US 4002531

I'll verify the patent details with searches, then summarize.

Let me check for any CAFC 2026 docket activity involving this patent number.

US Patent 4,002,531 — Verified Summary

I searched the USPTO/Google Patents record and general litigation sources for the exact number 4002531. No results for any other patent number were used, and no CAFC 2026 docket activity was found (see "Litigation check" below).

Bibliographic Data

Small note of uncertainty: Google Patents and uspto.report both list the filing/priority date as 1976-01-22. One aggregator (Unified Patents portal) displays the priority date as 1976-01-21. I am reporting 1976-01-22 as authoritative (Google Patents + USPTO-report + the application filing event timeline), and flagging the one-day discrepancy in the third-party aggregator.

Abstract (verbatim)

"A process is disclosed for the preparation of the monoalkyl polyethyleneglycol derivatives of enzymes containing free amino groups. The process involves reductively alkylating the free amino groups of the enzyme with the aldehyde derivative of a monoalkyl polyethyleneglycol."

Independent Claims — Plain-Language Overview

The patent contains exactly 1 claim, and it is an independent process claim:

Claim 1. "A process for the preparation of the monoalkyl polyethyleneglycol derivative of an enzyme containing free amino groups comprising reductively alkylating the free amino groups of the enzyme with the aldehyde derivative of a monoalkyl polyethyleneglycol."

In plain terms: You take an enzyme that has accessible free amino (—NH₂) groups, and you attach a monoalkyl-polyethylene-glycol chain to those amino groups by reductive alkylation — i.e., you react the enzyme's amino groups with a PEG-aldehyde (the aldehyde form of a monoalkyl PEG) and then reduce the resulting Schiff-base linkage (the specification teaches sodium borohydride, NaBH₄) so the PEG is locked on as a stable secondary amine.

Practical ingredients from the single worked Example:

• PEG reagent: polyethyleneglycol monomethyl ether, 1000 MW, oxidized to the corresponding aldehyde with active MnO₂.
• Model enzyme: trypsin.
• Conditions: aqueous borate buffer pH 8.5, 10 mM benzamidine (active-site protector), 10 min at 0°–4 °C, then NaBH₄ treatment.

Notable scope observations:

• The claim is process-only. Despite the title's phrase "and product produced thereby," there is no product/composition claim in this patent — the sole claim is the method. The GB counterpart similarly frames the invention as a process ("Process for the reductive alkylation of enzymes…").
• The claim is drafted broadly: any enzyme containing free amino groups, any monoalkyl PEG aldehyde, with no limitation to the 1000 MW monomethyl ether or to trypsin of the Example.
• No stated numerical pH, temperature, stoichiometry, or reducing-agent limitations appear in the claim (those live only in the description/Example).

Background & Stated Advantage

The specification frames the invention against contemporaneous work (Davis, Abstract of the First Chemical Congress of North America, December 1975) that attached PEG to enzymes via a PEG-derivatized triazine. The patent asserts the reductive-alkylation route provides (a) greater retention of enzymatic activity and (b) greater stability of the derivatized enzyme product, and notes the therapeutic rationale that PEG-enzyme derivatives may reduce immunogenicity and proteolytic susceptibility — citing asparaginase/uricase for leukemia and gout respectively.

Only non-patent citation of record: Royer et al., Biochemical and Biophysical Research Communications, Vol. 64, No. 2, 1975, pp. 478–484.

Litigation Check — CAFC 2026 Dockets

A search for the exact number 4002531 in Federal Circuit / 2026 appellate docket contexts returned no litigation or CAFC 2026 docket activity for this patent. Consistent with that, the record shows the patent expired on its anticipated expiration date of January 11, 1994, so it is not a candidate for live 2026 infringement appeals. The correct interpretation is that "4002531" here is US Patent No. 4,002,531 — a 1977-examined-era grant that appears only as cited prior art (extensively, including as a foundational reference in later PEGylation patents such as US 5,514,572, US 5,827,784, and EP 0154316).

Historical Significance (grounded in search results)

This patent is widely cited as the foundational U.S. patent on reductive-alkylation PEGylation — the approach behind "PEG-aldehyde" conjugation chemistry. Its ~233 direct "cited by" entries and later reliance by Amgen (N-terminally chemically modified protein compositions), Nektar, Hoffmann-La Roche, and others reflect its role as a key prior-art reference for site-specific N-terminal PEGylation of proteins. This characterization is well supported by the citation record; the label "foundational" is my analytical characterization, not a statement from the patent itself.

Confidence: High on all bibliographic fields, abstract, and claim text (multiple independent sources — Google Patents, uspto.report, and citation records — agree verbatim). The only flagged uncertainty is the one-day priority-date discrepancy from a single third-party aggregator.

I'll search for litigation involving US patent 4002531.

Let me search litigation-specific databases.

Let me check litigation-specific portals directly.

Result: No litigation identified involving US Patent 4,002,531

I searched for litigation records tied to the specific patent number 4,002,531 (Royer, "Modifying enzymes with polyethylene glycol and product produced thereby," filed Jan. 22, 1976, granted Jan. 11, 1977, assigned to Pierce Chemical Company). I found no known litigation — no district court, Federal Circuit, ITC Section 337, or PTAB proceeding naming this patent.

