 2014-05-06; current legal status "Expired - Lifetime."
  • Source of record: Google Patents US5627052A

(No proceedings to list)

There is no IPR, PGR, or CBM to describe. No petitioner, no panel, no institution decision, no Final Written Decision, no settlement, no appeal exists on this patent in the public record I can find. I am not going to fabricate proceeding numbers, panel compositions, or claim-level dispositions to fill this section.


Strategic summary

Claim status — CANCELED vs. SUSTAINED vs. UNTESTED. Zero claims of US 5,627,052 have been canceled through AIA trial proceedings, because no proceeding was ever brought. Equally, zero claims have been sustained by a PTAB panel — there is no FWD blessing any claim. Every claim is therefore UNTESTED at the PTAB. The claims as granted (directed to methods of producing proteins with a desired function, including identification of antibody-forming cells via indicator systems, recovery of RNA/DNA, amplification, and expression of the variable region) stand exactly as the examiner left them. Whatever narrowing occurred over this patent's life happened in prosecution/reexamination history, not at the Board.

Estoppel landscape. There is no § 315(e)(2) estoppel to map, because no IPR/PGR was instituted and no FWD issued. That cuts both ways: a defendant is not boxed out of any prior-art ground by statutory estoppel. However, this is largely academic — see the expiration point below. Any invalidity challenge today would more plausibly be framed in district court or as a defense in a licensing dispute, not as a fresh AIA petition (and a petition against expired claims has no practical commercial payoff).

Pattern signals. No petitioner has filed multiple IPRs against this patent — no petitioner has filed even one. There is no Unified Patents / defensive-aggregator record for this patent. The one pattern worth flagging is assignee-level, not patent-level: the University of British Columbia (a recorded assignee here) is a currently active PTAB litigant on unrelated later patents — e.g., Caption Health, Inc. v. University of British Columbia, IPR2025-01066 concerning U.S. 11,129,591, and IPR2025-01422 concerning U.S. 10,751,029, both arising from N.D. Cal. litigation. Those are different patents and different subject matter (AI-based medical imaging) and cast no light on the validity of US 5,627,052; I mention them only so you don't mistake the search hits for activity on this patent. The earlier asset-owner chain is also relevant: Abgenix (later Amgen Fremont) was an assignee, consistent with this Schrader "SLAM"-type B-cell cloning technology being commercialized rather than litigated. I found no Federal Circuit appeal involving this patent.

The controlling practical fact. The patent's term ended 2014-05-06. Even if a party wanted a PTAB ruling, an IPR challenging already-expired claims offers little leverage, and § 286's six-year damages lookback window closed years ago. For a defendant receiving an assertion today, the analysis is not "is this patent vulnerable at the PTAB" but "the asserted claims are expired and the damages tail has run" — a far stronger and cheaper position than any IPR.


Recommended next steps

  • If you are a defendant and a demand letter cites US 5,627,052: the dispositive point is expiration. Confirm the face of the patent and the structured record: anticipated expiration 2014-05-06, legal status "Expired - Lifetime" (Google Patents US5627052A; verify against USPTO PatentCenter for application 08/464,261). There is no FWD to quote — do not let opposing counsel imply one exists. Push for the patent's complete file history and transaction history, including the assignments to University of British Columbia and Abgenix Biopharma Inc.
  • Do not build a defense around an IPR on this patent. With no institution ever granted and the claims expired, a new petition is an expensive non-starter. Redirect budget to (i) the expired-patent / § 286 damages-window argument and (ii) checking whether the asserted claims are actually from a different, later UBC patent in the same technology space (that is where the live PTAB activity — and the live litigation — is).
  • If you are evaluating a portfolio or a license covering this family: treat the PTAB silence as no defensive reinforcement at all. There is no adjudicated invalidity and no adjudicated validity — just an expired grant. Any value attributed to US 5,627,052 today rests on prosecution history, continuations/related filings, and know-how, not on PTAB-tested claim scope.
  • Verification trail if you want to re-pull this yourself: ODP-structured list (empty, as provided); PTAB E2E / PTACTS search by application 08/464,261 and by patent 5627052; CourtListener for any CAFC appeal naming the patent (none found); USPTO Assignment recordation for the BR Centre → UBC → Abgenix chain.

Confidence statement: I am highly confident there are no AIA trial proceedings on US 5,627,052. I am not asserting that no district court litigation ever touched this patent — I did not locate a definitive docket confirming or excluding that, and I will not guess. If the demand letter you received references a litigation or a PTAB number, send it over and I will reconcile it against the record above.

Generated 9/29/2026, 12:43:37 PM

Ownership chain (3)

Asserters network →

Structured records extracted from the assignment-history narrative below. Each entity links to its full ownership-network profile.

  1. ? · recorded 2002-06-19 · Assignment

    BR Centre LimitedUniversity of British Columbia Foundation, The

    internal reorg

  2. ? · recorded 2002-06-19 · Assignment

    University of British Columbia Foundation, TheTHE UNIVERSITY OF BRITISH COLUMBIA

    internal reorg

  3. ? · recorded 2002-06-19 · Assignment

    THE UNIVERSITY OF BRITISH COLUMBIAAbgenix Biopharma Inc.

    transfer-to-operating-company

Assignment history

Inventors, original assignee, and the chain of ownership recorded with the USPTO — including the correspondent attorney who recorded each assignment, since shell-LLC chains often share one repeat-player attorney even when the entity names look unrelated. Surfaces NPE / patent-troll patterns: shell-entity transfers, known asserters in the chain, repeat correspondent fingerprints, pre-litigation assignments, and bankruptcy fire-sales.

✓ Generated

I'll research this patent's ownership record before drafting. Let me run several targeted searches.

Good progress. Now let me try to pin down the specific assignment records (reel/frame, correspondent) and the corporate history details.

Ownership reconstruction — US 5,627,052

Verification note before the sections. I could confirm the party-level assignment chain from USPTO-derived legal-events data (Google Patents) and from the published family, but I could not retrieve the reel/frame numbers, the execution dates, or the correspondent-of-record from the Assignment Center within this session (the Assignment Center and its legacy PDF mirror require interactive search). I have not invented those fields. Every reel/frame and correspondent slot below is marked as unretrieved, and the two places where a number/name is genuinely absent are flagged as gaps for manual pull.


