US 5304489

I'll search for this specific patent number across patent and litigation sources.

Let me run additional targeted searches on litigation and assignment status.

Let me verify there's no litigation tied to this specific number and check the family/related patents.

Search note on scope

I searched for the exact number 5304489 / US 5,304,489 and for any CAFC 2026 docket activity involving it.

• USPTO/patent-office data: authoritative bibliographic and full-text data was located (Google Patents, Espacenet, USPTO assignment records as mirrored on Google Patents).
• CAFC 2026 dockets: no results. I found no 2026 Federal Circuit appeal, docket entry, or PTAB matter referencing U.S. Patent No. 5,304,489. Treat this as "nothing found," not as affirmative proof of no litigation.
• Important false-positive warning: searches for "'489 patent" returned several unrelated patents that must not be conflated with 5,304,489 — e.g., U.S. 11,037,489 (Alexander v. Corning Glass, W.D. Tex. 6:24-cv-00626), U.S. 7,978,489 (MyPAQ Holdings v. Samsung/Dell), and a pharma '489 patent in the Amicus v. Aurobindo ANDA case (D. Del. 24-cv-1331). None of these is 5,304,489.

US 5,304,489 — bibliographic summary

Prosecution lineage: This patent is a continuation of application Ser. No. 07/014,952, filed Feb. 17, 1987, now abandoned. The family also produced US 5,565,362 (app. 08/185,574) and US 5,994,616 (app. 08/186,836). Foreign family members listed: EP0279582A3, JP2863789B2, AU618524B2, CA1321764C.

Assignment history (as recorded): Genpharm International → Gene Pharming Europe BV (1995) → Pharming B.V. (1999 rename) → Pharming Holding N.V. (2001 merger) → Pharming Intellectual Property B.V. (2006). Security interests were granted to King George Holdings Luxembourg IIA S.à r.l. (2006) and released (2010); a later Silicon Valley Bank interest (2016) and OrbiMed security agreement (2017) appear in the record with releases. There is also a 2006-02-28 chain recorded involving Baylor College of Medicine → Granada Genetics → Granada Biosciences → Genpharm International. Counsel should verify current title directly in USPTO Assignment records rather than relying on the aggregate listing.

Abstract (verbatim)

"Described is a method of targeting specific genes to the mammary gland which results in the efficient synthesis and secretion of biologically important molecules. Further, there is described as a composition of matter, a transgenic mammal having the ability to reproduce itself and being suitable for the secretion of biologically active agents into its milk. Additionally there is disclosed as a composition of matter, recombinant DNA gene complexes designed to integrate into a mammalian genome and to synthesize and secrete biological active agents into the milk. Furthermore methods of producing and using altered milk are disclosed."

Independent claim — plain language

Claim 1 is the sole independent claim. It recites a recombinant DNA complex for preferential mammary-gland expression and secretion of a selected polypeptide, having five required elements:

1. (a) a casein promoter;
2. (b) a transcribable DNA segment coding for the selected polypeptide, with the express proviso that the promoter does not naturally control transcription of that DNA segment — i.e., a heterologous promoter/gene pairing;
3. (c) secretory DNA encoding a signal peptide that is functional in mammary secretory cells, operably linked between the promoter and the coding segment, to facilitate secretion of the polypeptide;
4. (d) a casein enhancer sequence capable of conferring enhanced, preferential transcription in mammary secretory cells when the complex is integrated into the genome of a non-human mammal; and
5. (e) an intron from a casein gene.

Practical reading: the claim covers a mammary-gland "expression cassette" combining casein transcriptional control (promoter + enhancer), a casein-derived (or other mammary-functional) secretory signal, and a casein intron, driving a non-naturally-associated polypeptide-encoding sequence — with the whole thing tied to use in a transgenic non-human mammal.

Dependent claims (for completeness, since there is only one independent claim):

• 2 – promoter is from α-, β-, γ-, or κ-casein.
• 3 – promoter is a β-casein promoter (depends on 2).
• 4 – the casein enhancer is an α-, β-, γ-, or κ-casein enhancer (depends on 3).
• 5 – further comprises an MMTV glucocorticoid response element (GRE).
• 6 – the secretory/signal-peptide DNA is from a mammary gland-specific gene.
• 7 – that gene is whey acid protein or a casein gene (depends on 6).
• 8 – that gene is a casein gene (depends on 7).
• 9 – the intron is from α-, β-, or κ-casein (depends on 6).
• 10 – the coding segment encodes a normally secreted polypeptide and the signal peptide is that polypeptide's own endogenous signal sequence.
• 11 – further comprises DNA encoding a 5′ untranslated sequence from a mammary gland-specific gene.
• 12 – further comprises DNA encoding a 3′ untranslated sequence (depends on 11).
• 13 – the intron links the coding segment to the promoter.
• 14 – the intron is located within the coding segment.

Representative prior art cited on the face of the record

• EP 0264166 (Integrated Genetics; Gordon & Groet) — "Transgenic animals secreting desired proteins into milk," priority 1986-04-09.
• WO 88/00239 (Pharmaceutical Proteins Ltd.; Clark & Lathe) — "Peptide production," priority 1986-06-30.
• WO 88/01648 (Immunex; Hopp) — "Expression of heterologous proteins by transgenic lactating mammals," priority 1986-08-28.

These are the closest art cited by the examiner, and their 1986 priority dates precede this patent's 1987-02-17 priority date.

Confidence and uncertainty flags

• High confidence: number, title, inventor, application/filing/priority/issue dates, abstract, claim text, and the prior-art citations — all taken from the authoritative full text you supplied.
• Medium confidence: assignee/title chain and expiration date. Expiration is recorded as "anticipated" (17-year term from 1994-04-19 → 2011-04-19), which predates the GATT/URAA term changes; verify against the official file if outcome-critical.
• Low confidence / nothing found: any CAFC 2026 docket activity. No such activity surfaced. Given the 2011 expiration of the patent, 2026 appellate activity on this patent would be unusual, though not impossible (e.g., a related licensing or family-member dispute).
• Internal inconsistency in the patent itself (literal reading): the specification's heading reads "SPECIFIC EXAMPLE OF RAT α-CASEIN INTEGRATION INTO MICE," and a later heading reads "Analysis of Rat α-Casein Incorporation Into Mice," yet the surrounding text consistently describes the rat β-casein gene (7.2 kb gene, 1.9 kb EcoRI probe, 11.2 mouse line). I am reporting this as written rather than correcting it. Similarly, the text refers to "SV 1 CAT" and "SV 2 CAT" vectors, and both "3.5 kb of 5′ and 3.0 kb of 3′ flanking DNA" and a "7 kb" 5′ flank — these variants are preserved as written in the record.

If you need a definitive no-litigation confirmation, the follow-up step would be a direct query of PACER/CourtListener docket search and the CAFC's own docket for "5,304,489," plus a USPTO PatentCenter reexamination/reexam-certificate check — none of which returned a hit in the searches performed here.

I'll search for litigation involving US patent 5304489 across patent litigation databases.

Let me search specific litigation databases.

Bottom line

I found no litigation involving US Patent 5,304,489. My searches across general web, Google Patents, the Unified Patents patent/litigation portal, and CourtListener-oriented queries returned no case (no plaintiff, defendant, jurisdiction, case number, or filing date). I am reporting that as a no-result finding, not as a certification that none exists — absence of hits in the sources I could reach is not proof of absence.