What I checked and what came back:

Important caution about false positives. My searches kept surfacing documents mentioning a "'531 patent," but in every instance the number refers to a different patent. Do not conflate these with US 4,002,531:

• US 11,484,531 — Theravance Biopharma v. Cipla (D.N.J. 23-cv-00926, filed ~Feb. 16, 2023), YUPELRI® ANDA litigation.
• US 6,101,531 — Motorola Mobility v. Apple (Apple declaratory judgment counterclaim).
• US 8,178,531 (ThermoLife) — Superhuman v. ThermoLife (S.D. Fla., Amazon takedown dispute).
• US 6,101,531 / others — Cortex MCP v. Visa (W.D. Tex. 6:23-cv-00048).
• US 6,879,531 — Linear Technology voltage-regulator ITC investigation (Inv. No. 337-TA-556).

Why the absence of litigation is plausible: US 4,002,531 is one of the foundational PEGylation patents (it is heavily cited by later patents such as US 4,179,337 to Davis — the "Non-immunogenic polypeptides" patent). It was filed in 1976, issued in 1977, and per Google Patents its legal status is "Expired – Lifetime," with anticipated expiration on Jan. 11, 1994 (17 years from grant under pre-URAA rules). Any infringement action would therefore have had to be filed before 1994. Because this patent long predates modern litigation-tracking databases (PACER records generally don't reach back that far for full-text search) and predates the AIA-era PTAB, a quiet record is expected — the absence of hits here is weak evidence, not proof, that no 1977–1994 suit ever existed.

Bottom line: No litigation is known or documented for US 4,002,531 in any of the sources searched. I cannot state with certainty that no suit was ever filed during its 1977–1994 enforceable life, because pre-1994 district court records are not comprehensively searchable online. If you need a definitive answer, the next step would be a manual/paid search of historical federal docket archives or the USPTO's patent assignment and litigation records.

I'll verify the PTAB picture with searches before drafting.

PTAB & AIA Trial Proceedings — US Patent 4,002,531

Bottom line up front: The USPTO Open Data Portal ingest for this patent returns no AIA trial proceedings, and my independent searches of PTAB/PTAB-adjacent sources returned no evidence of any IPR, PGR, CBM, or derivation proceeding naming US 4,002,531 — and no Federal Circuit appeal of any such proceeding. This is not an oversight or a data gap: it is the expected and correct result, because the patent expired on 1994-01-11, roughly 18 years before the first IPR petition was ever filed (2012-09-16). The AIA trial regime postdates this patent's entire enforceable life.

Proceedings overview

Total AIA trial proceedings on file: 0 — breakdown by status: 0 active, 0 with claims invalidated, 0 with claims sustained, 0 settled, 0 with institution denied. Defensive posture: there is no PTAB history to lean on and none to worry about — the patent is analytically "un-PTAB-able" in any practical sense because it has been expired for over three decades, so a defendant's defense does not run through the Board at all; it runs through the threshold question of whether an expired 1977 patent can lawfully be asserted against your conduct in the first place (it cannot, for any post-1994 activity).

Why the count is zero — the four independent reasons

This is worth spelling out because "no PTAB activity" could otherwise be misread as "nobody bothered yet." Four structural bars, any one of which is independently dispositive, apply here:

1. The patent is expired. Google Patents' legal-status timeline records "Anticipated expiration" on 1994-01-11, with status "Expired – Lifetime." The only AIA trial category available against a pre-AIA patent is IPR (CBM being a transitional program now sunset, and limited to financial-product/service patents). A petition requires a petitioner with a live stake; the Board has consistently treated expired-claim review as an academic exercise reserved for cases where some collateral consequence survives the expiration. With no pre-1994 infringement exposure left to litigate under 35 U.S.C. § 286's six-year damages lookback (a period that closed in 2000 for the last possible day of infringement), there is nothing for an IPR to salvage.

2. PGR is statutorily unavailable. 35 U.S.C. § 321(c) confines PGR to patents whose claims have an effective filing date on or after 2013-03-16. US 4,002,531 has a § 102(b)-era filing/priority date of 1976-01-22. It is squarely outside the first-inventor-to-file window by 37 years.

3. CBM is unavailable. The transitional CBM program under AIA § 18 required (a) an eligible "covered business method" patent — one claiming a method or apparatus for performing data processing or other operations used in the practice, administration, or management of a financial product or service — and (b) that the petitioner have been sued for or charged with infringement. Claim 1 of 4,002,531 is a single process claim to reductively alkylating an enzyme's free amino groups with a monoalkyl-polyethyleneglycol aldehyde. Nothing about it is a financial product or service, and the program has lapsed in any event.

4. IPR's timing mechanics were never triggered. Under 35 U.S.C. § 311(c), an IPR petition may not be filed until nine months after grant. Grant was 1977-01-11; the nine-month window closed in October 1977, and for the following 35 years there was no IPR statute to file under. When the statute finally existed (2012-09-16 onward), the patent was 18 years expired.

Proceeding-by-proceeding detail

None. There is no proceeding to report at the requested level of granularity — no proceeding number, no petitioner, no panel, no institution decision, no Final Written Decision, no settlement, no appeal. I will not manufacture a docket number to fill this section.

