US 8377884

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

Let me search for the claims and any litigation specific to this patent.

Let me retrieve the actual claim text for US 8,377,884.

Summary: US Patent 8,377,884 B2

Important caveat up front: I was able to retrieve the patent's front matter, abstract, description and definitions, but not the numbered claim set for this specific patent. The sources fetched (Google Patents, FreePatentsOnline, patentimages) returned the specification text without the claims. I therefore cannot quote or precisely paraphrase the independent claims with authority, and I flag that uncertainty below rather than fabricate claim language.

Bibliographic data (high confidence — consistent across Google Patents, FreePatentsOnline, Wanfang)

Note on inventor spelling: Google Patents renders the fifth inventor as "Joshua R. Bliesath"; the published application US 2010/0331256 A1 renders it "Joshua R. Bilesath." I am reporting both literally rather than correcting either.

Abstract (verbatim, per the fetched sources)

"The present invention provides variants of C-type natriuretic peptide (CNP) comprising one or more deletions; additions of and/or substitutions with natural amino acids, unnatural amino acids and/or peptidomimetics (including peptide bond isosteres); amino acid extensions; and/or other chemical moieties such as, e.g., poly(ethylene glycol) and hydrophobic acids. 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, e.g., skeletal dysplasias and achondroplasia, and vascular smooth muscle disorders such as, e.g., restenosis and arteriosclerosis."

Plain-language overview of the claimed subject matter

Because the authoritative claim text was not in the retrieved material, the following is drawn from the specification and its "Definitions" section — i.e., the subject matter the patent describes as its invention — not from verified claim language. Treat it as a description of scope, not a claim-by-claim reading.

The patent is about making modified versions of C-type natriuretic peptide (CNP) that last longer in the body while still activating the CNP receptor (NPR-B) to raise cGMP. Wild-type CNP-22 is a 22-amino-acid peptide with a disulfide loop (Cys6–Cys22) and a very short half-life because it is chopped up by neutral endopeptidase (NEP) and cleared by the NPR-C receptor. The specification's embodiments are built around several general formulas (SEQ ID NOs 5, 6, 34, 46, 47, 48, 49, 50, 138):

1. Backbone/side-chain modified CNP variants. Peptides based on CNP22 or its cyclic core CNP17 (residues 6–22) in which one or more positions are changed with natural amino acids, unnatural amino acids, or peptidomimetics — including peptide-bond isosteres at NEP cleavage sites (e.g., Cys6–Phe7, Gly8–Leu9, Lys10–Leu11, Arg13–Ile14, Ser16–Met17, Gly19–Leu20). Substitution menus include D-Phe, N-methylated residues, halogenated phenylalanines, β-amino acids, tBu-Gly, Abu, Aib, norleucine, etc.
2. Size/mass-increased variants. Conjugating N- and/or C-terminal extensions (amino acid tails, PEG/PEO, hydrophobic acids, carbohydrates, bone-targeting moieties) to bring total mass into roughly the 2.6–7 kDa window — large enough to resist NEP yet small enough to reach growth-plate chondrocytes.
3. PEGylated, N-terminally extended variants. Specific emphasis on PEG (0.6–1.2 kDa, e.g., PEO12/PEO24) attached to an N-terminally extended CNP (e.g., GANRR-CNP22(K4R) = "CNP27(Arg4)"), where the residue immediately before Gly1 is a large/potentially positively charged residue such as Arg to preserve cGMP activity.
4. Variants with reduced NPR-C (clearance receptor) affinity, e.g., substitutions at glycine positions (G1R/E, G5R/Q/S, G8T/S/V/N, G15R/S/N/Cit, G19S/R/N, G21S/T/R).
5. Chimeras/fusions with fragments of IgG, HSA, fibronectin, fibrinogen, zinc-finger proteins, histidine-rich glycoprotein, osteocrin or FGF2.
6. Compositions and methods of use — pharmaceutical compositions and use for treating bone-related disorders (skeletal dysplasias such as achondroplasia) and vascular smooth muscle disorders (restenosis, arteriosclerosis).

Representative species named in the description include CNP-53, CNP-37 ("Analog BL"), CNP27(Arg4)/CNP27(Pro4), and the analogs lettered CA–DA and CH–DB.

Litigation / docket search — what I actually found

No CAFC 2026 docket or litigation specifically asserting US 8,377,884 was found. I must be explicit: the searches returned CNP-related BioMarin disputes, but the patents actually asserted are different patents in the same family, chiefly U.S. Reissue Patent RE48,267 and a patent referred to as the '106 patent:

• ITC Inv. No. 337-TA-1447, "Certain Drug Products Containing C-Type Natriuretic Peptide Variants, and Components Thereof," instituted May 2, 2025 (90 Fed. Reg. 19532; amended Sept. 17, 2025, 90 Fed. Reg. 44843). Complainant: BioMarin Pharmaceutical Inc. Asserted claims: claims 15–20 and 31–48 of RE48,267 — not 8,377,884. Respondents include Ascendis Pharma, Inc. (later Bachem AG and Wacker Biotech GmbH). Accused product: TransCon CNP (navepegritide).
• PTAB/PGR proceedings (ptacts.uspto.gov petitions 1558718 and related) in which Ascendis challenged CNP-variant claims, again directed at RE48,267 and the '106 patent, not 8,377,884.
• Parallel disputes in the U.S. district courts (N.D. Cal. case no. 3:25-cv-…, docket fragment gov.uscourts.cand.452409 addressing a BioMarin preliminary-injunction motion), the UPC (BioMarin filed against Ascendis in January 2025), plus Brazil, Denmark, Germany and South Korea.
• Settlement: On Aug. 31, 2026, BioMarin and Ascendis announced a global settlement/license: Ascendis pays BioMarin royalties of 20% of U.S. net sales and 18% in the EU, Brazil and South Korea on Yuviwel/navepegritide, from first commercial sale through May 20, 2030; all pending suits (including the ITC action) to be dismissed.

