US 3252973

I'll run a few targeted searches to check for any current USPTO or CAFC activity, then summarize from the authoritative patent text provided.

Search results / provenance

• USPTO / Google Patents record: https://patents.google.com/patent/[US3252973](/patent/US3252973)/en
• Full-text PDF (USPTO scan): https://patentimages.storage.googleapis.com/91/0d/1f/362c54ba195d7a/US3252973.pdf
• CAFC 2026 dockets: My searches returned no Court of Appeals for the Federal Circuit docket or 2026 litigation involving US 3,252,973. This is expected: the patent's term expired May 24, 1983 ("Expired – Lifetime"), so it cannot be asserted now. Uncertainty note: I could not query an authenticated PACER/CAFC docket system; my searches were web-based. I found no indication of any proceeding, but I cannot rule out a purely historical docket entry.

Bibliographic summary (from the authoritative patent text)

Abstract: This patent has no formal abstract — US patents of this era were not required to include one. The closest thing in the disclosure is the "Definitions" entry, which defines inert solvents as those that will not interact with the reactants so as to prevent or substantially interfere with formation of the desired penicillin or cephalosporin. The operative technical gist is stated in the specification: the desired reaction of a penicillin nucleus or cephalosporin nucleus with a monocarboxylic acid affording the desired carbacyl radical "is carried out by commingling a carbodiimide compound with the nucleus in an aqueous inert mutual solvent in the presence of at least one equivalent proportion of the monocarboxylic acid or a salt thereof."

Field: Semisynthetic β-lactam antibiotic manufacture. The disclosure positions the invention against (a) fermentation (which had produced only cephalosporin C among cephalosporins, and many penicillins not at all) and (b) prior acylation of the 6-aminopenicillanic acid (6-APA) or 7-aminocephalosporanic acid (7-ACA) nucleus with acid halides or anhydrides, which requires harsh acid conditions and is unusable where the acyl group is unstable as a halide.

Plain-language overview of the claims

Independent claims: 1, 2, 3, and 7. (Claims 4–6 depend on claim 3; claims 8–10 depend on claim 7.)

Claim 1 — the broad genus. A method of making an antibiotic that is either a penicillin or a cephalosporin, by:

1. dissolving 6-aminopenicillanic acid (6-APA) or 7-aminocephalosporanic acid (7-ACA) together with at least about an equimolar amount of the monocarboxylic acid whose acyl group corresponds to the side chain you want on the final antibiotic, in an aqueous, inert mutual solvent;
2. adding a solution of a carbodiimide in at least equimolar amount relative to the nucleus, where the carbodiimide has the structure R–N=C=N–R′ with R and R′ being aliphatic, cycloaliphatic, or phenyl groups (or substituted forms bearing amino, alkylamino, dialkylamino, phenyl, pyridyl, pyrimidyl, piperidyl, pyrryl, pyrrolidyl, or morpholinyl substituents);
3. letting the nucleus and the acid react to form the antibiotic; and
4. recovering the antibiotic from the reaction mixture.
   Plain version: put the bare penicillin/cephalosporin nucleus and a free carboxylic acid in water-miscible solvent, then add a carbodiimide dehydrating agent to couple them into the amide — no acid chloride needed.

Claim 2 — the aqueous carbodiimide variant. Same process as claim 1, but the carbodiimide must be a water-soluble carbodiimide and is added as an aqueous solution. (The specification defines soluble as > about 0.1% by weight, preferably > about 1%.)

Claim 3 — the penicillin species. A method of making a penicillin compound: dissolve 6-APA plus at least an equimolar amount of a monocarboxylic acid in an aqueous inert mutual solvent, add a carbodiimide solution (same R/R′ definition and stoichiometry as claim 1), react the two to form an N-carbacyl-6-aminopenicillanic acid, and recover it.

Claim 4 — limits claim 3's solvent to a water/dioxane mixture.
Claim 5 — limits claim 3's carbodiimide to N,N′-dicyclohexylcarbodiimide (DCC).
Claim 6 — limits claim 3's reaction to a pH between about 5 and about 8.

Claim 7 — the cephalosporin species. The parallel process for cephalosporins: 7-ACA plus at least an equimolar amount of a monocarboxylic acid in an aqueous inert mutual solvent, plus a carbodiimide solution as defined, to form an N-carbacyl-7-aminocephalosporanic acid, which is then recovered.

Claim 8 — limits claim 7's solvent to water/dioxane.
Claim 9 — limits claim 7's carbodiimide to DCC.
Claim 10 — limits claim 7's reaction to pH about 5 to about 8.

Practical/technical notes worth flagging

• Addition order is taught as critical in Example 1. Premixing nucleus + phenoxyacetic acid and then adding DCC gave ~400 penicillin G units/mL of penicillin V. Adding DCC to the nucleus first and the acid last gave only ~12 units/mL (essentially no penicillin V); adding the acid to DCC first and the nucleus last gave ~73 units/mL. Only the claim-1 sequence (nucleus + acid, then carbodiimide) is exemplified as effective — an inherency point for any later validity analysis.
• Working examples cover penicillin V, t-butyl penicillin (trimethylacetic acid), styryl penicillin (cinnamic acid), phenyl penicillin (benzoic acid), N-(3-indolepropionyl)-6-APA, N-hippuryl-6-APA, N-(N-acetylglycyl)-6-APA, N-phenylglycyl-6-APA, phenylmercaptomethyl penicillin (phenylmercaptoacetic acid), penicillin V with three different carbodiimides, and 7-(2′-thienyl)acetamidocephalosporanic acid (Example 13, cephalosporin nucleus).
• Disclosed utility/advantages: avoids strongly acidic halide routes, works with acids that are unstable as halides or at elevated temperature, widens access to products fermentation could not provide, and uses more readily available acids.

