US RE48267

I'll start by pulling what I can from authoritative sources for this specific number, then reconcile with the full text you supplied.

Good — the ITC and District Court hits are valuable. Let me pin down the actual reissue claims and any 2026 appellate activity.

US RE48,267 E — quick reference summary

Bottom line: This is a U.S. reissue patent owned by BioMarin Pharmaceutical Inc., titled "Variants of C-type natriuretic peptide." It is the patent BioMarin has asserted against Ascendis Pharma's TransCon CNP (navepegritide), and it is listed in the FDA Orange Book against VOXZOGO (vosoritide). I confirmed bibliographic data and the litigation posture, but I could not obtain an authoritative full claim set — see the explicit caveats below.

1. Bibliographic data (as reported by the sources)

⚠️ OCR caution (do not auto-correct): the scanned front page renders two inventor names as "Shimong Long" and "Augustus O. Olchamafe," and the examiner as "Bruce R. Campell." These are near-certain OCR artifacts of "Shinong Long," "Augustus O. Okhamafe," and "Bruce R. Campbell," but I am reporting the literal strings and flagging them rather than silently normalizing. Similarly, the reissue lists Price at "Munich (DE)," while other family documents list him in California.

2. Abstract (verbatim)

"The present disclosure provides variants of C-type natriuretic peptide (CNP), pharmaceutical compositions comprising CNP variants, and methods of making CNP variants. The CNP variants are useful as therapeutic agents for the treatment of diseases responsive to CNP, including but not limited to bone-related disorders, such as skeletal dysplasias (e.g., achondroplasia), and vascular smooth muscle disorders (e.g., restenosis and arteriosclerosis)."
(drugpatentwatch.com/p/patent/RE48267; confirms the PDF front page (57) abstract)

3. Plain-language overview of the independent claims

A significant conflict exists between two sources, and I want to flag it rather than paper over it.

Source A — DrugPatentWatch's claim listing (https://www.drugpatentwatch.com/p/patent-claims/RE48267) renders a claim set in which the independents are:

• Claim 1 — CNP-53 variant species. "A variant of C-type natriuretic peptide (CNP) selected from the group consisting of: … (Gly-CNP53) [SEQ ID NO:179]; … (Pro-CNP53) [SEQ ID NO:185]; … (Met-CNP53) [SEQ ID NO:190]; DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [CNP-53(M48N)] [SEQ ID NO:180]." In plain terms: a small, closed list of full-length 53-residue CNP molecules distinguished by the first residue and one internal substitution.
• Claim 5 — Method of treatment. Administering one of those CNP variants to treat a bone-related disorder/skeletal dysplasia, limited to achondroplasia, hypochondroplasia, short stature, dwarfism, and homozygous achondroplasia.
• Claim 6 — Method of recombinant production. Culturing a host cell containing a first polynucleotide encoding a CNP variant linked to a second polynucleotide encoding a cleavable peptide/protein, expressing the fusion polypeptide (directly linked or via a linker), for the same CNP-53 variant list.
• Claims 2–4 (pharmaceutical composition; lyophilized citrate/acetate-buffered formulation pH ~4–6; with isotonicity/bulking agent or antioxidant) and 7 (species of cleavable fusion partner — e.g., TAF12 and its mutants, KSI, MBP, β-gal, GST, thioredoxin) are dependent.

Source B — the ITC/Ascendis litigation record shows RE'267 has claims numbered at least through 48, with independent claims 15 and 18 that are not the claims described in Source A:

• Claim 15 (independent). "A macromolecule capable of releasing a CNP variant, comprising a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage, wherein hydrolysis of the hydrolysable linkage releases the CNP variant." In plain terms: a conjugate — peptide plus a synthetic polymer — joined by a bond that breaks by hydrolysis, such that the polymer is cleaved off and the CNP variant is set free. This is essentially a CNP prodrug claim.
• Claim 18 (independent). "A sustained release CNP variant formulation comprising a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage" — the same conjugate concept framed as a formulation.
• Claims 16–17 and 19–20 are dependent on them; claims 31–48 form further claim(s)/dependents (content not available to me). The parties litigated construction of "CNP variant," "sustained release CNP variant formulation," "hydrolysis," "coupled to … through a hydrolysable linkage," "macromolecule," "synthetic polymeric group," and "contacting the/a cell" — the last term indicating at least one method-of-use independent claim exists in the 31–48 range.

My assessment of the conflict (stated as uncertainty): these two descriptions are difficult to reconcile as a single 1–7 claim set. The litigation record (a Commission notice and a party's own DJ complaint) is the more reliable indicator of what RE'267 actually claims. It is plausible that (a) the DrugPatentWatch extract is a partial/stale or mis-mapped rendering of the family (note the sibling reissue RE46,707, same title, different inventors' addresses, filed Jan. 23, 2015 from app 14/604,262), or (b) claims 1–7 are indeed the opening claims of a 48-claim reissue. I could not resolve this, and the Google Patents text you supplied does not include a claims section at all. Any statement of RE'267's independent claims should be verified against the USPTO PatentCenter/Patent Public Search full text before being relied upon.

4. Litigation and docket status

• ITC Investigation No. 337-TA-1447, Certain Drug Products Containing C-Type Natriuretic Peptide Variants and Components Thereof. Complaint filed by BioMarin April 2, 2025; instituted May 8, 2025 (90 FR 19532–33). Asserted claims were 15–20 and 31–48 of RE'267. Respondents: Ascendis Pharma, Inc.; Ascendis Pharma A/S; Ascendis Pharma Growth Disorders A/S; Wacker Biotech GmbH (and Bachem AG added Sept. 2025). Accused product: TransCon CNP ("navepegritide"), a CNP prodrug with a linker and synthetic polymeric group.
• March 23, 2026: Commission declined to review Order No. 36, terminating claims 15–22, 31, 33, 35–40, 42, 44, and 45–48 from the investigation (claims 21–22 had been asserted for domestic-industry purposes only). By subtraction, the claims remaining live appear to be 23–30, 32, 34, 41, and 43 (my inference, not a stated source conclusion). This is a substantial narrowing of the asserted claim set.
• May 15, 2026: Commission declined review of Order No. 45 (respondent name change to Ascendis Pharma, LLC).
• N.D. Cal. declaratory judgment: Ascendis Pharma A/S et al. v. BioMarin Pharmaceutical Inc., 5:25-cv-03302 (filed April 11, 2025; § 271(e)(1) safe harbor, non-infringement and restraint on infringement statements); a further Ascendis DJ action appears at 4:25-cv-05696 (filed July 7, 2025; noted by third-party analytics as 3:25-cv-05696).
• Parallel ex-U.S.: BioMarin sued Ascendis in the UPC Munich Local Division (ACT_1613/2025; UPC_CFI_18/2025) on EP 3175863 B1, a counterpart; EPO opposition upheld EP 3175863 B1 in amended form Sept. 23, 2024, now on appeal; Danish revocation action (BS-14603/2025-SHR) stayed.
• Protest in reissue: the ITC complaint references an Ascendis-filed protest under 37 C.F.R. § 1.291 against the reissue application.
• Post-issue prosecution: a third-party tracker records a Certificate of Correction post-issue communication dated Oct. 14, 2025 (greyb/pharsight). Unverified against USPTO.

On the CAFC search specifically: I found no Federal Circuit appeal, oral argument, or docket entry involving RE48267 in my searches. Because a Federal Circuit docket is ordinarily visible only after an appeal is taken (e.g., from a final ITC determination or the N.D. Cal. case, both of which are still pending), the absence is expected at this stage — but I want to be explicit that this is a negative search result, not a confirmed "no appeal exists."

5. Commercial relevance

Per drugpatentwatch.com, RE48267 protects VOXZOGO (vosoritide), BioMarin's NDA 214938 (powder, subcutaneous; approved Nov. 19, 2021), with the listed patented use "USE TO INCREASE LINEAR GROWTH IN PEDIATRIC PATIENTS WITH ACHONDROPLASIA WITH OPEN EPIPHYSES." The family is reported as 45 members across 24 countries, with European patent 2432489 carrying SPCs in at least Luxembourg, the Netherlands, Denmark, Belgium, and Germany.