Inventors

John W. Schrader — sole named inventor (Espacenet lists one inventor, "SCHRADER JOHN W [CA]"; Google Patents likewise). At the time of filing he was a professor in the Department of Medicine, University of British Columbia (UBC), and was affiliated with UBC's Biomedical Research Centre (BRC) — the entity whose namesake ("B.R. Centre") is on the patent. This is corroborated by an NSERC Collaborative Health Research Projects award record listing "Schrader, John — The University of British Columbia, Department of Medicine" (2008 competition), and by Amgen Canada's own corporate fact sheet stating that Abgenix acquired "SLAM technology developed by UBC's Biomedical Research Centre."

Unusual patterns: none of the classic tells. This is not a multi-inventor team that scattered after filing — Schrader remained a UBC faculty member for decades after the 1990 priority filing (same institution on the 2008 NSERC record). There is no evidence of inventors departing the assignee within 12 months of filing.


Original assignee

B.R. Centre, Ltd. (also rendered "BR Centre Ltd" in the USPTO/Google record and "B R CENTRE LIMITED" on Espacenet) — a Canadian entity, [CA], tied to UBC's Biomedical Research Centre. On the PCT sibling WO 92/02551, the applicants are listed jointly as B.R. Centre Limited and The University of British Columbia — i.e., the university and its research-centre vehicle were both on the applicant side, with B.R. Centre, Ltd. as the issuing-patent assignee.

  • Primary line of business: university-affiliated biomedical research and technology commercialization (not a product company). The patent claims are methods — isolating a single antibody-forming cell and cloning its variable region — i.e., the foundational single-cell antibody-discovery method later commercialized as SLAM.
  • Product embodying the claims: no end product of B.R. Centre, Ltd. itself. The technology was monetized downstream through the UBC startup ImmGenics Pharmaceuticals (Vancouver, co-founded by John Babcook) and then through Abgenix.
  • Current status: not determinable with high confidence from sources retrieved. What is documented is that its interest did not stay put: the patent passed to the UBC Foundation and then to UBC itself (see timeline), after which UBC transferred it to Abgenix Biopharma.

Assignment timeline

All three records below are the entries surfaced under Google Patents' legal-events/current-assignee data, each dated 2002-06-19. Execution dates and reel/frame are not published in the sources I could reach.

  • Executed: not retrieved / recorded 2002-06-19 — Reel not retrieved

    • Conveyance: Assignment (per Google Patents reassignment record)
    • Assignor: BR Centre Limited
    • Assignee: University of British Columbia Foundation, The
    • Correspondent: not retrieved (gap — required for the repeat-correspondent test)
    • Context: internal reorganization — the research-centre vehicle's interest moved into UBC's foundation.
  • Executed: not retrieved / recorded 2002-06-19 — Reel not retrieved

    • Conveyance: Assignment
    • Assignor: University of British Columbia Foundation, The
    • Assignee: The University of British Columbia
    • Correspondent: not retrieved
    • Context: internal reorganization — foundation → university proper; a name/vehicle consolidation, not a sale.
  • Executed: not retrieved / recorded 2002-06-19 — Reel not retrieved

    • Conveyance: Assignment
    • Assignor: The University of British Columbia
    • Assignee: Abgenix Biopharma Inc. ("Abgenix Biopharma inc" as listed)
    • Correspondent: not retrieved
    • Context: transfer-to-operating-company — formalization of UBC/Abgenix's SLAM technology deal; Abgenix Inc. (Fremont, CA) had acquired UBC spun-out ImmGenics Pharmaceuticals in 2000 and stood up a Burnaby subsidiary, Abgenix Biopharma.

Downstream corporate event (not a USPTO assignment of this patent): 2006-04-03 — Amgen Inc. completed its acquisition of Abgenix, Inc. for ~$2.2B; the Burnaby group became Amgen British Columbia. Google Patents' "current assignee" list still surfaces all three of UBC Foundation, University of British Columbia, and Abgenix Biopharma Inc.

Patent term: anticipated expiration 2014-05-06 (Google Patents legal status: "Expired – Lifetime"). No post-2014 assignments.


Timeline diagram

timeline
    title Ownership of US 5627052
    1990 : Priority application filed
    1995 : Continuation application filed
    1997 : Patent issued to B R Centre Ltd
    2002 : B R Centre Ltd assigns to UBC Foundation
         : UBC Foundation assigns to University of British Columbia
         : UBC assigns to Abgenix Biopharma Inc
    2006 : Amgen acquires Abgenix Inc
    2014 : Patent expires

NPE / troll-pattern signals

  1. Shell-entity transfer — not present. The chain runs university research vehicle → UBC foundation → UBC → an operating biotech subsidiary. No "IP / Holdings / Licensing / Ventures" suffix appears; "B.R. Centre, Ltd." and "Abgenix Biopharma Inc." are not single-purpose licensing LLCs. Contrast the tell in the prompt (Delaware/Texas single-member LLC, registered-agent address): none of that is in this chain. Reels: unretrieved, but the 2002-06-19 party records support this call.

  2. Known asserter in the chain — not present. None of the recorded assignees (BR Centre Limited, UBC Foundation, University of British Columbia, Abgenix Biopharma Inc.) or the successor acquirer (Amgen Inc.) matches any of the listed NPE aggregators (Acacia, Marathon, IV, IPNav, Wi-LAN/Conversant, Vringo, Pendrell, Round Rock, etc.). Abgenix Biopharma was a genuine antibody-discovery R&D subsidiary (Burnaby R&D site, XenoMouse-adjacent platform); Amgen is an operating pharmaceutical manufacturer.

  3. Repeat correspondent across the chain — unclear (data gap). The signal would be a single attorney/firm appearing on multiple 2002-06-19 recordings. I could not retrieve the correspondent-of-record on any of the three entries, so I cannot confirm or exclude recurrence. This is the one test that must be run manually at the Assignment Center before relying on any NPE conclusion — it is the prompt's own designated "most useful tell," and it is exactly the field that is missing here.

  4. Cascading transfers — present in form, benign in substance. Three consecutive assignments, all recorded on the same day (2002-06-19), moving the patent through two UBC vehicles in quick succession. On its face this trips the "multiple consecutive assignments in <24 months" criterion. But the three links are two intra-university reorg steps plus a single outbound transfer to a third party — a classic chain-cleaning batch filed together to establish clean record title, not a run of unrelated LLCs. Because the assignments share a recording date rather than a staggered one, and the assignees are affiliates of one another (Foundation ↔ University), I read this as weak/benign, but it is the second-closest signal after #3.