One search hit styled "the '788 Patent" concerning LCD gamma-reference-voltage claims (a PTAB petition about Nonomura/Kang/Uehara) is an unrelated patent and must not be conflated with US 8,377,884.

What I could not confirm

• The exact independent claim language of US 8,377,884 (claim 1 and any other independent claims), and hence their precise count and scope.
• Whether US 8,377,884 was ever itself asserted in any 2025–2026 litigation or CAFC appeal. The record I retrieved associates the CNP enforcement campaign with RE48,267 (and the '106 patent), and family members such as US 8,198,242, US 8,598,121 and RE46,707 also exist.

If you need the verified claim set, the authoritative sources are the USPTO PatentCenter/Patent Full-Text (patft) record for 12/744,079 and the issued patent PDF (US 2010/0331256 A1 / US8377884B2), which I was unable to load claims from in this session.

Date note: your prompt states the current date as April 26, 2026, while my operating context and several retrieved items date to September 2026. I have reported the retrieved events (including the Aug. 31, 2026 settlement) as the sources present them.

I'll search for litigation involving US patent 8377884 across the sites you specified.

I found strong leads. Let me confirm the specific role of the '884 patent in the ITC action and the district court cases.

Bottom line

I found no case in which US 8,377,884 ("the '884 patent") was itself asserted as the patent‑in‑suit (i.e., no complaint or ITC complaint alleging infringement of the '884 patent that I could confirm).

What I did find is that the '884 patent plays a documented role in the BioMarin v. Ascendis CNP/achondroplasia dispute — as a prior-art reference / exhibit, not as the asserted patent. The patent asserted against Ascendis was U.S. Reissue Patent No. RE48,267 ("RE'267"), and Ascendis relied on BioMarin's own '884 patent as §102(e) prior art against it.

I also note the Google Patents record for US 8,377,884 carries a "Family has litigation" flag (Darts‑IP family 40364250), which is a family-level indicator, not evidence that the '884 patent specifically was sued on.

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Proceedings where US 8,377,884 appears

1. ITC Section 337 Investigation — Inv. No. 337‑TA‑1447

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

2. Ascendis Pharma A/S v. BioMarin Pharmaceutical Inc. (N.D. Cal.)

Ascendis's declaratory-judgment / "safe harbor" action

3. Other asserted fora (per BioMarin's settlement announcement)

BioMarin stated the settlement resolves "all claims relating to the asserted intellectual property, including litigation pending in Brazil, Denmark, Germany, South Korea and the Northern District of California." No court/case numbers were disclosed for the ex‑US actions in the sources I reviewed, and I could not confirm that the '884 patent (as opposed to the RE'267 family) was the instrument asserted in any of them.

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Settlement terms (affecting the above)

• Announced August 30, 2026 by BioMarin (Form 8‑K event date Aug. 30, 2026).
• Ascendis pays BioMarin a 20% royalty on U.S. net sales of Yuviwel (retroactive to first commercial sale) and 18% on net sales in the EU, Brazil and South Korea, until May 2030.
• BioMarin grants Ascendis a non-exclusive, worldwide, royalty-bearing license for navepegritide (all indications, including achondroplasia and hypochondroplasia, and combinations).
• All pending litigation to be dismissed with prejudice; the ITC Section 337 investigation dropped.

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Related PTAB proceedings (not on the '884 patent — for context only)

• PGR2026‑00013, Ascendis Pharma A/S v. BioMarin Pharmaceutical Inc. — challenges U.S. 12,233,106 ("Methods of Treating Skeletal Dysplasia").
• PGR2026‑00055, Zydus Pharmaceuticals USA Inc. (with Zydus Lifesciences Ltd. and Zydus Lifesciences Global FZE) v. BioMarin — also challenges U.S. 12,233,106.
• BioMarin asserted the RE'267 patent in the ITC (not '884).

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Caveats on my search

1. Asserted-vs-cited distinction. Every hit tying US 8,377,884 to litigation I found places it as a prior-art exhibit/reference (Ex. 32 in both the ITC and the N.D. Cal. filings), not as an asserted patent. I found no complaint, counterclaim, or ITC notice asserting infringement of the '884 patent.
2. Sources. I searched general web results surfaced from the ITC's Federal Register notice (usitc.gov), CourtListener/PACER docket 4:25‑cv‑05696, PTAB filings hosted at ptacts.uspto.gov, an archived N.D. Cal. filing (gov.uscourts.cand.452409), and BioMarin/Ascendis press releases. I was not able to retrieve a Unified Patents litigation caselist or a CAFC docket entry specifically naming 8,377,884 as the asserted patent.
3. Pre-2025 litigation. I found no earlier litigation asserting the '884 patent, but I cannot rule out a case that did not surface in these searches — treat the "none found" as a search result, not a definitive negative.
4. Identifier fidelity. I have not altered any number: the patent in question is US 8,377,884 B2 (App. No. 12/744,079, filed 2008‑11‑21, priority 2007‑11‑21, granted 2013‑02‑19, assignee BioMarin Pharmaceutical Inc.). Google Patents currently lists its legal status as "Expired – Fee Related," with an anticipated expiration of 2028‑11‑21.

If the question is really "was US 8,377,884 ever asserted in the BioMarin–Ascendis fight?" the answer is: no — BioMarin asserted RE48,267, and Ascendis used the '884 patent as its §102(e) prior-art weapon against RE'267.

I'll start by checking the structured data against what web search surfaces, since the ODP block says no AIA trials are indexed.

Let me probe the related CNP patents and any litigation/IPR chain.

Let me confirm whether any trial was ever filed against 8,377,884 specifically, and check the reissue/litigation history.

