Invalidity dossier

US 6018041

Current assignee: Hyseq, Inc.

Added 9/30/2026, 3:11:58 PM

At a glanceNo PTAB challenges2 lawsuits on fileasserted by Hyseq, Inc.Biotechnology

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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 information on this patent, including any litigation activity, then summarize.

Let me check for litigation history and confirm the CAFC docket situation.

US Patent 6,018,041 — Analyst Summary

Scope note on identifiers (interpreted literally): I was asked about US patent 6018041. My searches also surfaced a different, unrelated document bearing the number JP 6018041 (a Japanese patent held by SIGA Technologies covering polymorphs of tecovirimat/TPOXX, with a 2031 expiry — see the Roquette/CIK filing and drugpatentwatch result). These are distinct documents in different jurisdictions and I have not conflated them. All statements below refer to US 6,018,041.


1. Bibliographic Data

Field Value
Patent number US 6,018,041 (literal "6018041")
Title Method of sequencing genomes by hybridization of oligonucleotide probes
Application no. 08/902,167
Filing date July 29, 1997
Issue (grant) date January 25, 2000
Priority date April 1, 1987 (claimed from YU 00570/87A, Yugoslavia)
Inventors Radoje T. Drmanac (Beograd) and Radomir B. Crkvenjakov (Beograd)
Original assignee Hyseq, Inc. (Sunnyvale, CA); the Google Patents record lists current assignee as "Hyseq Inc"
Later reassignment 2004‑12‑14: security agreement recorded to NUVELO, INC. and AFFYMETRIX, INC. (assignor: Callida Genomics, Inc.)
Attorney firm Pennie & Edmonds LLP
Primary examiner Stephanie W. Zitomer
Status Expired – Fee Related; "Anticipated expiration" recorded 2008‑03‑30
Classification C12Q 1/6874 (sequencing by hybridisation); USPC 536/243, 435/6, 935/77, 935/78

Prosecution family (continuation chain): US 6,018,041 is a continuation of App. 08/461,106 (issued as US 5,667,972), itself a continuation of 08/045,912 (issued as US 5,492,806), a continuation of 07/723,712 (issued as US 5,202,231), a continuation of 07/175,088 (filed Mar 30, 1988, now abandoned). It has one child continuation, App. 09/489,421, issued as US 6,451,996.

Sources: Google Patents (https://patents.google.com/patent/US6018041/en), Justia (https://patents.justia.com/patent/6018041), uspto.report (https://uspto.report/patent/grant/6018041), idiyas (https://idiyas.com/patent/badge/6018041).


2. Abstract (as printed)

The conditions under which oligonucleotides hybridize only with entirely homologous sequences are recognized. The sequence of a given DNA fragment is read by the hybridization and assembly of positively hybridizing probes through overlapping portions. By simultaneous hybridization of DNA molecules applied as dots and bound onto a filter, representing single-stranded phage vector with the cloned insert, with about 50,000 to 100,000 groups of probes, the main type of which is (A,T,C,G)(A,T,C,G)N8(A,T,C,G), information for computer determination of a sequence of DNA having the complexity of a mammalian genome are obtained in one step. To obtain a maximally completed sequence, three libraries are cloned into the phage vector M13 … For a million bp of genomic DNA, 25,000 subclones of the 0.5 kbp are required as well as 700 subclones 7 kb long and 170 jumping subclones. Subclones of 0.5 kb are applied on a filter in groups of 20 each, so that the total number of samples is 2,120 per million bp. The process can be easily and entirely robotized for factory reading of complex genomic fragments or DNA molecules.

Subject matter in one line: a sequencing-by-hybridization (SBH) platform using overlapping / degenerate ("ordered") 11–20-mer probe groups hybridized to subclone libraries, with computer assembly of the resulting binary (+/−) hybridization data into sequence.


3. Plain-Language Overview of the Independent Claims

The patent has 18 claims, of which the independent claims are 1, 9, 11, 16, 17, and 18 (claims 2–8 depend from 1; 10 depends from 4; 12–15 depend from 1).

Claim 1 — Core overlapping-probe concept. A set of oligonucleotide probes, all the same length n, where each probe shares a contiguous n‑1 nucleotide overlap with at least one other probe. When hybridized to a nucleic acid, the probes (or a subset of them) can be assembled by overlap to determine a target sequence longer than n. In plain terms: a collection of probes designed so their sequences can be "stitched" together end-to-end into a longer read.

Claim 9 — Overlap defines a contiguous stretch. A probe collection where each probe has a contiguous common (overlapping) sequence with another probe, and at least a subset hybridizes to a fully complementary (perfect-match) region of a target. When the overlapping portions of the hybridizing probes are aligned, that subset defines a contiguous stretch of the target sequence. Essentially the operational counterpart of claim 1: the informative probes, once matched and overlapped, reconstruct a continuous sequence.

Claim 11 — Reading a subclone insert's ends. Same overlapping-probe framework, but expressly directed to a target that includes an insert of a subclone; here the hybridizing probes determine a terminal sequence of the insert (i.e., the probe set is used to read the ends of a cloned insert, e.g., near the vector–insert junction).

Claim 16 — The 8‑mer-core probe set. A set of probes comprising 65,356 subsets, each subset being the complete set of 64 probes of the formula NN(N8)N (an 8‑mer core with one unspecified/random base on each side, giving 11‑mers), each subset built on a unique octanucleotide N8. Upon hybridization, the probes or a subset determine a nucleic acid sequence. (This is the classical SBH "all 4⁸ cores × 4² flanking degeneracies" reagent set.)

Claim 17 — The three-tier GC-balanced probe set. A probe set organized into three groups of subsets, again for sequence determination:

  • (i) 1,024 subsets of 4 probes of formula N(N10), where N10 is a decanucleotide with G+C content of zero (all A/T);
  • (ii) 23,044 subsets of 16 probes of formula N(N9)N, where N9 has G+C content 1 or 2;
  • (iii) 56,064 subsets of 64 probes of formula NN(N8)N, where N8 has G+C content ≥ 3.

This mirrors the specification's strategy of balancing GC content across probe lengths so that all groups melt at comparable temperatures — a practical, complete reagent inventory for genome-scale SBH.

Claim 18 — Generic "ordered/degenerate probe group" claim (broadest conceptual coverage). A probe set of uniform length n, where n = 11 to 20, divided into groups, each group defined by a different fixed subsequence of length m (m = 5 to n) at a fixed position, each group containing all possible length‑n probes sharing that m-mer at that position (i.e., the remaining positions are fully degenerate). Each fixed subsequence overlaps by m‑1 with that of another probe; when hybridized, the shared subsequences of the hybridizing probes determine a contiguous target sequence longer than m. This is the claim that generalizes the (N2)N8(N1) idea to any core length and any n.


4. Notes, Anomalies, and Limitations (stated honestly)

  1. Numeric discrepancy in the claims — not corrected. Claim 12 recites "56064 subsets" (matching the count of octanucleotides with G+C ≥ 3: 65,536 − 9,472 = 56,064 — arithmetically correct). Claims 15 and 16 recite "65,356 subsets," whereas the specification repeatedly refers to 65,536 (= 4⁸) different 8‑mers. Per the "interpret literally / do not auto-correct" rule, I report 65,356 as the claim text actually reads and flag that the specification's figure is 65,536. Likewise, claim 17 recites 23,044 N(N9)N subsets, whereas the count of nonanucleotides with G+C of 1 or 2 computes to 23,040; I report the recited figure without adjustment. These appear to be scrivener's errors in the granted claims, but I have not verified them against the USPTO PatentCenter certified copy.

  2. Litigation. Google Patents flags the family (Family ID 27390498) as "Family has litigation — First worldwide family litigation filed" with a Darts‑IP link, so the family has documented litigation history. However, I could not retrieve any specific CAFC docket, complaint, or judgment identifying US 6,018,041 itself, and my targeted searches for a 2026 CAFC appeal returned no results. Because the patent's anticipated expiration is 2008‑03‑30 (expired ~18 years ago), a new 2026 appeal on this specific patent would be atypical. Treat any claim of current 2026 CAFC activity as unverified — I have not been able to confirm or deny it from authoritative dockets in this session.

  3. Data-source limitation. I did not obtain results directly from the USPTO PatentCenter/Patent Public Search or the CAFC docket system; the bibliographic and claim text above is drawn from Google Patents (the authoritative full text supplied to me), Justia, uspto.report, and idiyas, which are consistent with one another on the bibliographic fields. Where the assignee record is concerned, note that "current assignee" (Hyseq Inc) and the 2004 security-interest reassignment to Nuvelo/Affymetrix are two separate fields and should not be conflated.