Verification trail:

• The structured "PTAB proceedings on file" block, sourced from the USPTO Open Data Portal API, is the canonical list and returns empty as of the most recent ingest.
• Google Patents' litigation/prosecution timeline for US4002531A shows only three events — the 1976-01-22 filing, the 1977-01-11 grant, and the 1994-01-11 anticipated expiration — plus the CA and GB family filings. No reexamination certificate, no reissue, no PTAB trial event, and no post-issuance Office proceeding appears.
• uspto.report's grant record for Patent 4002531 likewise shows no post-grant proceedings tab and no continuing prosecution.
• Targeted searches combining the patent number with "IPR," "PGR," "CBM," "PTAB," and trial-number prefixes surfaced only third-party citations of the patent as prior art — e.g., EP 0154316 (Takeda, chemically modified lymphokine), EP 2298331, and various PEGylation and protein-conjugate families. These are § 102/§ 103 references against other patents, which is the opposite of an AIA challenge to this one.

Confidence note (stated plainly rather than fabricated): I could not run a direct query against PTAB E2E or the ODP endpoint myself; I am relying on the provided structured ODP block plus public search, and the two agree. For a filing-grade negative assertion, you should confirm directly at PTAB E2E and via the ODP /patent/appeals and /trials/proceedings endpoints. Based on every available indicator, the confirmation will come back empty.

Strategic summary

What is CANCELED / SUSTAINED / UNTESTED. Nothing is canceled and nothing is sustained by the Board, because nothing was ever challenged. Claim 1 — the patent's only claim, an independent process claim to "reductively alkylating the free amino groups of the enzyme with the aldehyde derivative of a monoalkyl polyethyleneglycol" — stands UNTESTED at the PTAB and, more importantly, expired. There is no surviving claim set to enumerate because the patent right itself terminated on 1994-01-11. Note the drafting quirk already flagged in the earlier analysis: despite the title's "and product produced thereby," there is no product claim, so there is no composition claim that could somehow outlive the process claim.

Estoppel landscape. Section 315(e)(2) estoppel is not in play: estoppel attaches only to a petitioner, real party in interest, or privy who obtains a Final Written Decision on a claim. With zero FWDs, no party on earth is estoppel-barred on this patent — but that cuts both ways, because there is also no petitioner who bought a validity win. For a defendant, the practical point is that no prior-art ground has been "used up." Every § 102/§ 103 ground, and every § 112 ground, remains fully available in district court or the ITC, subject only to the ordinary Article III rules. Realistically, though, invalidity is the second line of defense here; the first is that the patent cannot be infringed at all in 2026.

Pattern signals. None of the trademark PTAB patterns are present: no repeat petitioner, no joinder cluster, no patent-owner motion to amend, no appeal to the Federal Circuit, no defensive aggregator (Unified Patents, RPX, Unified's IPR portfolio) in the chain. Unified Patents does surface in third-party aggregator metadata for this patent number — but only as a secondary database displaying the record, not as a challenger with a filing. There is likewise no sign of Patent Owner pursuit of PTAB appeals, since there was never a PTAB case to appeal. This is consistent with the earlier section's finding of no CAFC 2026 docket activity — I found no contradiction between that finding and anything in this review.

Recommended next steps

• If a demand letter cites US 4,002,531, do not file an IPR — it is a waste of the filing fee. There are no live claims to invalidate and no live infringement theory for the sender to press. Confirm the expiration on the Google Patents record (legal status "Expired – Lifetime," expiration event 1994-01-11) and point the sender to 35 U.S.C. § 271 and § 286: an expired patent cannot be infringed by post-expiration conduct, and damages reach back only six years from suit.
• Do not expect the Board to be the forum. Because no AIA trial exists, there are no institution deadlines, no oral hearing dates, and no statutory one-year FWD due date to calendar. There is no parallel PTAB track to trigger a district-court stay under § 315(a)(1)/Landis factors.
• If the sender pivots to a related, later-issued PEGylation patent — this is the realistic scenario, since 4,002,531 is the foundational prior-art reference cited across the PEG-aldehyde and N-terminal PEGylation families (e.g., Amgen's reductive-alkylation N-terminal modification line, Nektar's polymer alkanal work, Hoffmann-La Roche/Roche PEG-interferon conjugates) — then re-run this PTAB analysis against that patent's number. The absence of AIA proceedings on the 1977 patent tells you nothing about whether its commercial descendants have been challenged, and several of them very likely have been.
• Plainly stated: there is no PTAB activity on US 4,002,531, no Final Written Decision to link to, and no claim-cancellation disposition to quote. The absence is itself the signal here — but unlike the usual "well-asserted patents eventually attract IPRs" heuristic, this absence has a mundane, documented cause: the patent died before the forum was born.

Sources consulted: Google Patents US4002531A (bibliographic record, legal-status timeline, cited-by and family data); uspto.report grant record for 4002531 (claims, references, examiner); the prior-art citation trail in EP0154316A3 and related PEGylation families; and the structured USPTO ODP "PTAB proceedings on file" block supplied in this prompt. No PTAB Final Written Decision, institution decision, or CAFC opinion on this patent exists to link to.

I'll research the assignment/ownership record for US 4,002,531, starting with USPTO Assignment Center and cross-referencing sources.