6. Explicit uncertainties

1. Claim set: I do not have a verified verbatim claim set for RE48267. The two claim descriptions above conflict; treat Source A as unreliable until checked.
2. Original patent identity: "US 8,598,121, issued Dec. 3, 2013, app 13/466,672 filed May 8, 2012" comes from an OCR of the reissue front page and should be confirmed.
3. CAFC: no 2026 Federal Circuit activity located for RE48267 (negative result only).
4. Date note: your prompt states the current date as April 26, 2026, yet my searches returned documents dated after that (e.g., the May 15, 2026 Commission determination, and trackers updated July/August 2026). I am reporting what the sources say without adjusting for that discrepancy.
5. Google Patents data (priority date 2009-05-20, expiration 2030-05-20, "Active" status, litigation flag) is explicitly labeled by Google as assumption-based, not a legal conclusion.

I'll research litigation involving US Patent RE48267. Let me run several targeted searches.

Let me dig deeper into the specific cases and check for PTAB proceedings and additional district court actions.

Litigation Involving U.S. Patent No. RE48,267 ("RE'267")

Important note on dates: Your prompt states the current date is April 26, 2026, but my system date is September 29, 2026, and the search results I retrieved include events through August 30–31, 2026 and a CAFC decision of March 26, 2026. I am reporting the full record including post-April-2026 events, since search results are to be treated as current ground truth. Flagging this so you can apply the correct cutoff for your purposes.

Bottom line: Yes — RE48,267 has been the subject of active, high-profile litigation. The patent covers BioMarin's VOXZOGO® (vosoritide) and was asserted against Ascendis Pharma's competing achondroplasia drug (TransCon CNP / navepegritide / "Yuviwel"). All identified proceedings now appear resolved by a global settlement announced August 30, 2026.

Summary of Known Proceedings

Details

1. USITC Investigation No. 337-TA-1447

Certain Drug Products Containing C-Type Natriuretic Peptide Variants, and Components Thereof

• Complainant: BioMarin Pharmaceutical Inc. (Novato, CA)
• Respondents: Ascendis Pharma, Inc. (Palo Alto, CA); Ascendis Pharma A/S (Hellerup, Denmark); Ascendis Pharma Growth Disorders A/S (Hellerup, Denmark); Wacker Biotech GmbH (Jena, Germany). Bachem AG (Bubendorf, Switzerland) was added by amended complaint (Order No. 15, Aug. 14, 2025, not reviewed Sept. 12, 2025).
• Complaint filed: April 2, 2025; instituted: May 8, 2025 (90 FR 19532-33).
• Asserted claims: claims 15–20 and 31–48 of RE'267. Accused products: "a prodrug of CNP, including the drug substance, the linker of the drug substance, and other components, such as the synthetic polymeric group, and vials, prefilled syringes, autoinjectors, or other presentations of TransCon CNP… for the treatment of achondroplasia."
• Relief sought: limited exclusion order and cease-and-desist orders.
• Key procedural rulings:
  • Target date set at Oct. 8, 2026 (Order No. 5); extended to Nov. 30, 2026 (Order No. 17) and then to Dec. 21, 2026 (Order No. 21, not reviewed Dec. 12, 2025). Final initial determination on violation due July 30, 2026.
  • March 23, 2026: Commission declined to review Order No. 36 (Mar. 3, 2026), terminating claims 15–22, 31, 33, 35–40, 42, 44 and 45–48 from the investigation (claims 21–22 having been asserted only for domestic-industry purposes). Note this was an unopposed motion by BioMarin.
  • May 15, 2026: Commission declined to review Order No. 45 reflecting respondent Ascendis Pharma, Inc.'s name change to Ascendis Pharma, LLC.
• Outcome: Under the August 30, 2026 global settlement, BioMarin will dismiss the pending Section 337 investigation.

2. Ascendis I — N.D. Cal. No. 4:25-cv-03302

• Plaintiffs: Ascendis Pharma A/S; Ascendis Pharma Growth Disorders A/S; Ascendis Pharma, Inc.
• Defendant: BioMarin Pharmaceutical Inc.
• Filed: April 11, 2025 (some dockets show this as 5:25-cv-03302).
• Cause: 28 U.S.C. § 2201 declaratory judgment of non-infringement; Ascendis also invoked the 35 U.S.C. § 271(e)(1) statutory safe harbor for its pre-approval manufacture/importation of TransCon CNP.
• Outcome: Ascendis voluntarily dismissed without prejudice on July 7, 2025, expressly stating it would refile to seek a mandatory stay under 28 U.S.C. § 1659(a)(2).

3. Ascendis II — N.D. Cal. No. 4:25-cv-05696

• Plaintiff: Ascendis Pharma A/S. Defendant: BioMarin Pharmaceutical Inc.
• Filed: July 7, 2025. Cause: 28 U.S.C. § 2201 declaratory judgment.
• Assigned to: Judge Yvonne Gonzalez Rogers; referred to Magistrate Judge Susan G. van Keulen. Patents listed on the docket: 8,198,242; 8,906,847; RE48,267.
• Ruling: On September 19, 2025, the district court granted BioMarin's motion for a discretionary stay under Landis v. North American Co. and denied Ascendis's motion for a mandatory stay as moot (finding the request untimely under the 30-day deadline of § 1659). One litigation database lists this docket as terminated 2025-09-09, consistent with the stay/dismissal activity.
• Outcome: Resolved by the August 2026 global settlement (parties agreed to resolve all claims pending in the N.D. Cal.).

4. Federal Circuit Appeal — Ascendis Pharma A/S v. BioMarin Pharmaceutical Inc. (opinion Mar. 26, 2026)

• Panel: Judge Stoll (author), joined by Judges Lourie and Chen. Precedential. Reported by one firm as 170 F.4th 1368 (Fed. Cir. 2026) — I have not independently verified that reporter citation.
• Holding: Affirmed. A party that voluntarily dismisses and refiles an identical declaratory judgment action cannot restart the 30-day clock for a mandatory § 1659(a)(2) stay. The court found Ascendis had Article III standing (BioMarin's stated intent to seek a preliminary injunction following FDA approval created a controversy of sufficient immediacy) and that the collateral-order doctrine supported jurisdiction, but found the district court's § 1659 error harmless because Ascendis was not entitled to a mandatory stay. The court noted FDA approval of Ascendis's drug occurred shortly after oral argument.
• Appeal docket number: not confirmed from my search results.

5. Related ANDA action (RE48,267 listed but NOT asserted)

• BioMarin v. Zydus (vosoritide ANDA). Per the complaint, Zydus's ANDA contained a Paragraph IV certification only as to U.S. Patent 8,198,242 (the '106 patent as referred to in the filing) and a Paragraph III certification as to RE48,267, i.e., Zydus did not seek approval before RE48,267's May 20, 2030 expiration. RE48,267 therefore does not appear to have been asserted in this action. I could not verify the case number, court, or filing date from the retrieved results, so I am not stating them.

6. Patent Trial and Appeal Board

• No IPR, PGR, or other PTAB proceeding against RE48,267 was identified in my searches. The PTAB documents that surfaced in results concerned unrelated patents.

Outcome / Current Status (as of the latest retrieved information)

On August 30, 2026, BioMarin announced binding terms with Ascendis Pharma A/S resolving all global patent and ancillary disputes:

• Ascendis pays BioMarin a 20% royalty on U.S. net sales of Yuviwel (navepegritide), retroactive to first commercial sale.
• Ascendis pays 18% on net sales in the EU, Brazil and South Korea, through May 2030.
• Ascendis receives a license to BioMarin's patents relating to Yuviwel for all current and potential indications (achondroplasia, hypochondroplasia) and for combination use.
• BioMarin will dismiss the ITC Section 337 investigation; the parties resolve all remaining claims, including litigation in Brazil, Denmark, Germany, South Korea and the Northern District of California.

Caveats

• I did not retrieve a BioMarin affirmative district court infringement suit on RE48,267; BioMarin's U.S. enforcement vehicle was the ITC action, while Ascendis was the district-court plaintiff (DJ actions).
• The N.D. Cal. docket numbers appear in both "4:25-cv-…" and "5:25-cv-…" forms depending on source (divisional filing designation); the CAFC opinion uses 4:25-cv-03302 and 4:25-cv-05696.
• Foreign case numbers (Brazil, Denmark, Germany, South Korea) were not available in my results.
• The CAFC appeal docket number and the exact F.4th citation were not independently confirmed.
• Because your stated date (April 26, 2026) precedes several events reported above (the May 2026 ITC order, the March 2026 CAFC decision postdates your date only marginally, and the August 2026 settlement postdates it substantially), confirm which cutoff you intend.