Explicit uncertainty flags

1. No formal abstract exists for this patent; the summary above is my synthesis of the specification, not a verbatim source document.
2. The OCR of the granted text garbles the carbon-number subscripts in the R/R′ definitions ("C –C aliphatic groups, C –C cycloaliphatic groups"). The specification's narrative version of the same definition is likewise subscript-garbled. Based on the enumerated radicals (methyl through dodecyl; cyclopropyl through cycloheptyl; plus phenyl), the intended ranges are C₁–C₁₂ aliphatic and C₃–C₇ cycloaliphatic, but I am flagging this as a reconstruction, not a verbatim reading.
3. Google Patents renders "Claims (1)" in its metadata, which is inconsistent with the ten claims actually appearing in the grant. The full text (claim numbering 1–10 with the dependency structure described above) is authoritative; I treat the "(1)" as a rendering artifact.
4. No CAFC 2026 docket activity was found, and none is legally possible given the 1983 expiry; I did not have PACER-level access to confirm this exhaustively.

I'll research litigation involving US Patent 3,252,973.

Let me run additional targeted searches to confirm.

Bottom line

No litigation involving U.S. Patent 3,252,973 is known or identifiable. I found no district court case, Federal Circuit/CCPA appeal, ITC investigation, PTAB/IPR/PGR proceeding, or pre-AIA interference that names US 3,252,973 as a patent-in-suit or as the subject of a validity challenge.

What the patent actually is (so the negative finding is anchored correctly)

• US 3,252,973, "Acylation via carbodiimides for penicillin and cephalosporin preparation," inventor Edwin H. Flynn, assignee Eli Lilly and Company (Indianapolis, Ind.).
• Application No. 229,231, filed October 8, 1962; granted May 24, 1966; 10 claims.
• Google Patents records the legal status as "Expired – Lifetime," with an anticipated expiration of May 24, 1983 (17-year pre-URAA term from issue). Source: https://patents.google.com/patent/US3252973/en
• The disclosed/claimed subject matter is a process for acylating 6‑aminopenicillanic acid or 7‑aminocephalosporanic acid with a monocarboxylic acid in the presence of a carbodiimide (claim 1), with dependent claims reciting water/dioxane solvent (claims 4, 8), N,N′‑dicyclohexylcarbodiimide (claims 5, 9), and pH 5–8 (claims 6, 10).

Because the patent issued in 1966 and expired in 1983, any infringement action would have had to be filed in that window — well before modern patent-litigation databases (Unified Patents portal, Docket Alarm, CourtListener/RECAP, Lex Machina) have reliable coverage.

Searches run and why the results are negative

I ran targeted searches on the literal number 3,252,973 / 3252973 and on litigation databases. Every substantive hit was for a different patent that is colloquially called "the '973 patent" — a very common shorthand. None of these involve US 3,252,973:

• Warsaw Orthopedic, Inc. v. NuVasive, Inc. (S.D. Cal. 3:08-cv-01512; Fed. Cir. 2013-1576/1577) — "the '973 patent" there is US 5,860,973 (spinal implants). CourtListener dockets 4190790 and 3069699.
• Medtronic Sofamor Danek USA, Inc. v. NuVasive, Inc. (S.D. Cal.) — again US 5,860,973 and related continuations-in-part.
• Pharmacia, Inc. v. Frigitronics, Inc. / Med‑Chem hyaluronic acid decisions — a different '973 (ultrapure hyaluronic acid, priority around Oct. 17, 1974). Source: BLR 1082 summary at journals.sagepub.com.
• Duplan Corp. v. Deering Milliken, Inc. — a Chavanoz-owned '973 concerning cellulose acetate yarn shrinkage.
• Infosint, S.A. v. H. Lundbeck A/S, 612 F. Supp. 2d 405 (S.D.N.Y. 2009) — a different '973.
• Illumina, Inc. v. BGI Genomics (N.D. Cal. 3:20-cv-01465) and Neurent Medical v. Aerin Medical — the '973 patents there are US 9,970,055‑family and US 12,096,973 respectively.
• The bare string "3252973" also surfaces non-patent hits: an Indian trade-mark application number and a SEC EDGAR accession for Ascendis Pharma. Neither is patent litigation.

Additionally, US 3,252,973 appears in the "Cited By" list of Google Patents — 13 later publications, including US 3,518,260 (Eli Lilly), US 3,490,033-type Lilly filings, EP 0 349 296 A3 (Ajinomoto), and various Yeda/Kureha cephalosporin patents. These are prior-art citations made during prosecution of later applications, not litigation. Likewise, the "Citations (5)" list (US 3,040,033; US 3,120,514; US 3,142,673; US 3,159,617; US 3,174,964) is examiner-cited prior art.

Caveats and how to verify definitively

1. I could not directly load a Unified Patents litigation caselist page for 3252973 (the portal is organized by patent number at https://portal.unifiedpatents.com/litigation/caselist?patents=3252973); my searches did not surface any caselist entry, but I am flagging that I did not retrieve that page's contents directly.
2. Pre-1983 federal district court patent suits are often not indexed in modern databases. A conclusive check for a 1966–1983 suit would require a Westlaw/Lexis full-text search of the Federal Supplement and Federal Reporter for "3,252,973" or "3,252,933" (typo variants) and Eli Lilly as plaintiff, plus the USPTO Patent Assignment and litigation-history records.
3. Google Patents, which is the authoritative text I was given, lists no "Litigation" section for this patent. On Google Patents, actively litigated patents generally show a "Litigation" tab; its absence is consistent with the negative finding.
4. I am not aware of any USPTO interference involving this patent, and I state that as a lack of knowledge rather than a confirmed negative.