  5. Pre-litigation transfer — not present. I found no infringement action naming US 5,627,052 in the searches run. The 2002-06-19 transfer to Abgenix Biopharma is not tied to any dated suit in the record retrieved; the downstream use of the technology was licensing/R&D and citation by later antibody patents (e.g., the Babcook et al. 1996 PNAS single-cell method; later Abgenix/Amgen filings citing the '052 patent). Absent a suit, this signal fails.

  6. Bankruptcy fire-sale — not present. No Chapter 7/11 assignor in the chain. Abgenix was acquired for cash (~$2.2B), not sold in bankruptcy.

  7. Privateering — not present. No operating company is shown transferring to an NPE that then asserts against the operating company's competitors; the terminal private-sector owner (Abgenix → Amgen) is an operating manufacturer itself.

  8. Defensive aggregator — not present. The chain does not terminate at RPX, AST, LOT, Unified Patents, or OIN. Inverse signal not triggered.


Verdict

Insufficient data.

Justification: the party-level chain is fully reconstructible — three assignments executed/recorded under the 2002-06-19 entries, moving US 5,627,052 from BR Centre Limited → University of British Columbia Foundation → The University of British Columbia → Abgenix Biopharma Inc. — and none of those parties, nor successor Amgen Inc. (which acquired Abgenix 2006-04-03), matches an NPE list, ships no products, or shows any bankruptcy or defensive-aggregator endpoint. That pattern points away from an NPE, but the two decisive fields required to close the analysis — reel/frame and correspondent-of-record on the three 2002-06-19 recordings — could not be retrieved, so the recurrence test (signal 3) and the pre-litigation test (signal 5) cannot be resolved either way. I am therefore declining to certify an "operating-company assertion" or "defensive" verdict on the strength of party names alone.

Verify manually at: https://assignmentcenter.uspto.gov/ (search patent number 5627052; the legacy PDF mirror at https://legacy-assignments.uspto.gov/ carries the recorded documents) — pull reel/frame, execution date, and correspondent for each of the three 2002-06-19 entries. Cross-check patent page: https://patents.google.com/patent/US5627052/en

Generated 9/29/2026, 12:44:03 PM

Prior art

Earlier patents, publications, and products that may anticipate or render the claims unpatentable.

✓ Generated

I'll research the prior art cited on the face of US 5,627,052 and any related citation records. Let me run several targeted searches.

I found the patent's front page is available. Let me pull the "References Cited" and citation tables directly.

Let me extract the patent's front-page "References Cited" (both U.S. Patent Documents and Other Publications).

Prior-Art Analysis — U.S. Patent No. 5,627,052

Scope, method, and an important limitation

Patent analyzed (literally): US 5,627,052 ("US5627052A"), Methods for the production of proteins with a desired function, inventor John W. Schrader, appl. no. 08/464,261, filed 1995-06-05 (continuation of 08/088,601, itself a continuation of 07/561,984, priority 1990-08-02), granted 1997-05-06, 38 claims, no drawings. Primary sources retrieved: https://patents.google.com/patent/US5627052A/en and the printed front page via https://patentimages.storage.googleapis.com/10/7d/2c/547f372716544c/US5627052.pdf

Per your instruction, references to similarly-numbered patents were rejected, not merged. Specifically excluded: US 5,005,062 (the Sofamor Danek '562 spinal-implant patent litigated against DePuy‑Motech), US 7,594,052, US 8,893,052, US 5,265,562. None of these is US 5,627,052 and none of their litigation/prior art is attributed here.

Two limitations you should know about before relying on this:

  1. I hit the search-step limit before retrieving a complete transcription of the front page's citation list. I recovered the "Other Publications" (non‑patent literature) portion and the references cited within the specification, but I did not obtain a verified, complete printout of any "U.S. PATENT DOCUMENTS" subsection of the front page. On the evidence I retrieved, US 5,627,052's front-page citation list appears to be predominantly (possibly entirely) non-patent literature — I saw no U.S. or foreign patent document listed among the front-page citations. Flag this as an open item to confirm against the granted patent's [56] field or Google Patents' "Patent Citations" table.

  2. The claim text was not in the material I was given. The full text supplied ends mid-description and does not include the 38 granted claims. Therefore I cannot cite literal claim numbers with confidence. My § 102 mapping below is expressed against claim families derived from the specification's two summarized aspects. Formal claim-by-claim § 102 conclusions require the granted claim set from USPTO Patent Public Search / PatentCenter.

Critical date for § 102(b) purposes: the priority date is 1990-08-02, so the one-year § 102(b) bar date is 1989-08-02. References published on or before that date are § 102(b) art; references published between 1989-08-02 and 1990-08-02 can at most be § 102(a) art (or § 102(e) if a U.S. patent/application publication).


Bottom line on anticipation

On the references I could retrieve, no single reference appears to anticipate any claim of US 5,627,052 under 35 U.S.C. § 102. The claimed subject matter is a combination: (i) suspending a population of antibody-forming cells in a medium containing an indicator system that reports a non-binding, functional activity (lysis, protection from cytopathic effect, growth/viability support, substrate modification, mimicry of a cytokine); (ii) identifying and isolating the individual cell responsible; (iii) determining the V-region (CDR) sequence of that cell's antibody; and (iv) synthesizing/expressing a protein bearing that sequence. Each retrieved reference supplies at most one or two of those elements. They are § 103 (obviousness) art, not § 102 anticipation art — with the caveat noted below on narrow dependent claims.

The only plausible anticipation theory I can construct from the retrieved art is against very narrow dependent claims that recite only the indicator-system element in isolation — and even that fails under anticipation law because a dependent claim incorporates every limitation of the claim from which it depends, so a reference disclosing only the indicator system cannot anticipate the full method.


Reference-by-reference analysis

Dates are publication dates (non-patent literature). "§102(b)" = published on or before 1989-08-02; "§102(a)" = published after that date but before the 1990-08-02 priority date.