Primary sources retrieved:

• ITC notice (institution): https://www.govinfo.gov/content/pkg/FR-2025-05-08/html/2025-07994.htm
• ITC notice (target date extension): https://www.usitc.gov/secretary/fed_reg_notices/337/337_1447_notice09152025sgl.pdf
• ITC notice (Order No. 45): https://regulations.justia.com/regulations/fedreg/2026/05/19/2026-10010.html
• ITC notice (partial termination, Order No. 36): https://www.usitc.gov/sites/default/files/secretary/fed_reg_notices/337/337_1447_notice03232026sgl.pdf
• CAFC opinion summary: https://ipwatchdog.com/2026/03/26/cafc-affirms-district-courts-denial-mandatory-stay-itc-respondent-voluntarily-dismissed-complaint/
• Pillsbury case chronology: https://www.pillsburylaw.com/en/news-and-insights/federal-circuit-timing-requirement-stay.html
• Ascendis I docket: https://dockets.justia.com/docket/california/candce/5:2025cv03302/[447936](/patent/447936)
• BioMarin settlement press release: https://www.biomarin.com/news/press-releases/biomarin-announces-global-settlement-with-ascendis-pharma-a-s-ascendis-will-pay-royalties-to-biomarin-on-yuviwel-sales-in-u-s-eu-brazil-and-south-korea/
• Patent-level litigation listing: https://www.drugpatentwatch.com/p/litigation/patent/index.php?query=RE48267

I'll start by checking for any PTAB proceedings on RE48267 that the ODP feed may not have indexed, plus any related litigation/appeal activity.

Let me dig into the PTAB proceeding referenced (Ascendis petition) and any IPR/PGR targeting RE48267 specifically.

Important nuance: the Ascendis PGR appears to target a different BioMarin patent (the '106 patent), not RE48267. Let me verify whether any IPR/PGR actually names RE48267, and pin down the related litigation and settlement timeline.

Proceedings overview

Zero AIA trial proceedings are on file against RE48267. The USPTO ODP structured feed returns none, and my independent web checks (PTACTS petition documents, third-party PTAB trackers, docket aggregators) surfaced no IPR, PGR, or CBM petition naming U.S. Reissue Patent No. 48,267 as the challenged patent. The tally is therefore: 0 proceedings — 0 active, 0 claims invalidated, 0 claims sustained by the Board, 0 settled, 0 institution denials.

Defensive posture: this is not a "hardened by IPR" patent and not a "claims 1–5 are dead" patent. It is an untested-before-the-Board patent. The closest PTAB activity is PGR2026-00013 (Ascendis v. BioMarin), but that petition challenges a different BioMarin patent, U.S. 12,233,106 B2 — not RE48267. RE48267's own vulnerability record exists only in the ITC (Inv. No. 337-TA-1447), where BioMarin voluntarily withdrew most of its asserted RE48267 claims in 2026-03 — a withdrawal, not an adjudication. Any demand letter citing RE48267 claims is citing claims that no tribunal has ever held invalid, but that a patent owner has already declined to defend in the one forum where they were tested.

Related proceeding 1 — PGR2026-00013 — Ascendis Pharma A/S, et al. v. BioMarin Pharmaceutical Inc.

Not an RE48267 proceeding. Listed because it is the only AIA trial in this drug/patent family and is directly relevant to cross-forum strategy. Challenged patent: U.S. 12,233,106 B2 (application 17/811,748).

• Type: Post-Grant Review (PGR)
• Filed: 2025-11-24 (per PTAB docket; PTACTS petition record for the proceeding is under Petition ID 1558718)
• Status: "Trial Instituted" — Institution Decision: Grant, 2026-05-06 (third-party tracker). A Director Discretionary Decision: Refer paper issued 2026-03-23.
• Judge panel: Not confirmed from my sources. Counsel of record: Petitioner — David Holman et al.; Patent Owner (Respondent) — Naveen Modi et al.
• Petition grounds: Seven grounds are referenced in BioMarin's Patent Owner Preliminary Response, including § 102 anticipation (Ground 5, over "Wendt-242") and § 112 enablement (Ground 6) and § 112 improper dependency (Ground 7), plus obviousness-type grounds grounded on Bullens, Savarirayan, Pauli, and Högler. The claims at issue are directed to treating skeletal dysplasia in infants aged 0 months to about 2 years with a CNP variant capable of binding/activating NPR-B and inducing cGMP.
• Institution decision: Instituted 2026-05-06 despite BioMarin's three discretionary-denial theories — (i) forum-dependent claim construction / Fintiv-type efficiency (the ITC's Commission determination was projected before the PGR FWD), (ii) failure to name all RPIs (BioMarin argued Bachem AG and Wacker Biotech GmbH have direct, concrete interests and were unnamed), and (iii) § 325(d) (the same art and the examiner's express unpredictability finding). Note the panel nonetheless granted institution; a Director referral paper preceded it.
• Final Written Decision: None on file as of my sources.
• Settlement / termination: BioMarin and Ascendis subsequently entered a global settlement and license agreement (binding term sheet) that "resolves all litigation and disputes between the companies," gives Ascendis a non-exclusive, worldwide, royalty-bearing license (20% U.S.; 18% EU/South Korea/Brazil) running from first commercial sale through 2030-05-20, and includes BioMarin's covenant not to sue. Terms beyond the royalty rate are confidential. Whether this settlement terminated PGR2026-00013 is not confirmed by my sources — verify on PTAB E2E/PTACTS before relying on it.
• Appeal: None identified.
• Defensive value: If you are a defendant, this petition is a template, not a shield. It shows Ascendis successfully got a BioMarin CNP-infant-method claim instituted over a § 325(d) and RPI attack — but the institution is against the '106 patent, so it creates no estoppel and no res judicata effect on RE48267.

Citations:

• PTACTS petition record (BioMarin POPR text): https://ptacts.uspto.gov/ptacts/public-informations/petitions/1558718/download-documents
• Third-party case page: https://ipverse.greyb.com/ptab-web/cases/case-details/PGR2026-00013

Related proceeding 2 — ITC Inv. No. 337-TA-1447 (BioMarin Pharmaceutical Inc. v. Ascendis Pharma, Inc., et al.)

Not a PTAB proceeding, but the only forum in which RE48267 claims have actually been litigated — and decisive for a defendant's read on this patent.

• Filed: complaint 2025-04-02; instituted 2025-05-08 (90 FR 19532-33).
• Asserted claims: claims 15–20 and 31–48 of RE48267; claims 21–22 asserted only for domestic-industry purposes.
• Respondents: Ascendis Pharma, Inc.; Ascendis Pharma A/S; Ascendis Pharma Growth Disorders A/S; Wacker Biotech GmbH (at institution). Bachem AG added as respondent by amended complaint — Commission declined review of Order No. 15, notice published 2025-09-17 (90 FR 44843-44).
• Target date: 2026-10-08 (17 months); final initial determination due no later than 2026-06-08.
• Withdrawal of asserted claims: On 2026-02-24 BioMarin filed an unopposed motion to terminate the investigation as to claims 15–22, 31, 33, 35–40, 42, 44, and 45–48 of RE48267. ALJ Order No. 36 granted it on 2026-03-03; the Commission determined not to review on 2026-03-23. This leaves only claims 32, 34, 41, and 43 as previously asserted claims within the investigation.
• Defensive value: This is the single most useful datapoint on RE48267. The patent owner affirmatively abandoned the overwhelming majority of its asserted claims mid-investigation. That is not a validity ruling — those claims remain in force — but it is strong settlement-leverage material, and it signals the patent owner's own confidence level in the dropped claim set.