Conclusion: Based on all searches performed, there is no known litigation involving US Patent 3,252,973. I cannot certify that no suit was ever filed during its 1966–1983 enforceability window, because reliable coverage of that era is incomplete — but nothing in the available record shows one.

I'll verify PTAB activity before reporting.

Proceedings overview

Total AIA trial proceedings on US 3,252,973: 0. Breakdown: 0 active / 0 claims invalidated / 0 claims sustained / 0 settled / 0 institution denials. The USPTO Open Data Portal returns no AIA trial proceedings, and independent searches of PTAB petition files and Federal Circuit/CourtListener material surfaced none. The defensive posture this gives a defendant is not "hardened patent" and not "claims canceled" — it is "expired patent, no PTAB docket, and no possible PTAB docket." US 3,252,973 issued 1966-05-24 with a 17-year term from grant under pre-URAA law, and its anticipated expiration is recorded as 1983-05-24 — roughly 29 years before the AIA's IPR/PGR/CBM provisions took effect on 2012-09-16. Any demand letter citing this patent number as a live, enforceable right is baseless on its face.

No proceeding numbers to report

Per the operating rule against fabricating identifiers, I am listing no ### IPR20xx-xxxxx entries, because none exist. Supplying plausible-looking numbers here would be the single most damaging error I could make in this analysis.

Why the docket is empty (and not merely "not yet found")

1. The AIA trial regime post-dates the patent by three decades. Inter partes review, post-grant review, and CBM review were created by the Leahy–Smith America Invents Act (Pub. L. 112-29) and became available for petitions on 2012-09-16. US 3,252,973 was already 46 years old and 29 years expired on that date. Nothing in the file history, the Google Patents "Cited By" list (13 later documents, all ordinary patent citations — e.g., US3340257 Fujisawa, US3518260 Eli Lilly), or the PTAB petition corpus indicates any petition was ever filed.

2. The prior post-grant vehicles did not reach it either.

• Ex parte reexamination (created 1980, effective 1981-07-01) potentially overlapped the last ~2 years of the patent's term, but I found no reexamination certificate for US 3,252,973 and no reexamination proceeding on record. Do not assume one exists.
• Inter partes reexamination (1999) applies only to patents issuing from applications filed on or after 1999-11-29. This application was filed 1962-10-08, so it was categorically ineligible.
• CBM review was limited to covered business methods and is now sunset; irrelevant to a 1962 antibiotic-process patent regardless.

3. Expired patents are not categorically outside PTAB jurisdiction — the Board has held it retains jurisdiction over expired claims (Sony Corp. v. Iancu, 924 F.3d 1235 (Fed. Cir. 2019); Wasica Fin. GmbH v. Cont'l Auto. Sys., 853 F.3d 1272 (Fed. Cir. 2017)), and expired claims are construed under Phillips rather than BRI. So the correct statement is not "the PTAB lacked power over this patent." The correct statement is: no one has ever filed, and there is no live controversy that would justify filing. A patent that expired 1983-05-24 cannot support infringement damages — 35 U.S.C. § 286 caps recovery at six years before suit — so there is no past-infringement exposure to litigate and no reason to spend IPR fees on a dead right.

4. Key dates, for the record:

5. What the patent actually covers (relevant if you are evaluating a demand letter's technical story): a process for acylating the penicillin or cephalosporin nucleus — 6-aminopenicillanic acid (6-APA) or 7-aminocephalosporanic acid (7-ACA) — with a monocarboxylic acid in an aqueous inert mutual solvent in the presence of a carbodiimide. Claims 1–2 are genus claims to penicillins and cephalosporins generally; claims 3–6 are penicillin-specific (claim 4 = water/dioxane solvent; claim 5 = N,N'-dicyclohexylcarbodiimide; claim 6 = pH about 5–8); claims 7–10 are the cephalosporin counterparts. The examiner cited US 3,040,033 (Celmer), US 3,120,514 (Doyle), US 3,142,673 (Hobbs), US 3,159,617 (Sheehan), and US 3,174,964 (Hobbs). All of that is now decades-old public-domain chemistry.

Strategic summary

Claim status. There is no PTAB claim-level disposition to report — no claim of US 3,252,973 was ever canceled or sustained in an AIA trial, because no trial occurred. Claims 1–10 all lapsed together on 1983-05-24 when the statutory term ran out. Nothing was narrowed by IPR; nothing was upheld by IPR. The entire claim set is expired and unenforceable, not merely "narrowed."

Estoppel landscape. Section 315(e)(2) estoppel is inapplicable — it attaches to a petitioner who filed an IPR that reached a final written decision, and there is no such petitioner and no such decision. Practically, this means two things for a defendant today: (a) there is no IPR-derived estoppel binding anyone, but (b) there is also no IPR record to lean on, so if you find yourself needing to attack the claims, you cannot point to a Board ruling. You also do not need to. The real doctrinal point is the opposite of estoppel: an expired patent's disclosure is prior art available to the public, and the specification of US 3,252,973 — carbodiimide-mediated acylation of 6-APA and 7-ACA in aqueous cosolvent — became free for anyone to practice on 1983-05-24. If a current patent is being asserted against you in this space, US 3,252,973 is a § 102/§ 103 reference, not a threat.

Pattern signals. None of the usual signals are present: no repeat petitioner (no petitioner at all), no patent-owner appellate activity (no FWD, hence no Federal Circuit appeal, hence no CourtListener or CAFC docket number to cite), and no defensive aggregator such as Unified Patents in the chain. The patent's only recorded owner is the original assignee, Eli Lilly and Company (Indianapolis, Indiana); inventor Edwin H. Flynn. There is no assignment activity suggesting a troll acquisition, and a 1966 Lilly patent would be a strange asset for an NPE to acquire — unless the point is to impress a target with an authentic-looking patent number rather than to assert a real right.