  4. Significance. This patent is a member of the foundational Hyseq SBH family (US 5,202,231; 5,492,806; 5,667,972; 6,018,041; 6,451,996) and is heavily cited as prior art in later sequencing-by-hybridization and array work (e.g., US 7,071,324; US 7,230,093; and numerous EP filings cite it as a cited reference).

Generated 9/30/2026, 3:21:15 PM

Cases on file (2)

Group view →

Specific litigation cases in our database that name US patent 6018041. The free-form analysis below may also discuss cases beyond this list.

Litigation summary

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

✓ Generated

I'll research litigation involving US patent 6018041 across several patent litigation sources.

Initial results include noise (unrelated '804 patents and a Japanese patent JP6018041). Let me run more targeted searches.

I've found the key Hyseq–Affymetrix litigation. Let me dig deeper to determine which patents were actually asserted and pin down case numbers and outcomes.

Litigation involving US Patent 6,018,041

Important scoping note: US 6,018,041 ("Method of sequencing genomes by hybridization of oligonucleotide probes," Drmanac & Crkvenjakov, assigned to Hyseq, Inc.) is one member of a patent family (Darts-IP family ID 27390498) that also includes US 5,202,231, US 5,492,806, US 5,667,972, and US 6,451,996. Litigation in this family is real, but the reported decisions I located generally name the earlier family members rather than the '041 patent by number. I have flagged precisely where that distinction matters below.

Confirmed family litigation (Hyseq / Affymetrix)

Item Detail
Plaintiff Hyseq, Inc. (Sunnyvale, CA)
Defendant Affymetrix, Inc. (Santa Clara, CA)
Jurisdiction U.S. District Court for the Northern District of California
Filing date March 4, 1997 (complaint for patent infringement)
Subject Hyseq's sequencing-by-hybridization patents (the Drmanac/Crkvenjakov family)
Outcome / status Settled — Hyseq's 2001 Form 10-K reports that "In October 2001, the Company entered into a settlement agreement with Affymetrix providing for the comprehensive settlement" of the dispute.

Grounding: the March 4, 1997 complaint and its N.D. Cal. venue are reported contemporaneously in Nature Biotechnology ("Litigation escalates for patents on a chip," Bains, 1997), which states Hyseq "filed a complaint on March 4 against Affymetrix ... for infringement of the patents ... HySeq is a private company set up specifically to exploit the technology and patents of Radoje Drmanac and Radomir Crkvenjakov." The settlement is reported in Hyseq's 10-K for FY2001 (SEC filing, Item 3 Legal Proceedings).

Related decision in the same dispute

  • Affymetrix, Inc. v. Hyseq, Inc., 132 F. Supp. 2d 1212 (N.D. Cal. 2001) — claim-construction (Markman) ruling. This action was brought by Affymetrix and asserted Affymetrix's own array patents (the '934, '305, '992, and '716 patents); Hyseq and Incyte were among the parties/defendants, and Synteni also featured in the related transfer dispute. This decision does not construe or address the '041 patent — it concerns Affymetrix's patents, not Hyseq's.

The specific question: was US 6,018,041 itself asserted?

I must be candid here rather than fabricate a record:

  • The '041 patent issued January 25, 2000, from application US 08/902,167 filed July 29, 1997 — i.e., after the March 4, 1997 complaint in Hyseq v. Affymetrix. It therefore could not have been in the original complaint; it could only have entered the case by amended pleading or a separate suit.
  • Google Patents' page for US 6,018,041 carries a "Family has litigation" / "First worldwide family litigation filed" indicator pointing to the Darts-IP litigation record for family 27390498 (https://patents.darts-ip.com/?family=27390498). This confirms that litigation exists somewhere in this family, but the link itself does not identify the case, the parties, or the specific patent asserted.
  • I did not locate a docket entry, complaint, judgment, or CAFC opinion that names 6,018,041 as an asserted patent, nor a case number for such a suit.

Conclusion: Litigation involving the Drmanac/Crkvenjakov family is known and documented (Hyseq v. Affymetrix, N.D. Cal., filed 1997; settled October 2001; plus the related Affymetrix v. Hyseq claim-construction action). However, I cannot state with high confidence that US 6,018,041 specifically was asserted as a patent-in-suit — I found no source confirming that. Verifying this would require the actual N.D. Cal. docket (e.g., Hyseq, Inc. v. Affymetrix, Inc., No. C-97-20188 filed 3/4/1997 and any consolidated/amended pleadings adding the then-new '041 patent) via PACER or the Darts-IP family record.

Sources that are NOT this patent (flagged per the strict-identifier rule)

Searching "6018041"/"'804" surfaces several unrelated matters; none involve US 6,018,041:

  • The many "'804 patent" hits (e.g., nCUBE v. SeaChange regarding a media-server patent; Cisco Systems v. BillJCo, IPR2022-00426; Apple v. BillJCo) refer to different patents whose numbers end in 804.
  • JP 6018041 (Siga Technologies/Tecovirimat TPOXX polymorphs) is a Japanese patent — not the US patent at issue.
  • The "Best Patents" citation lists in EP specifications (EP3102230B1, EP3900738A1, EP0969103A3, EP1408122A3) merely cite US 6,018,041 as prior art/bibliography; they are not litigation.

Summary

  • Known litigation: Hyseq, Inc. v. Affymetrix, Inc., N.D. Cal., filed March 4, 1997 — settled October 2001 (family-level; exact case number to confirm on PACER).
  • Related decision: Affymetrix, Inc. v. Hyseq, Inc., 132 F. Supp. 2d 1212 (N.D. Cal. 2001) — concerns Affymetrix's patents, not the '041.
  • US 6,018,041 specifically: no litigation in which it is named as the asserted patent was confirmed in the sources retrieved. Treat this as unverified rather than as "no litigation," because the Darts-IP family record indicates family litigation and the '041 issued mid-dispute.

Generated 9/30/2026, 3:21:09 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.

Current assignee: Hyseq, Inc.

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

I'll verify the structured "no proceedings" finding against the live web before writing this up.

Let me run more targeted searches to be thorough.

PTAB / AIA Trial Analysis — US 6,018,041

Cross-reference note: this section builds on the previously generated bibliographic, claim, and litigation sections and does not repeat them. No contradictions found — the earlier litigation section's finding (1997–2001 Hyseq v. Affymetrix district-court dispute, settled; no confirmed assertion of the '041 itself) is consistent with the PTAB picture below.


Proceedings overview

Total count: zero. The structured "PTAB proceedings on file" block — the canonical USPTO Open Data Portal list supplied in this prompt — reports: "The USPTO ODP API returns no AIA trial proceedings for this patent as of the most recent ingest." There are therefore no active proceedings, no proceedings in which claims were invalidated, none in which claims were sustained, none settled, and none in which institution was denied — the count is 0, not "unclear."

Bottom line for a defendant: the patent has not been hardened by surviving an IPR, and it has not been narrowed by one either. The absence of PTAB activity here is not a signal of strength or of weakness — it is a signal of mootness: on the record I retrieved, US 6,018,041 is expired (anticipated expiration recorded as 2008-03-30; legal status "Expired – Fee Related"), which is roughly four and a half years before the first AIA petition could be filed on 2012-09-16. Nobody petitions to invalidate a patent that has already lapsed. The practical effect is that there is no § 315(e)(2) estoppel of any kind against any party, and every prior-art ground remains un-adjudicated — but there is also no live patent right to attack, which is why this patent's real defensive history lives in the 1997–2001 district-court dispute, not at the Board.


Proceedings

None on file

I identified no IPR, PGR, CBM, or derivation proceeding naming US 6,018,041 (application 08/902,167) as the subject patent. No proceeding number is reported because none exists; per the operating constraints, I have not invented one.

What I did locate, and why none of it is a proceeding against this patent (flagged so it is not mistaken for PTAB activity):

Item surfaced in search Why it is not a proceeding on US 6,018,041
IPR2015-00776, IPR2014-01177, IPR2014-01463 — Crossroads Systems v. NetApp (U.S. Pat. No. 7,934,041) Different patent (Crossroads storage-networking '041). The "041 Patent" shorthand in those papers refers to 7,934,041, not 6,018,041.
IPR2025-01451 — Advanced Memory Technologies v. SK Hynix (U.S. Pat. No. 7,969,231) Different patent; no relationship to the Hyseq SBH family.
JP 6018041 (Siga Technologies / TPOXX tecovirimat polymorphs) A Japanese patent — a different document in a different jurisdiction.
EP 0969103 A3; EP 1408122 A3 search reports listing "US 6018041 A (25-01-2000)" These are citation/annex entries — the '041 cited as prior art — not proceedings against it.
Ex parte reexamination certificate US 6,355,432 C1 (Reexam Request No. 90/008,885, filed 2007-11-27, certificate issued 2008-12-30) The '041 appears only in the list of references cited in that reexamination of Affymetrix's Fodor patent. The reexam target was US 6,355,432; the '041 was art, not the patent under examination.

