US 5733761

I'll search for authoritative information on this patent number.

US 5,733,761 (queried as "5733761") — Analyst Summary

Search scope and sources actually consulted

I was not able to retrieve the authoritative granted claim set from the full text I was given (it is cut off mid-Example 1k, before the claims). See "Uncertainty" below.

Bibliographic data (high confidence)

• Patent number: US 5,733,761 (as rendered on Google Patents: US5733761A)
• Title: Protein production and protein delivery
• Inventors: Douglas Treco; Michael W. Heartlein; Richard F. Selden
• Original assignee: Transkaryotic Therapies, Inc. (TKT)
• Current assignee of record (per Google Patents): Shire Human Genetic Therapies Inc (successor-in-interest to TKT)
• Application number: US 08/451,893
• Filing date: 1995-05-26
• Priority date: 1991-11-05 (earliest priority claimed)
• Issue/publication date: 1998-03-31
• Status: Expired – Lifetime; anticipated expiration listed as 2015-03-31
• "Family has litigation" flag: Yes (Google Patents/Critical flag, Darts-IP worldwide litigation dataset)
• Representative classifications: A61K48/00 & A61K48/0066 (gene therapy); C12N15/90, C12N15/907 (homologous recombination in mammalian cells); C07K14/505 (EPO); C07K14/61 (growth hormone); C12N2830/42 (intron/splice element for transcription)

Note on the two dates: the "2015-05-26" that appears in the DrugPatentWatch table is simply 20 years from the 1995-05-26 filing date; Google Patents' stated anticipated expiration of 2015-03-31 differs from that, which usually reflects patent term adjustment / terminal disclaimer calculations. I am not certifying either date as the legally correct expiration.

Abstract

From the published patent abstract (PATENT ABSTRACTS record):

"The present invention relates to transfected primary, secondary and immortalized cells of vertebrate origin, particularly mammalian origin, transfected with exogenous genetic material (DNA) which encodes a desired (e.g., a therapeutic) product or is itself a desired (e.g., therapeutic) product, methods by which primary, secondary and immortalized cells are transfected to include exogenous genetic material, including DNA targeting by homologous recombination, methods for the activation and amplification of endogenous cellular genes, methods by which cells useful for large-scale protein production can be obtained, methods of producing clonal cell strains or heterogenous cell strains, and methods of gene therapy in which transfected primary, secondary or immortalized cells are used."

Plain-language overview of the disclosure

The patent is a core "transkaryotic"/endogenous gene activation patent. Rather than inserting a whole exogenous cDNA for a therapeutic protein, the disclosed method turns on a gene the cell already has by homologous recombination: a targeting construct carrying a strong promoter (e.g., mouse metallothionein-I) plus a suitable exon/splice element is integrated upstream of, or into, the endogenous gene at a preselected site. The activated endogenous gene can then be co-amplified using a linked amplifiable selectable marker (dhfr, ada, CAD), producing large amounts of protein. The spec exemplifies activation of the endogenous human EPO and hGH genes in primary/secondary human fibroblasts, delivery via implanted (optionally encapsulated) cells, and conversion of a genomic gene into an intronless cDNA copy for microbial expression.

Independent claims — plain-language overview

⚠️ Caveat first. The claim text below comes from a secondary database (DrugPatentWatch's claims page keyed to "5733761"), not from the authoritative printed claim set, which I could not obtain. The same DrugPatentWatch page contains an apparently anomalous entry tying 5,733,761 to NATPARA (parathyroid hormone, Takeda), which is inconsistent with this patent's subject matter and assignee history — so treat the claim mapping with caution. The claim language shown is nonetheless topically consistent with the TKT gene-activation family (which also includes US 5,641,670, US 5,733,746 and others), so it may belong to a sibling patent rather than to 5,733,761 itself.

Independent claims identified by number (from the partial text retrieved):

• Claim 20 — DNA construct (composition of matter). A DNA construct useful for altering expression of a "targeted gene," comprising a targeting sequence, a regulatory sequence, an exon, and an unpaired splice donor site. Dependent claims specify that the targeted gene is erythropoietin, and that the construct's exon may encode a protein fragment either the same as or different from the fragment encoded by the first exon of erythropoietin (claims 23, 25, 26).
• Claim 28 — Method of making a homologously recombinant cell in vitro. Transfect the cell in vitro with a DNA construct comprising (i) a targeting sequence, (ii) a regulatory sequence, (iii) an exon, and (iv) an unpaired splice donor site; then maintain the transfected cell in vitro under conditions appropriate for homologous recombination — where the targeted gene is not normally expressed in the cell and its expression is thereby altered. Dependents add a CAP site in the exon (29), and a protein selected from erythropoietin and growth hormone (30–33).
• Claim 45 — Method of altering expression of a targeted gene in vitro. Transfect the cell in vitro with the construct, maintain under homologous-recombination conditions to produce an HR cell, then maintain the HR cell under conditions appropriate for expression of the gene (gene not normally expressed in the cell).
• Claims 49 / 50 — Methods (species-limited). Independent methods as above, wherein the targeted gene is the erythropoietin gene (claims 57, 58 depend from 49 and 50 respectively).
• Claim 59 — Method of making a protein in vitro. Transfect the cell in vitro with the DNA construct, allow homologous recombination to give an HR cell, then maintain that cell under conditions appropriate for expression of the gene, thereby making the protein — again where the targeted gene is not normally expressed in the cell.

In plain terms: one composition claim covering the promoter/exon/splice-donor targeting construct, and a set of in vitro method claims covering (a) making the homologously recombined cell, (b) turning the dormant gene on, and (c) making the protein from it — with EPO- and GH-specific dependent claims.

Litigation / CAFC check

• No CAFC 2026 docket for US 5,733,761 was located. Given that the patent's listed legal status is Expired – Lifetime with an anticipated expiration in 2015, 2026 appellate activity concerning it would be improbable; my searches surfaced nothing.
• Historic TKT appellate litigation found: Genzyme Corp. v. Transkaryotic Therapies, Inc., No. 02-1312 (Fed. Cir. Oct. 9, 2003) (Rader, Schall, Linn, JJ.) — Fed. Cir. affirmed summary judgment of non-infringement and addressed construction of "chromosomally integrated," "regulatory sequence," and "stably" in patents on methods of producing human α-galactosidase A. On the record I retrieved, this appeal involved Genzyme's patent, not US 5,733,761. I cannot confirm from the sources reviewed that 5,733,761 itself was asserted in that appeal.
• Google Patents flags that the family has worldwide litigation (Darts-IP dataset), consistent with the TKT/Amgen EPO disputes of the 1990s–2000s, but I did not retrieve the specific case docket linking 5,733,761 to a particular suit.
• A related patent, US 5,733,746 (Treco, Mar. 1998), was cited in a later prosecution as "withdrawn" — worth noting if you are tracing the family, but I have not verified what that reference means here.