Proceedings overview

Total AIA trial proceedings on US 8,377,884: ZERO. The USPTO Open Data Portal block for this patent returns no IPRs, no PGRs, and no CBMs, and my independent web searches (PTAB E2E/PTACTs, docket aggregators, law-firm PTAB trackers, and news coverage of the BioMarin CNP patent estate) surfaced no petition ever filed against this patent number. The breakdown is therefore: active 0 / claims invalidated 0 / claims sustained 0 / settled 0 / institution denied 0 — and the honest bottom line for a defendant is not "the patent has survived two IPRs and is hardened." It is: the patent has never been tested at the PTAB at all, and its recorded legal status is "Expired – Fee Related." The absence of PTAB activity is a signal in itself, but here it is a weak one, because the patent's own status data explains it: challengers had no reason to spend $500K+ attacking a patent whose maintenance fees appear to have lapsed (see Strategic summary).

One important structural point before the empty proceeding list: US 8,377,884 is a pre-AIA patent (priority 2007-11-21; filed 2008-11-21), so Post-Grant Review was never available against it — only IPR and CBM. No IPR was ever filed.

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Proceedings on US 8,377,884

None. There are no proceeding numbers to report, and I will not invent any. If you are a defendant and a demand letter or complaint cites US 8,377,884, there is no PTAB record, no FWD, no IPR estoppel, and no claim that has been canceled by the Board. Any invalidity work you do is from scratch.

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Adjacent proceedings — do NOT let these be conflated with the '884 patent

These are real, verified proceedings in BioMarin's CNP patent family, but they involve different patent numbers. A defendant or an adversary briefing that cites them as "PTAB history on the '884 patent" would be wrong.

PGR2026-00013 — Ascendis Pharma A/S v. BioMarin Pharmaceutical Inc.

• Type: Post-Grant Review
• Target patent: U.S. Patent No. 12,233,106 ("the '106 patent") — not 8,377,884
• Filed: 2026 (2026 docket; exact filing date not confirmed in the sources I retrieved)
• Status: Petition filed; BioMarin filed a Patent Owner Preliminary Response seeking discretionary denial. No institution decision confirmed as of 2026-09-29.
• Petition grounds: § 102 anticipation and § 103 obviousness over Högler, Savarirayan, Pauli, Bullens, and Wendt-242 (U.S. Pat. No. 8,198,242 — a sibling of the '884 patent in the same CNP family); plus § 112 enablement of claims 1–14.
• Key PO arguments: (1) § 325(d) — the same core art (Bullens, Wendt-242, Savarirayan) was already before the Examiner; (2) discretionary denial for claim-construction inconsistency between the PGR and co-pending ITC Inv. No. 337-TA-1447; (3) failure to name Bachem AG and Wacker Biotech GmbH as real parties in interest.
• Source: BioMarin POPR, PGR2026-00013
• Note: This is PGR territory only because the '106 patent is post-AIA. It is a method-of-treatment patent, not the '884 variant-composition patent.

PGR2026-00055 — Zydus Pharmaceuticals USA Inc. (with Zydus Lifesciences Limited and Zydus Lifesciences Global FZE) v. BioMarin Pharmaceutical Inc.

• Type: Post-Grant Review
• Target patent: BioMarin's "Methods of Treating Skeletal Dysplasia" patent (the '106 patent family)
• Filed: 2026-06-05
• Status: Petition filed; no institution decision confirmed.
• Petition grounds: multiple §§ 102/103 grounds plus § 112 enablement. Ground 2 asserts anticipation of claims 1–7 and 9–14 by Wendt-242 (U.S. Pat. No. 8,198,242), arguing Example 19 of Wendt-242 taught treating "infant[s] (<1 year of age) to pre-adolescent (<13 years of age)" — encompassing the '106 claim's "about 0 month to about 2 years old" limitation — and disclosed Pro-Gly-wtCNP37.
• Source: Petition analysis, PGR2026-00055

Why the family context matters to you anyway: both PGRs lean heavily on Wendt-242 (US 8,198,242) as prior art. The '884 patent is in that same Wendt/Aoyagi-Scharber family and shares much of the same disclosure (CNP variants, NEP-resistance, PEGylation, bone-targeting). If the Board ever construed the Wendt-242 disclosure broadly in those PGRs, that reasoning would be portable to an '884 invalidity theory. That is the only way the existing PGRs touch your patent.

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Strategic summary

Which claims of 8,377,884 are canceled vs. sustained vs. untested. Every claim of US 8,377,884 is UNTESTED. No claim has been canceled, no claim has been sustained, and no claim has been construed by the Board. The patent is recorded on Google Patents with legal status "Expired – Fee Related" and an anticipated expiration of 2028-11-21. That status is a USPTO/Google annotation and not a legal conclusion, but for a defendant it is the single most important fact on this page: a patent that lapsed for non-payment of maintenance fees is generally unenforceable for the remainder of its term, and there is no PTAB record to consult because nobody needed one. Before you build any defense, pull the USPTO Patent Center maintenance-fee history and the fee-status event record for 12/744,079. If the lapse is real and unremedied, the entire PTAB question is academic.

Estoppel landscape. Because no IPR was ever filed against the '884 patent, there is no § 315(e)(2) estoppel — not against Ascendis, not against Zydus, not against anyone. That cuts both ways:

• No estoppel binds you. You are free to raise any § 102/§ 103 ground, including art that would have been available to a hypothetical earlier petitioner.
• No estoppel helps you either. There is no prior petitioner's invalidity work product you can inherit, and no FWD findings you can point the court to.
• Watch the reverse-direction estoppel risk: Ascendis filed PGR2026-00013 and Zydus filed PGR2026-00055 against sibling BioMarin patents. If either becomes a privy or real party in interest in a suit touching the '884 patent, its PGR estoppel under § 325(e)(2) is broad — it reaches grounds raised or that reasonably could have been raised in the PGR, and applies in district court and at the ITC. If you are aligned with either company, get that conflict cleared early.

Also note the practical bar. The '884 patent is pre-AIA and issued 2013-02-19. Any defendant served with a complaint asserting it more than one year ago is time-barred under § 315(b) from filing an IPR. Given that the patent is also recorded as fee-expired, an IPR is almost certainly not your play — a § 282 defense in litigation, or a Rule 12 motion if the patent is truly lapsed, is far cheaper.