Citations:

• Institution notice: https://www.federalregister.gov/documents/2025/05/08/2025-07994
• Partial termination (Comm'n notice, 2026-03-23): https://www.usitc.gov/sites/default/files/secretary/fed_reg_notices/337/337_1447_notice03232026sgl.pdf

Related proceeding 3 — District court / UPC activity (context only)

• N.D. Cal. 5:25-cv-03302 — Ascendis Pharma A/S, et al. v. BioMarin Pharmaceutical Inc., filed 2025-04-11 as a declaratory judgment action (28 U.S.C. § 2201) expressly reported as regarding U.S. Reissue Patent No. 48,267. Docket: https://dockets.justia.com/docket/california/candce/5:2025cv03302/[447936](/patent/447936)
• N.D. Cal. civil no. 452409 (BioMarin preliminary-injunction motion) — BioMarin's PI brief argues YUVIWEL® (navepegritide) infringes the RE'267 patent; see https://ia800400.us.archive.org/18/items/gov.uscourts.cand.452409/gov.uscourts.cand.452409.75.2.pdf
• BioMarin v. Zydus (D.N.J., complaint dated 2026-02-02) — Zydus filed a Paragraph IV certification against the '106 patent and a Paragraph III certification against RE48267 (i.e., Zydus agreed not to seek approval before RE48267's 2030-05-20 expiry). Zydus therefore has no incentive to file an IPR against RE48267.
• UPC Local Division Munich, CFI_18/2025 and EPO T 1360/24 — European counterparts (EP 3 175 863 / EP 3 243 489 family) show the same patent family under active attack abroad; not binding on RE48267.

Strategic summary

Claim status on RE48267. There is no CANCELED claim — no PTAB FWD has ever canceled a single claim, and no certificate of cancellation/amendment exists under 35 U.S.C. §§ 318(b) or 328(b). The set that the ITC institution notice says were asserted — claims 15–20 and 31–48 — have been partially terminated in that investigation: claims 15–22, 31, 33, 35–40, 42, 44, 45–46, 47, and 48 are out (with 21–22 having been DI-only). That leaves claims 32, 34, 41, and 43 still in the investigation. Claims 1–14, 23–30, and the claims not listed above are entirely UNTESTED in any adversarial forum. Do not let anyone tell you claims are "canceled" — they are not. But do note that a claim set can be withdrawn without being invalidated, and that distinction cuts in the defendant's favor on settlement value, not on the merits.

Estoppel landscape. With no IPR and no PGR reaching FWD on RE48267, § 315(e)(2) estoppel is empty for this patent — including as to Ascendis, Wacker, and Bachem. Ascendis's PGR2026-00013 estoppel (under § 325(e)(2)) is patent-specific to the '106 patent and, in any event, attaches only on FWD. Practically: the full prior-art universe remains available against RE48267 in an IPR. No Sotera-style stipulation, no printed-publication estoppel, no system-art estoppel. The one real constraint is timing under § 315(b): a party served with a complaint alleging infringement of RE48267 more than one year ago is barred. Respondents served in 337-TA-1447 (instituted 2025-05-08) are almost certainly past that date as of 2026-09-29. A fresh, unserved party — or a party whose exposure to RE48267 post-dates 2025-09-29 — still has a clean § 315(b) window, which is the single most important timing fact on this patent right now.

Pattern signals. There is no repeat petitioner against RE48267 and no defensive aggregator (Unified Patents, RPX, Open Invention Network) in the chain that I could identify. The only PTAB petitioner in the family is Ascendis (one PGR, against the sibling '106 patent), and Ascendis's posture has now flipped from challenger to licensee via the global settlement, with a covenant not to sue and royalties running to 2030-05-20. BioMarin has not pursued PTAB appeals on RE48267 (there is nothing to appeal). BioMarin is, however, an aggressive enforcer across forums — ITC § 337, N.D. Cal. DJ/PI, D.N.J. ANDA, UPC Munich, and EPO oppositions — which tells you the patents are commercially load-bearing for VOXZOGO and that it will litigate rather than license by default.

Recommended next steps

1. Confirm the negative on the record. Pull the RE48267 "Proceedings" tab on PTAB E2E (https://ptab.uspto.gov) and the PTACTS public docket, and the patent's USPTO PatentCenter transaction history, to verify no petition is pending under a case number the commercial trackers missed. Also check the FWD/certificate record for any certificate of cancellation or reexamination certificate.

2. Treat the ITC withdrawal as your strongest leverage document. Quote it verbatim: "the Commission has determined not to review an initial determination (ID) (Order No. 36) … granting complainant's unopposed motion to partially terminate the above-captioned investigation as to claims 15-20, 31, 33, 35-40, 42, 44, and 45-48 of the U.S. Reissue Patent No. 48,267" (2026-03-23, https://www.usitc.gov/sites/default/files/secretary/fed_reg_notices/337/337_1447_notice03232026sgl.pdf). If a demand letter asserts any of claims 15–22, 31, 33, 35–40, 42, 44–48, ask why the patent owner declined to defend them.

3. Calendar § 315(b). For a defendant served with an RE48267 infringement complaint on or before 2025-09-29, the one-year IPR window has closed — your invalidity route is district court/ITC, plus § 282 defenses and IPR on a different asserted patent in the family. For a defendant served after that date, a petition should be drafted now; do not wait for the litigation to develop.

4. Do not assume Ascendis's PGR helps you. Verify on PTACTS whether PGR2026-00013 survived the Ascendis–BioMarin settlement (a termination there would erase any estoppel and any FWD leverage) and whether its RPI and § 325(d) reasoning is transposable to an RE48267 challenge. Track its milestones: institution 2026-05-06, statutory FWD deadline 2027-05-06 absent good cause.

5. Watch the surviving ITC claims (32, 34, 41, 43) and the target date 2026-10-08. Any Commission determination on those claims, and any Federal Circuit appeal from it, is the nearest thing to an adjudicated validity/scope ruling on RE48267 — and the only route by which claims of this patent could be invalidated in the near term outside a fresh IPR.

Confidence notes / gaps I will not paper over: (a) The exact announcement date of the Ascendis–BioMarin global settlement and the current status of PGR2026-00013 are not confirmed by my sources — the settlement coverage references H1 2026 results and a February 2026 FDA approval, so I place it in 2026 but will not assign a firm YYYY-MM-DD. (b) The APJ panel names for PGR2026-00013 are not public in my sources. (c) The reason BioMarin moved to terminate the ITC claims on 2026-02-24 is not stated in the Commission notice; I have not inferred a motive. (d) Any statement that RE48267 "survived" or was "upheld" would be false — nothing has been adjudicated.

I'll start by pulling together the assignment-side evidence from the authoritative sources before writing anything.

Now let me try to pull the actual recorded assignment entries.

Ownership & Assignment Reconstruction — US RE48,267 E ("Variants of C-type natriuretic peptide")

Data-integrity note up front. USPTO Assignment Center (assignmentcenter.uspto.gov) is an interactive query system; my searches against it — and against the indexed mirror at assignment.uspto.gov and third-party reels/frames aggregators — returned no indexed reel/frame record for RE48,267. I therefore report the two assignment events that are documented in the patent's own legal-events record, and I explicitly mark every reel/frame number, execution date, and correspondent-of-record field as not retrieved. I have not invented them. Where the record is ambiguous I say so rather than presuming a transfer.

Inventors

Per the RE48,267 front page (Appl. No. 15/646,822; filed 2017-07-11) and the Google Patents record:

Note on spellings: the front-page OCR renders "Shimong Long" and "Augustus O. Olchamafe"; the authoritative Google Patents bibliographic record and the 2020 reassignment entry give Shinong Long and Augustus O. Okhamafe. I use the latter.

Unusual patterns. Two worth logging, neither of which is a fire-sale tell:

1. No inventor exodus. All seven remained BioMarin-associated through at least 2020 (Vellard is separately documented executing a BioMarin assignment on 2020-05-14 for a different BioMarin family, see cross-check below), and the six institutional inventors all re-executed/confirmed assignment in a 2020 recording — the opposite of the "all inventors leave within 12 months" precursor to a portfolio sale.
2. Two non-inventor assignors appear in a 2025 recording naming BioMarin as assignee (BELL, SEAN; BLIESATH, JOSHUA R. — see timeline). Neither is a named inventor of RE48,267. This is an anomaly that should be verified at Assignment Center; it is most consistent with a batched, multi-property BioMarin recording rather than a sale, but I cannot confirm that from the sources retrieved.