Explicit uncertainties

1. Claim set not authoritatively verified. The granted claims of US 5,733,761 were not present in the full text provided to me, and my retrieveable secondary source is internally inconsistent (the NATPARA entry). Do not rely on the claim summary above for a validity, infringement, or freedom-to-operate analysis without pulling the granted claims from USPTO PatentCenter/Patent Public Search.
2. Claim count and claim 1 were not retrieved; the highest claim number I saw was 59, so the patent has at least 59 claims.
3. Expiration date: two different dates circulate (2015-03-31 vs. 2015-05-26); I did not determine which is legally operative.
4. Assignee chain: Google Patents lists Shire Human Genetic Therapies Inc as current assignee, but this comes with Google's own disclaimer that assignee listings may be inaccurate; Takeda's acquisition of Shire post-dates any assignment recorded at issuance.
5. No CAFC 2026 activity found — this is a negative search result, not proof of absence.

I'll research litigation involving US patent 5733761, prioritizing live search results over my training data.

Initial searches returned patent citations rather than litigation records. Let me search litigation-specific sources.

The Amgen/TKT cases center on different patents ('080, '349, '422, '698, '933). Let me search specifically for litigation involving this patent's family and the patent number.

Summary of Findings

Important caveat up front: Based on my searches, I could not confirm any litigation in which US 5,733,761 was specifically asserted as a patent-in-suit (or challenged). I want to be explicit about that rather than imply otherwise. What I did find is the well-documented EPO patent litigation between Amgen and Transkaryotic Therapies (TKT) — the owner of the '761 patent — but that litigation involved Amgen's patents, not the '761. Details below.

1. Patent identification (confirmed via Google Patents)

Note: Google Patents carries a "Family has litigation" indicator with a Darts-IP link for family 27505771. That flag is family-level, not patent-level, and my searches did not resolve it to a specific case asserting the '761 itself.

2. Litigation I could confirm — but involving different patents

The dominant EPO litigation involving TKT (the '761's owner) is:

Amgen Inc. v. Hoechst Marion Roussel, Inc. (now Aventis Pharmaceuticals, Inc.) and Transkaryotic Therapies, Inc.

• Court / jurisdiction: U.S. District Court for the District of Massachusetts (Judge William G. Young)
• Case number: D. Mass. (I believe 00-cv-11996, but I am not fully certain of this number — flagging the uncertainty rather than guessing)
• Federal Circuit appeal: No. 01-1191, decided 2003; reported at 314 F.3d 1313 (Fed. Cir. 2003)
• Patents in suit: US 5,621,080; 5,756,349; 5,955,422; 5,547,933; 5,618,698 (none of these is US 5,733,761)
• Outcome/status: District court (Jan. 19, 2001) found TKT's gene-activated EPO infringed the '080, '349 and '422 patents. On appeal, the Federal Circuit affirmed in part, vacated in part, and remanded (314 F.3d 1313); the case continued through further district court proceedings (287 F. Supp. 2d 126; 339 F. Supp. 2d 202) and a second Federal Circuit appeal.
• Sources: https://law.justia.com/cases/federal/appellate-courts/F3/314/1313/[531650](/patent/531650)/ ; https://www.courtlistener.com/opinion/[211134](/patent/211134)/amgen-v-hoechst-marion-roussel-now-known-as-aventis-pharmaceuticals/

Parallel UK proceeding (same technology dispute, not a US patent):

• Kirin-Amgen Inc. and others v. Hoechst Marion Roussel Ltd and others, House of Lords, [2004] UKHL 46, decided 21 October 2004 — Amgen's EP 0148605B2 held not infringed by TKT's gene-activation method and invalid for over-broad claims. Source: https://www.parliament.the-stationery-office.co.uk/pa/ld200304/ldjudgmt/jd041021/kirin-1.htm

Why this matters for your question: In this litigation TKT was the defendant, and the '761 was not an asserted patent. The '761 appears in the record only as a cited reference (e.g., cited against later patents), not as a patent-in-suit. See, e.g., Google Patents citing "US5733761A" in later patent families.

3. What I could NOT establish

• No case identified in which US 5,733,761 itself was asserted or challenged.
• The searches returned the "Family has litigation" flag but did not surface the underlying case for family 27505771. Given the '761 is a TKT gene-activation patent and a sibling to US 5,641,670, the most likely litigation association is the Amgen/TKT EPO dispute family — but I could not verify that the '761 was ever formally in suit, and I will not assert it was.
• My docket-specific searches (Unified Patents, Docket Alarm, "5,733,761" + lawsuit) did not complete successfully (search step limit reached), so the picture is incomplete.

4. Recommended next steps to close the gap

If you need a definitive answer, I would check these directly (I could not fully query them here):

1. Darts-IP family record for family 27505771 (the source of the Google Patents litigation flag) — Darts-IP link: https://patents.darts-ip.com/?family=27505771
2. PACER / CourtListener docket search restricted to "5,733,761" as patent-in-suit.
3. PTAB records (IPR/PGR) — the '761 expired 2015, but check for any pre-expiration challenges.
4. USPTO Patent Center for the '761 (Appl. 08/451,893) — any litigation-related papers of record.

Bottom line: Publicly, the confirmed litigation tied to the '761's owner (TKT) and technology is the Amgen v. Hoechst Marion Roussel/TKT EPO dispute, which asserted Amgen's patents — not US 5,733,761. I found no confirmed case naming US 5,733,761 as an asserted patent, and I am flagging the family-level litigation flag as unresolved rather than overstating it.

I'll verify the structured "no PTAB activity" default with targeted searches before finalizing.

Confirming the structured default with a few more targeted queries on the patent and its TKT family siblings.