Pattern signals. No defensive aggregator (Unified Patents, RPX) has ever touched this patent. No serial petitioner exists. BioMarin does not appear to appeal PTAB outcomes aggressively in this family — its posture has been offensive litigation (ITC Inv. No. 337-TA-1447 asserting RE48,267, a reissue of 8,598,121, a continuation of 8,198,242) culminating in the 2026-08-30 global settlement with Ascendis, under which Ascendis pays BioMarin 20% of US Yuviwel net sales (retroactive to first commercial sale) and 18% in the EU, Brazil and South Korea through May 2030, resolving the ITC § 337 action and suits in Brazil, Denmark, Germany, South Korea, and the N.D. Cal. (BioMarin press release, 2026-08-30/31). That settlement strongly suggests the Ascendis PGR2026-00013 is now moot by agreement (the parties agreed to "resolve all claims relating to the asserted intellectual property") — but I could not confirm a termination order in PGR2026-00013, so verify it on PTAB E2E before relying on it. The Zydus PGR2026-00055 is not covered by that settlement and should still be live.

One final caveat on the family-litigation flag. Google Patents shows a "Family has litigation — First worldwide family litigation filed" annotation for this patent's family (Darts-IP family 40364250). That is a district-court/ITC signal, not a PTAB signal, and the litigation it reflects is the BioMarin–Ascendis and BioMarin–ITC activity described above — which is asserted on RE48,267 and the '106 patent, not on the '884 patent.

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Recommended next steps

1. If you are a defendant and the demand letter or complaint cites US 8,377,884: there is no FWD to link you to and no claim to quote, because no PTAB proceeding exists. Say so plainly in your file. The absence is not proof of strength — it is consistent with a patent that lapsed.
2. Verify fee status first (highest-value single action). Pull the maintenance-fee record for US 12/744,079 in USPTO PatentCenter. Confirm: (a) which of the 3.5-, 7.5-, and 11.5-year fees were paid; (b) whether the 6-month grace period has closed; (c) whether any petition to accept an unintentionally delayed payment under 35 U.S.C. § 41(c) / 37 C.F.R. § 1.378 is pending. A lapsed patent cannot be asserted; a petitioned-for revival is a fact question that changes your answer entirely.
3. Pull the complete family tree. Confirm the chain: US 8,198,242 → US 8,598,121 → RE46,707 and RE48,267; plus US 8,377,884 and any continuations. Note which family members are post-AIA (PGR-eligible) and which are not. Ascendis and Zydus both attacked post-AIA members; the '884 patent is a pre-AIA member.
4. Check PTAB E2E for the two live PGRs' status as of today. Docket links: PTAB E2E / PTACTs. Specifically look for (a) the institution decision in PGR2026-00013 and whether it was terminated per the settlement; (b) whether Zydus has sought joinder or coordinated filings; (c) any motion by BioMarin to amend claims in either PGR — amendments there, if allowed, would be to the '106 patent claims, not the '884 claims.
5. If you are aligning with Ascendis or Zydus, get a written RPI/privity analysis before sharing invalidity work product. Their PGR estoppel under § 325(e)(2) is the broadest estoppel in the AIA, and it would attach to any ground they raised or reasonably could have raised in the PGR.
6. Trial-stage timing (for awareness only, since no '884 proceeding exists): if anyone did file an IPR against the '884 patent, the statutory clock is 6 months to an institution decision from the petition filing date, then a hard 1-year deadline from institution to FWD under 35 U.S.C. § 316(a)(11). There is no such clock running here.

Confidence and gaps. High confidence that no AIA trial proceeding has ever been filed against US 8,377,884 — the ODP block is empty and my searches corroborate it. Medium confidence on the exact filing date of PGR2026-00013 and on the current procedural posture of both PGRs, since PTAB E2E was not queried live for this analysis. I did not find a Federal Circuit appeal of any FWD concerning this patent, which is consistent with there being no FWD. If you need the PGR docket states pinned down, query PTAB E2E directly rather than relying on this summary.

I'll research the assignment record for US 8377884 before assembling the timeline.

Let me dig into the assignment specifics and any post-issuance transfers or litigation.

Let me check the assignment record specifics and any reissue-related recordings.

Ownership & Assignment Analysis — US 8,377,884 B2

Patent: "Variants of C-type natriuretic peptides" · App. 12/744,079 · Filed 2008-11-21 · Priority 2007-11-21 · Granted 2013-02-19 · Original assignee BioMarin Pharmaceutical Inc. · Status: Expired – Fee Related (anticipated expiration 2028-11-21).

Data-access caveat (read first): My live queries returned the Assignment Center–indexed record (via Google Patents legal events and FPO mirrors) rather than a direct hit on https://assignmentcenter.uspto.gov/. I was able to confirm one recorded conveyance and its recording date, but I could not retrieve the reel/frame number or the correspondent-of-record in this session. I am therefore not supplying reel/frame identifiers — inventing them would be worse than omitting them. Verify directly at the Assignment Center search page for patent 8,377,884.

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Inventors

Six named inventors, all listed on the face of the patent:

Basis: The original assignment was executed in favor of BioMarin Pharmaceutical Inc. by all six inventors as assignors (see timeline), which establishes an employment/obligation-to-assign relationship with BioMarin for each.

Departure patterns: No verified data in this session showing inventors leaving BioMarin within 12 months of filing. Wendt, Bell, Bliesath and Wei recur on other BioMarin filings (e.g., US/JP family member AU-2008-289549, also listing Wendt, Bell and Kakkis), which is consistent with continued tenure rather than a mass exodus. Emil D. Kakkis is widely reported to have later left BioMarin and founded Ultragenyx Pharmaceutical — I flag this at low-to-moderate confidence, as it was not re-verified by a tool call in this session and the departure was not a within-12-months-of-filing event. Importantly, even if true, it did not precede any fire-sale: BioMarin retained the patent and later asserted it. No inventor-exodus signal.

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Original assignee

BioMarin Pharmaceutical Inc. (NASDAQ: BMRN), San Rafael, California.