One caution worth flagging. Demand letters that cite a patent-number family containing "973" frequently turn out to reference a different, live patent — the searchable corpus is thick with unrelated '973 patents (e.g., US 7,434,973; US 12,096,973; US 8,484,973 types). I cannot confirm from the record which patent any particular letter cites, but if you receive one naming "3,252,973," verify the number on the face of the letter against USPTO Patent Center before doing anything else. A demand built on an expired 1966 patent is either a clerical error or an intent-to-mislead problem, and both are worth documenting.

Recommended next steps

If you are a defendant and a demand letter cites US 3,252,973:

• Pull the face of the patent at Google Patents or Patent Center and note the expiration entry: 1983-05-24. There is no FWD to quote because there is none — your disposition authority is the patent's own term, not a Board ruling. State in your response letter that the patent expired 1983-05-24, that no reissue, reexamination certificate, or term extension of record extends it, and that 35 U.S.C. § 286 forecloses any damages theory.
• Preserve the letter and any accompanying claim-chart for a potential § 285 exceptional-case argument or an unfair-competition / state-law claim if the assertion is repeated after notice of expiration.

If you are evaluating a licensing or investment opportunity built on this patent: there is no asset. Zero remaining term, zero PTAB history, zero enforceable claims for a defendant to buy peace from.

If, contrary to the ODP ingest, you find a proceeding: PTAB petitions and institution decisions are public at PTAB E2E and the USPTO PTAB Decisions page; Federal Circuit dispositions are on CourtListener. Report the real docket number, and I will re-run this analysis against it. Do not accept a proceeding number from any source that cannot be matched to a PTAB E2E docket — for a patent that expired in 1983, a claimed IPR on file would be a strong indicator that the underlying document is fabricated.

Bottom line: No PTAB activity exists on US 3,252,973, none ever has, and — given a 1983-05-24 expiration and no live damages window — none is reasonably foreseeable. Treat the patent as prior art and as public-domain chemistry, not as a litigation risk.

I'll try to pull the assignment record directly from the USPTO sources before writing up the analysis.

Let me try a few more targeted queries against the assignment databases and Lilly's corporate history.

Summary of what I could and could not retrieve

I ran targeted queries against the USPTO assignment sources and cross-referenced Google Patents legal events and secondary hosts. I was unable to retrieve an Assignment Center record (reel/frame) for US 3,252,973 directly. The searches returned unrelated Lilly recordings (e.g., a modern Lilly employment assignment at reel 050008/0483, and a 2007 § 3.73(b) certificate citing reel 014132/0597 for a different Lilly application), which I am expressly not attributing to this patent. I am flagging the retrieval gap rather than filling it.

What I can state is grounded in the authoritative patent text you provided.

Inventors

• Sole inventor. No joint inventors appear on the grant.
• The "assignor to" recitation on the printed front page establishes that Flynn had already assigned his rights to Lilly at or before filing — the classic employment-agreement pre-filing assignment, not a post-issuance transfer.
• Departure pattern: not assessable. The 12-month inventor-departure tell you asked me to flag requires employment records I do not have and did not find. A sole in-house Lilly chemist of the 1962 vintage, assigning pre-filing to his employer, is the standard operating-company pattern, not the pre-fire-sale pattern. I have no evidence of any departure, and I am not inferring one.
• Name-alias caution: the many "Flynn et al." references in later pharma patents (e.g., the Vertex/Amgen-era US 2004/0171075, US 11,576,903 citation lists) are to Richard M. Flynn and others — different inventors. Do not merge them into this chain. I am treating "Edwin H. Flynn" as a single, non-recurring name in the record available to me.

Original assignee

• Entity on the issued patent: Eli Lilly and Company, Indianapolis, Indiana, a corporation of Indiana. Original and current assignee of record are the same per Google Patents (https://patents.google.com/patent/US3252973/en).
• Primary line of business: research-based pharmaceutical manufacturing. Lilly is one of the oldest continuously operating US drug manufacturers (founded 1876).
• Did they ship a product embodying the claims? Yes, demonstrably. Claim 3/claim 5 cover N-carbacyl-6-APA made with DCC; the specification's Example 1 and Examples 10–12 produce penicillin V via this route, and Example 13 produces 7-(2′-thienyl)acetamidocephalosporanic acid — i.e., cephalothin, which Lilly commercialized (Keflin). The strongest internal corroboration is the "Cited By" list in the record you supplied: US 3,488,729, "Cephalothin ester," filed 1966-08-22, assigned to Lilly — a Lilly follow-on filing that cites this patent as prior art. That is a Lilly line-of-business continuity signal, not an NPE signal.
• Current status: Operating, publicly traded, not acquired, not in bankruptcy. NYSE: LLY. This is not a "dissolved assignor" scenario.

Assignment timeline

Plain finding: I located no recorded post-issuance assignment for US 3,252,973. Google Patents' legal-events list for this patent contains only: application filed by Eli Lilly and Co (1962-10-08), priority to US229231A, application granted (1966-05-24), publication of US3252973A (1966-05-24), and anticipated expiration (1983-05-24). There is no "Assignment" legal event, and Google Patents shows no Litigation tab or assignee change.

The only transfer in the chain is the intrinsic pre-filing assignment from Edwin H. Flynn to Eli Lilly and Company, evidenced on the face of the grant. I could not retrieve its recording reel/frame, execution date, or correspondent of record, and I will not invent them.

Per your protocol, a patent with no Assignment Center post-issuance records is itself the finding: the original assignee (Lilly) retained ownership through expiry on 1983-05-24. The downstream sections below are therefore populated only to the extent assessable, and I have marked the unassessable ones as such rather than manufacturing a chain.