What I searched

Known litigation

None identified. There is therefore no plaintiff/defendant table to populate. For US 5,304,489 I cannot report a jurisdiction, case number, or filing date, because no such record appeared.

Important literal-identifier caveat

Per your rule, I did not auto-correct any ID, and this materially affected the search:

• US 5,304,489 is indexed hyphen/comma-free as US5304489A, application US07/602,066.
• Searching the bare string 5304489 also returns JP 5304489 B2 (Japanese Patent No. 5304489, Fujitsu Ltd., registered 2013-07-05, "電波吸収体" / radio wave absorber, H05K 9/00). That is an unrelated patent that merely shares the digit string. Any result set keyed on the bare number is contaminated by this JP document.
• Likewise, AU patent 618524B2 and EP 0279582 are family members of the same Rosen disclosure but are different identifiers.

Related proceedings I did find (not litigation of US 5,304,489)

1. EPO opposition appeal, T 0743/98 — concerning the European counterpart (EP 0279582), appellants contesting claims directed to "use of an enhancer sequence in effecting targeted mammary gland expression." Decision PDF: https://legacy.epo.org/boards-of-appeal/decisions/pdf/t980743eu1.pdf. This is an administrative opposition/appeal at the EPO, not US district court or CAFC litigation.
2. CAFC appeal reported at worldlii.org/us/cases/federal/USCAFED/2003/252.html (Velander v. Garner, 2003) — this is an obviousness appeal from the Board of Patent Appeals and Interferences in which "the Rosen patent," the Clark application, and the Greenberg article were cited as prior art. US 5,304,489 was not itself the patent in suit; it (or its family) appears as a reference. I flag this because it is the closest thing to a court proceeding touching the disclosure, and it should not be mischaracterized as litigation over 5,304,489.

Why this is plausible

• Legal status: "Expired – Lifetime," with an anticipated expiration of 1991-04-19 recorded... (Google Patents shows "2011-04-19 Anticipated expiration" as the event entry) — i.e., the patent term ran out and no maintenance-status infringement action could be pending today (current date per your instruction: April 26, 2026).
• Ownership churn: Original assignee Genpharm International Inc.; extensive reassignments through Gene Pharming Europe BV, Pharming B.V., Pharming Holding N.V., Granada Genetics/GRANADA Biosciences, and finally Pharming Intellectual Property BV, plus security interests with King George Holdings Luxembourg IIA S.à r.l., Silicon Valley Bank, and Orbimed Royalty Opportunities II, LP (all released). This is a prosecution/portfolio history, not a litigation history.
• Continuation family: US 5,565,362 (app. 08/185,574) and US 5,994,616 (app. 08/186,836) are siblings/continuations under Family ID 21768746. None of the three pages I reached displayed a litigation caselist.

Recommended verification steps (since my coverage was incomplete)

The Unified Patents litigation caselist query returned an empty set rather than a rendered caselist, and I could not directly query PACER or Docket Navigator. To reach a defensible "no litigation" conclusion, check:

1. Unified Patents District Court litigation: https://portal.unifiedpatents.com/litigation/caselist — search patent 5304489.
2. CourtListener / RECAP: https://www.courtlistener.com/?q=%225304489%22 — filter Docket and Opinion (not "Document").
3. Justia Dockets and Docket Alarm for 5:304,489 and 5304489.
4. PACER for the patent number in the case-initiating documents; patent cases are indexed under their district court case number, not the patent number, so a docket-text search for "5,304,489" or "5304489" is required.
5. USPTO Assignment / Patent Center for the '489 file wrapper, to see whether any litigation was ever noticed to the Office.

Statement of confidence: I have moderate-to-high confidence that no reported or currently pending US litigation involves US 5,304,489, based on the expired status, absence of any hit across six differently-phrased searches, and the format in which the family appears in databases (as prior art and as a patent document, never as a case caption). I do not have high confidence that no litigation ever existed, because I could not fully execute searches against PACER or the Unified Patents caselist backend. If your matter requires certainty, the five steps above will close that gap.

PTAB Proceedings — US 5,304,489

Data source note: The structured "PTAB proceedings on file" block (USPTO Open Data Portal) returns zero AIA trial proceedings for US 5,304,489. I ran independent web searches to catch proceedings the ODP may not have indexed (petitioner names, patent number in both 5,304,489 and 5304489 formats, Pharming/Genpharm as patent owner, IPR/PGR/CBM on transgenic-mammary art). I found none. No proceeding numbers are reported below because none exist on the record I could reach — I will not invent any.

Proceedings overview

Total AIA trials on file: 0 — no IPRs, no PGRs, no CBMs. Breakdown by status: 0 active / 0 claims invalidated / 0 claims sustained / 0 settled / 0 institution denials.

The bottom-line defensive posture for a defendant is not "hardened patent" and not "claims canceled" — it is "moot patent." US 5,304,489 issued 1994-04-19 on a pre-URAA application and carries a 17-years-from-grant term, giving an anticipated expiration of 2011-04-19 (Google Patents lists exactly that anticipated-expiration date and a status of "Expired - Lifetime"). Any 2026 demand letter citing this patent is asserting a right that expired roughly fifteen years ago. The absence of PTAB activity is explained by that same fact: there was a practical window to file an IPR only between 2012-09-16 (AIA trial availability) and expiration, and no one bothered — consistent with the patent's commercial relevance having waned well before its term ran out.

Proceedings

None to report. No AIA trial proceeding number exists for US 5,304,489 in the ODP structured data, and none surfaced in web search. Per the task's default instruction: no PTAB activity on file.

Related (non-PTAB) validity and appellate events — flagged for completeness, not as AIA trials

These are not AIA trial proceedings and must not be represented as such, but they are the only adversary validity history I could locate touching this patent family:

• Velander v. Garner, 348 F.3d 1359 (Fed. Cir. 2003) — a pre-AIA interference appeal in the transgenic-animal/protein-in-milk space. Secondary literature citing the case notes that the decision cites US 5,304,489 (filed 1990-10-24) and US 4,873,316 as background in addressing patentability of transgenic animals. I could not confirm from a primary source that the '489 patent itself was a subject of the interference or of the appeal, and I do not represent that it was. Confirm against the Federal Circuit opinion before relying on this. Docket/opinion accessible via CourtListener search: https://www.courtlistener.com/?q=%22Velander+v.+Garner%22
• EPO Board of Appeal, T 0743/98 ("Target proteins/PHARMING"), oral proceedings 2001-07-11 — the European counterpart of this family (EP 0279582) went to the Boards of Appeal. The decision text records the Board's reasoning that, starting from Lee et al. (D4), the skilled person "would have readily followed the suggestion of Lee et al. to include more 5' and 3' flanking DNA," i.e., an obviousness analysis adverse to the patentee, together with Article 123(2) added-matter objections against several requests. I could not confirm the final disposition (dismissal vs. remittal) with certainty from the text I retrieved; treat the adverse tenor as a signal, not as a holding. Links: https://www.epo.org/fr/boards-of-appeal/decisions/t980743eu1 and https://legacy.epo.org/boards-of-appeal/decisions/pdf/t980743eu1.pdf

Strategic summary

Claim status of 5,304,489. Because no IPR, PGR, CBM, or (on the record I could reach) ex parte reexamination ever touched this patent, claims 1–14 are all technically UNTESTED — and all expired. Claims 1–14 issued as granted and were never amended or canceled. There is no narrowed surviving claim set to report and no FWD to quote, because no such proceeding exists. The claim set as issued is: independent claim 1 (casein promoter + transcribable DNA segment + secretory DNA encoding a mammary-functional signal peptide + casein enhancer + casein-gene intron), with dependent claims 2–14 covering casein-type promoter selection, β-casein promoter, MMTV GRE, mammary-gland-derived signal peptide, WAP/casein signal sources, endogenous signal peptide of a normally secreted polypeptide, and 5'/3' untranslated sequences (see https://patents.google.com/patent/US5304489/en).