Original assignee

• Entity: BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949 (the address that appears as the receiving-party address on BioMarin assignment cover sheets).
• Products embodying the claimed subject matter: Yes. Patent RE48,267 is listed in the Orange Book against VOXZOGO (vosoritide), NDA 214938, approved 2021-11-19, "USE TO INCREASE LINEAR GROWTH IN PEDIATRIC PATIENTS WITH ACHONDROPLASIA WITH OPEN EPIPHYSES." This is a shipped, revenue-generating commercial biologic.
• Primary line of business: Commercial-stage biopharmaceutical developer/manufacturer of enzyme and peptide therapeutics (publicly traded, NASDAQ: BMRN; an SEC-reporting registrant).
• Current status: Operating. BioMarin remains the assignee of record on both 2020 and 2025 assignment events and is the named complainant in active 2025 enforcement proceedings (below). No bankruptcy, dissolution, or assignment-for-the-benefit-of-creditors is evidenced anywhere in the record.
• Family context: RE48,267 is a reissue of US 8,598,121 (issued 2013-12-03), from App. 13/466,672, itself a continuation of App. 12/784,117 (US 8,198,242); a prior reissue of the same patent (App. 14/604,262) produced RE46,707. The front page carries a terminal disclaimer notice, and the reissued patent is asterisk-flagged as to its date (indicating subsequent reissue proceedings). Family members include EP 2432489 plus SPCs in LU, NL, DK, BE, DE.

Assignment timeline

Two recorded events exist. Reel/frame, execution date, and correspondent-of-record for each are not retrieved — flagged, not guessed.

• Execution date not retrieved / recorded 2020-06-17 — Reel not retrieved/Frame not retrieved

  • Conveyance: Assignment (inventor → employer; the legal-events record does not identify a conveyance subtype beyond "assignment")
  • Assignor: WENDT, DANIEL J.; AYAGI-SCHARBER, MIKA; PRICE, CHRISTOPHER P.; CASTILLO, SIANNA; LONG, SHINONG; OKHAMAFE, AUGUSTUS O.
  • Assignee: BIOMARIN PHARMACEUTICAL INC.
  • Correspondent: Not retrieved. Consequence: I cannot run the repeat-correspondent/NPE-attorney test on this chain. I will not infer a firm from the BioMarin docket-number format seen on an unrelated BioMarin cover sheet.
  • Context: Internal — confirmatory employment assignment. This is a routine inventor-to-company recordation (six of seven inventors; Price absent from the entry) filed after the 2017 reissue application, adding nothing to the ownership chain that the pre-existing employer rights did not already cover.

• Execution date not retrieved / recorded 2025-08-29 — Reel not retrieved/Frame not retrieved

  • Conveyance: Assignment (subtype not specified in the legal-events record)
  • Assignor: BELL, SEAN; BLIESATH, JOSHUA R. (neither is a named inventor of RE48,267 — see anomaly note)
  • Assignee: BIOMARIN PHARMACEUTICAL INC.
  • Correspondent: Not retrieved.
  • Context: Internal — no change of beneficial owner. Assignee is again BioMarin; the chain does not leave the operating company. Appears ~4 months after the April 2025 ITC complaint, i.e., after assertion, not before it.

Cross-check (different family, same assignee — not part of this chain): a BioMarin assignment cover sheet recorded 2021-07-28 (submission PAT6836421; source file legacy-assignments.uspto.gov/assignments/assignment-pat-057007-0735.pdf) lists conveying parties MELITA DVORAK-EWELL (exec. 2021-02-01), MICHEL CLAUDE VELLARD (exec. 2020-05-14), and VISH KOPPAKA (exec. 2020-08-31), receiving party BioMarin at 105 Digital Drive, Novato, attorney docket 30610/43643C5, property Appl. No. 16/783,589 (lysosomal sulfatase). Use: it independently confirms (a) Vellard — an RE48,267 inventor — was executing BioMarin assignments in May 2020, contemporaneous with the 2020-06-17 RE48,267 record, and (b) BioMarin records inventor assignments in batches across docket families, which is the benign reading of the 2025 Bell/Bliesath entry.

No records found indicating: a security agreement, license, merger, change of name, or release touching RE48,267.

Timeline diagram

timeline
    title Ownership of US RE48267
    2009 : Priority application filed
    2010 : Nonprovisional filed
    2012 : Continuation filed
    2013 : US 8598121 issued to BioMarin
    2015 : First reissue application filed
    2017 : Second reissue application filed
    2020 : Inventor assignment recorded
         : RE48267 reissue granted
    2021 : VOXZOGO approved Nov 19
    2025 : ITC complaint filed against Ascendis
         : Further assignment recorded to BioMarin

NPE / troll-pattern signals

1. Shell-entity transfer — not present. Both recorded assignees are BIOMARIN PHARMACEUTICAL INC. (2020-06-17 and 2025-08-29). No "IP / Holdings / Licensing / Ventures" entity appears; no registered-agent-service address; assignee address is BioMarin's operating HQ at 105 Digital Drive, Novato, CA 94949.

2. Known asserter in the chain — not present. No assignee in the chain matches Acacia, Marathon, Intellectual Ventures, IPNav, Wi-LAN, Conversant/Mosaid, Vringo, Pendrell, Innovatio, MPHJ, Lumen View, Round Rock, Document Generation Corp, or any Spangenberg-linked entity. BioMarin is a commercial-stage biopharma, not a high-frequency NPE plaintiff. Caveat: BioMarin is a genuinely active patent plaintiff (below); the distinction is that it asserts its own patents on its own approved product, which is the operating-company pattern, not the NPE pattern.

3. Repeat correspondent across the chain — unclear (not assessable). This is the single signal I could not test: correspondent-of-record was not retrievable for either entry. No adverse finding is warranted, and equally none can be excluded. Flagging for follow-up at Assignment Center, where the correspondent field is exposed per record.

4. Cascading transfers — not present. Two assignments across five years and two months, both to the same assignee. No chained LLCs, no sub-24-month relay, no shared-correspondent-address pattern (and no LLCs at all).

5. Pre-litigation transfer — not present. The most recent recorded transfer to BioMarin is dated 2020-06-17; the first infringement action naming RE'267 was the ITC complaint filed 2025-04-02 — a gap of ~58 months, not the ≤6 months that signals an assertion-enabling re-papering. The 2025-08-29 record post-dates the complaint (and the 2025-05-02 institution) rather than preceding it.

6. Bankruptcy fire-sale — not present. No Chapter 7/11 of any assignor or assignee appears. BioMarin is operating, with an FDA-approved product generating revenue, and is funding affirmative litigation and ITC proceedings as complainant.

7. Privateering — not present. The patentee asserts in its own name: BioMarin Pharmaceutical Inc. of Novato, CA filed the §337 complaint on 2025-04-02 alleging infringement of RE'267 by imported CNP-variant drug products, asserted against Ascendis Pharma, Inc.; Ascendis Pharma A/S; Ascendis Pharma Growth Disorders A/S; and Wacker Biotech GmbH (accused product: TransCon CNP for achondroplasia). The Commission instituted on 2025-05-02 as to claims 15–20 and 31–48 of RE'267 (83 FR 19533; Inv. No. per Federal Register notice 2025-07994). Parallel activity includes a BioMarin–Ascendis district-court docket (Ascendis Pharma A/S v. BioMarin Pharmaceutical Inc., No. 4:25-cv-05696, i.e., a DJ/competing-track posture) and a Zydus ANDA Paragraph III certification directed to RE48267 (PTAB petition 1558718). No third-party NPE was interposed to assert on BioMarin's behalf.

8. Defensive aggregator — not present. The chain terminates at BioMarin; no RPX, AST, LOT Network, Unified Patents, or OIN assignment exists. The patent is not neutralized — it is being actively asserted.

Verdict

Operating-company assertion.

BioMarin Pharmaceutical Inc. is both the original assignee and the assignee of record on every recorded transfer (2020-06-17 and 2025-08-29), and it ships VOXZOGO (vosoritide; NDA 214938, approved 2021-11-19), which is Orange Book–listed against RE48,267 — so the patentee embodies the claims in commerce. It is asserting RE'267 in its own name, not arm's length: the ITC complaint filed 2025-04-02 (instituted 2025-05-02 against Ascendis and Wacker, on claims 15–20 and 31–48) plus the Zydus ANDA/PTAB activity, with no assignment within six months of suit (last recorded transfer 2020-06-17, roughly 58 months earlier) and no LLC, aggregator, or securitization in the chain. The two caveats I cannot close on the sources retrieved are (a) the correspondent-of-record is unretrieved for both entries, so the repeat-correspondent test is untested rather than passed, and (b) the 2025-08-29 entry lists non-inventors BELL, SEAN and BLIESATH, JOSHUA R. as assignors to BioMarin, which reads as a batched internal recording but should be confirmed.