Timeline diagram

The diagram is necessarily near-empty, because there is only one ownership step on record:

timeline
    title Ownership of US 3252973
    1962 : Filed by Edwin H Flynn
         : Assigned to Eli Lilly and Company
    1966 : Patent issued with 10 claims
    1983 : Term expired

NPE / troll-pattern signals

Verdict

Insufficient data — but with a substantive affirmative component.

There is no recorded post-issuance assignment chain for US 3,252,973. The only transfer is the intrinsic pre-filing assignment from Edwin H. Flynn to Eli Lilly and Company (face of the grant; application 229,231, filed 1962-10-08, issued 1966-05-24, expired 1983-05-24). Google Patents lists Lilly as both original and current assignee and shows no assignment legal event, no assignee change, and no litigation. Lilly is an operating pharmaceutical manufacturer that demonstrably practiced the disclosed chemistry (penicillin V per Examples 1 and 10–12; cephalothin chemistry per Example 13, corroborated by Lilly's own US 3,488,729 "Cephalothin ester" citing this patent).

Because the chain consists of a single employment assignment to a solvent, product-shipping operating company, no NPE or patent-troll signal is present where assessable. The verdict is stated as "insufficient data" rather than negative-of-NPE purely because I could not load the Assignment Center record itself to confirm the absence of unreported recordings.

Verification link: https://assignmentcenter.uspto.gov/ (search patent number 3252973); mirror at https://assignment.uspto.gov/patent/index.html. Google Patents corroboration: https://patents.google.com/patent/US3252973/en

Residual uncertainty: (a) I could not retrieve the reel/frame or correspondent for the intrinsic 1962 assignment, and pre-1970s recordings are often indexed only by reel/frame, not by patent number; (b) I could not directly load the Assignment Center result page, so the negative finding rests on the Google Patents legal-events list plus negative search results. A conclusive check would be a full-text search of the USPTO Patent Assignment Search by patent number and by assignor "Flynn, Edwin H." for the 1962–1966 window.

I'll research the USPTO record for US 3,252,973 and each of its cited patent references.

Prior-Art Analysis — US 3,252,973

Analyst's note on the constraint: I could not directly load an authenticated USPTO Patent Public Search / PatentCenter session. The bibliographic record below is the one reproduced for US 3,252,973 (Application Number 229,231, Filed 1962-10-08, Patented 1966-05-24) at https://patents.google.com/patent/US3252973/en and in the USPTO full-text PDF at https://patentimages.storage.googleapis.com/91/0d/1f/362c54ba195d7a/US3252973.pdf. I treat those as the USPTO record and did not substitute any similar-number result. Where I could not retrieve a reference's own disclosure text, I say so explicitly rather than paraphrasing from memory.

1. Confirming the target record (literal number, no substitutions)

Critical date for § 102 purposes: Because the application was filed October 8, 1962 and claims no earlier priority, the pre-AIA 35 U.S.C. § 102(b) one-year bar date is October 8, 1961. Pre-AIA law governs (pre-AIA § 102/§ 103 apply to applications filed before March 16, 2013).

2. The complete examiner-cited reference set

The grant prints two reference categories: "References Cited by the Examiner — UNITED STATES PATENTS" (five items) and "OTHER REFERENCES" (four items). I address all nine. I also flag a distinction: the Google Patents "Cited By (13)" list (US 3,518,260, US 3,348,729, EP 0 349 296 A3, the Yeda/Kureha cephalosporins, etc.) is a forward citation list — those are later documents that cited US 3,252,973 as prior art. They are not prior art against US 3,252,973 and are excluded from the § 102 analysis below.

3. The five United States patents cited by the examiner

3.1 US 3,040,033 — "New penicillins"

3.2 US 3,120,514 — "Aminoalkylpenicillins"

3.3 US 3,142,673 — "Derivatives of 6-aminopenicillanic acid"

3.4 US 3,159,617 — "Production of penicillins" — the most relevant reference

3.5 US 3,174,964 — "Derivatives of 6-aminopenicillanic acid"

4. The four "Other References"

5. Claim-by-claim § 102 exposure summary

Ranking of the cited references by relevance to US 3,252,973:

1. US 3,159,617 (Sheehan / Arthur D. Little) — the nearest prior art, because it is the carbodiimide-and-6-APA disclosure; this is the reference any § 102 challenge would have to start from, and it still misses the aqueous mutual solvent and the intermolecular free-acid acylation.
2. Sheehan, J. Org. Chem. 21, 439–441 (1956) and the Sheehan JACS paper — the enabling carbodiimide-coupling NPL, but pre-6-APA-nucleus chemistry.
3. US 3,142,673 and US 3,174,964 (Hobbs / Pfizer) — 6-APA acylation, but by acid derivatives in base, not by carbodiimides.
4. US 3,120,514 (Doyle & Smith / Beecham) — 6-APA-derived aminoalkylpenicillins.
5. US 3,040,033 (Celmer / Pfizer) — new penicillins; least relevant.
6. Eynde (1964) and Morton (1946) — not § 102 anticipatory art at all (the first appears date-anomalous; the second is a preface).

6. Why the negative result is structurally sound (and not just an artifact of my searches)

Two independent structural reasons support the "no anticipation" conclusion rather than leaving it as an absence of evidence:

1. All five US patents were examiner-cited ("References Cited by the Examiner," US 3,252,973 front page), and the application nevertheless issued with ten claims on May 24, 1966. Each was therefore considered and found to lack an element.
2. The specification itself distinguishes the art. US 3,252,973 frames the prior art as "acylation of the nucleus with the appropriate carboxyl halide or anhydride" and claims mild, aqueous, carbodiimide-driven coupling of a free monocarboxylic acid. The cited Pfizer and Beecham patents are squarely the acid-halide/base school; the Sheehan references are the carbodiimide school but in anhydrous media and, as to the nucleus, via intramolecular ring closure or acid-chloride acylation. Neither school, on the record, contains the claimed combination.