Proceedings overview

Total AIA trial proceedings on US 5,733,761: zero (0). The canonical USPTO Open Data Portal list supplied for this patent is empty, and my web searches surfaced no IPR, PGR, or CBM petition, institution decision, Final Written Decision, or Federal Circuit appeal arising from a PTAB trial on this patent. Breakdown: 0 active / 0 claims invalidated / 0 claims sustained / 0 settled / 0 institution denials — there is simply nothing to categorize.

Bottom line for a defendant: this is not a "hardened-by-surviving-IPR" patent, and it is not a "claims-1-5-canceled" patent. It is an untested-at-the-PTAB, expired patent. The claims have never been construed or adjudicated by the Board, no statutory estoppel attaches to anyone under 35 U.S.C. § 315(e)(2), and any challenger retains the full universe of § 102/§ 103 art. The reason is structural, not accidental: the patent issued 1998-03-31 from a 1995-05-26 filing with a 1991-11-05 priority date, making PGR categorically unavailable (PGR reaches only patents issuing from applications filed on or after 2013-03-16, 35 U.S.C. § 321(c)) and CBM ineligible (not a covered business method patent, and the program sunset 2020-09-16 under AIA § 18). That leaves IPR as the sole AIA vehicle — and IPR was never filed.

Corroboration caveat: I attempted four additional verification searches (family siblings 6,214,620 / 5,968,502 / 5,994,127; Unified Patents activity; PTAB E2E; year-by-year IPR number strings) but hit the tool-step limit before all returned. Results that did return were consistent with no PTAB activity (they surfaced only Amgen/TKT district court material and the sibling '502 patent's Orange/Purple Book listing). I am relying primarily on the structured ODP block, which is the authoritative source here, and I am flagging that my independent web corroboration is partial rather than exhaustive.

No proceedings to report

Because the structured list is empty, there is no {PROCEEDING_NUMBER} — {Petitioner} v. {Patent Owner} entry to populate. I will not generate placeholder or synthesized proceeding numbers. The relevant facts instead are these:

• Issuance / expiry: Granted 1998-03-31; expired 2015-03-31 (17-year pre-URAA term from grant). Status per Google Patents: "Expired - Lifetime."
• Assignee chain: Transkaryotic Therapies, Inc. (original) → Shire Human Genetic Therapies, Inc. (current listed). TKT was acquired by Shire in 2005, i.e., before the IPR regime matured into a routine biotech defensive tool and before the 2015 expiry.
• AIA window: IPR became available 2012-09-16; the '761 expired 2015-03-31. That is a ~2.5-year window in which an IPR could theoretically have been filed.
• Time bar never triggered: § 315(b) bars a petition filed more than one year after service of a complaint alleging infringement of the patent. My searches identified no case asserting the '761 itself, so on the available record the one-year clock likely never started for any party. See cross-reference to the earlier Litigation summary section, which likewise found no confirmed case naming the '761 as patent-in-suit.
• Cross-reference / consistency note: The earlier section flagged a family-level "Family has litigation" indicator (Darts-IP family 27505771). I found nothing to contradict that section. The confirmed litigation — Amgen Inc. v. Hoechst Marion Roussel, Inc. and Transkaryotic Therapies, Inc., D. Mass., aff'd in part/vacated in part, 314 F.3d 1313 (Fed. Cir. 2003) — asserted Amgen's patents ('080, '349, '422, '933, '698), with TKT as defendant. That is an Article III dispute, not a PTAB trial, and it is not a proceeding "on" the '761.

Strategic summary

Claim status — CANCELED / SUSTAINED / UNTESTED. There is no PTAB record to parse, so at the Board level every claim of the '761 is "untested." No claim has been canceled by the PTAB, no claim has been sustained by a Final Written Decision, and no substitute claim has been added by amendment. I deliberately do not state a claim count or list surviving claims: the authoritative full text provided in this prompt truncates before the claim set, and I will not invent claim numbers or quote dispositions that do not exist. If you need the claim set, pull it from the issued patent at https://patents.google.com/patent/US5733761/en or Patent Center for Appl. 08/451,893.

Estoppel landscape — there is none. This is the single most useful point for a defendant. Because no IPR was ever instituted on the '761, no § 315(e)(2) estoppel attaches to any party or privy. That means:

• No petitioner is barred from raising any § 102/§ 103 ground.
• Grounds that could have been raised in an IPR — including art a hypothetical petitioner would have "reasonably could have raised" — remain fully available in district court, IPR, or both.
• Conversely, a defendant gets no free ride: there is no prior FWD to point to, no Board-issued claim construction, and no Administrative Patent Judge credibility findings to leverage. Validity must be litigated from scratch under § 282, and the burden is the clear-and-convincing standard, not the PTAB's preponderance standard.

Pattern signals. No repeated-petitioner pattern (no petitioner at all). No patent-owner appeal activity, since there is no FWD to appeal. No defensive aggregator — Unified Patents never filed, and to my knowledge never targeted the TKT/Shire gene-activation portfolio. The absence of PTAB activity here is explainable and is itself the signal: this patent's family was litigated against its owner, not by its owner, and the patent expired in 2015 — before the 2015–2020 NPE-era IPR wave and before the biotech sector broadly adopted IPR as a standard defensive posture. Well-asserted patents eventually attract IPRs; the '761 was never asserted in a way that did.

Recommended next steps

1. Treat the absence as the finding, but close it out formally. The emptiness of the ODP list is corroborated but not yet exhaustively verified. Confirm by searching PTAB E2E (https://ptacts.uspto.gov/ptacts/) for the patent number and for family members, and check the "Trials" tab on the patent's Patent Center record for Appl. 08/451,893.

2. Check ex parte reexamination — which is not an AIA trial and therefore outside the structured block. Ex parte reexam is the one post-issuance PTO vehicle that (a) was available throughout the patent's life and (b) is not captured by an "AIA trial proceedings" list. Review the '761's file history for any reexam request or certificate. If a reexam certificate exists, the resulting claim amendments (not PTAB cancellation) would define the true scope you face.

3. Do not build a defense on PTAB history, because there is none. If you receive a demand citing the '761:

   • Confirm the assertion window: the patent expired 2015-03-31, so any recovery is limited to past damages within the § 286 six-year lookback and only for acts occurring before expiry.
   • Verify whether the '761 has ever been asserted as patent-in-suit in any district court action (PACER / CourtListener docket search on "5,733,761"). If it has not, be skeptical of any demand letter implying a litigation-tested patent.
   • Assess validity de novo — the full prior-art field is open, unencumbered by § 315(e)(2).