A. Hybridoma / monoclonal antibody production (the admitted background art)

Reference Citation Date §102 status Description Anticipation analysis
Kohler & Milstein "Continuous cultures of fused cells secreting antibody of predefined specificity," Nature 256:495–497 1975-08-07 §102(b) Foundational hybridoma/monoclonal antibody technology. Also cited as Eur. J. Immunol. 6:511–519 (1976) Does not anticipate. Discloses only cell fusion + screening for specificity. Lacks the single-cell isolation from a functional indicator, V-region sequencing, and recombinant protein production. Expressly identified as the prior art the patent improves upon.
Price, P. "Hybridoma Technology," Advances in Cell Culture 4:157–177 1985 §102(b) Review of hybridoma methodology and cloning/subcloning Does not anticipate. Review of conventional technology; no functional plaque-type indicator, no V-region sequencing.
Samoilovich et al. "Hybridoma Technology: New Developments of Practical Interest," J. Immunol. Methods 101:153–170 1987 §102(b) Review of hybridoma improvements Does not anticipate. Same gap as above.
Allen, P. "Construction of Murine T–T-Cell Hybridomas," in Monoclonal Antibody Production Techniques and Applications, L.B. Schook ed., Marcel Dekker, pp. 25–35 1987 §102(b) Hybridoma construction chapter Does not anticipate. Technique chapter only.
Aggarwal & Bringman "Production and Purification of Lymphokines and Their Monoclonal Antibodies," in Schook ed., op. cit., pp. 173–187 1987 §102(b) Lymphokine/mAb production and purification Does not anticipate. Antibody to lymphokines; not an antibody that mimics a lymphokine's function identified by an indicator system.

B. Functional screening of antibody-forming cells (closest to the "indicator system" element)

Reference Citation Date §102 status Description Anticipation analysis
Kanagawa, O. "Antibody-Mediated Activation of T Cell Clones as a Method for Screening Hybridomas Producing Antibodies to the T Cell Receptor," J. Immunol. Methods 110:169–178 1988 §102(b) Screens hybridomas by the functional ability of their secreted antibody to activate T-cell clones Most on-point retrieved reference for the "indicator system comprises a layer of cells whose growth, viability or function is affected by antibodies" claim family. But it does not anticipate: it screens hybridoma supernatants/clones, not individual B cells isolated from a functional plaque; and it contains no V-region sequencing or recombinant production step. Anticipates no full claim.
Mishell & Shiigi (eds.) Selected Methods in Cellular Immunology, W.H. Freeman 1980/1987 §102(b) Source (cited in spec.) for hemolytic plaque assays, TNP/cell staining, rosette methods Does not anticipate as a whole, but is the primary teaching of the plaque/hemolysis and rosetting indicator chemistries recited in the indicator-system-dependent claims. Again, no V-region sequencing or recombinant expression.

C. Isolation of V-region genes from single cells by PCR (closest to the "determining the amino acid sequence" element)

Reference Citation Date §102 status Description Anticipation analysis
Orlandi et al. "Cloning Immunoglobulin Variable Domains for Expression by the Polymerase Chain Reaction," Proc. Natl. Acad. Sci. USA 86:3833–3837 1989 (May) §102(b) PCR cloning of Ig variable domains for expression Closest art for the V-region amplification/expression step. Does not anticipate: starts from hybridoma/known cells, not from a single antibody-forming cell isolated out of a functional indicator system; no functional screening step.
Larrick et al. "Polymerase Chain Reaction Using Mixed Primers: Cloning of Human Monoclonal Antibody Variable Region Genes from Single Hybridoma Cells," Bio/Technology 7:934–938 1989 §102(a) (month uncertain — if pre‑1989‑08‑02, §102(b)) PCR cloning of human V-region genes from single hybridoma cells with mixed primers Very close to the single-cell → V-gene amplification element. Does not anticipate: no functional indicator system, and no selection of the cell on the basis of a non-binding biological activity.
Frohman et al. "Rapid Production of Full-Length cDNAs from Rare Transcripts: Amplification Using a Single Gene-Specific Oligonucleotide Primer," PNAS 85:8998–9002 1988 §102(b) RACE — amplification from rare transcripts Does not anticipate. Enabling technology for the cDNA/amplification steps only.
Loh et al. "Polymerase Chain Reaction with Single-Stranded Specificity: Analysis of T Cell Receptor σ Chain," Science 243:217–220 1989-01-13 §102(b) Single-sided PCR Does not anticipate. Enabling methodology only.
Rappolee et al. J. Cell. Biochem. 39:1–11 1989 §102(b) Amplification of minute amounts of RNA Does not anticipate. Supports the "recovering RNA from the isolated cell" step only.
Gonda et al. J. Virol. 61:2754–2763 1987 §102(b) RNA recovery method Does not anticipate. Method step only.

D. CDR grafting / engineering the transferred function (closest to the "transfer the desired function" element)

Reference Citation Date §102 status Description Anticipation analysis
Riechmann et al. "Reshaping Human Antibodies for Therapy," Nature 332:323–327 1988-03-24 §102(b) CDR grafting — transfers binding specificity from one antibody framework to another Closest art for transferring the function into another protein. Does not anticipate: grafting is performed from a known, pre-characterized antibody; no functional single-cell screening, no isolation of a low-frequency functional B cell.
Riechmann & Foote J. Mol. Biol. 203:825–828 1988 §102(b) Expression of Fv fragment in myeloma cells Does not anticipate. Expression framework only.
Huston et al. "Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in E. coli," PNAS 85:5879–5883 1988 §102(b) Single-chain Fv Does not anticipate. Alternative protein scaffold only.
Skerra & Plückthun Science 240:1038–1041 1988 §102(b) Antibody fragments expressed in bacteria Does not anticipate. Expression host art only.
Liu et al. "Chimeric Mouse–Human IgG1 Antibody That Can Mediate Lysis of Cancer Cells," PNAS 84:3439–3443 1987 §102(b) Chimeric antibody Does not anticipate. Chimeric antibody construction only.
Ward et al. Nature 341:544–546 1989-10-05 §102(a) Binding activities from E. coli Does not anticipate. § 102(a) only.
Huse et al. "Generation of a Large Combinatorial Library of the Immunoglobulin Repertoire in Phage Lambda," Science 246:1275–1281 1989-12-08 §102(a) Combinatorial Ig library Does not anticipate. Library approach, expressly distinguished from the invention's functional-screen approach.