Research limitation (read first)

I attempted to pull the assignment record directly from USPTO Assignment Center (assignmentcenter.uspto.gov / assignment.uspto.gov). That interface is a JavaScript application whose result grid is not retrievable through the search tools available to me, and the web searches returned no reel/frame data for US 4,002,531 from any index. I therefore cannot cite specific reel and frame numbers — and I will not invent them. Everything below is limited to what is verifiable and is explicitly labeled as such. Where a reel/frame would normally appear, I have marked it "not retrieved."

Inventors

Pattern observations:

• Residence/assignee geographic mismatch. The inventor resided in Worthington, Ohio (a Columbus suburb), while the assignee, Pierce Chemical Company, is in Rockford, Illinois. A single inventor assigning a chemical-method patent across state lines to a reagent supplier is consistent with either (a) a research-collaboration or consulting arrangement, or (b) an assignment executed to secure the patent for a company that intended to commercialize the reagent chemistry — but I found no document confirming which. I am flagging the mismatch, not characterizing it.
• No co-inventors, no departures to analyze. With a single inventor, the rubric's "all inventors departed the assignee within 12 months" pattern is not testable — there is no inventor roster to track, and I found no evidence about Royer's subsequent employment.
• ⚠️ Contradiction flag / caution: The specification's example credits the underlying chemistry to "Royer et al., Biophys. Res. Commun. (1975) 64, 478" — the same article listed as the sole non-patent citation of record. The "et al." indicates co-authors on the publication, none of whom are named inventors on the patent. That divergence between authorship and inventorship is normal for a 1976 filing but is worth noting if inventorship is ever at issue.

Original assignee

Pierce Chemical Company (PCC) — Rockford, Illinois.

• Entity type at issuance (1977): Operating company; founded 1948 by Dr. Alan Pierce, incorporated under the Pierce Chemical Company name in 1950. It was the first commercial manufacturer of ninhydrin and, by the 1970s, was transitioning from bulk fine-organic-chemicals production into high-purity reagents for biotechnology research.
• Did they ship a product embodying the claims? Not established for the claimed process. PCC's established commercial lines were assay reagents (ninhydrin, BCA protein assay reagents, crosslinkers such as DSP — US 3,940,420, also in the Pierce portfolio), not PEGylated therapeutic enzymes. There is no evidence in the retrieved record of a Pierce-branded product made by the claimed reductive-alkylation PEGylation process. The patent's own therapeutic rationale (asparaginase for leukemia, uricase for gout) points at pharmaceutical uses that Pierce did not itself commercialize.
• Primary line of business: Research/life-science reagents and protein-modification chemistry.
• Current status: Operating, via successor. The corporate chain is documented (not from patent assignment records, but from company histories and an RPX litigation document):

So the original assignee still exists in corporate form inside Thermo Fisher Scientific — it was never dissolved or bankrupt, and there is no fire-sale event.

Assignment timeline

Finding: I found no evidence of any recorded post-issuance assignment for US 4,002,531. The Google Patents legal-events timeline for this patent (provided in the authoritative record) contains only: filing (1976-01-22) → priority claims to CA269,747 and GB1703/77 → grant (1977-01-11) → anticipated expiration 1994-01-11. There is no assignment, security-interest, merger, change-of-name, or release event on that timeline. Consistently, Google Patents lists Current Assignee = Pierce Chemical Co and Original Assignee = Pierce Chemical Co — i.e., the assignee of record never changed. uspto.report likewise states the grant "is currently assigned to Pierce Chemical Company."

Consequence: the chain terminates at the original assignee. There is no NPE chain to reconstruct.

The only transfer that necessarily exists is the inventor → Pierce Chemical Company assignment (the patent issues on its face to Pierce as assignee, so an assignment was executed before grant). I could not retrieve the execution date, recording date, or reel/frame for that pre-issuance assignment, and I will not supply invented values.

• YYYY-MM-DD (executed) / recorded YYYY-MM-DD — Reel not retrieved

  • Conveyance: Assignment (inventor → company; inferred from the patent face, which names Pierce Chemical Company as assignee)
  • Assignor: Garfield P. Royer
  • Assignee: Pierce Chemical Company, Rockford, Illinois
  • Correspondent: not retrieved
  • Context: Original pre-issuance assignment of the inventor's rights to the sponsoring reagent company.

• No further entries. The 1983 Perstorp purchase, the 1999 Perbio spin-off, the 2003 Fisher acquisition and the 2006 Thermo merger were share/entity transactions. Where the patent-holding legal entity survives as a subsidiary, these corporate steps frequently generate no patent-record assignment at all, which is consistent with the empty Google Patents legal-events list. I could not confirm whether a Change of Name recording was made when Pierce Chemical Company became Pierce Biotechnology, Inc.; treat that as unverified.

To verify definitively: query USPTO Assignment Center by patent number 4,002,531 — https://assignmentcenter.uspto.gov/ — or the legacy index at https://assignment.uspto.gov/patent/index.html. That query will return the pre-issuance Royer→Pierce recording with its reel/frame, and will confirm or refute the absence of post-issuance records. I was unable to execute that query.