4. If a live case ever surfaces alleging infringement (none found), note that any IPR would now be unavailable as a practical matter — § 315(b) would likely be triggered by service, and the Board has historically been reluctant to institute on long-expired patents where no live claim scope remains to construe. That cuts against the IPR route and toward summary judgment on invalidity/squarely raising the expiry and damages defenses in district court.

Specific links for the record:

• Patent: https://patents.google.com/patent/US5733761/en
• USPTO ODP (source of the empty proceedings list): https://data.uspto.gov/
• PTAB E2E: https://ptacts.uspto.gov/ptacts/
• PTAB decisions portal: https://www.uspto.gov/patents/ptab
• CourtListener: https://www.courtlistener.com/

I'll research the assignment record for US 5,733,761, prioritizing live search results and flagging anything I cannot verify.

Let me verify the reel/frame record I've surfaced and check for any additional assignments.

I found concrete assignment records. Let me verify the reel/frame details and check for any additional links in the chain.

Assignment & Ownership Analysis — US 5,733,761

Scope note / research limit: I was able to retrieve the substance of the assignment chain from live sources, but my docket-level searches (USPTO Assignment Center, PacerMonitor, direct reel/frame lookups) were cut off by a search-step limit before I could open the Assignment Center record itself. Where a specific reel/frame or correspondent could not be independently confirmed, I say so rather than assert it. The primary ownership events below are corroborated by two independent sources plus a Delaware Chancery opinion.

Inventors

Pattern check — "all inventors departing within 12 months of filing": Not present. Each named inventor was a TKT employee/insider, and at least two (Selden, Heartlein) remained with the company for roughly a decade after the 1991 priority filing and through the fabrication of the platform. There is no evidence of the near-simultaneous inventor exodus that typically precedes a portfolio fire-sale. If anything, the inventor list is a founder-heavy roster, not a contractor roster.

Original assignee

Transkaryotic Therapies, Inc. ("TKT") — a Cambridge, Massachusetts biopharmaceutical company.

• Line of business: cell-based protein therapeutics built on the "transkaryotic" / gene-activation platform claimed in this patent (engineered cells that express a therapeutic protein, including delivered via implantable devices). TKT's lead commercial asset was Replagal (agalsidase alfa) for Fabry disease (approved in the EU; never U.S.-approved).
• Did it ship a product embodying the claims? Partially / indirectly. TKT commercialized protein therapeutics manufactured via the cell-engineering technology claimed here (Replagal being the flagship). The '761's claims are broad platform claims, so "embodying the claims" applies to the manufacturing platform, not a discrete device.
• Current status: Not operating as an independent entity; not in bankruptcy. TKT was acquired by Shire Pharmaceuticals Group plc in a merger completed 27 July 2005 (~$1.6B, $37.00/share). TKT was the surviving corporation and, per the Delaware Chancery record (954 A.2d 346, n.124), thereafter filed a certificate of amendment changing its legal name to Shire Human Genetic Therapies, Inc. Shire plc was later acquired by Takeda Pharmaceutical Company Limited (completed 8 Jan 2019), making Shire HGT an indirect wholly-owned Takeda subsidiary.

Assignment timeline

Chronological reconstruction from what is verifiable. Important caveat: the underlying ownership change here is a change of name, i.e., the same legal entity re-named after the merger — not a transfer to a different owner. That is materially different from an assignment in the NPE sense.

• 2006-01-17 (executed) / recorded 2006-12-04 — Reel 018590 / 0044 (reported by Plainsite as "Patent Assignment 18590/44")

  • Conveyance: Change of Name
  • Assignor: Transkaryotic Therapies, Inc.
  • Assignee: Shire Human Genetic Therapies, Inc., 700 Main Street, Cambridge, MA 02139
  • Correspondent: Not surfaced in the sources I could open. I will not invent one. (See "Repeat correspondent," below.)
  • Context: Change of name only / post-merger housekeeping. Reflects TKT's post-merger renaming to Shire HGT; ownership stayed inside the same corporate family.

• Same event, second reel/frame (unresolved discrepancy — flagging explicitly): A Google Patents assignment citation for this family reports a Change of Name, assignor TRANSKARYOTIC THERAPIES, INC., at Reel/Frame 018224/0390, executed 2006-01-17. Note the same execution date as the 018590/0044 record but a different reel/frame. Family-wide name-change recordings are routinely filed under more than one reel/frame (the Plainsite 18590/44 record expressly lists sibling application 09/312,245 → US 6,565,844, not the '761 itself). I could not confirm which reel/frame specifically covers US 5,733,761, and I flag 018224/0390 vs. 018590/0044 as an unresolved cross-source discrepancy rather than pick one.

• Original (pre-issuance) assignment, inventors → TKT: implied by the "Original Assignee: Transkaryotic Therapies Inc" designation, but no separate reel/frame was surfaced for an inventor-to-TKT employment assignment. Not confirmed.

• No post-2006 ownership-transfer assignment was found. The patent expired 2015-03-31, so the 2019 Shire→Takeda acquisition would not ordinarily generate a patent-assignment record. Google Patents still lists the current assignee as Shire Human Genetic Therapies, Inc.

Cross-source corroboration of the core event: In re Transkaryotic Therapies, Inc., 954 A.2d 346 (Del. Ch. 2008) independently confirms the corporate mechanics — merger consummated 27 July 2005, TKT the surviving corporation, followed by a certificate of amendment changing the name to Shire Human Genetic Therapies, Inc. This maps exactly onto a recorded "Change of Name" conveyance dated Jan 2006. Sources: Del. Ch. opinion · Plainsite assignment 18590/44 · Google Patents US5733761.

Timeline diagram

timeline
    title Ownership of US 5733761
    1991 : Priority date 5 Nov
    1995 : Application 08 451 893 filed
    1998 : Patent issued 31 Mar
    2005 : TKT merged into Shire 27 Jul
    2006 : Change of Name recorded 4 Dec
    2015 : Patent expired 31 Mar
    2019 : Shire acquired by Takeda

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. The only recorded conveyance is a Change of Name (reel 018590/0044, exec. 2006-01-17 / rec. 2006-12-04) from TKT to Shire HGT — the same legal entity renamed, at a Cambridge, MA operating-pharma address (700 Main Street). No "IP / Licensing / Holdings" LLC appears anywhere in the chain.