E. Sequencing / synthesis / expression enabling art

Reference Citation Date §102 status Description Anticipation analysis
Aebersold et al. "Covalent Immobilization of Proteins for High-Sensitivity Sequence Analysis: Electroblotting onto Chemically Activated Glass from SDS-PAGE Gels," Biochemistry 27:6860 1988 §102(b) Microsequencing of blotted Ig chains Does not anticipate. Supports the "determining the amino acid sequence directly" route only.
Clark-Lewis et al. Science 231:134–139 1986 §102(b) Efficient chemical synthesis of large proteins Does not anticipate. Enables the "synthesizing a protein" step only.
Kabat et al. Sequences of Proteins of Immunological Interest, U.S. Dept. of HHS 1987 §102(b) CDR definition/alignment reference Does not anticipate. Reference work.
Sambrook, Fritsch & Maniatis Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press 1989 §102(a) Standard cloning manual Does not anticipate.
Gunning et al. PNAS 84:4831–4835 1987 §102(b) p587 expression vector (basis for p587L) Does not anticipate. Vector art only.
Biocca et al. EMBO J. 9(1):101–108 1990 §102(a) Intracellular antibodies (no secretion signal) Does not anticipate. Supports the intracellular-antibody embodiment; dated after the § 102(b) barrier.
Lizardi et al. Bio/Technology 6:1197–1202 1988 §102(b) T7/Q-β replicase RNA amplification Does not anticipate. Alternative amplification route only.
Kingsman & Kingsman "Biotechnology," in Genetic Engineering: An Introduction to Gene Analysis and Exploitation in Eukaryotes, Blackwell Scientific, pp. 414–456 1988 §102(b) Genetic engineering textbook Does not anticipate.
Handbook of Experimental Immunology, D.M. Weir (ed.), Vol. 4, Blackwell Scientific 1986 §102(b) Immunization techniques Does not anticipate.

F. Assay chemistry for the indicator system (coating, coupling, substrates)

Reference Citation Date §102 status Description Anticipation analysis
Golub et al. J. Immunol. 100:133 1968 §102(b) Chromic chloride / carbodiimide coupling of antigen to particles Does not anticipate. Coupling chemistry for one indicator embodiment.
Parish & Hayward Proc. Roy. Soc. 187:47 1974 §102(b) Antigen coating of erythrocytes; rosette separation Does not anticipate. Indicator chemistry only.
Bayer & Wilchek "The Avidin–Biotin Complex as a Tool in Molecular Biology," TIBS 3(11):N257–N259 1978 §102(b) Avidin–biotin coupling Does not anticipate.
Wilchek & Bayer "The Avidin–Biotin Complex in Bioanalytical Applications," Anal. Biochem. 171:1–32 1988 §102(b) Avidin–biotin applications Does not anticipate.
Moav & Harris J. Immunol. 105:1512 1970 §102(b) Density-gradient cell separation Does not anticipate. Enrichment step only.
van Mourik & Zeijlemaker Methods in Enzymology 121:174–182 (1986) §102(b) Percoll density separation of cells Does not anticipate. Enrichment step only.
Reading, C.R. Methods in Enzymology 21:18–33 (1971) §102(b) In vitro immunization Does not anticipate. Source-of-cells step only.
Beckley et al. Can. J. Biochem. 59(6):430–435 1981 §102(b) Aerolysin precursor Does not anticipate. Substrate for the proteolytic-antibody indicator embodiment.
Howard & Buckley J. Bacteriol. 163(1):336–340 1985 §102(b) Proteolytic activation of aerolysin Does not anticipate. Same.
Zimmerman et al. Anal. Biochem. 78:47 1977 §102(b) Fluorogenic elastase substrate (N-acetyl-ala-pro-ala-7-amido-4-methylcoumarin) Does not anticipate. Substrate chemistry only.
Elms et al. Thromb. Res. 30:521 1983 §102(b) Anti-fibrin-degradation-product mAb Does not anticipate. Developing-antibody indicator chemistry only.
Lerner & Benkovic Bioessays 4:107–112 1988 §102(b) Catalytic (transition-state) antibodies Does not anticipate. Establishes catalytic antibodies exist; no single-cell functional isolation + V-region transfer workflow.

Note on family members: EP 0 542 810 A1 (1993-05-26) and CA 2,090,126 C (granted 2002-10-22), both in Schrader's name / UBC & B.R. Centre, are the same invention, not prior art against US 5,627,052. Do not treat them as § 102 references.


Summary: most material references (ranked) and their role

  1. Kanagawa 1988 (J. Immunol. Methods 110:169–178) — the single most relevant retrieved reference to the functional indicator concept; still not anticipatory.
  2. Larrick 1989 (Bio/Technology 7:934–938) and Orlandi 1989 (PNAS 86:3833–3837) — single-cell / PCR V-gene cloning; the closest art for steps (iii)–(iv).
  3. Riechmann 1988 (Nature 332:323–327) — CDR grafting; closest art for "transferring the desired function."
  4. Kohler & Milstein 1975/1976, Price 1985, Samoilovich 1987 — the hybridoma background the patent distinguishes itself from.
  5. Mishell & Shiigi (eds.) 1980/1987 — plaque/rosette indicator chemistry.
  6. Everything in sections E and F — enabling art for individual process steps (enrichment, coupling, sequencing, synthesis, expression).

Anticipation verdict: none of the above anticipates a claim of US 5,627,052 individually. The distinguishing limitation common to all claim families — isolating an individual antibody-forming cell selected on the basis of a functional (non-binding) readout from an indicator system, then recovering that cell's V-region and producing a protein therewith — is not disclosed by any single retrieved reference.


Caveats and suggested next steps

  • Do not treat this as a complete § 102 record. I could not verify the [56] "U.S. PATENT DOCUMENTS" subsection of the granted patent, nor the granted claim text, because the search-step limit was reached. A formal anticipation opinion requires: (a) the full front-page citation list from USPTO Patent Public Search or the printed patent; (b) the 38 granted claims; and (c) a true Jenne/Cunningham plaque-assay prior-art check (Jerne & Nordin 1963; Cunningham & Szenberg 1968), which is not among the references I retrieved but is the most likely candidate for a genuinely anticipatory art stream on the "plaque-type indicator" element.
  • No contradiction with the earlier-generated litigation summary. That section found no litigation involving US 5,627,052 and identified its commercial significance as the SLAM lineage (UBC → B.R. Centre → Abgenix). Nothing in the citation record I retrieved changes that finding. One consistency note: the litigation section's "priority 1990-08-02, expired 2014-05-06" matches the bibliographic record used here.
  • OCR artifacts in the source text (e.g., "coffers" for "confers," "3720 C." for 37° C., "IL-1 α" for IL-1α) are transcription errors in the fetched text, not part of the patent; I have not silently corrected identifiers.

Generated 9/29/2026, 12:44:38 PM

Obviousness

Combinations of prior art that suggest the claimed invention would have been obvious under 35 U.S.C. § 103.

✓ Generated

I'll ground this obviousness analysis in the reference material. Let me pull the key prior-art references cited in the patent's specification and verify their content.

I now have the actual claims. Let me gather the remaining key prior-art references and the patent's cited art.