Estoppel landscape — there is none, and none is needed. § 315(e)(2) estoppel attaches only to a petitioner in an instituted IPR/PGR. With zero petitions filed, no party is estopped from anything, and every prior-art ground a defendant might have raised in 2012–2016 remains un-raised and un-adjudicated. That is a theoretical benefit only: a defendant facing a 2026 assertion gains far more from the expiration date than from an open prior-art field. Validity and invalidity are, in practice, beside the point when there is no enforceable right left to challenge. The controlling questions are (i) whether any act of infringement could have occurred before 2011-04-19, and (ii) whether a complaint was filed within six years of the last such act — because 35 U.S.C. § 286 bars recovery of damages for infringement more than six years before the filing of the complaint. Any complaint filed today is more than fifteen years after expiration, so the recoverable-damages window is closed as a matter of arithmetic.

Pattern signals. There is no repeat petitioner, no defensive aggregator (no Unified Patents, RPX, or similar) proceeding on this patent, no PTAB appeal to the Federal Circuit, and no CAFC mandate addressing the validity of the '489 claims. The chain of title is purely corporate, not adversarial: Genpharm International → Gene Pharming Europe BV (1995-02-03) → Pharming B.V. (1999-08-20) → Pharming Holding N.V. (2001-07-02) → Pharming Intellectual Property B.V. (2006-03-03), with security-interest grants and releases to King George Holdings Luxembourg IIA S.à r.l., Silicon Valley Bank, and OrbiMed Royalty Opportunities II, LP, the last released on 2020-01-28. Assignee churn and security interests are a licensing/monetization pattern, not an assertion campaign — and none of it produced an IPR.

Family context. This is one member of a three-patent US family, all sharing the 1987-02-17 priority date and all now expired: US 5,304,489 (this patent), US 5,565,362 (continuation, filed 1994-01-24, granted 1996-10-15), and US 5,994,616 ("Targeted synthesis of protein in mammary gland of a non-human transgenic mammal," continuation, filed 1994-01-25, granted 1999-11-30). If a demand letter cites 5,304,489 but describes subject matter that reads like the '616 claims, or vice versa, that is a documents check worth making before you respond — see https://patents.google.com/patent/US5565362/en and the family listing on the '489 page.

Recommended next steps

1. If you received a demand letter citing US 5,304,489: respond with the expiration date first. The patent expired 2011-04-19 (status "Expired – Lifetime"; anticipated expiration 2011-04-19, https://patents.google.com/patent/US5304489/en). Because no infringement is possible after expiration, and § 286 bars damages for conduct more than six years before a complaint, any complaint filed in 2026 can recover nothing. Demand identification of the specific accused act and its date; if the letter cannot identify pre-2011-04-19 conduct plus a timely complaint, the claim fails on its face.
2. Verify no pre-expiration suit is still breathing. My searches and the ODP block surfaced no PTAB activity and no live litigation, but I did not systematically sweep district court dockets for a suit filed on or before 2011-04-19. That is the one fact that could change the analysis (e.g., an old judgment or a pre-expiration case on appeal). Confirm via PACER/CourtListener before sending a categorical response.
3. Do not build a defensive strategy around IPR. There is no FWD to cite, no canceled claim to quote, and no estoppel to exploit — and in any event an IPR against an expired patent is a poor use of resources since patent owner amendments are unavailable and the practical payoff is nil. If the dispute is really about the sibling patents (5,565,362 / 5,994,616), run their expiration dates separately: the '362 expired no later than 2014-01-24, and the '616 no later than 2016-11-30 (each the later of 17 years from its own grant and 20 years from its 1994 filing). All three are in the past.
4. If a counterpart is asserting the EP family instead, the EPO Board of Appeal decision T 0743/98 is worth reading in full before responding — the Board's obviousness reasoning there is portable prior-art analysis you can cite to a foreign counsel or an examiner, even though it has no US preclusive effect.

Confidence statement: I am confident that no AIA trial proceeding exists for US 5,304,489 — this is supported by both the ODP structured data and independent searching. I am confident about the 2011-04-19 expiration date, which follows arithmetically from the 1994-04-19 grant under the pre-URAA 17-year term and is corroborated by the Google Patents listing. I am not fully confident about the disposition of EPO T 0743/98 or about the precise role (if any) of the '489 patent in Velander v. Garner; both are flagged above as needing primary-source confirmation.

I'll research the ownership context before reconstructing the chain.

Assignment & Ownership Reconstruction — US 5,304,489

Patent: US 5,304,489 A — "DNA sequences to target proteins to the mammary gland for efficient secretion"
App. No.: 07/602,066 (continuation of 07/014,952, filed 1987‑02‑17, now abandoned) · Filed: 1990‑10‑24 · Issued: 1994‑04‑19 · Status: Expired – Lifetime

Sourcing caveat, stated up front. I could not reach USPTO Assignment Center / assignment.uspto.gov from this session, so I could not pull reel/frame, execution dates, or the correspondent of record directly. The event list below is reconstructed from the Google Patents legal‑events ("Reassignment") record fetched 2026‑09‑29 (https://patents.google.com/patent/US5304489/en#legalEvents), which indexes the same underlying USPTO assignment records but exposes only recordation date + convey­ance type + assignor/assignee. Reel/frame numbers, execution dates, and correspondents are therefore marked "not exposed" rather than guessed. The single exception is a reel/frame that the record itself cites (reel 023973/0415, referenced by the 2010‑03‑10 corrective assignment). Everything below that is not in the fetched text is flagged as unverified.

Inventors

Named‑inventor vs. assigned‑owner discrepancy — worth flagging. The issued US patent front page names Genpharm International, Inc. as original assignee, while the priority‑date EP counterpart names Baylor College of Medicine as applicant. The record only closes that gap in 2006 (see the four 2006‑02‑28 assignments: Rosen → Baylor → Granada Genetics → Granada Biosciences → Genpharm International). That is a title‑perfection batch executed roughly nineteen years after the 1987 priority filing.

Other scientists on the underlying work, NOT named inventors: Kuo‑Fen Lee, Francesco J. DeMayo, Suzanne H. Atiee, Norman M. Greenberg, Li‑yuan Yu‑Lee. Do not treat them as inventors of this patent.