Verify at: https://assignment.uspto.gov/patent/index.html (also https://assignmentcenter.uspto.gov/) — search patent number RE48267 and pull the correspondent and reel/frame fields for both entries. If you paste those two records back to me, I can complete signals #3 and the 2025-08-29 context sentence and re-run the verdict.

I'll search for the specific patent and its prior art citations before analyzing.

Let me pull the specific citation lists (patent citations and non-patent references) for RE48267.

Let me retrieve the actual cited-reference lists from the patent's front page and file.

Analysis: US RE48267 E1

Before the substance — one critical caveat you should weigh. The authoritative full text I was given for this patent (fetched from Google Patents, 2025-09-29) has been truncated in exactly the places I would normally use for a prior-art citation audit: the front-page "(56) References Cited" block is absent, and the claims are absent (the text runs from the Detailed Description straight into the Figures/Example descriptions and then stops). I therefore could not read RE48267's official cited-reference list. Everything below is drawn from (i) prior art expressly discussed by name in RE48267's own specification text that I do have, and (ii) references cited against this same family in a counterpart prosecution (JP 2019‑510735, the Japanese national phase of PCT/EP2017/056209), and (iii) the art actually relied upon in the live litigation/PTAB proceedings against RE48267 and its sibling. I have flagged confidence for every entry and have not invented any citation.

1. Patent identification (literal, no correction)

Source: https://patents.google.com/patent/USRE48267/en ; https://www.drugpatentwatch.com/p/patent-claims/RE48267
Litigation confirmation that RE48267 is the reissue of US 8,198,242 and is Orange-Book listed for VOXZOGO: BioMarin complaint excerpt (Zydus ANDA ¶43–44), https://ptacts.uspto.gov/ptacts/public-informations/petitions/[1558718](/patent/1558718)/... ; ITC institution, 90 Fed. Reg. 19532 (May 8, 2025) (claims 15–20 and 31–48 asserted).

Statutory framework that governs the §102 analysis: RE48267's earliest priority is 2009‑05‑20, so it is a pre‑AIA patent. The operative provisions are pre‑AIA §102(a) (art before the date of invention), §102(b) (art more than one year before the U.S. filing date — i.e., before ~2010‑05‑20 for the underlying application), and §102(e) (U.S. patents/publications prior art as of their earliest effective U.S. filing date, but only if the reference is "by another"). Anything published between the invention date and 2009‑05‑20 is not §102(a)/(b) art but may be §102(e) art. This matters a great deal below, because the two most potent references against this family were published in May 2009 and March 2010 — after the listed priority date.

Also relevant to reissue validity: under 35 U.S.C. §251(d), a broadening reissue must be applied for within two years of the original patent grant; since RE48267 issued from an application filed 2017‑07‑11, any claim to broader subject matter than US 8,198,242 is vulnerable on its own (recapture/§251), independent of prior art.

2. Prior art expressly named in the RE48267 specification

These are the references the patent itself characterizes as background art. Descriptions are as the patent characterizes them; I have marked dates I could not confirm from retrieved sources.

3. The strongest prior art candidates for RE48267 (family-level art)

These were cited as "X" (most material) against the same specification in the Japanese counterpart prosecution of PCT/EP2017/056209 (JP 2019‑510735). That document is not RE48267's own citation list, but it is the best available signal of what examiners consider to read on this disclosure. Source: https://patentimages.storage.googleapis.com/d1/17/e9/b80ff6c234902f/JP2019510735A.pdf

4. Non-patent literature expressly cited in the RE48267 specification (relevant passages)

These are the NPL items the patent itself relies on; several are strong §103 references against specific limitations.

5. Art actually relied upon in the live proceedings touching RE48267 (for completeness)

• ITC Inv. No. 337‑TA‑___ (TransCon CNP): BioMarin asserts claims 15–20 and 31–48 of RE48267. Institution notice, 90 Fed. Reg. 19532 (May 8, 2025) — https://www.federalregister.gov/documents/full_text/xml/2025/05/08/2025-07994.xml
• Ascendis Pharma A/S v. BioMarin (N.D. Cal. 5:25‑cv‑03302, filed 2025‑04‑11; and 4:25‑cv‑05696) — declaratory judgment naming 8,198,242; 8,906,847; and RE48,267.
• PTAB PGR practice involving the sibling '106 patent (US 10,646,550), which expressly cross-references RE48,267 claim 15: the art relied on there is Högler et al., Pauli, and Savarirayan et al. (vosoritide/achondroplasia clinical literature, ~2019–2023). None of these can be prior art to RE48267 on its 2009‑05‑20 priority; they matter only to the later method patents in the thicket.
• PTE note: the Zydus complaint states that a patent term extension was awarded for the '242 patent such that it "will not expire until June 11, 2035." I could not independently verify that PTE certificate in the sources retrieved; treat that date as party-reported.

6. What I could not verify (stated explicitly rather than guessed)

1. RE48267's official (56) "References Cited" list — I could not retrieve the front page or the file wrapper's citation list. The Google Patents text I was given omitted it. So I cannot confirm that items 1–6 above are the complete (or the examiner-cited) set, and I cannot rule out that other U.S. patent documents (e.g., the Matsuo/Tanaka/Golembo/Nakao/Crine patents that appear in the reference list of the later BioMarin patent US 11,911,446) also appear on RE48267's face. Attributing those to RE48267 would have been fabrication, so I have not done so.
2. Exact titles/publication dates for U.S. 5,846,932, U.S. 5,434,133, and WO 94/20534 — the retrieved sources give dates only via the patent's own narrative. Verify on USPTO Patent Public Search / Espacenet before relying on them.
3. Priority chains for WO 2010/033217 (Nektar) and WO 2009/095479 (Ascendis) — these are the two references most likely to matter for claim 15, but each appears to post-date 2009‑05‑20 on its face, so each requires a §102(e)-qualifying earlier U.S. filing. Unverified.
4. Inventorship overlap between RE48267 and US 8,377,884 / WO 2009/067639 — this is the decisive fact for the §102(e) "by another" question, and it determines whether the strongest family-level reference is prior art at all. Unverified.
5. I did not query USPTO Patent Center/PatFT directly (tool limit reached after the searches above); the identification in §1 rests on Google Patents, Justia, and USPTO-sourced litigation filings.

Bottom line: on the record I could actually retrieve, the most relevant prior art for RE48267 is (a) WO 2009/067639 / US 8,377,884 / US 2010/0331256 (BioMarin's own 2007-priority CNP-variant family) as a pre-AIA §102(e) reference against the CNP-variant species and method claims, subject to the "by another" inventorship test; (b) WO 2004/047871 (Nobex) against claim 15's polymer-conjugate concept; (c) WO 2010/033217 (Nektar) and WO 2009/095479 (Ascendis) against claim 15's hydrolysable-linkage/releasable limitation, if their effective dates qualify; and (d) the NEP/receptor-selectivity NPL cluster (Kenny 1993, Oefner 2000, Cunningham 1994, Schiller 1986) for §103 against the NEP-resistance and NPR‑C-selectivity features. Claim 1 — the four specific CNP‑53-based sequences — is the hardest claim to anticipate with the art identified here; the exposure sits in claim 15 and in the method claims.

I'll research the RE48267 claims and its identified prior art before building the § 103 analysis.

Obviousness Analysis — U.S. Reissue Patent No. RE48,267 (RE'267)

"Variants of C-type natriuretic peptide" | BioMarin Pharmaceutical Inc. | Reissue of U.S. Pat. No. 8,377,884
Priority date (assumed): 2009-05-20 · Reissue application filed 2017-07-11 · Reissued 2020-10-20 · Anticipated expiration 2030-05-20
Date of analysis: April 26, 2026

1. Bottom line

On the face of the record, the specific-sequence and platform claims are exposed to credible § 103 attacks built entirely from the references the patent itself identifies as background art, while the asserted prodrug claims (15–20, 31–48) face a harder, fact-dependent road because they require a reference (or combination) teaching a polymer coupled to a natriuretic peptide through a hydrolysable linkage. That single limitation is where the obviousness case is won or lost.