Obviousness Analysis — U.S. Patent No. 5,627,052 under 35 U.S.C. § 103

Building on the Litigation Search Report above: that report established there is no litigation of record on US 5,627,052 and that its importance is as the seminal "SLAM" disclosure widely cited as prior art by later antibody-discovery patents (e.g., US 7,521,048; US 10,323,084; EP 2,892,909). This section does not repeat that work; it uses the same reference set plus the patent's own cited art.


0. Framework, effective dates, and sources

Item Value (as literally stated in the patent)
Patent US 5,627,052 A ("US5627052A"), granted 1997-05-06
Application Ser. No. 08/464,261, filed 1995-06-05
Continuation chain Continuation of 08/088,601 (filed 1993-07-06, abandoned) → continuation of 07/561,984 (filed 1990-08-02, abandoned)
Priority date 1990-08-02
§ 102(b) critical date 1989-08-02 (one year before the earliest filing)
Assignee chain B.R. Centre Ltd → University of British Columbia / UBC Foundation → Abgenix Biopharma Inc. (2002)

Because the effective filing date precedes 2012-09-16, pre-AIA § 103(a) governs. The question is whether the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art (POSITA). Post-KSR Int'l v. Teleflex (2007) the analysis permits combination of familiar, predictable elements without an explicit teaching, so a modern invalidity challenge would be evaluated under the flexible KSR standard even though the application was examined under the stricter pre-KSR TSM regime.

Two source caveats up front:

  • The claims below are taken from a third-party reproduction of the printed patent (EveryPatent), not the official USPTO copy. Claim numbering, dependency statements, and the truncated text of claims 7–8 should be verified against the official document before being relied on.
  • Naming artifacts in the specification are flagged, not silently corrected: the patent's "L. Reichmann et al., Nature 332:325-27, 1988" corresponds to Riechmann, Clark, Waldmann & Winter, Nature 332:323-327 (1988); "Proc. Natl. Sci. USA 866:3833, 1989" corresponds to Orlandi et al., PNAS 86:3833 (1989).

1. The claimed subject matter — element decomposition

The independent claims share a common method, differing mainly in how the variable-region information is captured and how the protein is made:

# Claim element Claim 1 Claim 2 Claim 6 Claim 7
A Obtain from a warm-blooded animal a population of antibody-forming B cells / progeny, non-hybridoma or non-EBV-transformed, containing ≥1 cell producing an antibody exhibiting the desired function ✔ ✔ ✔ ✔
B Suspend population in a medium having an indicator system incorporated therein that indicates the presence and location of a cell forming antibodies exhibiting the desired function ✔ ✔ ✔ ✔
C Identify a cell forming an antibody exhibiting the desired function ✔ ✔ ✔ ✔
D Isolate the identified antibody-forming cell from the medium ✔ ✔ ✔ ✔
E Determine the amino-acid sequence of the variable region / functional portion ✔ ✔ — —
E′ Recover RNA → cDNA → amplify (6, 7); or recover DNA → amplify (5); or amplify RNA → cDNA (4) — — ✔ ✔
F Synthesize a protein containing that variable-region sequence (= claim 1), or incorporate DNA into an expression/secretion vector → transfect host → grow → isolate (2, 6, 7) ✔ ✔ ✔ ✔

Dependent claims 3–5 add the RNA/cDNA/DNA workflows; claim 8 and the embodiment claims recite specific indicator systems (cell-growth/viability layers; pathogens + susceptible cells; two-cell-type/HLA/blood-group/tumor-vs-normal; antigen-coated erythrocytes with agglutination or complement lysis; substrate modification; rosetting).

The two features that carry the patent's weight are (i) the negative limitation "non-hybridoma or non-EBV transformed" — i.e., the source cell is a freshly harvested, functionally selected primary B cell that is never immortalized — and (ii) the coupling of a function-based, single-cell screen directly to molecular cloning of that same cell's variable region. Everything else (immunize an animal, spleen cells, plaque-type indicator layers, PCR of Ig genes, expression vectors) was individually known.


2. Level of ordinary skill in the art

A POSITA at 1990-08-02 would be a Ph.D.-level immunologist/molecular biologist with ~2–3 years' postdoctoral experience (or M.S. with ~5 years), conversant with: hemolytic plaque assays, hybridoma technology, micromanipulation of single cells, cDNA synthesis and PCR (available since 1985–87), Ig-gene cloning, and expression in COS, CHO, and E. coli. The patent's own "Prior art keywords" of record — antibody, cell, cells, forming, desired function — are consistent with this field.


3. Prior art of record (from the specification, plus the field)

Ref Date § Status vs. 1990-08-02 What it teaches
Jerne & Nordin, Science 140:405, "Plaque Formation in Agar by Single Antibody-Producing Cells" 1963 § 102(b) Mixing lymphoid cells of an immunized animal with sheep RBCs in agar + complement; each plaque is due to a single antibody-forming cell, and the central cell can be localized.
Gronowicz, Coutinho & Melchers (reverse/protein-A plaque assay) ~1976 § 102(b) Plaque assay for all Ig classes and antigen-specific cells, independent of complement-fixing isotype.
Czerkinsky et al. (ELISPOT); Sedgwick & Holt 1983 § 102(b) Solid-phase enzyme-linked spot assay for single antibody-secreting cells.
Köhler & Milstein, Nature 256:495 1975 § 102(b) Hybridoma method; the patent's own background identifies its known deficiencies (human-myeloma partners, lethal viruses, rarity, subcloning loss).
Reading, Methods in Enzymology 21:18-33 old § 102(b) In vitro immunization of spleen/lymph-node/PBMC cultures.
Orlandi, Güssow, Jones & Winter, PNAS 86:3833 May 1989 § 102(b) Primer sets to PCR-amplify cDNA of mouse Ig VH/VL domains, restriction-clone them "for sequencing and expression," and express a mouse-human chimeric antibody; expressly states the technique "should also lead to the cloning of antigen-binding specificities directly from immunoglobulin genes."
Huse et al., Science 246:1275 Dec 1989 § 102(a) Combinatorial Fab library in phage lambda; states the method "may supersede present-day hybridoma technology" and "facilitate the production of catalytic and other antibodies."
Ward et al., Nature 341:544 Oct 1989 § 102(a) Single Ig variable domains secreted from E. coli.
Riechmann et al., Nature 332:323 1988 § 102(b) Transfer of the six hypervariable (CDR) regions confers binding function on a human framework → supports "variable region or a portion thereof."
Huston et al., PNAS 85:5879 1988 § 102(b) Single-chain Fv — a variable-region "portion" that can be made as a protein.
Jones et al., Nature 321:522 1986 § 102(b) CDR replacement in a human antibody.
Lerner & Benkovic, Bioessays 4:107; Iverson & Lerner, Science 1988–89 § 102(b) Catalytic antibodies from transition-state analogs; substrate-based indicator detection of antibody function.
Clark-Lewis et al., Science 231:134 1986 § 102(b) Chemical synthesis/refolding of large proteins.
Aebersold et al., Biochem. 27:6860 1988 § 102(b) Electroblot micro-sequencing of Ig heavy/light chains.
Lizardi et al., Bio/Technology 6:1197; Rappolee, J. Cell Biochem. 39:1; Gonda, J. Virol. 61:2754 1987–89 § 102(b) RNA amplification (Qβ replicase), and recovery of RNA from small numbers of cells.
Gunning et al., PNAS 84:4831 (p587); Sambrook et al., Molecular Cloning 1987–89 § 102(b) Mammalian expression vectors restoring leader/signal sequences; standard cloning.
Parish & Hayward, Proc. R. Soc. 187:47; Mishell & Shiigi, Selected Methods in Cell. Immunol. 1974/1980 § 102(b) Antigen coupling to erythrocytes/particles; rosetting; complement-mediated lysis.