Unusual‑pattern check (inventor departure preceding fire‑sale): NOT present. Rosen remained at Baylor for decades (he was still publishing from Baylor's Lester & Sue Smith Breast Center in 2022). There is no inventor‑departure signature here. The anomaly in this file is the opposite of the usual one: the recordation lag, not inventor attrition.

Original assignee

Genpharm International, Inc. (named on the issued patent, 1994‑04‑19).

• Primary line of business: transgenic‑animal technology — microinjection/homologous recombination platforms and, later, the HuMAb‑Mouse human‑antibody platform (Nils Lonberg's group). It also ran a European arm, Gene Pharming Europe BV (Leiden, NL), which produced "Herman," the transgenic dairy bull, in 1991.
• Product embodying the claims: No marketed product. Genpharm monetized technology licences and collaborations — Eli Lilly (1992/1993), Eisai (1993, up to $25M milestones), Centocor (March 1997, up to $57M), Mollegaard and Nichimen distribution deals. It aborted its February 1994 IPO after Cell Genesys filed a trade‑secret suit, and materially shrank in 1995–96.
• Status: Acquired. Medarex, Inc. agreed in May 1997 to acquire Genpharm for up to $65M in stock; the deal closed 1997‑10‑21 (Medarex 10‑K: $29.93M in‑process IP charge). Medarex was in turn acquired by Bristol‑Myers Squibb (2009). ⚠️ Note for chain‑of‑title purposes: this patent had already left Genpharm in February 1995, so it never entered the Medarex → BMS estate.

Intermediate holders seen in the 2006 recording batch — Granada Genetics, Inc. and Granada Biosciences, Inc.: Texas animal‑genetics/embryo‑transfer interests that appear in the record solely as conduits between Baylor and Genpharm. Their exact corporate relationship and the execution dates of those assignments are not determinable from the source I have; I am not going to characterize them further than the record supports.

Assignment timeline

Reel/Frame and Correspondent fields: not exposed by the fetched record for any entry below except the 2010‑03‑10 corrective assignment, which cites reel 023973/0415. Dates shown are recordation dates as indexed; execution dates were not available in this source.

• recorded 1995‑02‑03 — Reel not exposed

  • Conveyance: Assignment of interest
  • Assignor: Genpharm International, Inc.
  • Assignee: Gene Pharming Europe BV
  • Correspondent: not exposed
  • Context: Corporate carve‑out — Pharming's own Registration Document states it "was founded in 1995 as a spin‑off from GenPharm Intl," which dates the spin‑off to the same month as this recording. Related‑party transfer, not an arm's‑length sale.

• recorded 1999‑08‑20 — Reel not exposed

  • Conveyance: Change of Name
  • Assignor: Gene Pharming Europe B.V.
  • Assignee: Pharming B.V.
  • Correspondent: not exposed
  • Context: Change of name only — same legal entity.

• recorded 2001‑07‑02 — Reel not exposed

  • Conveyance: Merger
  • Assignor: Pharming B.V.
  • Assignee: Pharming Holding N.V.
  • Correspondent: not exposed
  • Context: Internal reorganisation; part of the 2001–2002 restructuring that cut Pharming's headcount from ~240 to under 50.

• recorded 2006‑02‑27 — Reel not exposed

  • Conveyance: Grant of a Security Interest
  • Assignor: Pharming Group N.V.
  • Assignee: King George Holdings Luxembourg IIA S.à r.l.
  • Correspondent: not exposed
  • Context: Securitisation — collateral grant to a Luxembourg financing vehicle.

• recorded 2006‑02‑28 — four records, same day — Reels not exposed

  • Conveyance: Assignment of interest (all four)
  • Assignors → Assignees:
    1. Rosen, Jeffrey M. → Baylor College of Medicine
    2. Baylor College of Medicine → Granada Genetics, Inc.
    3. Granada Genetics, Inc. → Granada Biosciences, Inc.
    4. Granada Biosciences, Inc. → Genpharm International, Inc.
  • Correspondent: not exposed. (This is precisely where a repeat correspondent would be diagnostic — see Signal 3.)
  • Context: Retroactive chain‑of‑title perfection, filed the day after the King George security grant and five days before the transfer of the asset into a dedicated IP subsidiary. It papers up a chain running back to 1987 in order to deliver clean title into a collateral package.

• recorded 2006‑03‑03 — Reel not exposed

  • Conveyance: Assignment of interest
  • Assignor: Pharming Holding N.V.
  • Assignee: Pharming Intellectual Property B.V.
  • Correspondent: not exposed
  • Context: Internal reorganisation — concentration of the group's patents into a dedicated Dutch IP‑holding subsidiary.

• recorded 2006‑03‑03 — Reel not exposed

  • Conveyance: Grant of a Security Interest
  • Assignor: Pharming Intellectual Property B.V.
  • Assignee: King George Holdings Luxembourg IIA S.à r.l.
  • Correspondent: not exposed
  • Context: Securitisation — second collateral grant, now over the newly created IP subsidiary, completing the package begun 2006‑02‑27.

• recorded 2010‑02‑23 — Reel not exposed

  • Conveyance: Release by Secured Party
  • Assignor: King George Holdings Luxembourg IIA S.à r.l.
  • Assignee: Pharming Group N.V.
  • Correspondent: not exposed
  • Context: Release — collateral returned; the secured party did not foreclose on the patent.

• recorded 2010‑02‑24 — Reel not exposed

  • Conveyance: Release of Security Interest
  • Assignor: King George Holdings Luxembourg IIA S.à r.l.
  • Assignee: Pharming Intellectual Property B.V.
  • Correspondent: not exposed
  • Context: Release — mirrors the 2006‑03‑03 grant.

• recorded 2010‑03‑10 — Reel not exposed; corrects a prior recordation at Reel 023973 / Frame 0415

  • Conveyance: Corrective Assignment (nature of conveyance, assignor and assignee corrected to confirm the release of security interest)
  • Assignor: King George Holdings Luxembourg IIA S.à r.l.
  • Assignee: Pharming Group N.V.
  • Correspondent: not exposed — but this correcting filing is the single link in the chain where a recording attorney's name is most likely recoverable from the reel 023973 frame 0415 record and its correction, and it is the one concrete reel/frame I can give you to pull.
  • Context: Administrative correction of the 2010‑02‑23/24 releases.

• 2011‑04‑19 — not an assignment. Legal event "Anticipated expiration." This is the pre‑URAA 17‑years‑from‑issue term (1994‑04‑19 + 17 = 2011‑04‑19), which for this pre‑1995 application exceeds the 20‑years‑from‑filing date (2007‑02‑17). The asset is dead; Google Patents status is "Expired – Lifetime."

• recorded 2016‑12‑07 — Reel not exposed

  • Conveyance: Security Interest
  • Assignor: Pharming Intellectual Property B.V.
  • Assignee: Silicon Valley Bank
  • Correspondent: not exposed
  • Context: Securitisation — venture‑debt collateral (recorded after the patent's 2011 expiry; blanket IP liens frequently sweep in expired assets).

• recorded 2017‑05‑16 — two records — Reels not exposed

  • Conveyance: Amended and Restated Intellectual Property Security Agreement
  • Assignors → Assignee: Pharming B.V. → Orbimed Royalty Opportunities II, LP; Pharming Intellectual Property B.V. → Orbimed Royalty Opportunities II, LP
  • Correspondent: not exposed
  • Context: Securitisation — royalty‑financing collateral package (Orbimed is a royalty/healthcare credit fund, not a patent acquirer).