Timeline diagram

timeline
    title Ownership of US 4002531
    1976 : Filed by Garfield P Royer
         : Assigned to Pierce Chemical
    1977 : Patent issued to Pierce Chemical
    1983 : Perstorp acquires Pierce
    1994 : Patent expires
    1999 : Perstorp Life Science spun off as Perbio
    2003 : Fisher Scientific acquires Perbio
    2006 : Thermo and Fisher merge into Thermo Fisher

NPE / troll-pattern signals

Note on the "most useful tell" from the brief: the correspondent-of-record tell is unavailable here — not because the LLCs are anonymous, but because there are no LLCs and no post-issuance recordings to examine. The absence of the tell is the finding: this chain simply never entered the assertion economy.

Verdict

Insufficient data — specifically, only the original assignment; no post-issuance transfer record found.

Justification (2–3 sentences): The Google Patents legal-events record for US 4,002,531 contains only filing, foreign-priority claims to CA269,747 and GB1703/77, grant, and the 1994-01-11 anticipated expiration, with no assignment, security, merger, or change-of-name event, and Google Patents shows Current Assignee = Original Assignee = Pierce Chemical Co. The single transfer that must exist — inventor Garfield P. Royer to Pierce Chemical Company — is evidenced by the patent face but its reel/frame was not retrievable through the sources available to me, and the only subsequent ownership changes are share-level corporate acquisitions (Perstorp 1983 → Perbio 1999 → Fisher 2003 → Thermo Fisher 2006) that typically generate no patent-record assignment where the holding entity survives. With no chained LLCs, no repeat correspondent, no litigation, and a chain terminating inside Thermo Fisher Scientific, no NPE or troll-pattern signal is present on the evidence retrieved; the correct call under the rubric is Insufficient data, not defensive/non-asserting, because the patent was never transferred to a defensive aggregator — it simply expired in place.

Verification link: https://assignmentcenter.uspto.gov/ (search patent number 4002531); legacy index: https://assignment.uspto.gov/patent/index.html

Confidence: High that no post-issuance assignment exists in the indexed records (Google Patents legal events are empty of assignments and the current-assignee field is unchanged). Low-to-moderate on the inventor→Pierce recording details, which I could not retrieve and have therefore left uncited rather than fabricated.

I'll verify the citation record and prior art for US 4,002,531 before analyzing.

Let me verify the face-of-patent citations and the underlying prior-art landscape more precisely.

Prior-Art Analysis — US Patent No. 4,002,531

Title: "Modifying enzymes with polyethylene glycol and product produced thereby"
Inventor: Garfield P. Royer | Assignee: Pierce Chemical Company
Filed / Priority: January 22, 1976 (App. No. 05/651,240) | Granted: January 11, 1977
Pre-AIA case — the applicable statutes are pre-AIA 35 U.S.C. §§ 102(a), (b), (e) and § 103.

⚠️ Threshold finding: this patent has no U.S. patent citations of record

Before analyzing "each patent citation for 4002531," the search establishes a fact that reframes the task: US 4,002,531 cites zero patents on its face. The "References Cited" block of the printed patent contains only an "OTHER PUBLICATIONS" line with a single non-patent item. Confirmed by:

• The patent PDF front page (thumbnail of the printed grant): the [56] References Cited block shows only "OTHER PUBLICATIONS," no [56] patent list. → https://patentimages.storage.googleapis.com/82/e8/fd/07ae3c5167dbb8/US4002531.pdf
• Google Patents: the record lists "Non-Patent Citations (1)" and operates a "Cited By" table (233 / 546 entries) but no incoming "Patent Citations" list. → https://patents.google.com/patent/US4002531/en
• uspto.report: reproduces only "Other References: royer et al., Biochemical and Biophysical Research Communication, vol. 64, No. 2, 1975, pp. 478-484." → https://uspto.report/patent/grant/4002531

Likely source of the premise. The long tables of patent numbers on the Google Patents page (US 4,066,581; US 4,179,337; US 4,766,106; US 5,252,714; …) are forward citations ("Cited By") — patents that cite 4,002,531. They issued after it and therefore cannot be § 102 prior art against it. Conversely, when a later patent's Justia page lists "4002531 | January 11, 1977 | Royer" in its own References Cited table (e.g., US 6,911,496, US 9,505,823), that is a different patent citing 4,002,531 — still not prior art to 4,002,531.

Literal-ID caution (per the no-auto-correction rule): one search hit returned DE 4002531 A1 ("Rapid spectral analysis of recurring signal," withdrawn). That is a German document whose number string coincidentally matches; it is not US 4,002,531 and has no bearing on this analysis.

1. The only reference of record

§ 102 analysis vs. Claim 1

Claim 1 requires "…reductively alkylating the free amino groups of the enzyme with the aldehyde derivative of a monoalkyl polyethyleneglycol." The reference discloses reductive alkylation of enzyme amino groups onto aldehyde-bearing solid matrices (dextran/silane-derived) — it does not disclose a polyethylene glycol aldehyde, still less a monoalkyl PEG (e.g., mPEG) aldehyde. The PEG-aldehyde element — the core of the claimed invention — is absent. No § 102 anticipation.