• Primary line of business: Commercial-stage biopharmaceutical R&D and manufacturing for rare genetic diseases. Operates a Novato, California cGMP manufacturing facility (~553,000 sq ft).
• Product embodying the claims: Yes. BioMarin commercializes VOXZOGO® (vosoritide), a CNP analog approved by FDA in 2021 as the first therapy for achondroplasia. This patent family is the CNP-variant platform underlying that program. The ITC complaint affirmatively states Voxzogo is manufactured by BioMarin substantially at its Novato facility — i.e., domestic industry is being practiced.
• Current status: Operating. Publicly traded, no bankruptcy, no dissolution.

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Assignment timeline

One recorded assignment is confirmed on the face of the indexed record. Post-issuance, the patent was taken into reissue (RE48,267) and became the asserted patent in BioMarin's enforcement campaign — but I found no recorded post-issuance assignment changing ownership.

• 2008-11-21 (application filed) / recorded 2010-10-05 — Reel/frame not retrieved (see caveat)

  • Conveyance: Assignment (recorded as a "reassignment" of interest in the application)
  • Assignor: Wendt, Dan J.; Bell, Sean; Bliesath, Joshua R.; Wei, Dong; Aoyagi-Scharber, Mika; Kakkis, Emil D.
  • Assignee: BioMarin Pharmaceutical Inc.
  • Correspondent: Not retrieved in this session — cannot confirm or flag recurrence.
  • Context: Initial inventor-to-company assignment of the application; the entire chain originates and terminates at BioMarin.

• No further recorded assignments found. Ownership has remained with BioMarin Pharmaceutical Inc. from 2010 to the present. There is no LLC, no IP-holding spin-out, no security interest, no license recorded against the patent on the indexed record.

Related legal events (not assignments, listed for completeness):

• 2013-02-19 — Patent granted.
• Reissue — The patent was reissued as RE48,267 (reissue application 15/646,822, "Variants of C-Type Natriuretic Peptide"). Reissue is a USPTO re-grant of the same patent to the same owner, not a transfer of title.
• 2025-01 — BioMarin filed an ITC Section 337 complaint against Ascendis Pharma concerning RE'267 (proceeding 337-TA-1447), plus parallel actions in Brazil, Denmark, Germany, South Korea, and N.D. Cal.
• 2026-08-30 — Global settlement: Ascendis takes a non-exclusive worldwide license to BioMarin's CNP patents; Ascendis pays 20% U.S. / 18% EU-Brazil-South Korea royalties through May 2030 (BioMarin Form 8-K, event date 2026-08-30).

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Timeline diagram

timeline
    title Ownership of US 8377884
    2007 : Priority application filed
    2008 : US application filed by BioMarin
    2010 : Inventors assign rights to BioMarin
    2013 : Patent US 8377884 issues
    2016 : Reissue application filed
    2021 : VOXZOGO approved and shipping
    2025 : BioMarin files ITC case vs Ascendis
         : Parallel suits in four countries
    2026 : Global settlement with Ascendis
         : Ascendis pays 18 to 20 percent royalties

(The 2016 reissue-filing year is approximate based on the 15/646,822 application series; all other years are anchored to the patent record, the ITC filings, and the BioMarin 8-K.)

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NPE / troll-pattern signals

Net count: zero NPE signals of any strength. Signals 1, 2, 4, 5, 6, 7 and 8 are affirmatively negative; only signal 3 is unrated for lack of correspondent data.

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Verdict

Operating-company assertion.

BioMarin Pharmaceutical Inc. has owned US 8,377,884 continuously since the single recorded inventor-to-company assignment (recorded 2010-10-05; reel/frame not retrievable in this session), and there is no post-issuance transfer to any shell, NPE, or aggregator. BioMarin ships a product embodying the claims — VOXZOGO® (vosoritide), approved 2021 and manufactured in Novato, California — and asserted the reissued patent directly in its own name against a genuine competitor, Ascendis Pharma, in ITC investigation 337-TA-1447 plus suits in Brazil, Denmark, Germany, South Korea and N.D. Cal., settling on 2026-08-30 for 18–20% royalties. That is the archetype of operating-company assertion, and it is the opposite of an NPE pattern.

Verify at: https://assignmentcenter.uspto.gov/ (search "8377884") — and cross-check RE48,267, whose assignment record is Exhibit 2 to BioMarin's ITC complaint. Open item: the reel/frame and correspondent-of-record must be pulled from the live Assignment Center to close signal #3; I deliberately did not guess them.

I'll research US 8,377,884's cited prior art and its claim set. Let me run several targeted searches.

Key finding already: the '884 patent itself was argued as prior art (pre-AIA §102(e)) in the CNP litigation. Now let me pull the front-page citations and the actual claims.

I have the front-page citation list forming. Let me retrieve the full set of cited references and the claim text.

Prior-Art Analysis — US 8,377,884 B2 ("Variants of C-type natriuretic peptides")

0. Identification and methodological note (please read first)

I searched for the literal number 8377884 and no other. The record retrieved is US 8,377,884 B2, Appl. No. 12/744,079, PCT/US08/84270, filed 2008‑11‑21, priority 2007‑11‑21 (U.S. prov. 60/989,497) and 2008‑06‑13 (61/061,488), granted 2013‑02‑19, assignee BioMarin Pharmaceutical Inc. I did not return results for numerically similar patents (e.g., 8,377,788, 8,377,884's reissue RE48,267, or the unrelated "'788 patent" about LCD gamma-reference voltages that surfaced in an earlier search and must not be conflated here).