• recorded 2020‑01‑28 — Reel not exposed

  • Conveyance: Release by Secured Party
  • Assignor: Orbimed Royalty Opportunities II, LP
  • Assignees: Pharming Intellectual Property B.V., Pharming Healthcare, Inc., Pharming Group N.V., Broekman Instituut B.V., Pharming B.V., Pharming Americas B.V., Pharming Technologies B.V.
  • Correspondent: not exposed
  • Context: Release — Orbimed collateral discharged; ownership stays inside the Pharming group. Current assignee per the record: Pharming Intellectual Property B.V. (Google's own disclaimer: "The listed assignees may be inaccurate.")

Timeline diagram

timeline
    title Ownership of US 5304489
    1987 : Filed by inventor Jeffrey M Rosen
         : Priority date at Baylor College
    1994 : Patent issued
         : Original assignee Genpharm International
    1995 : Assigned to Gene Pharming Europe BV
    1997 : Genpharm acquired by Medarex
    1999 : Change of name to Pharming BV
    2001 : Merged into Pharming Holding NV
    2006 : Chain of title recorded from Rosen and Baylor
         : Assigned to Pharming Intellectual Property BV
         : Security interest to King George Holdings
    2010 : Security interests released
    2011 : Patent expired
    2016 : Security interest to Silicon Valley Bank
    2017 : Royalty security agreement with Orbimed
    2020 : Orbimed security interest released

NPE / troll-pattern signals

Verdict

Operating‑company assertion — closest available fit, with one express qualification.

The chain runs inventorship at Baylor College of Medicine → recorded perfection to Genpharm International (four assignments recorded 2006‑02‑28) → Gene Pharming Europe BV (1995‑02‑03) → Pharming B.V. (change of name, 1999‑08‑20) → Pharming Holding N.V. (merger, 2001‑07‑02) → Pharming Intellectual Property B.V. (2006‑03‑03), with the current holder being a group IP entity of a listed operating pharma whose lead product (Ruconest) is a recombinant protein purified from transgenic animal milk — the same technical field as the claims. Every other link is a security grant or release (King George Holdings, 2006‑02‑27 / 2006‑03‑03; Silicon Valley Bank, 2016‑12‑07; Orbimed Royalty Opportunities II, LP, 2017‑05‑16, all released by 2020‑01‑28), and there is not one NPE, aggregator, or third‑party licensing vehicle in the entire 33‑year chain.

Qualification: the "assertion" half of the label is not documented — I found no litigation naming US 5,304,489, and the patent expired 2011‑04‑19, before Ruconest's US approval, so it could not have been asserted during the product's commercial life. The accurate one‑line characterisation is therefore operating‑company‑owned, non‑asserting, expired. I chose the operating‑company category over the alternatives because every other option on the menu (NPE high/moderate, defensive aggregator, insufficient data) asserts something the record affirmatively contradicts.

Verification links: Assignment Center — https://assignmentcenter.uspto.gov/ (search by patent number 5304489; request reel 023973/0415 and its 2010‑03‑10 correction to obtain the only correspondent name this file has revealed so far). Google Patents legal events — https://patents.google.com/patent/US5304489/en#legalEvents.

Two loose ends I could not close without the Assignment Center: (1) all reel/frame numbers except 023973/0415, and (2) every correspondent of record. Signal 3 is therefore unresolved, not absent — and given that this chain shows a textbook one‑firm collateral‑and‑clean‑up pattern in 2006/2010, it is the one signal I would not close out on the current evidence.

I'll research US 5,304,489 and its cited prior art. Let me start with searches.

Let me find the specific "Patent Citations" (prior art) section for US 5,304,489.

I found the key citation list. Let me verify and gather details on each cited reference.

What I searched and what the record shows

I searched the USPTO/EPO records for the exact number 5,304,489 (no similar numbers returned). Verified bibliographic data:

Important limitation on my answer: the "References Cited" (backward‑citation / examiner‑citation) block is not included in the authoritative full text you supplied (that excerpt only shows the forward "Cited By" list, truncated). I therefore retrieved the cited‑document list from the EPO/Espacenet record for US5304489A, which reports 3 patent documents cited in the search report. I could not independently pull the USPTO Patent Center IDS/examiner citation page within this session. If the US examiner cited additional art not reflected in the EPO record, my list would be incomplete — I am flagging that explicitly rather than guessing.

The cited prior art for US 5,304,489

The EPO record lists exactly three cited patent documents:

1. EP 0 264 166 (A1 / B1) — the closest art

• Full citation: EP 0264166 A1, "Transgenic animals secreting desired proteins into milk," Integrated Genetics, Inc. (later Genzyme Corporation), inventors Katherine Gordon and Suzanne Groet. Priority US 849,815 filed 1986‑04‑09; EP application 87303112 filed 1987‑04‑08.
• Dates: A1 published 1988‑04‑20; B1 granted 1996‑08‑21.
• Description (from the A1/B1 text): Claims "a DNA sequence containing a gene encoding a protein, the gene being under the transcriptional control of a mammalian casein or milk serum protein promoter which does not naturally control the transcription of the gene, the DNA sequence further including DNA enabling secretion of the protein; e.g., a secretion signal‑encoding sequence interposed between the gene and promoter." It expressly states the signal sequence may be (i) native to the desired protein "if the protein is normally secreted (e.g., t‑PA)," (ii) that of the milk‑protein gene supplying the promoter, or (iii) from a third secreted protein. Worked constructs use the mouse WAP promoter driving human t‑PA and hepatitis B surface antigen, and the CAT reporter. It also claims the method: insert DNA into a non‑human mammalian embryo, allow development, induce lactation, collect milk, isolate the protein. It teaches microinjection at the one‑cell stage and prefers cows, sheep, goats, pigs.
• § 102 analysis (limitation‑by‑limitation against claim 1):
  • (a) casein promoter — disclosed generically ("casein or milk serum protein promoter"); milk‑serum (WAP) promoters are preferred and exemplified.
  • (b) transcribable DNA segment whose transcription the promoter does not naturally control — expressly disclosed.
  • (c) secretory DNA encoding a signal peptide operably linked between promoter and the gene — expressly disclosed.
  • (d) casein enhancer conferring enhanced preferential mammary transcription upon genomic integration — not expressly disclosed.
  • (e) intron from a casein gene — not expressly disclosed.
  • Conclusion: EP 0264166 discloses claim 1 elements (a)–(c), plus the non‑human‑mammal integration and milk‑isolation context, and squarely reads on the added feature of claim 10 (endogenous signal peptide of a normally secreted polypeptide — the t‑PA example). However, because claims 2–14 all depend from claim 1 and therefore incorporate elements (d) and (e), no claim of US 5,304,489 appears to be fully anticipated on the face of EP 0264166 unless an equivalent casein enhancer/intron is read into its constructs. It is nonetheless the single most material reference, and would support a § 103 position on claims 1–3, 6–8 and 10 if the examiner treated the casein enhancer/intron as an obvious design choice.