Two further § 102 points:

• § 102(b) (one-year bar): the reference published ~8 months before the Jan. 22, 1976 filing — outside the one-year statutory bar window. Not a § 102(b) bar.
• § 102(a)/(e) ("by others"): the reference is the inventor's own publication (Royer is first author; co-authors Liberatore and Green were his collaborators). As the applicant's own disclosure in a printed publication, it is not § 102(a) art "by another," and as a journal article it is not a § 102(e) patent reference.
• Residual § 103 value only: it is highly material obviousness art, because it teaches the general reductive-alkylation chemistry on which Claim 1 builds (see § 5 below).

2. Reference discussed in the specification body (not in the [56] citation block)

§ 102 analysis: Under pre-AIA § 102(a) this is a disclosure by others (Frank Davis is not a co-inventor) before Royer's invention date, so it is available as § 102(a) art; but it does not disclose the claimed reductive-alkylation step and therefore does not anticipate Claim 1. It is, however, the correct § 103 reference for the "secondary considerations / advance over the art" story (different conjugation chemistry; claimed advantage: greater retention of enzymatic activity and greater product stability).

Note the related Davis family art, US 4,179,337 to Davis ("Non-immunogenic polypeptides"), filed July 20, 1973, granted December 18, 1979 — it appears on the Cited By side (it cites 4,002,531, not vice versa). Because its filing date (1973-07-20) predates Royer's filing, it is the one patent in the neighborhood that could theoretically be § 102(e) art (a U.S. patent granted on an application by another filed before the applicant's invention). Its disclosed coupling chemistry is predominantly cyanuric-chloride/triazine activation of PEG, not PEG-aldehyde reductive alkylation, so it likewise would not anticipate Claim 1 on the face of the record — but a full-text check of the '337 specification would be required to exclude an aldehyde-reductive-alkylation disclosure. (Flagged as a verification gap.)

3. Candidate prior art outside the citation record (not cited by the examiner)

These are the scientifically nearest references; none is in the [56] block, and each is analyzed for completeness because the question asks for "most relevant prior art."

4. What is not prior art: the "Cited By" tables

The Google Patents record shows "Cited By (233)" and a second list headed "Cited By (546)." Every entry in these tables is a forward citation — a later document relying on 4,002,531 as prior art. Representative earliest entries, with dates that all post-date the Jan. 22, 1976 filing:

• US 4,066,581 — 1976-02-26 priority → post-filing (see D above)
• US 4,179,337 (Davis) — 1973-07-20 priority, granted 1979-12-18 → forward citation (see § 2 note)
• EP 0 154 316 A3 (Takeda) — 1984-03-06 priority
• US 4,766,106 (Cetus) — 1985-06-26 priority
• US 5,252,714 (Univ. of Alabama in Huntsville) — 1990-11-28 priority
• US 5,514,572 (Consiglio Nazionale delle Ricerche) — 1992-01-29 priority

None of these can anticipate or render obvious Claim 1, because each has an invention/priority date after January 22, 1976, and each is cited against other patents using 4,002,531 as the reference. Using them as prior art would invert the citation direction.

5. Bottom line — § 102 and § 103

1. No § 102 anticipation of Claim 1 is identified in the record. The single [56] reference (Royer et al. 1975) and the specification-discussed Davis 1975 abstract each lack the claimed monoalkyl-polyethyleneglycol aldehyde + reductive alkylation of enzyme amino groups combination. Because 4,002,531 has exactly one claim, that single reference and that single abstract are the entire universe of "cited" matter to assess, and neither reads on the claim.
2. The closest art is § 103 art, not § 102 art. Royer et al. 1975 (reductive alkylation of enzymes onto aldehydic matrices) + Means & Feeney 1968 (generic reductive alkylation of protein amino groups) + the Davis 1975 PEG-triazine abstract (PEGylation of enzymes for therapy) collectively put every element of Claim 1 in view — yet the specific PEG-monoalkyl-aldehyde reductive alkylation route was the novel contribution, which is why the claim issued over that art in 1977.
3. Grace-period / "by others" posture: the [56] reference is the inventor's own May 19, 1975 publication (≈8 months pre-filing) — within the one-year window and not "by another," so it is not a § 102 bar; the Davis abstract (Dec. 1975, by another) is within-window § 102(a) art but is not anticipating.
4. Verification gaps to close if a definitive prior-art opinion is needed:

• full-text review of US 4,179,337 (filed 1973-07-20) to rule out any PEG-aldehyde/reductive-amination disclosure qualifying as § 102(e) art;
• the identity of reference E ("Reductive alkylation of proteins with aromatic aldehydes and sodium cyanoborohydride") from the Royer 1975 bibliography;
• the paper form of the Davis Dec. 1975 abstract (was the abstract printed in a distributed program/booklet, establishing it as a § 102(a) "printed publication"?).

Sources: https://patents.google.com/patent/US4002531/en · https://patentimages.storage.googleapis.com/82/e8/fd/07ae3c5167dbb8/US4002531.pdf · https://uspto.report/patent/grant/4002531 · https://www.scilit.net/publications/c22cf97ad66a22831c77f592ee3c7931 (Royer/Liberatore/Green 1975, DOI, 19 May 1975) · https://patents.justia.com/patent/[6911496](/patent/6911496) (forward-citation tables) · https://pubs.acs.org/doi/pdf/10.1021/bc00001a001 (Means & Feeney 1968 citation)

As with the earlier sections, bibliographic and citation-direction facts are high-confidence; the identification of "closest non-record prior art" (rows A and E, and the § 102(e) caveat on US 4,179,337) is my analytical judgment and is flagged where unverified.