Two limitations you should weigh:

1. I could not query USPTO PatentCenter / Patent Full-Text (patft) directly in this session. The citation data below is the front-page "References Cited" list as mirrored by Google Patents for US 8,377,884 (https://patents.google.com/patent/US8377884/en, "Patent Citations (24)"). That mirror is normally faithful to the USPTO face-page, but it is a mirror, not the primary USPTO record. Verify against PatentCenter before relying on it.
2. I again could not load the numbered claim set of the '884 patent. Google Patents returned the specification and "Definitions" section but not the claims, and my independent claim searches returned claim text for other BioMarin patents (e.g., EP 4,029,512 A1's claim 1 to CNP‑38/CNP‑35/CNP‑34, and the '106 patent's claims in the PTAB petition). Therefore I cannot state with authority which claim numbers a given reference anticipates. In Section 4 below I map references to claim themes inferred from the specification, and I label that inference as such. This is a real gap, not a stylistic hedge.

Google Patents also reports the examiner/classifier "prior art keywords" as: cnp, seq, cnp22, amino acid, gly — i.e., the art unit's focus was CNP peptide sequence variants.

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1. The full cited-reference list (as retrieved)

Google Patents shows 24 front-page patent citations for US 8,377,884. My retrievals captured 18 of them, listed verbatim below with the dates as rendered. Six entries remain unretrieved (see §5).

Statutory-category check: The '884 patent is pre‑AIA (filed 2008‑11‑21, priority 2007‑11‑21). Every reference above has a publication/grant date or a § 102(e) filing date well before the 2007‑11‑21 priority date, so all 18 qualify as prior art in at least one pre‑AIA § 102 subsection. Items 17 and 18 (WO 02/074234 and the family) and items 1–16 are all printed/patented more than one year before the critical date, so § 102(b) is triggered for all except US 7,256,253 (granted 2007‑08‑14, i.e. less than one year before) and US 7,276,481 (granted 2007‑10‑02, less than one year before) — both of which nevertheless qualify under § 102(a) and § 102(e).

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2. Why the "cited" list alone does not answer the anticipation question

Being on the face of the patent means the examiner considered the reference; it does not mean the reference anticipates any claim. The legally meaningful signal in this record is different and stronger: the applicant used defensive "optionally excludes" language against three of these references, which is the classic tell that the drafter believed the reference disclosed species falling within the claimed genus.

From the '884 specification (verbatim from the authoritative full text supplied):

• *"the present invention optionally excludes the peptides of SEQ ID NOs 1‑4 and 6‑71 as specifically disclosed in U.S. Pat. No. 7,276,481"*;
• "the invention optionally excludes peptides of SEQ ID NO 5, disclosed generically in U.S. Pat. No. 7,276,481, wherein such peptides are variants of CNP17 having at least one natural amino acid substitution at Leu9, Lys10, Leu11, Ser16, Met17, Gly19, and/or Leu20";
• "optionally excluded are CNP17 variants in which CNP17 or variants thereof contain N‑Me‑Phe7, or N‑Me‑Phe7 and N‑Me‑Leu11";
• *"the present invention optionally excludes the peptides of Compound Nos. 1‑27, and SEQ ID NOs 1‑17, 22‑24, 30, 31 and 40‑42 as specifically disclosed in U.S. Pat. No. 5,434,133"*, plus "peptides of SEQ ID NOs 18‑21 and 25‑29";
• "the invention optionally excludes the peptides of SEQ ID NOs 1‑4 and 9 as specifically disclosed in WO 94/20534."

The third bullet is especially consequential: an "N‑Me‑Phe7" carve-out is only necessary if a claim otherwise reads on an N‑methylated-Phe7 CNP17 — which is one of the very peptide-bond-isostere embodiments the '884 spec touts at the Cys6–Phe7 NEP cleavage site.

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3. Most relevant prior art, ranked

Tier 1 — references the patentee itself carved out (highest anticipatory risk):

1. US 7,276,481 B2 (Prochon Biotech; grant 2007‑10‑02; prio. 2001‑03‑20) — CNP‑17 genus. Under § 102(a)/(e) and, via its publication, § 102(b) (WO 02/074234, 2002‑09‑26). This reference and its PCT sibling are also the ones Ascendis has been arguing in the co-pending litigation (see §6).
2. US 5,434,133 A (Suntory; grant 1995‑07‑18) — CNP‑22 analogues with defined position‑6/7/9/11/22 substitutions. Pure § 102(b) art. Its EP sibling EP 0 497 368 A1 (1992‑08‑05) is the parallel European publication.
3. WO 94/20534 A1 / US 5,583,108 A (Mayo; 1994‑09‑15 / 1996‑12‑10) — vasonatrin and analogs. § 102(b).

Tier 2 — background/structural art that could anticipate specific dependent claims if the claims are broad:

1. US 5,352,770 (Matsuo) — porcine CNP‑22 identical to human CNP‑22; § 102(b).
2. US 6,034,231 and US 6,020,168 (Suntory) — human/porcine CNP gene and precursor; § 102(b) as to nucleic-acid and CNP‑53 claims.
3. US 5,846,932 (Genentech; 1998‑12‑08) — natriuretic analogs with reduced NPR‑C affinity; § 102(b) as to the "reduced NPR‑C affinity" claim theme.
4. US 6,407,211 (Mayo; 2002‑06‑18) — chimeric natriuretic peptides; § 102(b) as to chimera claims.
5. WO 00/61631 A1 (AstraZeneca; 2000‑10‑19) — NPR‑C antagonist pentapeptides.
6. US 5,252,714 (UAH; 1993‑10‑12) — PEG‑propionaldehyde; § 102(b) only if a claim recites that reagent/chemistry per se.

Tier 3 — machinery/adjunct art unlikely to anticipate peptide claims:

1. US 7,256,253 (Conjuchem; 2007‑08‑14) — peptide–albumin-binding conjugates; § 102(a)/§ 102(e).
2. US 5,665,704 (Genentech; prio. 1993‑11‑12) — family sibling of 5,846,932.
3. US 6,136,040 (Washington University; 2000‑10‑24) — FGF‑9 knockout model; § 102(a) only for animal-model/screening claims.

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4. Best-effort § 102 mapping (inferred claim themes, not verified claim numbers)

Because I do not have the '884 claim set, I map to the five claim themes the specification presents as the invention (consistent with the earlier-generated summary). Treat every claim number below as unverified.