Example 1 addition-order evidence: In US 3,252,973, premixing nucleus + phenoxyacetic acid then adding DCC gave ~400 penicillin G units/mL of penicillin V, whereas adding DCC to the nucleus first gave ~12 units/mL and adding acid to DCC first gave ~73 units/mL. Any § 102 theory built on a reference that merely "reacted 6-APA with an acid and a carbodiimide" would still have to reckon with the claimed sequence (nucleus + acid first, then carbodiimide solution), which only claim 1 as exemplified establishes.

7. Explicit uncertainty flags

1. Database provenance. I did not open an authenticated USPTO Patent Public Search / PatentCenter session; the record above is the USPTO front-page/Google Patents rendering of US 3,252,973. I am not certifying a live USPTO legal-status field beyond "Expired – Lifetime (anticipated expiration May 24, 1983)."
2. Not retrieved in full: the specifications of US 3,040,033 and US 3,174,964. Their entries above are title/class/family-level descriptions, not disclosure readings.
3. Highest-priority verification item: US 3,159,617. I confirmed from the Sheehan memoir that it granted Dec. 1, 1964 on Ser. No. 810,231, filed May 1, 1959, and that dicyclohexylcarbodiimide is named in its description; I did not read its claims. A complete read is required before the "no anticipation" finding on claims 1/3/5 can be called final.
4. Sheehan JACS item date is unknown from the granted OCR (page numbers blank). Without the year I cannot resolve whether it is § 102(b) (≤ Oct. 8, 1961) or only § 102(a).
5. Sheehan J. Org. Chem. 21, 439–441 (1956) title not retrieved; my characterization of its subject matter is a reconstruction from author/journal/year, not a verified reading of the article.
6. US 3,120,514 date conflict (1958-10-06 priority vs. Ser. No. 223,255 filed 1962-09-12) is unresolved. Under either date it is § 102(e) art, but the discrepancy should be resolved from the granted front page.
7. Eynde citation anomaly: the printed citation ("Industria Chimique Belge 29(1), pp. 1-522 (1964)") is inconsistent with both the Oct. 8, 1962 filing date and normal pagination; I treat it as a citation/OCR defect and do not rely on it.
8. Legal framework: Under pre-AIA § 102 (correct for this filing), § 102(e) reaches a US patent "granted on an application for patent by another filed in the United States before the invention thereof by the applicant." I have assumed the § 102(e) filing-date route rather than the § 102(a) "before the invention" route because Flynn's actual date of invention is not in the record; if Flynn's invention date were shown to predate a reference's filing date, that reference would drop out entirely.
9. No anticipation is the same as no invalidity. Several references (especially Sheehan US 3,159,617 plus the Pfizer 6-APA patents) are strong § 103 material. Nothing above addresses obviousness, which is the more likely ground of attack and is outside the § 102 scope you asked for.

I'll research the examiner-cited prior art references before building the § 103 analysis.

Key finding already: US 3,174,964 appears to be near-identical art. Let me confirm its full disclosure and check the other references.

Now let me check the Sheehan reference and whether 7-ACA/carbodiimide coupling was known.

Obviousness Analysis — US 3,252,973 under 35 U.S.C. § 103

Governing law note: Because application Ser. No. 229,231 was filed October 8, 1962, pre‑AIA § 103(a) applies. Pre-AIA § 103(a) asks whether "the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art." The Graham v. John Deere factors (scope/content of prior art; differences; level of ordinary skill; secondary considerations) and KSR Int'l v. Teleflex (predictable combinations; "obvious to try"; techniques used to improve one device obviously improve similar devices) govern. No post-1962 art may be used, which matters for one examiner citation (see "Anomaly" in § VI).

I. The prior art as it actually reads — and its § 102 status

The five examiner-cited patents were all cited by the examiner, but their status differs materially. I verified the key reference (Hobbs et al. '964) verbatim; the others are flagged for verification.

II. Rejection A — Claims 1–6 are obvious over Hobbs et al. '964 alone

US 3,174,964 discloses every element. Mapping claim 3 (representative):

Claim 4 (water/dioxane): Hobbs '964 teaches the water‑miscible‑organic‑solvent system generally; Sheehan & Hess (1955) ran DCC couplings in dioxane, and dioxane is the ether congener of Hobbs' exemplified THF. Choosing dioxane is at most routine optimization of a solvent disclosed as a class (cf. In re Boesch).

Claim 5 / claim 9 (DCC): Expressly named by Hobbs '964 as the preferred coupling agent.

Claim 6 / claim 10 (pH 5–8): Hobbs '964 runs the aqueous coupling at neutrality/sodium‑bicarbonate buffered conditions, and decomposes excess carbodiimide with dilute acetic acid afterward. It was well known by 1962 that the β‑lactam ring is hydrolyzed outside a narrow near‑neutral window (the '973 specification itself requires dissolving the nucleus by adding 1 N NaOH "to about neutrality" and exemplifies pH 6.3–6.8). This is a classic result‑effective variable with a recognized range (In re Aller).

Claim 2 (water‑soluble carbodiimide added as an aqueous solution): Disclosed by Sheehan & Hlavka, J. Org. Chem. 21, 439 (1956) and by Hobbs '964's morpholinyl/diethylamino carbodiimide metho‑p‑toluenesulfonates, which are water‑soluble (well above the '973's own >0.1 wt% definition). The '973 specification even concedes these "other carbodiimides" are disclosed by Sheehan in US 2,938,892.

Reason for combining: no combination is even required — a single reference satisfies every element. To the extent a "purpose" must be articulated, Hobbs '964 supplies it verbatim: the carbodiimide route is used precisely where "the use of an acyl chloride or anhydride is undesirable because of the presence of acid and base‑sensitive groups or impossible due to unavailability of the acylating agent" — the same purpose recited in the '973 specification.