Where the absence could hide (honest limitation): PTAB filings and decisions are public at the Board's E2E system (https://ptacts.uspto.gov/ptabweb/) and on CourtListener (https://www.courtlistener.com/), and the ODP feeds those. I could not query ODP/PTAB E2E or PACER directly in this session; my finding rests on (a) the canonical structured block and (b) independent web searches, which returned no PTAB docket naming the '041. I also searched for Federal Circuit activity on "6,018,041" and returned no results — consistent with there being no FWD to appeal. I did not find evidence of any pre-AIA inter partes reexamination of the '041 itself, but I also cannot rule one out from the sources retrieved; that would require the certified file wrapper.


Strategic summary

Claim status: everything UNTESTED; nothing CANCELED and nothing SUSTAINED by the Board. All 18 claims — including the independent claims 1, 9, 11, 16, 17, and 18 — stand exactly as granted, never having been construed or adjudicated in an AIA trial. Notably, the scrivener's-error anomalies flagged in the earlier claim section — claim 12's "56064 subsets," claims 15 and 16's "65,356" subsets (the specification says 65,536 = 4⁸), and claim 17's "23,044" N(N9)N subsets (the arithmetic count is 23,040) — have therefore never been tested in a claim-construction or § 112 challenge at the Board. Those numerals would have been obvious IPR and § 112 material had the patent still been asserted when the AIA came online.

Estoppel landscape: none, and that cuts both ways. Because no IPR was ever filed or instituted, § 315(e)(2) estoppel does not bind any petitioner or privy — there is no prior IPR record to estop anyone, and no "grounds raised or reasonably could have been raised" that are foreclosed. Equally, though, there is no § 315(b) one-year bar running against anyone: the last service of an infringement complaint in this family ended with the October 2001 settlement, so no statutory clock is ticking. All prior-art grounds — including the four independent 1988–1991 disclosures (Southern's 1988 GB filing, the Fodor/Affymetrix array work, and the other independently-developed SBH disclosures recounted in the 1997 Nature Biotechnology report) — remain available in the abstract, in both district court and an IPR.

Pattern signals: none of the usual ones. There is no serial petitioner, no defensive aggregator (no Unified Patents petition appears anywhere in this family), no Director Review request, and no patent-owner appeal. The patent owner did not pursue the Board aggressively, because the technology dispute was resolved commercially in 2001 — five years before the '041 issued into a family that was already settled. The one structural point worth recording for a practitioner: even if a challenger today wanted to attack the '041 at the Board, the available vehicle set is nearly empty — PGR was unavailable as a matter of law (it requires a patent with an effective filing date on or after 2013-03-16, and this patent's chain originates in 1987–1988), and CBM was unavailable on its face (the claims are sequencing-by-hybridization biochemistry, not a "covered business method" for a financial product or service, and the CBM transition program has in any event sunset). IPR was the only door, and it is now moot.


Recommended next steps

  1. If you have received a demand letter citing US 6,018,041, check the expiration first. The record shows anticipated expiration 2008-03-30 and status "Expired – Fee Related." A party asserting an expired patent for ongoing conduct has no case, and past-damages exposure under the § 286 six-year look-back closed out years ago. Do not spend IPR money on a dead patent.
  2. Verify the expiration basis against the certified file wrapper. My reconstruction is that the patent lapsed for non-payment of a maintenance fee (which the "Expired – Fee Related" status indicates), and that this occurred well before AIA trials opened on 2012-09-16. There is a technical wrinkle I want flagged rather than glossed: this application was filed 1997-07-29 but claims a chain back to 1988-03-30, so the term analysis could in principle reach a pre-URAA § 154(c) "greater of" comparison (20 years from 1988-03-30 = 2008-03-30, versus 17 years from the 2000-01-25 grant = 2017-01-25). I have not verified which controls, and I would not assert either date as fact. Confirm via USPTO PatentCenter maintenance-fee and file-wrapper records before relying on it in a letter.
  3. If a live family member is being asserted (e.g., a continuation such as US 6,451,996, if it were revived or still within term for past conduct), re-run the PTAB check per patent number — my no-proceedings finding is for 6,018,041 only. Do not extrapolate it to the rest of the Drmanac/Crkvenjakov family, which I did not exhaustively check at the Board.
  4. Preserve the invalidity record regardless. Because no IPR estoppel attaches, if any live member of this family is ever asserted, a defendant retains the full prior-art menu — the 1988–1991 independent disclosures, and the "seven companies" gene-chip priority disputes described in Nature Biotechnology (May 1997) — with no Board-imposed narrowing of what can be raised.
  5. Do not cite this patent's "Family has litigation" flag as PTAB history. That Darts-IP indicator on Google Patents refers to the district-court family litigation (Hyseq v. Affymetrix, N.D. Cal., filed 1997-03-04; settled October 2001), not to any AIA trial.

Sources for the negative finding: canonical PTAB proceedings block (USPTO ODP, per prompt); USPTO PTAB E2E — https://ptacts.uspto.gov/ptabweb/; CourtListener search — https://www.courtlistener.com/; and the search results recited in the table above. No proceeding number, panel, FWD, or appeal docket is cited for US 6,018,041 because — on the record retrieved — none exists.

Generated 9/30/2026, 3:22:00 PM

Ownership chain (2)

Asserters network →

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

  1. ? · recorded 2004-12-14 · Security Agreement

    Callida Genomics, Inc.Nuvelo, Inc. and Affymetrix, Inc.

    securitization

  2. ? · Assignment

    Radoje T. Drmanac; Radomir B. CrkvenjakovHyseq, Inc.

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 the assignment chain for US 6,018,041 through the USPTO Assignment Center and related sources.

Let me dig into the specific assignment records and corporate history.

Let me look at Google Patents legal events and search for the specific assignment records.

Assignment & Ownership Analysis — US 6,018,041

Scoping / sourcing statement (read first). I was unable to open the USPTO Assignment Center search results directly in this session (tool-step limit reached). The reconstruction below therefore rests on: (a) the Google Patents record for US 6,018,041 including its Legal Events tab (authoritative full text supplied to me), (b) SEC 10-K filings of Affymetrix, Hyseq/Nuvelo and the successor registrant, (c) the NIST/ATP program evaluation of the Hyseq project, and (d) the litigation-history literature. I could not retrieve recorded reel/frame numbers or correspondent-of-record data, and I say so explicitly at each link rather than inventing them. Verify against https://assignmentcenter.uspto.gov/ or https://assignment.uspto.gov/patent/index.html by searching patent number 6018041.


Inventors

Inventor Address of record on the patent Employer at time of filing (1987–88) Later trajectory
Radoje T. Drmanac Beograd, Yugoslavia (per patent front page / Google Patents) Belgrade molecular-biology institute (Belgrade/Yugoslavia) — the patent lists Belgrade; note the 1988 US parent (07/175,088) predates any US employer Group leader, Argonne National Laboratory (US) before 1994; co-founded Hyseq (≈1994), SVP Research 1994–98, CSO 1998–2001; co-founded Callida Genomics (2001), CSO 2001–04, President from 2004; later co-founder/CSO of Complete Genomics
Radomir B. Crkvenjakov Beograd, Yugoslavia Same Belgrade institute lineage Not determined from the sources retrieved

Pattern notes (what is and is not present):

  • The classic fire-sale tell — "all inventors depart the original assignee within 12 months of filing" — is not present and, in any event, cannot apply: the named assignee (Hyseq) was not formed until roughly 1992–94, years after the 1987 Yugoslav priority filing and the 1988-03-30 US parent filing. This is an inventor-to-later-company alignment, not an early-inventor walkout.
  • One genuine coincidence worth flagging: Drmanac's departure from Hyseq (2001) falls in the same window as the October 2001 Affymetrix settlement and the formation of Callida Genomics (2001) — the entity that later appears as the assignor on this patent's only recorded post-issuance transfer (2004 security agreement, below). The lead inventor leaving at the moment the IP is spun into a JV is a structural pattern, though here it reads as a founder continuing his own technology, not as abandonment.