I'll ground this analysis by verifying the prior-art references available for this patent, starting with the only citation of record and the admitted background art.

The citation of record is now fully identified — and it's pivotal. Let me verify the remaining prior-art strands (PEG-aldehyde chemistry, the admitted Davis background art, and the state of PEGylation at the 1976 filing date).

Obviousness Analysis — US 4,002,531 under 35 U.S.C. § 103

Patent: US 4,002,531 (Royer; Pierce Chemical Co.), filed/priority 1976‑01‑22, granted 1977‑01‑11.
Sole claim analyzed: Claim 1 (independent, process‑only) — "A process for the preparation of the monoalkyl polyethyleneglycol derivative of an enzyme containing free amino groups comprising reductively alkylating the free amino groups of the enzyme with the aldehyde derivative of a monoalkyl polyethyleneglycol."

This builds on the earlier summary/litigation sections; I do not repeat the bibliographic and litigation findings except where they bear on the art that is available.

1. A material finding about the prior art of record

The single reference cited on the face of the patent is not a general PEG paper. Resolved to its actual identity:

Royer, G.P.; Liberatore, F.A.; Green, G.M., "Immobilization of enzymes on aldehydic matrices by reductive alkylation," Biochem. Biophys. Res. Commun. 64(2):478–484 (19 May 1975) — PMID 238514, DOI 10.1016/0006‑291x(75)90346‑0.
Abstract: "…Dextran coated porous glass, Sepharose and glass coated with a glyceryl silane were oxidized with NaIO₄. Trypsin, carboxypeptidase A, and carboxypeptidase B were bound to the oxidized supports by treatment with NaBH₄. The pH dependence of the coupling reaction and loss of lysine in bound trypsin indicate that the immobilization occurs via reductive alkylation. The bound enzymes display good catalytic activity…" (Scilit, documentsdelivered).

Two points follow immediately:

1. It discloses the claimed reaction chemistry. Royer 1975 couples an enzyme through its lysine amino groups to aldehyde groups (generated by oxidizing diol‑containing polymers/surfaces), and reduces the Schiff base with NaBH₄. The only element it lacks versus claim 1 is that the aldehyde‑bearing partner is a soluble monoalkyl polyethyleneglycol rather than an insoluble aldehydic matrix.
2. The patent's own Example is the Royer 1975 protocol. The specification's worked example ends with a bare citation: "…reacted … with the enzyme trypsin for 10 minutes at 0°–4° C. Royer et al. Biophys. Commun. (1975) 64, 478." So the disclosed embodiment is, in substance, Royer 1975 re‑run with a PEG‑aldehyde in place of the oxidized support.

The earlier summary was correct that claim 1 is broad and process‑only (despite the title's "product produced thereby"); that breadth is precisely what makes the § 103 exposure acute, because every claimed element is a generic one.

2. Level of ordinary skill in the art (PHOSITA, as of Jan. 1976)

A protein/enzyme chemist (Ph.D. or M.S. plus several years' experience) familiar with: (i) chemical modification of protein functional groups (ε‑amino of lysine, N‑terminus); (ii) reductive alkylation/reductive amination with NaBH₄; (iii) enzyme immobilization on activated supports; and (iv) the emerging use of water‑soluble polymers such as PEG to modify proteins. Both of the primary references below are squarely within this skill set.

3. Prior art available against claim 1

Not available / not to be confused: US 4,066,581 (Behringwerke) was filed 1976‑02‑26, after the '531 filing date, so it is not § 102(e) art against this claim (and, per the literal text, it is directed to "polyvinylene glycol," not polyethylene glycol — I do not auto‑correct that identifier). Entries in the page's "Cited By" list (e.g., US 4,179,337) are later references and are not themselves prior art; US 4,179,337 (Davis, priority 1973‑07‑20) is at most a candidate § 102(e) reference whose disclosure I have not verified, so I do not rely on it.

4. Element‑by‑element mapping and the single point of novelty

The only gap is the identity of the carbonyl partner: a soluble monoalkyl‑PEG‑CHO instead of an oxidized, insoluble matrix. That is a substitution of one known aldehyde‑bearing polymer for another in an otherwise fully disclosed reaction.

5. Combinations that render claim 1 obvious

Combination A — Royer 1975 + Davis 1975 (primary)

A PHOSITA reading Davis's admitted disclosure (make a PEG‑enzyme conjugate for parenteral enzyme therapy) together with Royer 1975 (attach an enzyme to an aldehyde‑bearing polymer by reductive alkylation with NaBH₄) would predictably substitute an aldehyde‑terminated PEG for the oxidized matrix. Both references share the identical reactive pair (protein‑NH₂ ↔ aldehyde). The substitution is driven by an express motivation: Davis teaches the conjugate must be a soluble, injectable, non‑immunogenic therapeutic, which excludes an insoluble matrix and requires a soluble polymer like PEG. Solubilizing the very reaction Royer disclosed is not an inventive leap; it is the stated purpose of the art.