Anticipation requires a single reference to disclose every limitation "arranged as claimed." Several references above would be far more naturally deployed as § 103 combinations (and indeed the AlphaFold-era caution applies: a quoted "excludes" clause is evidence the applicant feared § 102, not proof it applies).

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5. What I could not confirm

• 6 of the 24 front-page citations. My retrieved snippet rendered items 1–18 above and then was truncated. The unretrieved six include at least the reference associated with Yeda (US 6,265,632 B1) whose subject matter I could not verify, and possibly others. I am not going to invent them. The six missing entries should be read off the actual PatentCenter/patent-PDF face page.
• The number and text of the claims of US 8,377,884. My claim searches returned claim text for EP 4,029,512 A1 and for the '106 patent (in the PTAB petition), not for the '884 patent. I do not have claim 1.
• Whether any citation was designated by the examiner as the basis of a § 102 rejection during prosecution (as opposed to merely being listed under "References Cited"). That requires the file wrapper.
• The "Other Publications" (NPL) list for the '884 patent — I retrieved NPL lists for other patents (US 8,357,656; US 9,187,525) but not for the '884 patent. Non-patent literature (e.g., Kenny et al., Biochem. J. 291(Pt 1):83‑88 (1993) on NEP hydrolysis of CNP; Schiller, BBRC 138:880‑886 (1986) on the CNP17 loop) is cited in the specification and should be checked as § 102(b) art in its own right.

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6. Material development you should not miss: the '884 patent is now being used as § 102 art

This is the flip side of your question and it is the live controversy in this family. In Ascendis Pharma A/S v. BioMarin Pharmaceutical Inc., N.D. Cal. No. 4:25‑cv‑05696, BioMarin's filing (Doc. 75‑2, filed 2026‑03‑18; mirrored at CourtListener https://www.courtlistener.com/docket/70727928/75/2/ and https://ia800400.us.archive.org/18/items/gov.uscourts.cand.[452409](/patent/452409)/gov.uscourts.cand.452409.75.2.pdf) states, verbatim:

"Ascendis appears to pin its hopes in the ITC primarily on the argument that the RE'267 patent is anticipated under 35 U.S.C. § 102(e) by BioMarin's own U.S. Patent No. 8,377,884 ('884) and its WO counterpart (WO 2009/067639 ('WO639'))."

BioMarin's two counter-arguments are worth recording because they are the operative § 102 defenses:

1. Pre‑AIA § 102(e) "by another" fails — the portions of '884/WO639 relied on and the RE'267 claims must represent work of a common inventive entity, not merely different listed inventors (Riverwood Int'l). BioMarin's brief: "the '884/WO639 references are not prior art under pre‑AIA 35 U.S.C. § 102(e) … so the entire argument fails out of the gate."
2. Even if they were prior art, the '884/WO639 references do not disclose CNP 38, the variant required by asserted method claim 50 of RE'267: "the claims of the '884 patent do not recite the CNP variants of the domestic industry claims … CNP‑38." (BioMarin Opposition to Summary Determination at 6.)

Note the asymmetry and the drafting significance: the '884 specification's own broad genus, which I analyzed above for anticipatory effect against CNP candidates, is precisely what is now being asserted against a later BioMarin reissue. Any position you take on '884's § 102 scope has direct consequences for RE'267: the broader '884's disclosure reads, the more potent it is as § 102(e) art against RE'267 — but a narrower reading protects '884's own claims. That tension is the analytical heart of the current dispute.

Cross-reference to previously-generated sections: the earlier summary identified the ITC action (337‑TA‑1447) and the PTAB/PGR petitions as directed at RE48,267 and the '106 patent, not at 8,377,884, and noted the Aug. 31, 2026 global settlement. Consistent with that, I found no CAFC appeal or asserted claim of US 8,377,884 itself. The one place '884 appears in litigation is as asserted prior art, per the quotation above — which reconciles with, and does not contradict, the earlier sections.

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7. Bottom line

• US 8,377,884 cites 24 patent references; I recovered 18. The three that matter most — US 7,276,481 B2, US 5,434,133 A, and WO 94/20534 A1 — are the ones the applicant expressly "optionally exclude[d]", and those are the references most likely to be asserted as anticipatory (§ 102(a)/(b)/(e)) against broad CNP‑variant claims, particularly a claim to a CNP17 variant with an N‑methylated Phe7 or a substituted Leu9/Lys10/Leu11/Ser16/Met17/Gly19/Leu20.
• I could not verify claim numbers or claim text for the '884 patent, so I deliberately did not fabricate a claim-by-claim anticipation chart. To close that gap, the authoritative sources are the USPTO PatentCenter record for application 12/744,079 (claims + "References Cited" face page + "Other Publications") and the issued patent PDF.
• The record's most newsworthy § 102 fact is directional: the '884 patent is being used as § 102(e) prior art against BioMarin's own RE48,267, and that argument is being resisted on the "by another / common inventive entity" ground and on the ground that '884 does not disclose CNP‑38.

I'll first attempt to close the biggest gap flagged in the prior-art section — the missing claim text — before analyzing § 103.

Let me try two more targeted routes for the '884 claim text.

I now have the actual claim text. Let me verify one cross-reference that materially affects the analysis — which patent RE48,267 reissues (the prior sections are internally inconsistent on this).

Update to the previously generated sections

Two corrections and one new fact before the analysis proper.

1. The claim text has now been retrieved. The earlier Patent-summary, Litigation-summary and Prior-art sections all flagged the same gap: "I could not retrieve the numbered claim set for this specific patent." That gap is now closed. US 8,377,884 has 24 claims, of which claim 1, claim 10 and claim 24 are independent (claim 1 and claim 24 are formula/structural claims; claim 10 is a closed Markush claim). Independent claims 1, 10 and 24 are reproduced verbatim in §2 below, sourced from Google Patents Claims (24) and the Justia mirror of the same patent. The earlier sections' "best-effort §102 mapping" and "inferred claim themes" are superseded — they should not be relied on now that real claim language exists. I flag this as an update, not a contradiction: the earlier statement was accurate as of that session.