Original assignee

Entity named on the issued patent: Hyseq, Inc., Sunnyvale, California.

  • Line of business: DNA-array / sequencing-by-hybridization (SBH) tools and gene discovery; the commercial vehicle for the Drmanac–Crkvenjakov SBH patents. Founded ≈1992–94.
  • Product embodying the claims: Partial / unclear. Hyseq developed and licensed SBH technology and gene-discovery services; the physical "sequencing chip" commercialization was largely delegated to the Callida Genomics / N-Mer joint venture created with Affymetrix at the 2001 settlement (Affymetrix was the exclusive chip/system supplier). So Hyseq was an operating life-sciences company, but I did not find evidence it sold an instrument that practiced the '041 claims on a standalone basis.
  • Corporate fate: Hyseq → renamed Hyseq Pharmaceuticals → merged with Variagenics → Nuvelo, Inc. (2003) → Nuvelo was acquired by ARCA biopharma (the successor registrant whose 10-Ks still list the Hyseq merger exhibits; NASDAQ: ABIO). Callida Genomics and N-Mer were sold by Nuvelo on 2004-12-03.
  • Current status of the patent: Expired – Fee Related; Google Patents records "Anticipated expiration" on 2008-03-30 (20 years measured from the 1988-03-30 parent filing, 07/175,088). The asset has been in the public domain for ~18 years.

Assignment timeline

Caveat on precision: Of the links below, only Event C appears on the Google Patents Legal Events record with a concrete date. No reel/frame numbers were retrievable in this session, and the correspondent of record could not be captured. They are marked "not retrieved" rather than guessed. If a full Assignment Center pull shows additional links I could not see, treat this section as a floor, not a ceiling.

A. Inventors → Hyseq, Inc. (executed between 1987 priority and 2000 issue; exact date unknown) — Reel not retrieved / Frame not retrieved

  • Conveyance: Assignment (original)
  • Assignor: Radoje T. Drmanac; Radomir B. Crkvenjakov (as joint inventors)
  • Assignee: Hyseq, Inc., Sunnyvale, CA
  • Correspondent: not retrieved
  • Context: Initial perfection of the inventors' rights in the company — anomalously delayed, because the assignee did not exist at the 1987–88 filing date.

B. Hyseq, Inc. → Callida Genomics, Inc. (≈2001–2002; exact date unknown) — Reel not retrieved / Frame not retrieved

  • Conveyance: Assignment (intra-group spin-off / IP contribution)
  • Assignor: Hyseq, Inc. (soon Hyseq Pharmaceuticals)
  • Assignee: Callida Genomics, Inc. (SBH JV with Applied Biosystems; Affymetrix held a minority stake/option)
  • Correspondent: not retrieved
  • Context: Internal reorg / spin-off — the NIST-ATP evaluation states Callida "inherited all the intellectual property related to Hyseq's ATP-funded project," which expressly included this family. This is the transfer that makes Callida the assignor in Event C. Whether this specific transfer was formally recorded at the USPTO is not confirmed in my sources.

C. Callida Genomics, Inc. → Nuvelo, Inc. and Affymetrix, Inc. — recorded 2004-12-14 — Reel not retrieved / Frame not retrieved

  • Conveyance: Security Agreement (Google Patents Legal Events: "Assigned to NUVELO, INC., AFFYMETRIX, INC. … SECURITY AGREEMENT; Assignors: CALLIDA GENOMICS, INC.")
  • Assignor: Callida Genomics, Inc.
  • Assignees: Nuvelo, Inc. (parent) and Affymetrix, Inc. (cross-license partner)
  • Correspondent: not retrieved
  • Context: Securitization / collateral grant, adjacent to the corporate divestiture on 2004-12-03 — not a transfer to an unrelated asserter.

D. Divestiture of Callida Genomics and N-Mer, Inc. (2004-12-03, SEC-reported) — Reel/Frame n/a (not confirmed as a recorded patent assignment)

  • Conveyance: Corporate sale of subsidiaries
  • Assignor: Nuvelo, Inc.; Assignee/purchaser: not identified in the filings retrieved
  • Context: Restructuring / divestiture; Nuvelo reported a related capital-loss carryforward of ~$7.9M.

Recorded post-issuance activity, in short: one link (Event C, a security interest in 2004). There is no recorded transfer to a licensing LLC, no cascading chain of assignees, and nothing after 2004.


Timeline diagram

timeline
    title Ownership of US 6018041
    1987 : Yugoslav priority filing
    1988 : US parent application filed
    1994 : Hyseq founded
    1997 : Continuation application filed
    2000 : Patent issued to Hyseq
    2001 : Affymetrix litigation settled
         : Callida Genomics spun off
    2003 : Hyseq becomes Nuvelo
    2004 : Security interest to Nuvelo and Affymetrix
         : Callida and N-Mer divested
    2008 : Patent expires fee related

NPE / troll-pattern signals

  1. Shell-entity transfer — not present. The single recorded post-issuance link (2004-12-14) runs from Callida Genomics to Nuvelo and Affymetrix as a security agreement. The assignee names carry no "IP / Licensing / Holdings / Ventures" suffix; Nuvelo was a NASDAQ-listed drug developer and Affymetrix a NASDAQ-listed array maker; Callida was an operating JV with an exclusive supplier relationship. No single-member Delaware/Texas LLC appears anywhere in the chain.

  2. Known asserter in the chain — not present. No assignee matches the public NPE directories (Acacia, Marathon, Intellectual Ventures, Wi-LAN/Conversant, Vringo, Pendrell, Round Rock, Lumen View, Spangenberg entities, etc.). Every entity in the chain is an operating life-sciences company or its corporate parent/JV.

  3. Repeat correspondent across the chain — unclear (data not retrieved). I could not obtain correspondent-of-record data for any link, so I can neither confirm nor rule out a recurring recording attorney. This is the one signal I flag as unverified rather than absent.

  4. Cascading transfers — not present. Two ownership-relevant events span ~3 years (2001 spin-off; 2004 security agreement) and seven years total from issue (2000) — no rapid multi-LLC chain and no shared registered-agent address evidence.

  5. Pre-litigation transfer — not present (inverse relationship). The litigation came first: the Drmanac family was asserted in 1997–98, before this patent issued (2000-01-25) and before the 2001 spin-off and 2004 security interest. The chain was not arranged ahead of a suit; the transfers followed a settlement.

  6. Bankruptcy fire-sale — not present. I found no Chapter 7/11 sale of this patent. The 2004-12-03 event was an ordinary divestiture of subsidiaries (with a reported capital loss), and Nuvelo's later absorption into ARCA biopharma was a corporate merger/acquistion, not an insolvency sale of the IP.

  7. Privateering — not present. The 2001 arrangement is a strategic alliance/co-ownership, not classic privateering: Affymetrix took only a minority stake plus an option in Callida and an exclusive supply role, and the parties settled by cross-licensing — the opposite of an operating company arming an NPE to harry competitors.

  8. Defensive aggregator — not present (but a defensive outcome occurred). The chain does not terminate at RPX, AST, LOT, Unified Patents, or OIN. However, the October 2001 cross-license and JV effectively neutralized the SBH family between the two principal disputants and took it off the assertion market — a defensive result achieved contractually, not by aggregation.


Verdict

Operating-company assertion.

Justification: The only assertion in this patent's history was by an operating biotech (Hyseq, Inc.) against its direct competitor Affymetrix, in the N.D. Cal. family litigation filed 1997 and settled October 2001 — i.e., the patent was a tool of operating-company competition, not NPE monetization. The sole recorded post-issuance transfer, recorded 2004-12-14, is a Security Agreement from Callida Genomics to Nuvelo and Affymetrix (an intra-group/partner financing instrument), not a transfer to a licensing shell, and it is the only such event before the patent expired fee-related, with anticipated expiration 2008-03-30. No shell-entity, known-asserter, cascading-transfer, fire-sale, privateering, or defensive-aggregator signal is present; the correspondent-recurrence signal is unverified because I could not pull correspondent data.

Verification: search patent number 6018041 at https://assignmentcenter.uspto.gov/ (or https://assignment.uspto.gov/patent/index.html) to confirm the Callida Genomics → Nuvelo/Affymetrix security-agreement reel/frame and to check for the unretrieved Hyseq → Callida link.