2. Known asserter in the chain — Not present. Neither Transkaryotic Therapies, Inc. nor Shire Human Genetic Therapies, Inc. appears on the RPX / Unified Patents / Patent Progress high-frequency-plaintiff lists. (Related to the prior litigation section: TKT was a defendant in Amgen's EPO suit, not an asserter here, and — as that section established — US 5,733,761 itself was not an asserted patent.)

3. Repeat correspondent across the chain — Unclear / could not assess. The correspondent of record was not surfaced in the records I could open, so I cannot confirm or rule out a recurring filing attorney. This is the single biggest evidentiary gap in this report; it is a data gap, not a negative finding.

4. Cascading transfers — Not present. One ownership-relevant event in 2006, then nothing. No chain of LLCs, no back-to-back transfers inside 24 months, no shared-address cluster.

5. Pre-litigation transfer — Not present. The 2006 name-change predates any assertion and, in any event, is not a transfer to a litigating party.

6. Bankruptcy fire-sale — Not present. TKT was sold via an all-stock/cash merger at $37/share, not a Chapter 7/11 sale. (TKT did face shareholder appraisal and fiduciary litigation over the merger — see 954 A.2d 346 — but that is litigation over deal price, not insolvency.)

7. Privateering — Not present. Shire retained the asset inside its own corporate subsidiary rather than handing it to an independent NPE to assert against competitors.

8. Defensive aggregator (anti-NPE) — Not present. The chain does not terminate at RPX, AST, LOT, Unified, or OIN. It terminates at an operating pharma (Shire HGT, now a Takeda subsidiary).

Verdict

Insufficient data.

Justification: on the merits, the record affirmatively shows an operating-company chain with no NPE characteristics — the sole recorded conveyance is a post-merger Change of Name from Transkaryotic Therapies, Inc. to Shire Human Genetic Therapies, Inc. (exec. 2006-01-17 / rec. 2006-12-04, reel 018590/0044, address 700 Main Street, Cambridge, MA), which is a renaming, not an ownership transfer, and which is corroborated by In re Transkaryotic Therapies, Inc., 954 A.2d 346 (Del. Ch. 2008). None of the eight NPE signals is present. However, because (a) the correspondent of record was never surfaced, (b) two conflicting reel/frames (018590/0044 vs. 018224/0390) could not be reconciled, and (c) I could not open the Assignment Center record directly, the record is best characterized as original-assignee-retained / name-change only rather than a fully reconstructed chain. This is a "no NPE evidence" result, not a positive NPE finding.

Verify directly at: https://assignmentcenter.uspto.gov/ (search by patent number 5733761) and the indexed mirror https://assignment.uspto.gov/patent/index.html — specifically confirm whether the '761 itself sits on reel 018590/0044, reel 018224/0390, or both, and capture the correspondent attorney of record for the 2006 Change of Name, which is the missing link in signal #3.

I'll research the prior art cited against US 5,733,761, building on the patent identification already established. Let me search multiple sources.

I have partial citation data. Let me retrieve the complete "Referenced Cited" lists from Justia and Google Patents, and verify the key references.

Scope, method, and honesty caveat

I attempted to pull the face-of-the-patent citation list for US 5,733,761 from the USPTO. Direct access to USPTO PatentCenter / the full-text database was not available to me within this session; my retrieval came through the Google Patents and Justia mirrors of the USPTO record. I hit the tool-step ceiling partway through, so the list below is what I could actually retrieve and verify, not a guaranteed-complete transcription of the patent's front page. I flag each item's confidence. I did not substitute results for similar numbers (e.g., JP 5733761 B2, which is an unrelated cellulose/resin patent, is excluded).

Sources actually used:

• https://patents.google.com/patent/US5733761/en (authoritative full text supplied)
• https://patents.justia.com/patent/5733761 ("Referenced Cited" tables)

1. Same-number confirmation

This is consistent with the record already established in the earlier litigation section (US 5,733,761; Treco/Heartlein/Selden; Transkaryotic Therapies; Appl. 08/451,893; priority 1991-11-05; granted 1998-03-31), so I will not re-state it. One correction to carry forward: do not confuse US 5,733,761 with the "5733761" appearing in Google Patents forward citations (e.g., as a reference cited by later patents) nor with JP5733761B2. Only US 5,733,761 is in scope.

2. Patent citations appearing on/for US 5,733,761 ("Referenced Cited")

2a. U.S. Patent Documents (confirmed from the Justia "Referenced Cited" table)

2b. Foreign Patent Documents (as listed in the Justia table)

Contradiction/flag to raise: The presence of 1992–1994 PCT publications (WO 92/20808, WO 93/04169, WO 94/05784, WO 94/12650) on a patent with a 1991-11-05 priority date is anomalous for pure § 102(b) art. It strongly suggests either (a) they were cited as § 102(e)/intervening art, or (b) they are applicant's-own/related disclosures listed for completeness during the 1995 continuation prosecution. I could not resolve which, and I will not assert one.

3. Most relevant prior art and § 102 map

Because I do not have the literal claim text of the '761 in front of me (the supplied full text is the description, not the claims), the following is a provisional § 102 mapping keyed to the subject matter the specification emphasizes: (i) transfecting primary/secondary/immortalized vertebrate cells with exogenous DNA; (ii) homologous-recombination activation of a normally silent endogenous gene by inserting/replacing a regulatory sequence; (iii) amplification via an amplifiable selectable marker (dhfr, ada, CAD); (iv) in vitro protein production; (v) gene therapy/delivery, barrier devices, vaccination, antibody production.

Ranked by anticipatory risk:

1. US 5,272,071 (Chappel) — highest risk. Its disclosure of homologous-recombination gene activation maps directly onto the '761's core method (targeting a regulatory sequence to activate an endogenous gene). It is the reference an examiner would use for a § 102 rejection of method/construct claims if those claims are not entitled to the 1991-11-05 priority (making Chappel § 102(e) art). If the claims are entitled to 1991-11-05, Chappel's Dec. 21, 1993 issue date removes it from § 102(a)/(b) and leaves only § 102(e) (§ 103 for obviousness).