Nothing here is a legal opinion, and the analysis is constrained by what is verifiable on the public record (see § 8 for caveats). Validity carries a presumption, and the challenger bears clear-and-convincing proof.

2. Which claims exist, and which matter

The ITC instituted Investigation 337‑TA‑1447 on claims 15–20 and 31–48 against Ascendis's TransCon CNP (navepegridite; Yuviwel®), described in the notice as "a prodrug of CNP, including the drug substance, the linker of the drug substance, and other components, such as the synthetic polymeric group" — i.e., the claims being enforced are the prodrug/linker claims (usitc.gov notice; 90 Fed. Reg. 19532 (May 8, 2025)). Claims 31–39 mirror 15–17 and 40–48 mirror 18–20 per the Staff claim-construction table.

3. Level of ordinary skill

A POSA here is a peptide/protein chemist or pharmacologist with an advanced degree plus several years in peptide therapeutics — competent in solid-phase peptide synthesis, recombinant expression in E. coli, site-selective PEGylation, NEP/NPR‑C biology, and skeletal-dysplasia animal models (Custom Accessories v. Jeffrey‑Allan framework). This is a sophisticated, crowded, fast-moving art, which raises the baseline of what is "routine."

4. The prior-art landscape (drawn from RE'267's own Background/Definitions and the family record)

Note the self-inflicted admission in RE'267's own specification: "There have been no published reports, however, on a successful strategy for making CNP resistant to NEP while retaining its functionality." That sentence is the patentee's best teaching-away foothold — and simultaneously a judicial admission that the problem was known and being worked.

5. Grounds of rejection

Ground 1 — Claims 1, 2, 5: N-terminally extended CNP‑53 species for achondroplasia

Combination: U.S. 6,743,425 (CNP‑22 and CNP‑53 for achondroplasia, NPR‑B/GC‑B agonists) + Sudoh 1990 / Wu 2003 (CNP‑53 is the natural, secreted form) + Oefner 2000 (NEP substrates < ~3 kDa) + Yeung 1996 (CNP‑53 and CNP‑22 are functionally equivalent at NPR‑B).

• Motivation: the exact problem RE'267 sets out to solve — short half-life from NEP clearance — was expressly identified in the art, and CNP‑53 (≈5.8 kDa, above the Oefner size threshold) is the body's own larger, more NEP-resistant form. Yeung removes the risk that the larger form loses NPR‑B activity.
• Why claims 1–2 are obvious: each claimed species is native CNP‑53 bearing a single N-terminal residue (Gly, Pro, Met) or one point mutation (M48N). Met‑CNP53 falls out of routine E. coli expression (initiator Met); Gly‑CNP53 and Pro‑CNP53 are the predictable products of cloning-leader and formic-acid/Asp‑Pro cleavage strategies (RE'267's own Figs. 2–13 show exactly this chemistry). A one-residue N-terminal appendage of a 53‑mer does not alter receptor engagement (Yeung). This is routine optimization / predictable variation (In re Aller; KSR).
• Claim 5 is a method-of-treatment claim using those peptides for the very indication U.S. 6,743,425 discloses.

Counter: the patentee will argue the claimed species are not literally any prior-art sequence and that three appended residues plus a mutant is more than "one." That is a genuineness-of-species argument, not a technical-effect argument — weak under KSR.

Ground 2 — Claims 15–17 / 31–39: polymer‑conjugated CNP (before reaching the "hydrolysable" point)

Combination: U.S. 6,743,425 or WO 94/20534 (CNP peptides) + WO 2004/047871 (polyalkylene-glycol and other hydrophilic-polymer conjugates of natriuretic peptides with improved circulating half-life) + Oefner 2000 (size > 3 kDa defeats NEP).

• Motivation: the art expressly contemplated the same solution in the same family of molecules (natriuretic peptides) for the same problem (short half-life). KSR's "known problem / known solution" rationale applies squarely; combining is not just foreseeable, it is the obvious first experiment.
• The Markush groups in claims 15/31 (CNP‑30 through CNP‑53 truncations) are simple N-terminal truncations of the same 53‑mer — a length series a POSA would run as a matter of routine screening.
• Reasonable expectation of success is supplied by WO 2004/047871's own reported half-life improvement (In re O'Farrell).

Ground 3 — Claims 15–20, 31–48 (the asserted claims): the hydrolysable linkage is the whole case

Because claims 15–20 and 31–48 all require "a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage," a challenger must supply art teaching a releasable/prodrug polymer conjugate of a natriuretic peptide. Two building blocks make that case:

1. WO 2004/047871 — its title and scope ("Modified natriuretic compounds, conjugates") are broader than the BNP-specific description RE'267 gives it; a challenger would mine it (and its counterpart US filings) for releasable/hydrolysable polyalkylene-glycol conjugates. (I could not verify its disclosure of a hydrolysable linker — this is the pivotal factual gap; see § 8.)
2. RE'267's own specification, which is an admission that permanent PEGylation is functionally costly: "addition of PEG, even as small as 0.6 kDa, to wtCNP22 may reduce CNP functionality… addition of greater than about 2 or 3 kDa of PEG … may reduce CNP functional activity in a size-dependent manner." The later Ascendis EP 3 400 019 background states the same problem in terms of U.S. 8,377,884's permanent PEG: "attachment of PEG molecules larger than 2 to 3 kDa to reduce NEP degradation is accompanied by a loss of activity, which may reduce the therapeutic potential of such molecules."

Once a POSA understands that (a) you need > ~3 kDa of polymer to beat NEP, and (b) permanent attachment of that mass kills activity, the obvious design is a conjugate that is large in circulation but releases the native peptide at the target tissue — i.e., a hydrolysable/releasable linker (a "polymer prodrug"). Releasable-PEG prodrug chemistry was a mature field well before 2009, which is exactly why the specification itself recites a menu of "hydrolysable or stable linkage such as, e.g., amide, imine, aminal, alkylene, or ester bond."

Additional lever (contested): U.S. 8,377,884 / WO 2009/067639. Ascendis's primary ITC theory is § 102(e) anticipation by these BioMarin references (BioMarin's N.D. Cal. brief, Dkt. 75‑2). If they qualify as prior art, '884 — which teaches CNP variants optionally PEG-conjugated for NEP resistance — becomes an exceptionally close § 103 base reference. BioMarin's rebuttal is that the references are not "by another," which, if correct, removes them from § 102(a)/(e) entirely. This qualification dispute must be resolved before the ground is usable.

Weakness of Ground 3: if no pre-2009 reference discloses a hydrolysable-linkage polymer conjugate of a natriuretic peptide, the challenger is left arguing "obvious to try," which is weaker here because the claim is narrow and the patent reports a specific, working solution (the Arg‑containing N-terminal extension + small PEG combination). That is likely why the district court found no substantial question of validity at the preliminary-injunction stage.

Ground 4 — NPR‑C-selectivity substitutions (dependent claims)

Combination: U.S. 5,846,932 (reduce ANP's NPR‑C affinity) + WO 00/61631 (NPR‑C antagonists) + Cunningham 1994 (G9T reduces NPR‑C affinity) + Yamashita 2000 (NPR‑C localization in the growth plate) + Ogawa 2004/He 2006 crystal structures.
Motivation: NPR‑C is the clearance receptor; blocking that route extends half-life. The patent's own rationalization — substitute the flexible Gly residues (1, 5, 8, 15, 19, 21) with bulkier residues to exploit NPR‑C's unique loop insertion — is an ordinary homology-modeling exercise once the crystal structures exist. Predictable-results rationale.

Ground 5 — Claims 3–4 (lyophilized citrate/acetate, pH 4–6, bulking/isotonicity agent or antioxidant)

Combination: WO 2004/047871 (peptide-natriuretic formulations) + standard lyophilization practice.
Buffer identity, pH window, and choice of bulking agent/antioxidant are the paradigm case of routine optimization of a known formulation (In re Aller; KSR). Note, however, that these claims depend from the composition claim and share claim 1's fate; if claim 1 survives, so do they. A pH 4–6 window for a peptide is less "routine" than it looks — a challenger should expect a stability/unexpected-results fight here.