Open items a follow-up pull should close

  1. Reel/frame and correspondent for the 2004-12-14 security agreement (the one confirmed recorded link).
  2. Whether the Hyseq → Callida Genomics transfer (Event B) was ever formally recorded — if it was not, the recorded chain may read simply inventors → Hyseq, then Callida (as assignor) → Nuvelo/Affymetrix, an apparent break in the record of title.
  3. Identity of the purchaser of Callida Genomics / N-Mer on 2004-12-03, to establish whether any post-2004 owner of record exists.

Generated 9/30/2026, 3:22:17 PM

Prior art

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

✓ Generated

I'll research the prior art references cited in and against US 6,018,041. Let me run targeted searches.

Let me target the specific prior-art citation lists for this patent.

Let me try to retrieve the front-page references via alternate patent databases.

Scope note and method (read first)

You asked me to (a) search the USPTO database for the specific number 6018041, and (b) work through "each patent citation for 6018041," giving citation, date, description, and the claim(s) each might anticipate under § 102.

Two honesty constraints must be stated up front, per the operating rules:

  1. I could not retrieve the certified front‑page "References Cited" (U.S. Patent Documents) list for US 6,018,041 from an authoritative source in this session. My queries for the front‑page citation list returned only third‑party mirrors (Justia, uspto.report, everypatent) and unrelated documents. I did not obtain results directly from USPTO Patent Public Search / PatentCenter; the records I have are the full text supplied to me plus public mirrors, which are consistent on the bibliographic fields already reported in the prior section. I am not going to invent a citation list.

  2. The authoritative full text of US 6,018,041 (Google Patents) that I was given contains no "Patent Citations" subsection. It contains only forward‑looking sections: "Cited By (126)" and "Families Citing this family (589)." On Google Patents, when an "References Cited / Patent Citations" block exists it is rendered; its absence here is consistent with this patent's face carrying few or no U.S. patent documents in its "References Cited" list (plausible given a 1987 priority and a continuation filing whose examiner citations were largely the inventors' own earlier family members and non‑patent literature). I flag this as an inference, not a verified fact.

Identifier discipline: all statements below refer to US 6,018,041 (App. 08/902,167; priority YU 00570/87A, 1987‑04‑01; filed 1997‑07‑29; issued 2000‑01‑25). I have not conflated it with JP 6018041 (Siga Technologies/tecovirimat), nor with the many "′804 patent" hits in my search results (nCUBE v. SeaChange, Cisco/BillJCo IPR2022‑00426, Apple v. BillJCo, etc.).

Because the front‑page patent citations could not be verified, the § 102 analysis below is built on the prior art that the patent text itself identifies — the substantive, checkable references — plus the family members. I label each one's § 102 posture honestly.


A. The critical date and the § 102 frame

US 6,018,041 is a continuation of 08/461,106 → 08/045,912 → 07/723,712 → 07/175,088 (filed 1988‑03‑30), claiming priority to YU 00570/87A (1987‑04‑01).

  • If the claims are entitled to the 1987‑04‑01 priority (and the earlier provisional/foreign filing), prior art must predate that date.
  • Even taking the earliest U.S. filing (1988‑03‑30), the § 102(b) one‑year critical date is 1987‑03‑30.
  • Therefore the references actually cited in the specification (all 1977–1987) are the correct universe to examine, and any reference dated on or after April 1987 is generally not § 102 prior art unless priority is pierced (see § E).

B. References cited within the specification (the substantive prior art)

These are the references the applicants themselves identified in the "State of the Art" and body sections. For each: full citation, date, description, and § 102 exposure.

# Full citation Date What it discloses Claims it could arguably bear on / § 102 verdict
1 Maxam, A. M. & Gilbert, W., Proc. Natl. Acad. Sci. USA 74, 560 1977 Chemical‑degradation DNA sequencing (base‑specific cleavage). Background chemistry only. Does not disclose hybridization‑based sequencing or any probe set. No anticipation of claims 1, 9, 11, 16, 17, 18.
2 Sanger, F., et al., Proc. Natl. Acad. Sci. USA 74, 5463 1977 Dideoxy chain‑termination sequencing. Background only. No anticipation of any claim.
3 Wallace, R. B., et al., Nucleic Acids Res. 6, 3543–3557 1979 Hybridization conditions under which an oligonucleotide discriminates complete homology from a single‑base mismatch. This is the closest "premise" reference: it supports enablement of specific oligo hybridization, but discloses no overlapping/degenerate probe set and no sequence determination by probe overlap. No anticipation of claims 1, 9, 11, 16–18. Relevant only under § 103 as background.
4 Wood, W. I., et al., Proc. Natl. Acad. Sci. USA 82, 1585–1588 1985 Use of 3 M tetramethylammonium chloride so that T_m depends only on probe length, not GC content. Enabling teaching; no probe‑set architecture. No anticipation. Note: this reference is the technical basis for the GC‑balanced probe‑group design of claim 17, but a melting‑condition paper cannot anticipate a reagent set.
5 Al‑Hakim, A. H. & Hull, R., Nucleic Acids Res. 14, 9965–9976 (cited as "Al‑Hakin") 1986 Sensitivity of detection with (biotinylated) probes. Detection methodology only. No anticipation.
6 Lin Chao, S. & Bremer, L., Mol. Gen. Genet. 203, 150–153 1986 Plasmid copy number / amplification (pBR322, chloramphenicol). Vector‑copy‑number teaching for colony hybridization. No anticipation of any claim; supports § 112 enablement, not § 102.
7 Twigg, A. J., et al., Nature 283, 216–218 cited as 1987 pAT/pUC plasmid multiplication efficiency. Flag (literal, not auto‑corrected): the citation as printed reads "1987, Nature, 283, 216–218"; Nature volume 283 corresponds to 1980, so the printed year is internally inconsistent. Either way, plasmid biology only. No anticipation.
8 Research News, Science 232, 598–1599 (sic) 1986 Reports of discussions on sequencing the human genome. Policy/feasibility discussion. No technical probe disclosure. No anticipation.
9 Commentary, Nature 325, 771–772 1987 Japanese sequencing‑center capacity/cost figures. Economics/commentary. No anticipation.
10 Applicant's own Patent Application No. 5724, dated March 24, 1987 (the YU priority/co‑pending application) 1987‑03‑24 The applicants' own primer‑mixture amplification concept (cited for the whole‑genome amplification passage). Not prior art against the '041 — it is the applicants' own earlier application from which the '041 ultimately derives priority; applicants' own work cannot be § 102(a)/(b) prior art against a claim entitled to that filing. Not anticipatory.

Bottom line for Section B: None of the specification‑cited references discloses the claimed subject matter — a plurality of uniform‑length overlapping probes whose overlapping sequences, upon hybridization, determine a target sequence longer than a single probe. Every one of these references predates the claimed probe‑set concept and therefore none is a § 102 anticipation of independent claims 1, 9, 11, 16, 17, or 18. They are § 103 background at most.


C. Family members (same inventors, common priority)

Document Issued / filed § 102 status vs. the '041
YU 570/87 (priority document) 1987‑04‑01 Priority document; not prior art.
US App. 07/175,088 filed 1988‑03‑30 (abandoned) Parent; not prior art.
US 5,202,231 issued 1993‑04‑13 Same family/priority — not § 102(a)/(b)/(e) prior art to a continuation entitled to the same priority.
US 5,492,806 issued 1996 Same family; not prior art.
US 5,667,972 issued 1997‑09‑16 Immediate parent; not prior art.
US 6,451,996 issued 2002 Child continuation; postdates the '041; not prior art.

Key point (the only place § 102 could bite): these family members are disclosure‑identical to the '041. They become § 102 prior art only if a challenged claim of the '041 is not entitled to the 1987/1988 priority (i.e., if the claim lacks § 112 support in the parent), in which case the earlier‑issued US 5,202,231 (1993) could be § 102(b) prior art against that claim. This is a real vulnerability worth flagging, because of the numeric/scope anomalies noted in the earlier section — e.g.:

  • Claim 16 recites "65,356 subsets" (specification says 65,536 = 4⁸);
  • Claim 17 recites 23,044 N(N9)N subsets (arithmetic gives 23,040);
  • Claim 18 claims a genus n = 11–20, m = 5 to n, which is broader than the specific (N2)N8(N1) / N(N9)N / N(N10) sets emphasized in the 1988 disclosure.

If a court found any of these claims unsupported by the parent, US 5,202,231 and US 5,667,972 would move from "family" to "prior art," and their near‑identical disclosure would be a strong § 102 challenge. I state this as an analytical flag, not as an established fact.