2. WO 91/06667 (Skoultchi, PCT/US90/06436) and WO 91/06666 — published May 1991, i.e., before the priority date → genuine § 102(b) art. These describe gene activation via homologous recombination and are the references most capable of anticipating method claims that are not limited to the specific cell types/constructs of the '761.

3. WO 90/11354 (Oct. 1990) — § 102(b) art for homologous-recombination/gene-targeting method claims broadly.

4. WO 91/09955 (July 1991) — § 102(b) art that combines promoter-replacement activation with amplifiable marker DNA (ada/dhfr/CAD). Directly anticipates the '761's "activate + amplify the endogenous gene" combination claims if those claims are generic.

5. US 4,822,736 (Kellems) — § 102(b) art for the amplification element alone; anticipates only broad claims to selecting amplified gene copies, not claims tied to homologous-recombination activation.

6. US 4,656,134 (Ringold) — § 102(b) art for the generic "exogenous DNA expressed in cultured cells" element; unlikely alone to anticipate the targeting/activation claims.

Net assessment: The '761's novelty/non-obviousness rests on the combination — homologous-recombination replacement of an endogenous regulatory region to activate a silent endogenous gene plus co-amplification via a linked amplifiable marker, in primary/secondary (non-immortalized) cells. The § 102(b) PCTs (WO 90/11354, WO 91/06666/067, WO 91/09955) are the only cited references capable of full anticipation; Chappel is the dominant § 102(e)/§ 103 reference. The remaining foreign references are, on the retrieved data, either not verified or post-priority-date and thus unlikely to support a standalone § 102 rejection.

4. What remains unverified (please treat as gaps, not findings)

• The complete U.S. "Referenced Cited" list — I retrieved only the three US patents above before the tool budget expired; the Google Patents "Citations" block was not fully captured.
• The literal claim set of the '761, which is required to make a binding § 102 element-by-element comparison (anticipation requires every limitation disclosed in a single reference).
• Subject matter/titles for most EP/GB/WO numbers (I marked "not verified" rather than guess).
• Whether any of the post-priority PCTs were cited as § 102(e) art.

Recommended next steps: (1) pull the front page (Item [56] "References Cited") and the full claim set from USPTO PatentCenter for Appl. 08/451,893; (2) pull the file history to see which of these references were used in actual § 102/§ 103 rejections vs. merely listed; (3) cross-check Chappel's effective filing date to confirm § 102(e) applicability.

I'll ground this analysis in verifiable prior art before drawing conclusions. Let me run targeted searches.

Key prior art has surfaced. Let me verify the two closest references and the front-page citations.

Obviousness Analysis — US 5,733,761 under 35 U.S.C. § 103

Note on inputs. The "Prior Art section" of the page supplied to me contained only (a) the Prior art keywords (dna, sequence, exon, cells, gene) and (b) the internal Definitions block. The front‑page list of cited references and the granted claims were not present (the fetched full text truncates mid‑Example 1k). I therefore built the reference inventory below from independent verification, and I flag every item I could not verify. The claim characterization is taken from the previously generated section, with its reliability caveat preserved.

Nothing in the live searches contradicted the prior sections; two things confirmed them: the family's 1991‑11‑05 priority (US 07/787,840 and 07/789,188) and the inventors (Selden, Heartlein, Treco, assignee Transkaryotic Therapies) appear on the family's EP/PCT members — EP 0 750 044 A3 and WO 93/09222 A2. One item the previous section flagged as unresolved (the family litigation flag) is now partly resolved and turns out to be directly relevant to § 103 — see § 3.

1. Governing law and critical dates

The application was filed 1995‑05‑26, well before the AIA's first‑inventor‑to‑file provisions (effective 2013‑03‑16). Pre‑AIA § 103(a) applies, and the controlling obviousness framework is Graham v. John Deere, 383 U.S. 1 (1966), as relaxed by KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007) (no rigid teaching‑sampling‑teaching requirement; "obvious to try" and "predictable result" rationales available).

Key point: the prior art window that matters is everything before November 5, 1991. Both of the two closest references (below) fall inside that window, one of them by roughly two years.

2. Level of ordinary skill in the art ("PHOSITA")

A person of ordinary skill in the 1991 art would hold a Ph.D. (or M.S. plus several years' experience) in molecular biology/genetics and would routinely practice: (i) construction of mammalian expression/targeting plasmids; (ii) gene transfer into cultured cells (electroporation, calcium phosphate, lipofection, retroviral vectors); (iii) homologous recombination/gene targeting and selection schemes (neo/G418, TK/ganciclovir, gpt, positive‑negative selection); (iv) promoter/enhancer and splice‑site manipulation; and (v) gene amplification by dhfr/MTX, CAD/PALA, or ada/adenosine‑analog selection. The patent's own specification assumes exactly this skill level — it cites Thomas & Capecchi (1987) for the neo cassette, Hamer & Walling (1982) for mMT‑I, Lin et al. (1985) for the EPO sequence, and Semenza et al. (1990) for EPO upstream regulation.

3. Prior art inventory

Not verified / deliberately excluded. WO 91/12650 and WO 94/12650 surfaced in a citation trail as "gene activation" references; I did not verify their applicants or teachings, and WO 94/12650 is post‑priority in any event. TKT's own family members — WO 93/09222, EP 0 750 044, EP 0 649 464, US 5,641,670, US 5,733,746, US 6,063,630, US 6,270,989, US 6,354,241, US 6,565,844, US 6,846,676, US 6,214,622 — are same‑inventive‑entity/same‑family and are not § 102/§ 103 art against the '761 (they raise obviousness‑type double patenting, a separate issue).

4. Limitation mapping (using the previously generated claim characterization)

Every element of the characterized independent claims reads on PA‑1 + PA‑2 alone, with only the "exon + unpaired splice donor" element requiring PA‑10. That is the entire § 103 battleground, and it is narrow.

5. The combinations, and why the PHOSITA would have made them

Combination A (primary): PA‑1 (Chappel '071) + PA‑2 (WO 91/06667 / Cell Genesys)

Covers: claims 20, 28, 45, 49, 50, 59 in their broadest form (construct + in vitro activation of a non‑expressed endogenous gene).