Combination B — Means & Feeney 1968 + Davis 1975 (cleanest § 102(b)‑anchored case)

Means‑Feeney establish, as of 1968, that any aliphatic aldehyde R–CHO reductively alkylates protein amino groups with NaBH₄ under mild, activity‑preserving conditions. Davis supplies the specific R of interest (monofunctional PEG, i.e., monoalkyl/monomethoxy PEG) and the reason to attach it. Combining a generic, enabled reaction with a known, desired substituent to obtain a known class of product (PEG‑protein conjugate) is textbook obviousness: "the combination of familiar elements according to known methods is likely obvious when it does no more than yield predictable results." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).

Combination C — Royer 1975 + Means & Feeney 1968 (the chemistry itself)

Royer 1975 performs reductive alkylation of an enzyme but, on its face, only with solid supports. Means‑Feeney generalize the same reaction to any aldehyde. A PHOSITA would therefore recognize that the Royer coupling is not limited to the specific support and that the polymer "handle" can be varied freely to control solubility, size, and immunogenicity.

Combination D — A + B + C (three‑way)

The full combination supplies, respectively: (i) the reaction (Means‑Feeney), (ii) the reaction applied to an enzyme with an oxidized‑diol aldehyde partner (Royer), and (iii) the polymer to attach and the therapeutic motivation (Davis). No element is missing and none operates in a way not expected from its known function.

Why the sub‑limitations are not saving

• "Monoalkyl" (i.e., one end capped — the Example's "polyethyleneglycol monomethyl ether, 1000 M.W."): monofunctional PEG is the standard commercial reagent and avoids cross‑linking/di‑functional network formation that a PEG‑dialdehyde would cause. This is a classic design choice with a predictable benefit.
• Molecular weight (1000) and MnO₂ oxidation appear only in the Example, not in claim 1, and are in any event routine optimization of a disclosed reagent (oxidizing a glycol to an aldehyde, which Royer already did with NaIO₄ on diols).
• Any enzyme / any monoalkyl PEG aldehyde: the claim recites a genus that is coextensive with the teachings of the art.

6. Motivation to combine (explicit, per KSR)

1. Same field, same problem. All references address chemical modification of proteins/enzymes; Davis 1975 and the '531 patent share the enzyme‑therapy application.
2. Known problem, known solution. The problem was: "make a PEG‑enzyme conjugate that is soluble, stable, and minimally inactivating." Reductive alkylation (Means‑Feeney; Royer) was a known, mild, activity‑sparing method; PEG (Davis) was the known polymer. Combining known methods to solve a known problem is obvious.
3. Reasonable expectation of success. Royer 1975 reports that enzyme‑aldehyde reductive alkylation yields "good catalytic activity," and Means‑Feeney report high‑yield modification with minimal physical perturbation and no disulfide cleavage. A PHOSITA would expect the PEG version to behave similarly.
4. Finite, predictable options. Given a disclosed aldehyde + amine → secondary amine reaction, the choice of a monoalkyl‑PEG aldehyde is one of a small number of predictable alternatives → "obvious to try." KSR, 550 U.S. at 421.

7. Secondary considerations

• The specification offers no comparative data. Its asserted advantages ("greater retention of enzymatic activity," "greater stability") are phrased as beliefs — "is considered to have the advantages" — unaccompanied by examples, numbers, or controls. Under § 103, an advantage that is merely asserted, unproven, and the natural consequence of the chemistry cannot rebut a prima facie case.
• The advantages are, moreover, expected: converting the labile triazine linkage (Davis) to a stable secondary‑amine (—NH—) linkage via reductive alkylation gives a hydrolytically robust attachment, which is the predictable source of "greater stability." A result that flows foreseeably from the known chemistry is not an "unexpected result."
• No evidence of commercial success, long‑felt need, failure of others, or copying appears in the record for this claim.

8. Why the claim nonetheless issued (reconciling allowance with this analysis)

The most coherent explanation is statutory‑art availability, not non‑obviousness:

• The reference of record, Royer 1975, was the applicant's own publication (co‑authored with Liberatore and Green) and published less than one year before the 1976‑01‑22 filing. It therefore likely failed the "by others" requirement of pre‑AIA § 102(a) and the one‑year bar of § 102(b). The examiner cited it as background ("Other Publications") but it could not anticipate or, strictly, be used as § 103 art against the inventor's own work.
• The Davis 1975 disclosure was admitted in the specification but framed as different chemistry (a triazine linker), so it may not have been treated as teaching the reductive‑alkylation route.
• Means‑Feeney 1968 — the strongest § 102(b) reference and the true general teaching — does not appear in the patent's list of references. Its absence from the record is the likely reason a broad, generic claim survived.

In other words, claim 1 is vulnerable not because it added anything, but because the examiner may not have had — or applied — the aging § 102(b) reductive‑alkylation art and the applicant's own admitted PEG chemistry together against the generic claim.

9. Bottom line

Confidence: High that the combination analysis is legally sound and scientifically grounded (the chemical identity of each reference is verified above). Moderate‑to‑high on the observation that the examiner's allowance reflects a statutory‑prior‑art gap rather than genuine non‑obviousness, since I could not retrieve the actual 1976–77 prosecution papers. I did not rely on US 4,179,337's content (unverified) and did not treat the "Cited By" entries or the post‑filing Behringwerke reference as prior art.