D. Forward citations (patents citing US 6,018,041) — cannot anticipate

The Google Patents record shows 126 "Cited By" entries and 589 "Families Citing this family." Representative examples from the record supplied to me include US 6,261,776, US 6,310,189, US 6,329,140, US 6,434,316, US 6,355,432, US 6,379,895 (Affymetrix), US 5,700,637 / US 6,054,270 / US 7,811,751 (Oxford Gene Technology, from Southern's GB 8810400D0), and US 6,531,775 (Drmanac). By definition these postdate the '041's priority and publication, so none can be § 102 prior art. Their relevance is the reverse direction: they are the art that treats the '041 as background/prior art. I include them only to distinguish them from actual prior art.


E. Genuinely relevant art outside the patent's own citations (flagged as not-from-the-citation-list)

If priority were ever challenged, the following contemporaneous SBH disclosures (all after 1987‑04‑01) would matter — but as § 103, and only if the priority date were pierced; they are not § 102 art against claims entitled to the 1987 priority:

  • Southern, E. M., GB application 8810400.0 (filed 1988‑05‑03), later US 5,700,637 / US 6,054,270 — analyzing polynucleotide sequences by hybridization to arrays.
  • Lysov, Yu. P., et al., Dokl. Akad. Nauk SSSR (1988), and Bains, W. & Smith, G. C., J. Theor. Biol. (1988) — theoretical SBH algorithms.
  • US 5,503,980 / US 6,007,987 (Boston University, "positional sequencing by hybridization") and US 5,552,278 (Spectragen) — post‑date the '041's priority.

Caveat: I am reporting these from training knowledge; unlike Sections B–D I did not verify their full bibliographic details from an authoritative source in this session, so treat the exact volume/page data as unconfirmed.


F. Summary table of § 102 verdicts

Reference Date § 102 anticipation of the '041? Reasoning
Maxam & Gilbert 1977 1977 No Different sequencing chemistry.
Sanger et al. 1977 1977 No Different sequencing chemistry.
Wallace et al. 1979 1979 No Mismatch discrimination only; no probe‑set/overlap concept.
Wood et al. 1985 1985 No Melting‑temperature conditions only.
Al‑Hakim & Hull 1986 1986 No Detection sensitivity only.
Lin Chao & Bremer 1986 1986 No Plasmid copy number only.
Twigg et al. (printed 1987) 1987 (vol. 283 → 1980) No Plasmid biology; date inconsistency flagged.
Research News, Science 1986 1986 No Feasibility commentary.
Commentary, Nature 1987 1987 No Economics commentary.
Applicant's YU App. 5724 (1987‑03‑24) 1987 No Applicant's own priority application.
US 5,202,231 / 5,492,806 / 5,667,972 / 6,451,996 1993–2002 No (unless priority pierced) Same family/priority; disclosure‑identical.

Net conclusion: On the record available to me, no reference cited in US 6,018,041, and no patent citation retrievable for it, anticipates any of independent claims 1, 9, 11, 16, 17, or 18 under § 102. The '041's own cited art is either unrelated sequencing chemistry (Maxam‑Gilbert, Sanger), enabling hybridization/detection/vector methodology (Wallace, Wood, Al‑Hakim, Lin Chao, Twigg), or commentary. The only realistic § 102 exposure comes from the applicants' own earlier family members (US 5,202,231 et al.) if a claim's priority is successfully challenged — which hinges on the § 112 support questions raised by the claim‑number anomalies (65,356 vs. 65,536; 23,044 vs. 23,040; and the breadth of claim 18's genus), already flagged in the earlier section.


G. What I could not do (stated rather than fabricated)

  • I did not obtain the certified front‑page "References Cited" list for US 6,018,041 from USPTO PatentCenter/Patent Public Search. My searches for it returned only unrelated documents and third‑party mirrors.
  • I therefore cannot certify that the patent's face contains no U.S. patent‑document citations; I can only report that the authoritative full text I was given omits any "Patent Citations" block.
  • I found no § 102 reference that anticipates the '041, and I am not asserting that none exists — only that none appears in the sources I could retrieve.

Recommended verification step (not possible within this session's tooling): pull the certification copy of US 6,018,041, App. 08/902,167, from USPTO PatentCenter, and read the front‑page "(56) References Cited" block and the examiner's PTO‑892/Notice of Allowance in the file wrapper — that is the only authoritative way to enumerate the exact patent citations for this specific number.

Generated 9/30/2026, 3:22:15 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 analysis by checking what the "Prior Art" section of the record actually lists, and whether any invalidity/examiner citation history exists for this family.

Let me pull the examiner-cited prior art for the parent patent (same specification) and check the pre-1987 mixed-probe-pool art relevant to the degenerate-group claims.

Let me verify the pre-1987 data-assembly and colony/plaque-hybridization references that would supply the "computer assembly" and "subclone library" elements.

Obviousness Analysis — US 6,018,041 under 35 U.S.C. § 103

Scope note. I build on the earlier bibliographic, claim-mapping and litigation sections rather than repeating them. Two cross-checks against those sections are flagged in §7 below. All statements about the prior art are grounded in the documents located in this session; where I rely on general knowledge rather than a retrieved source, I say so.


1. Legal framework and the reference date (the controlling variable)

US 6,018,041 issued 25 Jan 2000 from App. 08/902,167, filed 29 Jul 1997. Because it was filed before 16 Mar 2013, pre‑AIA § 103 governs (obviousness judged from the perspective of a person having ordinary skill in the art — "PHOSITA" — at the time the invention was made, with no "obvious to try" expansion via post‑KSR law being mandatory for the original examination, though KSR now informs any hypothetical re-analysis today).

The reference date is the pivotal question, and there are three candidates:

Candidate date Basis Consequence
1 Apr 1987 Foreign priority, YU 00570/87A (per Google Patents family record) Only pre‑April‑1987 art counts. This is the date the patentee will assert.
30 Mar 1988 U.S. parent App. 07/175,088 (the abandoned first U.S. filing) Opens up art published Apr 1987–Mar 1988.
29 Jul 1997 Actual filing of 08/902,167, if a given claim lacks § 112 support in the 1987/1988 disclosure Opens up the entire 1988–1997 SBH literature — including the four independent groups the Nature Biotechnology article identifies as having described the concept 1988–1991 (https://www.nature.com/articles/nbt0597-406a.pdf).

I treat 1 Apr 1987 as the presumptive date for the primary analysis (§§2–6) and then show in §8 why the 1997 fallback is a real risk for the narrow probe-set claims.


2. What the "Prior Art" section of the record actually discloses

Read literally, the section headed "STATE OF THE ART / Prior Art" on the page grounds only four things:

  1. Recombinant DNA technology permits multiplication/isolation of genomic DNA fragments of 200–500 bp, giving enough material to sequence a cloned fragment.
  2. Maxam & Gilbert chemical degradation sequencing (Maxam, A.M. & Gilbert, W., 1977, Proc. Natl. Acad. Sci. 74:560) — gel-based, 1–500 bp, one-nucleotide resolution.
  3. Sanger dideoxy sequencing (Sanger, F. et al., 1977, PNAS 74:5463).
  4. The genome-sequencing problem statement: 4×10⁶ bp (E. coli) to 3×10⁹ bp (mammals); the "3 billion dollars / ten years / big organized centers" consensus (Research News, 1986, Science 232:598); and the Japanese center's ~1 million bp/day at ~17¢/bp (Nature 325:771‑772).

Neither independent reference is a § 103 primary reference for the claimed probe sets. They are motivation evidence: they establish (a) the long-felt, recognized need to sequence large genomes faster and cheaper than gels, and (b) that the art's entire sequencing paradigm was gel electrophoresis. Everything else in the document is the applicant's own disclosure.

Per the instruction to use this section, I note its most important analytical consequence: the admitted prior art contains no hybridization-based sequencing, no probe sets, and no computational assembly of hybridization data. Every § 103 ground below therefore has to bridge a gap from gel sequencing to SBH.


3. Third-party art with confirmed pre-1987 dates

These are the references the specification itself cites as known techniques — i.e., applicant-admitted prior art — plus one retrieved by search. All are pre-1 Apr 1987.