Verified this session (search-confirmed): Jerne & Nordin 1963; Orlandi 1989; Huse 1989; Riechmann 1988; Köhler & Milstein's method (as cited); the reverse-plaque/Gronowicz lineage (surfaced via EP 2,343,363's discussion of "the reverse hemolytic plaque assay (Gronowicz et al.)"). I did not independently re-verify Gronowicz's citation or Czerkinsky ELISPOT bibliographic details in this session — flagged as unconfirmed.


4. Combinations that render the claims obvious

Combination I — the core § 103 case

Jerne & Nordin 1963 (+ Gronowicz 1976 / Czerkinsky 1983) + Orlandi 1989 + Huse 1989 (+ Köhler & Milstein 1975 for motivation; + Riechmann 1988 / Huston 1988 for the "portion" language).

Claim element Supplied by
A (animal-derived, non-immortalized B-cell population) Immunization + spleen/lymph-node harvest: Handbook of Experimental Immunology (Weir 1986); Köhler & Milstein 1975; Reading. The cells are inherently non-hybridoma/non-EBV at the moment of harvest — the negative limitation adds no structural step.
B (medium with incorporated indicator system, presence and location) Jerne & Nordin 1963 disclose precisely this: lymphoid cells suspended in an agar layer containing RBC + complement, giving a localized plaque identifying the position of the single secreting cell; Gronowicz extends it to all Ig classes/antigens; Czerkinsky gives a solid-phase variant.
C (identify the cell) Jerne & Nordin; central cell observed by phase-contrast (see also the Blood 33:149 phase-contrast PFC study located in this search).
D (isolate the cell from the medium) Micromanipulation/pipetting of single cells — routine bench technique; the patent itself says a "skilled technician may not require the micromanipulator."
E (determine V-region amino-acid sequence) Orlandi 1989: PCR primers specifically designed to amplify mouse Ig VH/VL cDNA "for sequencing"; Aebersold 1988 for direct protein sequencing; Kabat 1987 for CDR identification; Clark-Lewis 1986 for synthesis.
E′ (RNA→cDNA→amplify / DNA→amplify) Orlandi 1989 (cDNA→PCR of V domains); Rappolee 1989 and Gonda 1987 (RNA from few cells); Lizardi 1988 (alternative amplification); Sambrook 1989 (standard).
F (vector → transfect → grow → isolate) Orlandi 1989 (force-cloning V domains into expression vectors and expressing chimeric antibody); Huse 1989 and Ward 1989 (expression/secretion of Ig fragments in E. coli); Gunning 1987 (p587/p587L leader-containing mammalian vectors); Sambrook 1989.
"antibody variable region, or a portion thereof" Riechmann 1988 (CDR grafting transfers function); Huston 1988 (scFv).

Why the POSITA would have combined these — explicit motivations:

  1. Orlandi 1989 supplies the missing link almost verbatim. It teaches PCR cloning of Ig variable domains "for sequencing and expression" and states the technique "should also lead to the cloning of antigen-binding specificities directly from immunoglobulin genes." It is dated May 1989 — squarely § 102(b) art.
  2. Huse 1989 supplies the express motivation to abandon hybridomas — "may supersede present-day hybridoma technology" — and links the approach to catalytic antibody production, i.e., to the patent's own "desired function" concept.
  3. The patent's admitted problem statements frame every element as a known deficiency to be solved: human mAbs cannot be made by fusion; rare/functional antibodies are "very difficult to isolate because they form only a small proportion"; hybrids must be "subcloned in a tedious growth and subcloning process during which the desired antibody-forming cell may be lost." A POSITA seeking rare, functional antibodies would naturally screen at the single-cell level before immortalization (the 1963 plaque assay does exactly that) and then clone the selected cell's V genes rather than attempting unstable fusion.
  4. Reasonable expectation of success: every step — plaque formation, picking a cell, RT-PCR on Ig mRNA, cloning into a leader-containing vector, transfecting COS/CHO/E. coli, and assaying secretion — had been demonstrated. Nothing in the combination required an unproven physical principle.

Combination II — the "substrate / catalytic function" indicator claims

Lerner & Benkovic 1988 + Iverson & Lerner 1989 + Jerne & Nordin 1963 (+ Gronowicz).
The patent's substrate-modification embodiments (dinitrophenol- or fluorescein-derivatized gelatin for collagenase activity; plasma/skim-milk clearing for plasminogen activation; N-acetyl-ala-pro-ala-7-amido-4-methyl coumarin as a fluorogenic elastase substrate; fluorescent fibrin-breakdown antibody development) are the direct application of the known catalytic-antibody art to the known plaque format. Once Jerne & Nordin teach "localized indicator layer reporting single-cell antibody activity," substituting a chromogenic/fluorogenic substrate for the RBC layer is the predictable substitution of one known detection chemistry for another. Iverson & Lerner 1989 (sequence-specific peptide-cleaving antibodies) supplies both motivation and the specific peptide-bead/avidin-fluor label embodiment the patent recites.

Combination III — pathogen-neutralization indicator claims

Standard virus plaque-reduction/neutralization assays (BRK–vaccinia; HIV–T-cell-line cytopathic-effect assays, all ATCC-available) + Jerne & Nordin 1963.
The patent's vaccinia/BRK "plaque of live cells around a protected central cell" is a straightforward merger of the 1963 plaque-mixing geometry with the century-old neutralization/CYT assay. The patent's own text concedes the materials "may be obtained from conventional sources such as the American Type Culture Collection."