Motivation to combine — this is unusually strong, because the two references are not merely combinable, they were actually combined by the relevant art:

1. Same problem, same solution, same era. PA‑1 (filed Dec 1990, priority Dec 1989) and PA‑2 (filed Nov 1990, priority Nov 1989) are near‑contemporaneous and are directed at the identical problem: activating a silent endogenous gene by homologous insertion of a heterologous regulatory element.
2. Interference No. 105,114 — an actual interference between the Chappel/ARS '071 patent and Cell Genesys claims (the D. Mass. § 146 appeal references "the '114 Interference" and the Board's decision that "CGI Claims 107‑109 Are Unpatentable"). An interference is per se evidence that the two disclosures were regarded as claiming the same invention — i.e., that a PHOSITA would view them as alternative/substitutable teachings for one problem. This is the KSR "simple substitution of one known element for another" rationale in its most concrete form.
3. Redundancy argument forecloses attack. Because each reference independently contains the full concept, this is not a case where the motivation must be inferred — it is a case where "the improvement is not inventive, it is the straightforward application of a known concept."
4. Predictability of result. PA‑11 (promoter insertion) taught, a decade earlier, that juxtaposing a strong heterologous promoter with a cellular gene switches that gene on. Routine screening (Southern blotting, PCR, ELISA — all used in the '761's own Examples) makes the outcome verifiable, not speculative.

Combination B: A + PA‑4 (targeting methodology) + PA‑3 (vector architecture)

Covers: the "maintain under conditions appropriate for homologous recombination," "select," and "identify the HR cell" steps.

Motivation: PA‑1 and PA‑2 disclose the strategy; PA‑3/PA‑4 supply the enabling routine detail (homology‑arm length, selectable marker insertion, G418/6‑TG selection, PCR/Southern confirmation). Combining a known method with the standard tools for practicing it is the paradigm of § 103 ("known technique to improve a similar device in the same way"). The '761 spec itself treats Thomas & Capecchi (1987) as the starting point for its neo cassette — an express admission that this element was conventional.

Combination C: A (or B) + PA‑5 (amplification)

Covers: the amplification-dependent claims and the spec's central "activate‑then‑co‑amplify" teaching.

Motivation:

1. PA‑2 expressly supplies the missing element — its granted claim recites an "amplifiable gene" together with the heterologous regulatory sequence, defines the desired relationship ("so that said endogenous target gene is capable of being amplified when said amplifiable gene is amplified"), and names dhfr, MT‑I, ada and ornithine decarboxylase. Nothing more is needed for the amplification limitations.
2. PA‑5 supplies the enabling mechanics — dhfr/MTX and CAD/PALA amplifications are documented, and the co‑amplification of linked sequences (the property the '761 exploits) is an inherent, long‑known consequence of the amplification mechanism.
3. Productive‑result motivation — both gene‑activation references state that the purpose is commercial‑scale protein production; increasing copy number of the activated locus was the standard way to increase output. "Obvious to try" with a high expectation of success.

Combination D: A + PA‑7 (EPO and hGH gene sequences/regulation) + PA‑6 (mMT‑I)

Covers: the EPO‑specific (claims 23, 25, 26, 30?–33, 57, 58) and GH‑specific dependent claims.

Motivation: EPO and hGH were the flagship therapeutic proteins of the period, both cloned and sequenced (PA‑7), and both were known to be transcriptionally silent in fibroblasts — making them the natural targets for an activation strategy aimed at fibroblasts (PA‑8). The mMT‑I promoter (PA‑6) was the standard strong, inducible promoter used in exactly this laboratory context (and is the promoter used in the '761's own pXGH5). Selecting a known, valuable, silent gene and a known strong promoter is "the application of a known technique to a known device ready for improvement." The one wrinkle the patentee might point to — replacing hEPO exon 1 with hGH exon 1 while preserving the reading frame and secretion — is performed on published sequences by a PHOSITA following the genetic code; it is design work, not invention.

Combination E: A + PA‑8 (implanted engineered fibroblasts) + PA‑9 (barrier devices)

Covers: the delivery/implantation and encapsulated‑cell subject matter.

Motivation: The patent itself concedes that "presently‑available approaches to gene therapy make use of infectious vectors" and that the object is a better delivery route. PA‑8 teaches the exact delivery modality the '761 claims (autologous/allogeneic fibroblasts engineered ex vivo, then implanted for systemic protein delivery). PA‑9 supplies the immunoisolation concept and the specific membrane materials the '761 recites (cellulose, cellulose acetate, polysulfone, PVDF, PVC). The motivation is the standard one — avoid immune rejection, permit retrieval, allow xenogeneic/allogeneic donors — and the '761 articulates no more than that.

Combination F (the narrow point): A + PA‑10 (splice‑donor/expression‑vector art)

Covers: the "exon … and an unpaired splice donor site" limitation.

Motivation: Once the PHOSITA has decided to drive an endogenous gene with an upstream promoter, and once the target gene's sequence and exon structure are in hand (PA‑7), the need to obtain a properly processed, translatable, secretable transcript dictates the design: place an exon immediately downstream of the promoter and terminate it in a splice donor, so that splicing fuses it to the next available downstream acceptor. That is precisely what the SV40 16S splice cassette did in the '761's own pCDNEO, and it follows mechanically from the known GT‑AG splicing rule. The alternative designs (using the endogenous exon 1) were available and were in fact also disclosed by the patentee (pXEPO‑11 uses the natural hEPO exon 1). Where a reference discloses a small number of alternatives and one is selected for a predictable reason, the selection is obvious.

Caveat I must flag: I could not verify that any single pre‑1991 reference expressly recites an "unpaired splice donor site" as a construct element in a gene‑targeting vector. If the '761's claims genuinely turn on that precise element, this is where a nonobviousness argument would be fought — but the argument is weak, because the element is a mechanical consequence of known splicing rules rather than an unpredictable discovery.

Combination G (aggregate predictability of result): A + PA‑11

The proposition that inserting a strong promoter upstream of a cellular gene activates that gene was established biology long before 1991 (promoter insertion in retrovirally induced lymphomas). That the activated gene can then be selected, amplified, and harvested is routine biotechnology. The overall result — "a cell that makes a lot of a protein it previously made none of" — was the expected, not the unexpected, consequence of the combination.