Ref Date Teaching URL
Wallace, Shaffer, Murphy, Bonner, Hirose & Itakura, NAR 6(11):3543‑3558 10 Aug 1979 11‑, 14‑ and 17‑base oligomers form duplexes with a single base-pair mismatch; a single mismatch depresses T_m ~10 °C, "making it possible to eliminate the formation of the mismatched duplexes by the appropriate choice of hybridization temperature"; expressly discussed "with respect to the use of oligonucleotides as probes for the isolation of specific cloned DNA sequences." https://pubmed.ncbi.nlm.nih.gov/[158748](/patent/158748)/
Wood, Gitschier, Lasky & Lawn, PNAS 82(6):1585‑1588 Mar 1985 Tetramethylammonium chloride makes melting "controlled as a function of probe length only," independent of base composition; "especially helpful whenever a highly complex library is screened with a pool of oligonucleotide probes, which usually vary widely in base composition." https://eurofarma.ovidds.com/resolver/full?rft...id=info%3adoi%2f10.1073%2fpnas.82.6.1585
Wallace, Johnson, Hirose, Miyake, Kawashima & Itakura, NAR 9(4):879‑894 25 Feb 1981 Synthesised a mixture of thirteen‑base oligonucleotides (RβG13Mix, representing 8 of the possible codings); the mixture "hybridize[d] specifically to globin DNA under conditions where oligonucleotides forming single base pair mismatches do not," and "hybridize[d] specifically to colonies containing a plasmid with a globin DNA insert." https://www.ncbi.xyz/pmc/articles/PMC326719/
Al-Hakim & Hull, NAR 14:9965‑9976 1986 (cited in the specification) sensitivity of labelled probes permitting ~10× fewer bacterial colonies cited at p. in the '041 specification
Staden, NAR 6(7):2601‑2610 11 Jun 1979 Computer programs (OVELAP/XMATCH) that search for overlaps between sequences from different clones and join them into longer sequences; "it is now possible to sequence whole genomes without the need of restriction maps." https://pubmed.ncbi.nlm.nih.gov/[461197](/patent/461197)/
Grunstein & Hogness, PNAS 72(10):3961‑3965 Oct 1975 Colony hybridization to isolate cloned DNAs containing a specific gene (general knowledge — I did not retrieve a primary copy this session) —
Southern, J. Mol. Biol. 98:503‑517 1975 Transfer/detect specific sequences on filters (general knowledge) —
Pörschke & Eigen, J. Mol. Biol. 62:361‑381 1971 "Co‑operative non‑enzymic base recognition" — contiguous/stacked short oligomers (I rely here on a citation-list string, not a retrieved primary copy; treat as lower confidence) —

Not prior art (flag, per the strict-identifier rule): Bains & Smith (J. Theor. Biol. 135:303‑307, 1988); Lysov et al. (1988); Khrapko et al. (1989); Pevzner (1989); Drmanac et al., Genomics 4:114‑128 (1989) and Science 260:1649‑1652 (1993); and Southern's GB 8810400 / EP 0 356 021 — filed 3 May 1988, after the 1987 priority and even after the Mar 1988 U.S. parent. That is why Hyseq and six other companies opposed the Southern EP patent (Nature Biotech, supra). None of these may be used against the 1987 date, but all become available if a claim's effective date slides to 1997 (§8).


4. Proposed § 103 grounds

Ground 1 — Claims 1, 2, 6, 9 and 18 (the "overlapping probe set / ordered probe group" genus)

Combination: Wallace 1979 + Wood 1985 + Staden 1979, in view of the genome-sequencing problem admitted in the specification's Prior Art section.

  • Wallace 1979 supplies the claim 1/9 core capability: 11‑mers (expressly, "11 … bases long") hybridize to a target and can be made to discriminate perfect complementarity from a single mismatch by temperature. Claim 2/6's "n is an integer from 11 to 20" is a straight read-off of Wallace's 11/14/17‑mers, and claim 9's "hybridizes to a completely complementary region" is Wallace's stated premise.
  • Wood 1985 supplies the uniformity condition that makes a panel of probes workable: with TMAC, stringency is a function of length only, so probes of differing GC content can be used as a set; Wood expressly contemplates "a pool of oligonucleotide probes" against a "highly complex library."
  • Staden 1979 supplies the assembly step — the conceded motivation that raw fragment data can be ordered by computational overlap detection into a longer, contiguous sequence. Claim 1's "the probe sequences or a subset of the probe sequences determine a sequence of the nucleic acid that is longer than n" and claim 9's "defines a contiguous stretch" are the probe-level analogue of Staden's OVELAP.
  • Claim 18's "group defined by a different predetermined subsequence of fixed length m … each group including all possible combinations of probes of length n having the same subsequence of length m" is the mathematical dual of Wood's pool: once one has decided to hybridize a pool whose members share a common core, enumerating "all possible" members across that core is routine combinatorial design, and the m‑1 overlap requirement follows arithmetically from the definition of a contiguous overlap.

Motivation to combine: the admitted prior-art section frames the unmet need (genome-scale sequencing at <17¢/bp and in <10 years); Wallace names the goal ("isolation of specific cloned DNA sequences") and provides the discrimination; Wood provides the pooled-probe/GC-independent stringency tool specifically for "highly complex gene libraries"; Staden provides the computational ordering already used for whole-genome projects. The structural link is direct: shorter probes = more of them = need for uniform stringency (Wood) and computational ordering (Staden).

Weakness (significant). No one reference — or any combination — teaches using an exhaustive or near-exhaustive panel of probes to deduce unknown sequence de novo. Wallace and Wallace 1981 use probes to find a sequence already known from protein data. This is the classic "obvious to try" gap, and it is exactly where a validity challenge would founder at the 1987 date.


Ground 2 — Claims 12, 13, 14, 15, 16, 17 (the enumerated probe-set/composition claims)

Combination: Wallace 1981 + Wood 1985 + Ground 1, optionally in view of standard phosphoramidite synthesis (Matteucci & Caruthers, JACS 103:3185‑3191, 1981; Beaucage & Caruthers, 1981) (general knowledge).

This is the strongest ground, because these claims recite essentially nothing but an arithmetic inventory once the SBH premise is conceded:

  • Claim 16/15 — "65,356 subsets … each … the complete set of 64 probes having the formula NN(N8)N … wherein the octanucleotide of each subset is unique." That is simply all 4⁸ octanucleotide cores, each with a fully degenerate 2‑base/1‑base flank. Wallace 1981 already taught that a mixture of oligonucleotides sharing a common core and differing outside it will hybridize specifically (RβG13Mix — 8 of the possible codings). Replacing "8 of the possible" with "all 64 of the possible, for each of 4⁸ cores" is (i) a finite, fully predictable set, (ii) derivable by hand arithmetic, and (iii) precisely the kind of "finite number of identified, predictable solutions" that KSR treats as obvious.
  • Claim 17 — the three-tier GC-balanced inventory (1,024 N(N10) all‑A/T; 23,044 N(N9)N with GC 1–2; 56,064 NN(N8)N with GC ≥ 3). The purpose of the tiering is exactly Wood 1985's problem statement: probes "vary widely in base composition," so stringency must be normalised. Wood's TMAC solves it by condition; claim 17 solves the same problem by redistributing probe length across GC classes — an equivalent, and in view of Wood, an obvious, alternative design choice.
  • Claims 13/14 are simple sub-combinations of the claim‑17 tiers.
  • Synthesis feasibility is not a bar: by 1985–87 automated phosphoramidite synthesis made thousands of defined oligomers routine.

Motivation: Wood 1985 identifies the GC-content/pool-stringency problem and offers a solution; a PHOSITA seeking a complete pooled-probe reagent inventory for a complex library would predictably normalise by GC class. No unexpected property is asserted in the specification for the specific counts as such; the specification presents them as the output of an arithmetic design exercise ("About 81,000 such ONP groups are necessary… The average value of their Ao… is about 30,000").

Weakness. The claims still carry the functional limitation that the set, upon hybridization, "determine[s] a sequence of the nucleic acid." If the functional language is treated as a capability inherent in the set (cf. In re Schreiber), Ground 2 survives; if it is treated as a required prior-art disclosure of actual sequencing, Ground 2 collapses back into Ground 1's gap. Expect the patentee to argue the latter, plus In re Deuel-type reasoning ("the prior art did not disclose these specific probe sequences").


Ground 3 — Claims 4, 10 and 11 (subclone = vector + insert; reading insert termini)

Combination: Grunstein & Hogness 1975 (colony hybridization of cloned inserts) + M13 cloning methodology (Messing; Sanger et al., 1980 — the specification itself concedes "M13 … allows easy cloning of DNA inserts from 100 to 7,000 bp") + Wallace 1979 (mismatch-discriminating 11‑mers) + the admitted need to "confirm the ends of inserts" (specification, p. describing the additional 2,048 ONPs of the N6(N5)/(N5)N6 type).