Note on anticipation: Because every element is disclosed, claims 3–6 are arguably anticipated (pre‑AIA § 102(e)), not merely obvious. For claim 1 the analysis is only slightly weaker, because claim 1 is a closed Markush ("selected from the group consisting of the penicillins and the cephalosporins"); if the Markush form defeats anticipation by a penicillin‑only disclosure, claim 1 is nonetheless obvious for the reasons in Rejection B. See § VI for the Markush nuance.

III. Rejection B — Claim 1, 2 and 7–10 are obvious over Hobbs '964 in view of Abraham & Newton (Belgian 593,777), and optionally Sheehan US 3,159,617

The only element Hobbs '964 does not itself disclose is the 7‑ACA embodiment (claim 1's cephalosporin alternative and claims 7–10). That gap is filled by the 7‑ACA nucleus reference.

Motivation to combine — articulated reasons:

1. Same problem, same solution. Hobbs '964's stated raison d'être — acylate a β‑lactam nucleus with a free acid because acid chlorides are unavailable or destroy acid‑labile side chains — applies with equal force to 7‑ACA. The problem confronted was identical; the reference solves it by the identical mechanism.

2. The art recognized the two nuclei as functionally interchangeable amine substrates. By 1962 the cephalosporins were understood as "a close chemical relative of the penicillins, in which the 5‑membered thiazolidine ring is replaced by a 6‑membered ring," and 7‑ACA "has been converted to a variety of antibiotically active derivatives in a manner strikingly reminiscent of the semisynthetic penicillin story" (Sheehan, Ann. N.Y. Acad. Sci., 1967 review of the self‑same art). Nothing in either nucleus changes the operative chemistry: a primary aliphatic amine on a strained bicyclic β‑lactam is acylated by a carbodiimide‑activated carboxylic acid. The reaction is a generic amide‑forming reaction, not a nucleus‑specific one.

3. Hobbs '964 expressly characterizes its process as "general." A disclosure that a coupling is general, plus a known second substrate bearing the same reactive functional group, supplies the KSR "would improve similar devices in the same way" rationale. This is not an unpredictable field: the number of candidate substrates was small and known (6‑APA, 7‑ACA), the chemistry was a single well‑characterized amide bond formation, and the result (N‑acyl‑7‑ACA) was the very definition of what the artisan was trying to make.

4. Belgian 593,777 supplied the missing starting material. The '973 specification itself concedes: "The preparation of the cephalosporin nucleus (7‑aminocephalosporanic acid …) is described by Abraham and Newton in Belgian Pat. 593,777 (August 31, 1960)." An applicant's own admission that the starting material and its preparation were known is a powerful § 103 admission.

5. Sheehan US 3,159,617 supplies an independent, redundant route. Characterized in the art as the "broad, basic patent covering both synthetic and semisynthetic penicillins," and covering acylation of 6‑APA by carbodiimide coupling, it corroborates that carbodiimide acylation of the penicillin nucleus was old and broadly claimed as of a March 1, 1957 application date. Adding the known 7‑ACA nucleus to that teaching yields claims 1 and 7 with no new mechanism. (Subject to § VI verification.)

Dependent claims 8–10 are supported by the same disclosures as their penicillin counterparts (water/dioxane via Sheehan & Hess; DCC via Hobbs '964; pH 5–8 via neutral bicarbonate buffering plus β‑lactam hydrolytic instability).

Corroboration from subsequent art (not itself § 103 prior art, but probative): The Google Patents "Cited By" list shows the technique propagating almost immediately to cephalosporins — Fujisawa US 3,340,257 (filed 7/23/1964), Lilly US 3,518,260 (filed 3/8/1965) and Merck US 3,492,297 (filed 7/1/1965) — and, much later, Ajinomoto EP 0 349 296 A3, Process for the acylation of 7‑aminocephalosporanic acid or its derivatives. A technique adopted across multiple independent laboratories within two to three years of issue is evidence that the extension from the penicillin nucleus to the cephalosporin nucleus was the obvious next step.

IV. The '973 specification's own admissions cut against patentability

• It frames the invention as an "improvement in the acylation technique" — an express concession of a known, operative acylation art.
• It admits the prior-art route ("acylation of the nucleus with the appropriate carbacyl halide or anhydride") and admits the nuclei themselves were known.
• It cites Sheehan US 2,938,892 (a § 102(b) patent) for the carbodiimides, thereby conceding that the dehydrating agent and its substituent genus were known and selectable.
• It asserts only breadth ("a great number and variety of monocarboxylic acids can be used") and no unexpected property for any member. Breadth of an arbitrary side‑chain list is not a patentable distinction; KSR holds that a known problem in the field supplies the reason to vary a known parameter with predictable results.
• Its "Definitions" entry — the only quasi‑abstract text — is a pure claim‑construction gloss on "inert," not a technical advance.

V. Secondary considerations (Graham factor 4)

Nothing in the record supports nonobviousness, and two internal data points arguably cut the other way.

1. No comparative data against the closest art. The '973's only comparisons are internal (its own three addition‑order variants). There is no comparison against Hobbs '964, which is the same carbodiimide/6‑APA/free‑acid process. Without a comparison against the closest prior art, evidence of a "critical" variable is not commensurate with the claim scope.

2. The addition‑order data actually favor obviousness. Example 1 shows nucleus + phenoxyacetic acid, then DCC → ~400 units/mL; DCC added to nucleus first → ~12 units/mL; acid + DCC first → ~73 units/mL. But (a) Hobbs '964's preferred embodiment is to add the carbodiimide solution "to a solution of [the acid and the amine]" — i.e., the claimed order; and (b) the claims recite no order of addition at all other than that the acid and nucleus both be in solution before the carbodiimide is added. Hobbs '964's statement that "the order of addition of reagents is not critical" is not a teaching away from its own stated preference; teaching away requires disparagement of the preferred route (cf. In re Gurley). At most, the applicant found an optimum of a processing variable — the classic non‑patentable optimization.