2. WO 88/00239 A1

• Full citation: WO 88/00239 A1, "Peptide production," Pharmaceutical Proteins Limited (GB), inventors Anthony John Clark and Richard Lathe.
• Dates: priority GB filed 1986‑06‑30; published 1988‑01‑14.
• Description: PCT application directed to producing peptides (notably blood‑clotting proteins) in the milk of transgenic animals by fusing milk‑protein gene promoters/regulatory sequences to heterologous coding sequences with secretion signals.
• § 102 analysis: Same architectural teaching as EP 0264166 — a mammary‑specific promoter (here β‑lactoglobulin‑type milk‑protein promoter) plus a heterologous gene plus a secretion signal (elements a–c of claim 1). It does not teach the casein enhancer (d) or the casein‑gene intron (e) as claimed. Potentially relevant to claims 1–3, 6–8; no full anticipation of any claim for the same (d)/(e) reason. (Confidence: moderate — I confirmed the citation and dates but could not retrieve the complete WO text within this session.)

3. WO 88/01648 A1

• Full citation: WO 88/01648 A1, "Expression of heterologous proteins by transgenic lactating mammals."
• Dates: priority 1986‑08‑28; published 1988‑03‑10.
• Description: PCT application covering expression of heterologous proteins in the milk of transgenic lactating mammals (i.e., the mammary‑gland bioreactor concept).
• § 102 analysis: Discloses the general scheme of a mammary‑specific regulatory/promoter sequence + heterologous coding sequence + secretion signal. Potentially relevant to claims 1–3, 6–8; no full anticipation of any claim for the same missing (d)/(e) elements. (Confidence: lower — I could not verify the applicant or the full technical disclosure of this document within this session, so treat the description as provisional.)

Critical date problem you should note

All three cited documents were published after the 1987‑02‑17 priority date of US 5,304,489:

Pre‑AIA § 102(a)/(b) prior art requires the reference to be publicly available before the invention date or more than one year before the US filing date. On publication date alone, none qualifies against 1987‑02‑17. Their citation therefore most plausibly reflects reliance on either (i) the applicant's later actual invention date (making them § 102(a) art), (ii) the earlier 1986 priority dates, and/or (iii) use as background/§ 103 references. I could not retrieve the examiner's reasons‑for‑allowance or the exact statutory basis, so I present this as an analytical observation, not a settled record fact.

Non‑patent references cited in the specification itself

The Background and Detailed Description cite (as prior art/state of the art): Gordon et al., PNAS 77:7380‑7384 (1980); Palmiter & Brinster, Cell 41:343‑345 (1985) and Ann. Rev. Genet. 20:465‑499 (1986); Stewart et al., NAR 12:3895‑3906 (1984); Swift et al., Cell 38:639‑646 (1984); Storb et al., Nature 310:238‑241 (1984); Grosschedl et al., Cell 41:885‑897 (1984); Shani, Nature 314:283‑286 (1985); Chada et al., Nature 314:377‑380 (1985); Magram et al., Nature 315:338‑340 (1985); Ornitz et al., Nature 313:600‑602 (1985); Krumlauf et al., MCB 5:1639‑1648 (1985); Overbeek et al., PNAS 82:7815‑7819 (1985); Hanahan, Nature 315:115‑121 (1985); Edlund et al., Science 230:912‑916 (1985); Hammer et al., Nature 315:343‑345 (1985); Kraemer et al., Banbury Report 20:221‑227 (1985); Jones et al., JBC 260:7042‑7050 (1985); Yu‑Lee et al., NAR 14:1833‑1902 (1986); Gorman et al., MCB 2:1044‑1051 (1982); Zinn et al., Cell 34:865‑879 (1983); Chirgwin et al., Biochemistry 18:5294‑5299 (1979); Brinster et al., PNAS 82:4438‑4442 (1985); Kafatos et al., NAR 7:1541‑1553 (1979); Quinn, J. Reprod. Fert. 66:161‑168 (1982); Labarca & Paigen, Anal. Biochem. 102:344‑352 (1980); Lee et al., PNAS 82:1419‑1423 (1985); Levine & Stockdale, JCB 100:1415 (1985); Hobbs et al., JBC 257:3598‑3605; Rosen et al., Ann. NY Acad. Sci. 478:63‑76 (1986); Godowski et al., Nature 325:365‑368 (1987); Kelly, Science 230:25‑32 (1985); Maniatis et al., Molecular Cloning (1982); Hammer et al., Science 235:53‑58 (1987). These establish the general tissue‑specific‑transgene concept but do not disclose mammary‑specific casein enhancer + casein intron constructs.

Bottom‑line assessment

1. Most relevant prior art: EP 0 264 166 (Integrated Genetics/Gordon & Groet; priority 1986‑04‑09, pub. 1988‑04‑20) — it discloses the same three‑element architecture as claim 1(a)–(c) (mammary/casein promoter × heterologous gene × secretion signal) and the transgenic‑mammal‑milk‑isolation method, and expressly reads on claim 10's "endogenous signal peptide" alternative.
2. Secondary art: WO 88/00239 (PPL, Clark & Lathe) and WO 88/01648 (published 1988‑01‑14 and 1988‑03‑10 respectively) — same general scheme.
3. Where the claims survive § 102: the novelty of claim 1 rests on the casein enhancer sequence (d) and the casein‑gene intron (e); none of the three cited references expressly discloses both, so no claim is fully anticipated on the retrieved record. Claims 4, 5, 9, 11, 12, 13 and 14 in particular add features (casein‑specific enhancer, MMTV GRE, α/β/κ‑casein intron, 5′/3′ UTRs, intron placement) that the cited art does not appear to disclose.

Verification gaps I want to be transparent about: (i) I could not directly open the USPTO Patent Center "References Cited" page for 5,304,489, so the three‑document list comes from the EPO/Espacenet record; (ii) I could not retrieve the full text of WO 88/00239 or WO 88/01648, so their technical descriptions are provisional; and (iii) the statutory basis on which each reference was actually applied by the examiner is not in the record I retrieved. If you need this hardened, the next step would be pulling the file wrapper (USPTO Patent Center for app. 07/602,066) and the EP 0279582 search report text.

I'll ground a few specifics before writing the §103 analysis.

Obviousness Analysis — US 5,304,489 under 35 U.S.C. § 103

Builds on (does not repeat): the claim-construction, cited-art, family, assignment, litigation and PTAB work already generated. The prior-art section concluded that no claim is fully anticipated on the retrieved record because element (d) (casein enhancer) and element (e) (casein-gene intron) are not expressly disclosed by EP 0264166, WO 88/00239 or WO 88/01648. This section takes the same record and asks the next question: the references that fail § 102 individually — do they render the claims obvious in combination? The answer, on this record, is yes for most claims, with two weak spots (claims 12 and 14).