6. KSR rationale matrix

7. § 102 overlap risk (worth stating, because it shadows the § 103 analysis)

PA‑2 is not merely a § 103 reference; it is a candidate § 102(a)/§ 102(e) anticipation of the broadest construct and method claims. The granted claims of the family member EP 0 747 485 B1 recite, in substance: a construct with an amplifiable gene and/or a heterologous regulatory sequence plus flanking homology to a region "within or proximal to" an endogenous target gene; integration by homologous recombination; operative association; amplification of the endogenous gene; expression controlled by the regulatory sequence; endogenous gene "normally not expressed"; the host cell being a "primary cell" / "fibroblast"; the target gene being "erythropoietin"; and a host cell bearing a CMV promoter/enhancer operatively associated with the human EPO gene.

If the '761's claim 20 and method claims are as characterized in the prior section, the claim charts against PA‑2 approach identity of subject matter. The only daylight is the "exon + unpaired splice donor" element and the hGH/EPO chimeric‑transcript specifics. Practical consequence: the patentee's § 103 defense is effectively forced onto that narrow element — which is exactly why Combination F matters most.

Additionally, PA‑1 is a § 102(g)(2) candidate (Chappel, 1989) and PA‑2 a § 102(g)(2) candidate (Cell Genesys/Skoultchi, 1989) — both predate TKT's November 1991 filing by about two years, and the '114 interference indicates the Office treated the two as priority‑competing. I did not retrieve the final interference judgment (I have only the § 146 motion papers), so I present this as a risk, not a conclusion.

8. Secondary considerations, and how they fare

What the patentee could argue:

1. Skepticism / unexpected success in primary and secondary (non‑immortalized) human cells. Gene targeting had been demonstrated chiefly in mouse ES cells and immortalized lines; the '761 gives real data in secondary human fibroblasts (targeting ratio ~1/712; hEPO secreted from targeted clones). This is the patentee's best argument.
2. Long‑felt need for gene therapy that avoids retroviral vectors (insertional mutagenesis, replication‑competent virus, limited cloning capacity, short‑lived expression) — the '761's own background section lists these.
3. Commercial success — TKT's gene‑activated EPO program and the Amgen/TKT litigation.

Why these are likely to fail or be discounted:

• The "need" and the "solution" are stated in the prior art itself. PA‑1 and PA‑2 both articulate the same motivations (avoid episomal/CDNA instability; exploit the intact genomic locus including intronic enhancers; obtain stable, amplifiable, high‑level expression). The background section of a contemporaneous gene‑activation EP publication (EP 0 779 362 A1, EPO publication server) does so at length — "It would be most desirable to develop a method of induction of gene expression that would produce a cell line that has incorporated the positive attributes of the existing methods but somehow circumvents the unattractive features." Where the asserted advantage is recited in the prior art, it cannot be an unexpected result.
• Cell type is a species limitation, not the inventive concept. The characterized independent claims recite "a cell," not a primary fibroblast. The "primary/secondary cell" feature lives in dependent claims and in the Definitions block, which is a claim‑construction matter. Even for those dependents, PA‑2's granted claims expressly specify "a primary cell" and "fibroblast, lymphocyte, epithelial or endothelial cell" — so even the species argument is pre‑empted.
• The targeting‑frequency data cut against the patentee. The spec reports ~1 in 700 targeted‑to‑non‑targeted events with routine drug selection — i.e., a screenable, unsurprising frequency, not an unexpected technical feat.
• Commercial success is weakly linked to the claims and largely attributable to the biologics regulatory pathway and to the value of EPO itself, not to the claimed activation method (the same EPO was already produced commercially from CHO cells). Nexus is the weak link.
• No teaching away. Nothing in PA‑1, PA‑2, or PA‑10 dissuades the PHOSITA from the claimed route; if anything the whole field was moving toward it.

9. Patentee's best rebuttals, and my assessment

10. Bottom line, confidence, and residual gaps

Conclusion. On the record I can verify, there is a strong, multi‑path § 103 case against US 5,733,761:

• PA‑1 (Chappel, US 5,272,071) + PA‑2 (WO 91/06667 / Cell Genesys; EP 0 452 484 / EP 0 747 485) discloses every core element — targeting sequence, regulatory sequence, homologous recombination, activation of a normally silent endogenous gene, and an amplifiable marker — and the two were actually in interference (Interference No. 105,114), which is about as direct a "motivation to combine" as a § 103 record can contain.
• Dependent subject matter falls to ordinary secondary references: dhfr/CAD/ada amplification (PA‑5), EPO and hGH sequences and regulation (PA‑7), mMT‑I (PA‑6), cell implantation and immunoisolation (PA‑8, PA‑9), and standard targeting methodology (PA‑3, PA‑4).
• The only meaningful resistance point is the "exon + unpaired splice donor" limitation, and even that is vulnerable as an obvious design choice dictated by known splicing rules (PA‑10), especially given the patentee's own disclosure of a second, equivalent embodiment.
• I would expect a § 102 anticipation challenge to be at least as dangerous as the § 103 challenge, given how closely the EP 0 747 485 B1 claim language tracks the characterized '761 claims.

Confidence levels. High confidence in the bibliographic/priority facts and in the content of PA‑1 and PA‑2 (both independently sourced). Moderate confidence in the limitation mapping, because the '761's granted claims were not in the text I was given, and the previously generated section already flags that its claim text came from a secondary database with an internal inconsistency (a NATPARA entry that does not match this patent's subject matter). If the claim mapping is wrong — e.g., if the "unpaired splice donor" claim belongs to a sibling such as US 5,641,670 rather than to 5,733,761 — the § 103 conclusion for the actual '761 claims could differ materially, and this analysis must be re‑run against the granted claims from USPTO Patent Public Search / PatentCenter (App. 08/451,893).

Explicit gaps I did not close.

1. The granted claim set of US 5,733,761 (claim 1 in particular) — not retrieved.
2. The front‑page reference list of the '761 — not present in the provided text; the cited prior art used here was reconstructed.
3. Whether the Chappel '071 was before the examiner and overcome, and on what basis (this would sharpen the analysis considerably — if '071 and the Cell Genesys art were considered, novelty must reside in the splice‑donor/exon element or in the construct architecture).
4. The final judgment in Interference No. 105,114 (I have only the § 146 motion papers and a deposition notice).
5. WO 91/12650 (and WO 94/12650) — surfaced in a citation trail; applicant and teaching not verified, so excluded.
6. Whether the '761's claims are entitled to the 1991‑11‑05 priority for § 102(b) purposes (assumed, not verified claim‑by‑claim).