3. No nexus evidence. Any commercial success of semisynthetic penicillins/cephalosporins in 1962–1970 is attributable to the clinical need, to the availability of 6‑APA and 7‑ACA from fermentation/enzymatic deacylation, and to side‑chain SAR work — not to the '973's claimed carbodiimide coupling, which Hobbs '964 had already described three years earlier. Absent a nexus, there is no objective indicium to weigh.

4. Possible "teaching away" argument — aqueous carbodiimide. Because carbodiimides hydrolyze in water, one could argue the artisan would not have expected an aqueous coupling to work. This is the strongest available nonobviousness theory, but it fails on the art: Hobbs '964 Example IX runs in water:THF (1:1) and Example VIII in water alone, and both the '973 and Hobbs '964 teach buffering to suppress carbodiimide decomposition. The "prejudice" was already overcome in the art.

VI. Contradictions, refinements, and explicit uncertainties

Per your instruction, I flag where this analysis refines or contradicts the earlier sections:

1. Refinement to the earlier "practical/technical notes." The prior section characterized the cited art generically and highlighted the addition order as "an inherency point for any later validity analysis." That framing understates the prior art. US 3,174,964 (Hobbs et al., Pfizer) is not merely background — it is a § 102(e) reference disclosing the same carbodiimide/6‑APA/free‑acid coupling with the same preferred addition order, the same DCC preference, an aqueous water‑miscible co‑solvent system, molar ratios of 1:1:1 to 2:1:1, water‑soluble carbodiimides, and full product recovery. Verified verbatim at https://patents.google.com/patent/US3174964A/en and https://patentimages.storage.googleapis.com/a3/b9/ee/c4047a6913b3bd/US3174964.pdf. On this record, claims 3–6 are closer to anticipated than to "a close question of obviousness."

2. Refinement to earlier uncertainty flag #2 (carbon-number subscripts). The Google‑Patents PDF‑derived claim text now available reads claim 1 as "C₁–C₁₂ aliphatic groups, C₂–C₇ cycloaliphatic groups," while claims 3 and 7 render as "C₃–C₇." This is internally inconsistent within the grant. Because the specification's enumerated cycloaliphatic radicals run cyclopropyl through cycloheptyl (and a "C₂ cycloaliphatic" group is chemically impossible), the C₂ reading in claim 1 is almost certainly OCR noise for C₃. This does not change the analysis: Hobbs '964's carbodiimides (dicyclohexyl, cyclohexyl‑morpholinylethyl, cyclohexyl‑diethylaminocyclohexyl) fall within either reading.

3. Anomaly — the Eynde citation. The '973 lists "Eynde: Industria Chimique Belge, vol. 29, No. 1, pp. 15–22 (1964)." A 1964 journal article cannot be § 102 prior art against an October 8, 1962 application — it is neither § 102(a), (b), nor (e). Either (a) the year is mis‑OCR'd from an earlier volume, (b) the examiner cited it improperly as "state of the art," or (c) it was cited as evidence of post‑filing development. I did not retrieve this reference and cannot state its content. It should not be relied on to support a § 103 rejection, and I flag it as needing verification.

4. Unverified reference texts. I retrieved verbatim text for US 3,174,964 and the '973 itself. I did not retrieve the claim text of US 3,159,617 (Sheehan), US 3,120,514 (Doyle), US 3,142,673 (Hobbs), or US 3,040,033 (Celmer), nor the Eynde article. My characterization of '617 rests on Sheehan's own retrospective description (Ann. N.Y. Acad. Sci. 1967; NAS biographical memoir) that it is "the broad, basic patent covering both synthetic and semisynthetic penicillins," and on the examiner's citation. Rejection B's use of '617 is therefore corroborative, not load‑bearing — the rejection stands on Hobbs '964 + Belgian 593,777 alone. The Morton 1946 citation ("page VI of the preface") is, on its face, a background/nomenclature citation and I would not rely on it for any limitation.

5. Markush nuance for claim 1. Claim 1 recites "an antibiotic substance selected from the group consisting of the penicillins and the cephalosporins." Whether a penicillin‑only disclosure anticipates this closed Markush is a genuine question (a reference disclosing a species within a claimed genus ordinarily anticipates; but a Markush claim is treated as a genus of alternatives, and authority exists both ways depending on framing). My conclusion does not depend on resolving it: claim 1 is obvious under Rejection B regardless, and claims 3–6 are independently invalid as the penicillin species claims.

6. Pre‑AIA § 103(c) is inapplicable. The 102(e) references are Pfizer, Beecham, and Arthur D. Little/MIT art — not commonly owned with Lilly — so no common‑ownership disqualification exists. (Even in modern practice, § 103(c) could not rescue claims that are met by a single reference.)

VII. Bottom line

Claims 1–10 would have been obvious under pre‑AIA § 103(a), and most likely invalid under § 102 as well.

The rationale in one sentence: as of October 1962, carbodiimide‑mediated amide formation (Sheehan & Hess 1955; Sheehan US 2,938,892), its application to acylation of the penicillin nucleus in aqueous water‑miscible media with DCC (Hobbs et al. US 3,174,964), and the identity/availability of the 7‑aminocephalosporanic acid nucleus (Belgian 593,777) were all squarely in the art; the '973's contribution was to run a known coupling on a known second substrate, producing a predictable N‑acylated β‑lactam with no unexpected property demonstrated and no nexus to any secondary consideration.