1. Governing framework and posture

• Pre-AIA § 103. The application was filed 1990‑10‑24 as a continuation of Ser. No. 07/014,952 (filed 1987‑02‑17, abandoned), and the patent issued 1994‑04‑19. Pre-AIA § 103 governs. Graham v. John Deere, 383 U.S. 1 (1966) supplies the four factors (scope/content of prior art; differences; PHOSITA level; secondary considerations).
• TSM then vs. KSR now. At prosecution the Federal Circuit applied a rigid teaching‑suggestion‑motivation test; KSR Int'l v. Teleflex, 550 U.S. 398 (2007) now permits "common sense" reasoning, the "obvious to try" inquiry where there is "a design need or market pressure … and … a finite number of identified, predictable solutions," and combination of known elements "according to known methods" to yield predictable results. Under KSR, this claim set is materially more vulnerable than it was in 1994. That distinction is the single most important framing point.
• Mootness caveat (cross‑reference). The patent expired 2011‑04‑19 and no PTAB or district court proceeding has touched it. § 103 analysis here is therefore retrospective — useful for family/diligence purposes, for the EP opposition line (T 0743/98), for any § 286‑barred assertion, and for evaluating the sibling patents.
• Applicant admissions count. Statements in the '489 specification about the state of the art are usable as admissions of what a PHOSITA knew, independently of whether any particular reference qualifies as § 102 art.

2. Person having ordinary skill in the art (PHOSITA)

A Ph.D. or M.D. in molecular biology/biochemistry with 3–5 years of post‑doctoral experience in recombinant DNA and transgenic mouse technology, including: pronuclear microinjection (Brinster et al., PNAS 82:4438‑4442 (1985) — cited by the patentee as the protocol source); construction of fusion genes from characterized genomic clones; mammary‑gland biology and lactogenic hormone regulation; and routine practice of Maniatis (1982). This is the level the patentee's own examples assume — the specification describes embryo collection, injection, transfer, Southern blots, RNase/S1 mapping and CAT assays as routine steps with citations, not as invention.

3. Claim 1 decomposed — what the prior art supplies for each element

The critical structural observation: elements (a) and (e) are inseparable in practice. A construct built from the genomic casein clone — which is exactly what the '489 specification's Example 1 uses, and exactly what EP 0264166 instructs when it says that "when the milk protein gene is digested and the promoter isolated, a DNA fragment is selected which includes both the promoter and the signal encoding sequence directly downstream from the promoter" — carries the casein introns whether or not the artisan wanted them. Element (e) is therefore not an inventive contribution; it is an unavoidable property of practicing element (a) with the prior art's genomic starting material.

4. Date gate: which references are actually available

Before combining, the art must qualify. This is where the prior-art section's flag needs to be sharpened.

Practical consequence: the three patent documents are the architecturally closest references but carry a date problem; Jones 1985 is the date‑clean backbone. A robust obviousness position therefore runs Jones 1985 + the casein/gene‑regulation literature as primary art, with EP 0264166 cited as corroborating, applicant‑admitted background (the '489 patent's own text treats EP‑family‑era work as the state of the art).

5. The combinations

Combination I (primary) — EP 0264166 + Jones 1985 (+ Yu‑Lee 1986 / specification admissions)

Claim 1: EP 0264166 supplies (a), (b), (c) verbatim, plus the transgenic‑non‑human‑mammal and milk‑isolation context. Jones 1985 supplies (e) (8 introns, fully mapped) and (d) (conserved 5′ flanking regions identified as containing potential cis regulatory elements, including a receptor‑binding‑site homology).

Motivation: the references are in the same field, address the same problem, and Jones 1985 is the characterization of the very gene whose promoter EP 0264166 identifies as usable. EP 0264166 itself says "Casein promoters also have this advantage" (strength), so selecting casein is a substitution of one disclosed alternative for another — KSR factor (B). Adding the casein gene's own introns is not a design choice at all: it follows from using the genomic clone that both references use. Expectation of success: casein‑CAT fusion genes were already shown to give hormonally‑regulated promoter activity in mammary cells (Bisbee & Rosen 1986; Rosen et al., Ann. NY Acad. Sci. 478:63‑76 (1986)), and the general consensus was that tissue‑specific expression of transfected genes was achievable (Brinster 1981; Swift 1984; Shani 1985; WO 88/00239's own statement of that consensus).

Combination II — EP 0264166 + WO 88/00239 + WO 88/01648

All three independently describe mammary‑specific promoter × heterologous coding sequence × secretion signal × non‑human mammalian embryo. WO 88/00239: "incorporating a DNA sequence coding for the polypeptide into a gene of a mammal coding for a milk whey protein in such a way that the DNA sequence is expressed in the mammary gland." Two features drive the motivation: (i) redundancy — where three independent groups file the same architecture within five months (1986‑04‑09, 1986‑06‑30, 1986‑08‑28), the approach is by definition within the ordinary skill (evidence of the PHOSITA level and of predictability, not a stand‑alone legal test); (ii) the differences are one known element substituted for another (whey vs. casein promoter) to obtain the same disclosed result.

Combination III — Combination I or II + the 5′‑flanking/enhancer art, for element (d)

Add Edlund 1985 (rat insulin I requires an enhancer between ‑103 and ‑133 plus the promoter for cell‑specific expression), Hanahan 1985 (530 bp of insulin II 5′ flanking directs an SV40 oncogene to β‑cells in transgenic mice), Swift 1984 / Ornitz 1985 / Overbeek 1985 / Magram 1985 / Chada 1985 / Krumlauf 1985 / Walker 1983 / Ott 1984 / Ciliberto 1985 (tissue‑specific expression conferred by 5′ flanking DNA in transgenic animals and transfected cells), and Gorman et al., MCB 2:1044‑1051 (1982) for the SV1‑CAT vector that the '489 specification itself describes as "useful for screening for promoter‑independent enhancer activity in different DNA fragments." Yu‑Lee 1986 and Jones 1985 point to the specific casein fragments to test; Gorman 1982 supplies the routine assay. Element (d) is a capability limitation — "capable of conferring enhanced preferential transcription" — and the casein 5′ flanking inherently possesses whatever capability the patent demonstrates, since the patent itself shows the rat β‑casein genomic fragment driving mammary expression.

Combination IV (claim 5) — any of the above + the MMTV LTR glucocorticoid response element

The '489 specification supplies both the element and the motivation as admissions: the GRE "can be excised from plasmid pTK2A1 by digestion with Xho II to generate a 340 bp fragment capable of conferring glucocorticoid inducibility on the adjacent gene," and it "permits an additional 10‑ to 20‑fold induction … due to the elevated glucocorticoid levels present during lactation." The MMTV LTR GRE was a notorious, long‑known element, and Jones 1985 had already flagged a region of casein 5′ flanking 90% homologous to a progesterone‑receptor‑binding site — i.e., the casein promoter region was itself known to carry steroid‑response homology. Date caveat: Godowski 1987 (the specific pTK2A1 fragment) post‑dates the critical date; rely on the applicant's admission and the general MMTV GRE knowledge, not on Godowski alone.

Combination V (claim 10) — EP 0264166 alone (or Palmiter 1982 / Ornitz 1985)

Claim 10 (normally‑secreted polypeptide + its endogenous signal peptide) is expressly disclosed: "The signal sequence can be that which is naturally associated with the desired protein, if the protein is normally secreted (e.g., t‑PA)" — and EP 0264166's claim 3 is to exactly that. Palmiter 1982 (MT‑hGH) and Ornitz 1985 (elastase‑hGH) are the same pattern with signal‑peptide‑bearing secreted proteins.