  • Claim 4's "subclone comprises a vector and an insert" is the universal state of cloning art (Grunstein & Hogness; M13/plasmid vectors).
  • Claim 10's N6(N5) / (N5)N6 probes ("N6 is the sequence of the terminal six nucleotides of a terminus of the vector, N5 is the complete set of 5‑mers") are fully determined by arithmetic once (a) the vector is chosen and (b) one decides to read outward from the vector–insert junction. The vector sequence is public; enumerating the 4⁵ = 1,024 possible 5‑mers is trivial; the specification itself states the count (2,048 ONPs = 1,024 × 2 orientations) as a design consequence.
  • Claim 11's "determine a terminal sequence of said insert" is precisely the purpose of vector-flanking probes, a well-known stratagem (M13 sequencing primers read out from the vector junction).

Motivation: reading the ends of an insert is an expressly recognized need in the art and in the patentee's own text; no new physical principle is required. This is the most defensibly obvious claim set in the patent.


Ground 4 — Claims 7 and 8 (target length 100–7,000 nucleotides)

The specification concedes this element as prior art: "This vector [M13] allows easy cloning of DNA inserts from 100 to 7,000 bp long." A claim to a probe plurality "wherein the nucleic acid is 100 to 7,000 nucleotides" adds nothing beyond the admitted cloning capacity of the admitted vector. § 103 rejection over the admitted art plus Ground 1 or Ground 3 would be close to unanswerable on the merits.


5. The motivation-to-combine showing, consolidated

A ROOT PHOSITA would be a molecular biologist with several years of cloning/sequencing experience and access to an oligo synthesis facility and sequencing-assembly software. The articulated motivations are:

  1. Recognized, unmet, quantified need — the Prior Art section itself quantifies the failure of the gel paradigm (3×10⁹ bp; 10 years; $3×10⁹; 10 centres). KSR "design incentive."
  2. The enabling tool was in hand — Wallace 1979 (11‑mers, mismatch discrimination) and Wood 1985 (length-only stringency, explicitly for probe pools on highly complex libraries) together remove the two objections (specificity; GC spread) that had kept short oligomers out of sequencing.
  3. The pooling precedent existed — Wallace 1981 shows a degenerate oligo mixture used against a clone library, including colony hybridization.
  4. The assembly tool existed — Staden 1979 shows computational overlap-joining of fragment sequences into whole genomes, and Staden explicitly ties it to the genome-scale ambition.
  5. The reagent supply was routine — automated phosphoramidite synthesis.
  6. Same field, same problem, same components — no field-of-use barrier; all references are in molecular biology/nucleic-acid analysis.

6. Counterarguments the patentee will (and should) press

  • Hindsight is severe here. The Nature Biotechnology commentary states that after the 1987 Yugoslav filing "the concept was described by no less than four other groups between 1988 and 1991 — all apparently independently" (https://www.nature.com/articles/nbt0597-406a.pdf). Simultaneous independent invention by four groups, plus the co-inventors' own later reduction-to-practice papers, is objective evidence that the concept was not, in fact, obvious to the art in 1987. Under WBIP v. Kohler that is probative evidence of non-obviousness. A serious § 103 challenge must distinguish this — but it cuts strongly for the patentee on the genus claims (1, 9, 18).
  • Teaching away / scepticism. The pre-1987 consensus was that 8‑mers "cannot form a stable hybrid" (the patent's own framing, echoing the art), and the 4×10⁶ synthesis burden of all 11‑mers was regarded as "impracticable." Art that treats a route as unworkable can support non-obviousness.
  • The claims do not fall with the specification. Ground 1's gap (no reference teaches de novo sequence deduction from a probe panel) is not cured by Staden 1979, which orders already-read gel sequences, not hybridization signals.
  • No single-reference § 103. There is no pre-1987 reference that discloses any one of claims 1, 9, 16, 17 or 18 in full, so every ground is a combination, increasing the motivation burden.

7. Cross-checks against the earlier sections (no contradiction found; two additions)

The earlier summary flagged two numerical anomalies. My independent arithmetic confirms and extends them:

Claim Recited Actual combinatorial count Verdict
12 56,064 subsets (NN(N8)N, GC ≥ 3) 65,536 − 256 − 2,048 − 7,168 = 56,064 recitation correct
13/17 23,044 subsets N(N9)N (GC = 1 or 2) C(9,1)·2·2⁸ + C(9,2)·4·2⁷ = 4,608 + 18,432 = 23,040 recitation off by 4
14/17 1,024 subsets N(N10), GC = 0 2¹⁰ = 1,024 correct
15/16 65,356 subsets 4⁸ = 65,536 recitation off by 180

Consistent with the earlier section: I report the claim text literally and do not auto-correct. For § 103 purposes this matters, because a rejection/support analysis that assumes the claim recites "65,536" is analysing a claim that was not granted (and, conversely, the granted 65,356-subset claim is not the complete set its specification describes — arguably a § 112 written-description problem rather than a § 103 one).

No contradiction with the litigation section: I likewise found no source naming US 6,018,041 itself as an asserted patent, so the § 103 questions above would be hypothetical — relevant to what the N.D. Cal. case would have turned on (Hyseq, Inc. v. Affymetrix, Inc., filed 4 Mar 1997; settled Oct 2001) had it reached judgment on the later-issued '041.


8. The priority-date exposure (the single biggest § 103 risk)

If any of claims 12–17 is not supported by the 1987 Yugoslav application or the 30 Mar 1988 U.S. parent — plausible, because the GC-tiered inventory (claim 17) reads as a refinement that the specification presents as a later design calculation, and because the counts recited in claims 13–17 do not match the specification's own figures — its effective date slides to 29 Jul 1997. That converts the following into prior art against those claims only:

  • Drmanac, R., Labat, I., Brukner, I. & Crkvenjakov, R., "Sequencing a Megabase Plus DNA by Hybridization: Theory of the Method," Genomics 4:114‑128 (1989) — the inventors' own publication, which (per uspto.report's listing for this patent) lays out the same probe-count algebra: https://uspto.report/patent/grant/[6018041](/patent/6018041)
  • Bains & Smith, J. Theor. Biol. 135:303‑307 (1988); Lysov et al. (1988); Khrapko et al. (1989); Pevzner (1989) — all listed in the reference lists retrieved above.
  • *Drmanac et al., Science 260:1649‑1652 (1993)* and *Strezoska et al., PNAS 88:10089‑10093 (1991)* — actual SBH working examples.
  • Southern's GB/EP filings (1988/1990) and later array art.

On that footing the narrow probe-set claims become very hard to sustain, because the whole genome-scale SBH framework — including probe counting, redundant/degenerate groups, and assembly — would be in the prior art in the same field by the same or adjacent inventors, and the remaining delta (which GC strata to assign to which core length) is an optimisation.


9. Bottom line

Claims § 103 vulnerability Strongest combination
7, 8 Very high Applicant's own M13 "100–7,000 bp" admission + Ground 1/3
10, 4, 11 High Grunstein & Hogness 1975 + M13 + Wallace 1979 + conceded need to confirm insert ends
12, 15, 16, 17, 13, 14 High if the effective date is 1997; Moderate at 1987 Wallace 1981 + Wood 1985 + Ground 1 (pooled/degenerate probes; GC normalisation)
1, 2, 6, 9, 18 Low–Moderate Wallace 1979 + Wood 1985 + Staden 1979 + admitted genome need
Whole patent at the 1987 date Low overall Hindsight objection + four independent 1988–1991 disclosures are strong objective non-obviousness evidence

Confidence and caveats. I have verified Wallace 1979, Wood 1985, Wallace 1981 and Staden 1979 from retrieved sources (URLs above). Grunstein & Hogness 1975, Southern 1975, Matteucci & Caruthers 1981 and Pörschke & Eigen 1971 are stated from general knowledge / from second-hand citation lists and should be verified against primary copies before being relied on in a written opinion. I did not locate the examiner's actual citation list or any § 103 rejection in the file history for US 6,018,041, and I did not retrieve the USPTO PatentCenter certified copy; the claim-text anomalies in §7 are therefore reported as they appear on the public record, and I flag rather than resolve them. Finally, since the patent's anticipated expiration was 30 Mar 2008 (per the Google Patents record), any present-day § 103 analysis is retrospective — its practical significance lies in what it would have meant for the 1997–2001 Hyseq v. Affymetrix dispute, not in any live 2026 controversy (consistent with the earlier section's finding that no current CAFC activity on this patent could be verified).

Generated 9/30/2026, 3:23:14 PM

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