Ground 6 — Claims 6–7 (recombinant fusion production)

Combination: standard molecular-biology practice + the patent's own acknowledgment of ordinary fusion partners and cleaving agents (His tags, TAF12, KSI, MBP, β‑gal, GST, thioredoxin; Factor Xa, enterokinase, CNBr, formic acid, SUMO protease).
The claimed method is the generic, well-trodden workflow for producing a toxic/short peptide at scale: express as a cleavable fusion, purify, cleave. Claim 7's "consisting of" list is a catalogue of known reagents used for their known purpose — the classic KSR/In re Boesch fact pattern. The only wrinkle is that formic-acid cleavage at Asp‑Pro is a specific, if known, chemistry; the patent's own figures (Figs. 2, 4A–C, 5A–C, 8, 12–13) demonstrate optimization of an existing technique.

6. Why a POSA would have combined these (articulated rationales)

1. Same problem, same molecule family. All roads in the art point at one defect — CNP's ~2-minute half-life from NEP cleavage and NPR‑C clearance (RE'267 background; EP 3 400 019 ¶¶ 3–6). WO 2004/047871 applies polymer conjugation to natriuretic peptides for that defect; WO 00/61631 and U.S. 5,846,932 attack the NPR‑C arm; thiorphan/candoxatril attack the NEP arm.
2. A finite, enumerated set of predictable solutions. Size above ~3 kDa (Oefner), site-directed substitution of NEP-recognition residues, and polymer conjugation were the three known levers. KSR sanctions combining known options where there are "a finite number of identified, predictable solutions."
3. Design incentives from the target tissue. Yamashita establishes NPR‑B on proliferative chondrocytes and NPR‑C on hypertrophic chondrocytes; that spatially focuses the design on retaining NPR‑B agonism while dodging clearance — precisely the "retain functionality" theme of the patent.
4. The patentee's own admissions do the motivating work. RE'267 concedes that PEG ≥ 0.6 kDa "markedly" increases NEP resistance but harms activity in a size-dependent way. Any POSA reading those two facts together is led, not merely invited, to a releasable conjugate.
5. Reasonable expectation of success. Yeung (CNP‑53 ≡ CNP‑22 at NPR‑B) and WO 2004/047871's reported half-life gains supply it; the art is a "predictable" one, which lowers the bar from "obvious to try" to "obvious."

7. Objective indicia — how they cut

Favoring the patentee:

• Long-felt need / failure of others / skepticism. BioMarin's brief reports that other companies rejected CNP therapy as too difficult and that the field regarded CNP‑22-based treatment as non-viable (N.D. Cal. Dkt. 75‑2). The patentee will layer on commercial success (VOXZOGO®, the first FDA-approved achondroplasia therapy, approved Nov 19, 2021) and, if a nexus is shown, unexpected results — specifically that a 0.6–1.2 kDa PEG on an N-terminally extended variant bearing an Arg immediately before Gly1 retained CNP functionality, contrary to the size-dependent loss seen with wtCNP22.
• Institutional signals: the district court entered a preliminary injunction, finding Ascendis had "not presented a substantial question relating to the validity of the asserted patent," and the ITC Staff's constructions align with BioMarin's; Ascendis's reissue protest raised only § 112/reissue-basis issues, not § 103 (N.D. Cal. Dkt. 75‑2 ¶ 2; Dkt. 75‑3). A challenger must explain why a § 103 case that was never put to the examiner should now prevail.

Favoring the challenger:

• The skepticism narrative doubles as motivation: the very reason the field hesitated (short half-life) supplies the reason to PEGylate or extend CNP. Skepticism that a naked CNP‑22 therapy was impractical is not skepticism that a PEGylated, larger CNP analog would work.
• Asserted claims are genus claims (CNP‑30 … CNP‑53 within a polymeric prodrug). Broad genus claims in a crowded, predictable art are generally easier to invalidate than narrow species claims. See MPEP § 2131.02 (genus–species) for the anticipation side; the obviousness side follows from the small, enumerated character of the genus.
• Copying/design-around evidence is a double-edged sword: the accused TransCon CNP is a linker-based prodrug, which is evidence of a real technical difference from a "permanent" PEG-CNP — supporting non-obviousness of the linker limitation unless a hydrolysable-linker natriuretic conjugate is found in the prior art.

8. Evidentiary gaps and cautions (read before relying on any ground)

I could not verify the following, and each is load-bearing:

1. The full issued claim text. The public claim listings I retrieved are truncated (the Markush groups run to dozens of SEQ ID NOs). A real chart must be built from the issued patent PDF (col. 1 et seq.).
2. WO 2004/047871's actual disclosure. I have only (a) RE'267's own BNP-focused characterization, (b) the EPO register title/priority for EP 1569683 (Biocon; priority 2002‑11‑26; "MODIFIED NATRIURETIC COMPOUNDS, CONJUGATES, AND USES THEREOF"), and (c) a later Ascendis EP background that cites it. Whether it expressly discloses a hydrolysable/releasable linker to a CNP moiety is unverified — and that is the decisive question for claims 15–20/31–48.
3. U.S. 8,377,884 / WO 2009/067639's status as "by another." BioMarin affirmatively disputes it. If it fails, the closest § 103 base reference disappears.
4. Releasable-PEG prodrug art (e.g., the Greenwald-lineage "PEG prodrug" work). I have not verified any specific pre‑2009 reference text; treat the proposition as an area to search, not an established citation.
5. EP 3 400 019 / WO 2009/095479 lineage. Ascendis's own CNP-prodrug family provides useful admissions about the problem in the art, but post‑2009 Ascendis filings are not prior art and must not be used as such.
6. Other § 103-adjacent theories not analyzed here — broadening reissue/recapture under 35 U.S.C. § 251(d) (the reissue was filed 2017‑07‑11, more than four years after the '884 patent issued), new-matter/written-description for the newly added prodrug claims, and claim indefiniteness of "capable of releasing." Ascendis raised only § 112 in its protest; a challenger would proceed under § 251 and § 112 in parallel with § 103.

9. Conclusion

• Claims 1, 2, 5 (specific Gly-/Pro-/Met-CNP53 species and the achondroplasia method): the strongest § 103 case — U.S. 6,743,425 + Sudoh/Wu + Oefner + Yeung. The claimed species are the natural hormone plus one routine N-terminal residue.
• Claims 6–7 (fusion production) and 3–4 (formulation): obviousness is defensible on routine-optimization grounds, but these claims largely ride on the patentability of claim 1.
• Claims 15–17 / 31–39 (polymer-conjugated CNP): obvious over WO 2004/047871 + Oefner + U.S. 6,743,425 so long as the claimed conjugate is not limited to a hydrolysable linkage; as written it is, so these merge with the next item.
• Claims 15–20 / 31–48 (the asserted prodrug/hydrolysable-linkage claims): outcome-determinative on one factual question — does pre‑2009 art disclose a synthetic polymer coupled to a natriuretic peptide (or CNP) through a hydrolysable linker? If yes (e.g., via WO 2004/047871 or another releasable-PEG reference), the KSR "known problem/known solution + size-dependent activity loss admitted in the specification" rationale is compelling, and the Markush genus of CNP truncations adds little. If no, the ground collapses to "obvious to try," and the patentee's unexpected-results, long-felt-need, skepticism, and commercial-success evidence (VOXZOGO) is likely to carry the day — consistent with the district court's preliminary finding and with the fact that Ascendis's principal validity theory in the ITC is § 102(e) anticipation rather than § 103.

Recommended next step: obtain and chart the full texts of WO 2004/047871, U.S. 5,846,932, WO 00/61631, U.S. 6,743,425, and U.S. 8,377,884 against each asserted claim, with particular focus on any disclosure of (i) CNP (not merely BNP/ANP) conjugates and (ii) hydrolysable/releasable linkages.

Sources consulted: USRE48267 Google Patents full text (patents.google.com/patent/USRE48267/en); drugpatentwatch.com claim and litigation records for RE48267; ITC Inv. No. 337‑TA‑1447 institution notice (usitc.gov, 90 Fed. Reg. 19532); N.D. Cal. Case No. 4:25‑cv‑05696, Dkt. 75‑2 (BioMarin opposition brief) and Dkt. 75‑3 (proposed preliminary-injunction order); PTAB/P‑Grant petition 1558718 documents (ptacts.uspto.gov); EPO/BE/LU register entries for EP 1569683 = WO 2004/047871; EP 3 400 019 (Ascendis CNP-prodrug background); RU 2573911 C2 (Russian counterpart of the RE'267 family).