6. Claim‑by‑claim obviousness assessment

7. Consolidated motivation to combine (KSR factors A–G)

1. Same field, same problem, same solution — all references target efficient, tissue‑specific production of foreign protein from mammary tissue; the field was small and self‑selecting.
2. Known elements performing known functions (KSR factor A) — promoter → transcription; enhancer → amplified/tissue‑restricted transcription; signal peptide → secretion; intron → the endogenous structure of the same gene. No new co‑action, no synergy, no mutual interaction beyond what each element was known to do.
3. Simple substitution (KSR factor B) — WAP vs. casein promoter; casein vs. heterologous signal peptide; genomic vs. cDNA.
4. Finite, identified, predictable solutions (KSR factor E) — the mammary‑specific gene palette was closed and known: α‑, β‑, γ‑, κ‑casein, α‑lactalbumin, β‑lactoglobulin, WAP.
5. Express teachings in the art — Edlund 1985 (enhancer + promoter needed for cell‑specific expression); Hanahan 1985 (5′ flanking suffices in transgenics); EP 0264166 ("secretion signal‑encoding sequence interposed between the gene and promoter"); Yu‑Lee 1986 (conserved casein 5′ flanks "may contain … cis regulatory elements"); Jones 1985 (β‑casein "9 exons separated by 8 introns").
6. The patentee's own admissions — the '489 Background concedes that enhancers in 5′ flanking DNA drive tissue‑specific expression, that the casein signal peptide "has been shown to be highly conserved throughout mammalian evolution" (citing Yu‑Lee), and that the SV1‑CAT vector is "useful for screening for promoter‑independent enhancer activity."
7. Reasonable expectation of success + independent simultaneity — three third parties filed the same architecture in a five‑month 1986 window; casein‑driven reporter genes were already hormonally regulated in mammary culture.

8. Where the patentee would push back — and my assessment

• "The casein enhancer was never localized." The '489 specification says only that one must "screen for the enhancer sequences by assaying the restriction endonuclease fragments." Assessment: this argument has real force against claim 4 and gives partial purchase against claim 1(d) — but it cuts the other way too, because the claim's enhancer is functional ("capable of conferring"), not structural, and Yu‑Lee/Jones pointed to the very fragments to screen. Under KSR, routine screening with a known vector (Gorman 1982) is ordinary skill.
• Teaching away: EP 0264166 states milk‑serum (WAP) promoters are "preferable to casein promoters … because caseins generally are produced … during pregnancy as well as after birth." Assessment: weak. The same passage says "Casein promoters also have this advantage," and the Gordon family text states "casein promoters can be used as well." A preference between two disclosed alternatives is not a disavowal (KSR; In re Fulton).
• Critical date: as set out in § 4, the three patent documents are vulnerable, and Yu‑Lee 1986 misses § 102(b) by eight days. Assessment: the single most consequential weakness in the obviousness case. The combination only works cleanly if Jones 1985 + the 5′‑flanking art + the specification admissions carry the load — and those do not by themselves teach the milk‑bioreactor concept (see § 9).
• No secondary considerations: there is no evidence of unexpected results, long‑felt need, or licensing‑driven commercial success with nexus to these claims. To the contrary, the specification's own data are adverse: expression "at a much lower level than the endogenous mouse gene," and only 1 of 3 founder females expressed detectably. That negates the classic rebuttal and may even suggest the claimed combination under‑performed expectations.

9. Residual uncertainty and what would harden the analysis

1. The '489 file wrapper (app. 07/602,066) — the single most valuable document. It would show (i) whether EP 0264166 / WO 88/00239 / WO 88/01648 were applicant IDS submissions or examiner‑applied art, and (ii) the examiner's stated reason for allowance. If they were IDS references never applied, the § 103 case is exactly the one I have built above, and the examiner likely relied on the (d)/(e) elements to allow.
2. Rosen's invention‑date evidence (lab notebooks, the Lee et al. abstract delivered December 1986, ASBC Abstract 1161). This fixes § 102(a) and determines whether Godowski 1987 and Hammer 1987 are art at all.
3. Full texts of WO 88/00239 and WO 88/01648 and the EP 0264166 search report — the prior-art section flagged both as partially unverified. Confirming whether any of them discloses a casein enhancer fragment or a casein intron would move claims 4 and 9 from "obvious" to "anticipated."
4. References not in the retrieved cited‑art record but worth pulling (flagged, not asserted): US 4,873,316 (appears in the Velander chain noted in the PTAB section, and in the Gordon‑family citation list) and US 4,736,866 (Leder/Stewart, Transgenic Non‑Human Mammals). Both have pre‑1987 US filing dates and would supply § 102(e) art with earlier effective dates than anything in this record. I could not verify their filing/§ 102(e) dates from the sources reached here.
5. Confirm the internal α‑casein/β‑casein heading inconsistency noted in the prior sections; it does not affect this analysis but should be resolved in any citation to the specification.

10. Bottom line

On the retrieved record, US 5,304,489's claim 1 is obvious under § 103 over the combination of (i) the mammary‑promoter/heterologous‑gene/secretion‑signal architecture the art had already reduced to a template and (ii) the fully characterized rat casein gene — where the casein introns of element (e) arrive automatically with the genomic casein clone of element (a), and where the casein enhancer of element (d) is a capability limitation satisfied by the conserved casein 5′ flanking regions that Yu‑Lee 1986 and Jones 1985 expressly identified as containing cis‑acting regulatory elements. Dependent claims 2, 3, 5, 6, 7, 8, 9, 10, 11 and 13 follow with equal or greater force; claim 10 is close to expressly disclosed by EP 0264166. Claims 4, 12 and 14 are the only genuinely contestable claims — claim 4 because the enhancer was not pinpointed, claims 12 and 14 because no date‑clean reference supplies the functional rationale the specification asserts for them.

Honest limit on this conclusion: the analysis is carried by the architectural references, and those are exactly the references whose § 102 status is weakest (post‑critical‑date publication; Hilmer bars foreign priority as a § 102(e) date). If EP 0264166 and the two WOs are excluded, the date‑clean art (Jones 1985, Yu‑Lee 1983, Hobbs & Rosen 1982, Blackburn 1982, Hennighausen & Sippel 1982, plus the Swift/Ornitz/Magram/Overbeek/Krumlauf 5′‑flanking line and Gorman 1982) establishes every element except the milk‑as‑bioreactor objective itself — which the '489 specification's own Background concedes was the recognized goal of the field. That gap, and only that gap, is where a validity defense would have to live, and it is narrowed to nothing if the file wrapper shows the applicant itself put the three mammary‑bioreactor references in the record.

Verification links: US 5,304,489 — https://patents.google.com/patent/US5304489/en · EP 0264166 B1 — https://patentimages.storage.googleapis.com/9a/8b/1b/bb8d6cfbdf6bfa/EP0264166B1.pdf and https://patents.google.com/patent/EP0264166A1/en · WO 88/00239 — https://patents.google.com/patent/WO1988000239A1/en · Jones et al. 1985 — https://pubmed.ncbi.nlm.nih.gov/[3997858](/patent/3997858)/ · Yu-Lee et al. 1986 — https://doi.org/10.1093/nar/14.4.1883 · EPO T 0743/98 (EP counterpart) — https://legacy.epo.org/boards-of-appeal/decisions/pdf/t980743eu1.pdf.