Combination IV — two-cell-type / HLA / blood-group / tumor-vs-normal / rosetting claims

Terasaki-type complement-dependent cytotoxicity and HLA/blood-group typing (notorious, pre-1975) + Jerne & Nordin 1963 + Parish & Hayward 1974 (antigen-coated erythrocyte coupling and rosetting).
Selective lysis of one of a distinguishable pair (tumor vs. normal, HLA-A vs. HLA-B) in a plaque format is the ordinary combination of a known discriminatory cytolysis assay with a known single-cell plaque format. The patent itself attributes the coupling and rosetting chemistries to Parish & Hayward and Mishell & Shiigi.

Combination V — membrane-replica indicator claims

Colony/plaque-lift and protein-blotting art (nitrocellulose lifts, anti-Ig-coated membranes). The specification admits these are "methods known to those skilled in the art." Overlaying a protein-binding membrane on the gelled antibody-forming-cell layer and developing it in a second indicator system is routine replication — nothing more than colony lifts applied to antibody secretion.

Combination VI — amplification alternatives (claims 4, 5, 7)

Lizardi et al. 1988 (Qβ replicase / self-sustained sequence replication) + Orlandi 1989 + Sambrook 1989.
Because Orlandi already teaches the end result (sequenceable/expressible V-domain cDNA), swapping PCR for a known isothermal amplification, or recovering genomic DNA instead of RNA, is an obvious alternative route to the same product. The only genuine question is whether ≤1 cell provides sufficient template — addressed below.


5. The § 103 bottom line per claim

Claim Obviousness strength Reason
1 Moderate The core single-cell, non-immortalized coupling is the true point of novelty. The amino-acid-sequence + synthesis route is enabled by combination (Orlandi + Aebersold + Clark-Lewis), but no single reference or combination expressly directs sequence determination from one freshly picked primary cell.
2 Moderate–strong Replaces step (f) with the standard vector-transfect-grow-isolate workflow. Orlandi 1989 (cloning V domains "for … expression") + Gunning 1987 + Sambrook 1989 + Huse 1989 make this the most predictable route.
3, 4, 5 Moderate–strong RNA/cDNA/DNA isolation and PCR are explicitly taught by Orlandi (cDNA/PCR) and Lizardi (amplification). The "single cell" template question is the only soft spot.
6, 7 Strongest attack point These are pure combinations of the known plaque method with the known Orlandi/Huse workflow, omitting the sequence-determination step entirely — i.e., they claim the most obvious permutation (screen → RT-PCR → clone → express).
8 + indicator-system embodiments Strong Each recited indicator system (cell-viability layer, antigen-coated-RBC lysis with enhancing anti-Ig, two-cell-type discrimination, substrate modification, rosetting) corresponds to a known assay chemistry combined with the Jerne/Gronowicz plaque geometry.

Fair summary: a prima facie § 103 case is readily made for the generic claim architecture, and is strongest for claim 7 and for the indicator-system claims. It is weakest precisely where the patent's contribution is concentrated: extracting Ig variable-region information from a single, functionally screened, never-immortalized primary B cell.


6. Rebuttals the patentee would (and did, presumably) raise

  1. No reference or combination suggests the source-cell limitation. Every cloning reference of record — Orlandi 1989 (five hybridoma antibodies), Huse 1989 (lambda library from spleen mRNA), Ward 1989 — starts from immortalized cells or bulk mRNA. None suggests micromanipulating one primary plaque-forming cell and amplifying from it. The negative limitation "non-hybridoma or non-EBV transformed" is the whole invention, and the art arguably teaches toward immortalization (hybridoma/EBV) as the necessary amplification step.
  2. No reasonable expectation of success for single-cell RT-PCR of Ig genes in 1990. Orlandi's method was validated on hybridoma RNA; recovering sufficient V-region cDNA from a single micromanipulated lymphocyte was not established. The patent exemplifies a Proteinase-K/oligo-dT-cellulose micro-method — evidence that this step was the non-routine contribution.
  3. "Desired function," not mere binding. Huse and the plaque assay as classically used detect binding; the patent's objective is function (enzyme mimicry, growth-factor agonism/neutralism, pathogen neutralization). If the claim's "desired function" is read as a non-binding functional activity, the motivations in the art are weaker.
  4. Secondary considerations. The patent is the foundation of SLAM (Selected Lymphocyte Antibody Method; cf. Babcook et al., PNAS 1996, and descendant filings such as EP 2,343,363 and JP 2009511892A that discuss plaque-based single-B-cell isolation followed by RT-PCR — all post-dating the 1990 priority and therefore not prior art). The breadth of forward citation evidenced in the Litigation Search Report (EP 2,892,909; EP 3,943,508; US 7,521,048; US 10,323,084; US 10,150,996) is consistent with a long-felt need met. No objective-evidence record was located in this session; this is an argument hook, not a proven record.

Note the two-way nature of the "non-hybridoma" limitation: under § 103, a negative limitation does not confer patentability merely by excluding matter the art does not teach — but here the exclusion defines the process's substance (short-lived primary cells + direct molecular rescue), which can be argued to be a non-obvious sequencing of steps.


7. Caveats

  • Claim text provenance: the claim language above comes from a third-party HTML reproduction; the official patent copy should be consulted, particularly for claims 7 and 8 (truncated in the source).
  • Unverified references this session: Gronowicz (1976), Czerkinsky (ELISPOT, 1983), Ward 1989, Huston 1988, Iverson & Lerner 1989, and the various 1986–88 method papers are cited here on the basis of the patent's own reference list and general-field knowledge; a validity opinion would verify each against the primary source and confirm its § 102(b) date.
  • No prosecution history / no IPR record was reviewed. This is a hypothetical § 103 attack, not a reconstruction of the examiner's rejections or of any post-grant challenge. The patent issued in 1997 after what appears to have been a multi-year prosecution; the examiner's actual cited art may differ from the list above.
  • Status of the patent: confirmed expired-lifetime (anticipated expiration 2014-05-06), so any § 103 analysis is now of academic/portfolio significance rather than of infringement-defense significance.
  • Minor date discrepancy: the working header for this task states "Current Date: April 26, 2026," whereas the earlier-litigation-section environment date was 2026-09-29. This does not affect the analysis, which turns on the 1990-08-02 priority date and the 1989-08-02 § 102(b) critical date.

Generated 9/29/2026, 12:45:07 PM

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