2. Contradiction between two prior sections on RE48,267 — flagged, not silently corrected. The Assignment-History section states the '884 patent "was reissued as RE48,267 (reissue application 15/646,822)." The PTAB section, by contrast, describes RE48,267 as *"a reissue of 8,598,121, a continuation of 8,198,242."* These cannot both be right. This session's searches provide evidence for the second version:

• RE48,267's own face page (patentimages, USRE48267.pdf) shows Reissued Oct. 20, 2020, applicant BioMarin, inventors Wendt, Aoyagi-Scharber, Vellard, et al. — a different inventor roster from the '884's six.
• The Ascendis DJ complaint timeline records "RE'267 Patent Earliest Priority Date 2009‑05‑20."
• US 8,377,884's priority is 2007‑11‑21 and it granted 2013‑02‑19.

A reissue carries the original patent's priority date and cannot add new matter. RE'267's 2009‑05‑20 priority therefore cannot be the reissue of the '884 patent. This is corroborated by the fact that Ascendis is using the '884 patent as §102(e) prior art against RE'267 — impossible if RE'267 were the reissue of '884. Conclusion (medium-high confidence): RE48,267 is the reissue of US 8,598,121, not of US 8,377,884. The Assignment-History section's statement appears to be an error and should be corrected in the file.

3. New docket identifier. This session surfaced Ascendis Pharma A/S v. BioMarin Pharmaceutical Inc., N.D. Cal. No. 3:25‑cv‑03302 (filed 2025‑04‑11), a §271(e)(1) declaratory-judgment action. The earlier Litigation-summary section cited 4:25‑cv‑05696. I am not auto-correcting either number; both appear in the record and may be related or consolidated filings. Also new: RE'267 independent claim 1 is a Markush of four sequences (SEQ ID NOs 179, 180, 185, 186), and the ITC asserted claims 15–20 and 31–48.

4. Date note (carried forward). The task header states the current date as April 26, 2026; my operating context and the retrieved sources date to September 2026 (the Aug. 30–31, 2026 BioMarin–Ascendis settlement, a Sept. 22, 2025 claim-construction appendix, etc.). The earlier sections flagged this same discrepancy. I report events as the sources present them and do not auto-correct the stated date.

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Obviousness Analysis — US 8,377,884 B2 under 35 U.S.C. § 103

1. Governing law and framework

Pre-AIA §103 applies. The '884 patent's earliest effective filing date is 2007‑11‑21 (provisional 60/989,497), so the pre-AIA version of §103(a) governs under AIA §3(n)(1). KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), decided April 2007, applies to the examination and to any post-issuance validity challenge.

The Graham v. John Deere factors govern: (1) scope and content of the prior art; (2) differences between the prior art and the claims at issue; (3) the level of ordinary skill; and (4) secondary considerations. Under KSR, a claim is obvious where the claimed combination was "the product not of innovation but of ordinary skill and common sense," including where the art presents "a finite number of identified, predictable solutions" or where the variation is "a predictable use of prior art elements according to their established functions."

Two doctrines are unusually load-bearing here:

• Obviousness of ranges. Where the prior art discloses a value or range overlapping or encompassing the claimed range, the claimed range is prima facie obvious absent a showing of criticality. In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003); In re Woodruff, 919 F.2d 1575 (Fed. Cir. 1990); MPEP §2144.05.
• Obviousness of a genus/Markush from a finite set. A claimed Markush group assembled from a small number of known substituents, each performing its known function, is obvious. KSR; In re Rosati.

No PTAB proceeding exists (per the earlier PTAB section), so there is no Board construction to import and no §315(e)(2) estoppel. Any validity fight would be a §282 district-court or ITC fight on clear-and-convincing evidence.

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2. The claims — verbatim scope (newly retrieved)

Claim 1 (independent)

"1. A variant of C-type natriuretic peptide (CNP) having a total mass in the range from about 2.6 kDa to about 7.0 kDa, and having the formula: (SEQ ID NO: 35)
(x)-Gly1-Leu2-Ser3-(Arg)4-Gly5-(Cys)6-(Phe)7-(Gly)8-(Leu)9-(Lys)10-(Leu)11-Asp12-Arg13-(Ile)14-(Gly)15-Ser16-(Met)17-Ser18-Gly19-(Leu)20-Gly21-Cys22-(z)

• (x) is an amino acid sequence comprising from 1 to 40 amino acids and is optionally conjugated with a PEG polymer or a derivative thereof at the N-terminus of the variant; and
• (z) may be absent or may be selected from the group consisting of bone- or cartilage-targeting moieties; moieties that reduce renal clearance; hydrophilic polymers; amino acid sequences comprising one or more amino acids; carbohydrates; hydrophobic acids; and combinations thereof."

Claim 10 (independent)

"10. A variant of C-type natriuretic peptide (CNP) comprising the amino acid sequence set out in SEQ ID NO:35 (CNP22K4R) which is selected from the group consisting of: … [Markush list of analogs AY, CI, AZ, BA, CH, CG, CK, CL, CN, CM, CO, CP …]"

Claim 24 (independent)

"24. A variant of C-type natriuretic peptide (CNP) having a total mass in the range from about 2.6 kDa to about 7.0 kDa, which comprises: (a) a hydrophilic polymer, and (b) any one of ER-CNP22(K4R) (SEQ ID NO: 39), R-CNP22(K4R) (SEQ ID NO: 41), and GANQQ-CNP22(K4R) (SEQ ID NO: 69), wherein the hydrophilic polymer is attached to the peptide at the N-terminus, the C-terminus or an internal site, or a combination thereof."

Element-by-element breakdown of claim 1

Approximate masses (avg. residue masses + 18.02 Da water; approximations only)

Two construction points that matter:

1. Is (Arg)4 limiting? Claim 1's formula is tethered to "SEQ ID NO: 35," which the specification defines loosely as "wtCNP22 or a variant thereof (e.g., one having addition(s), deletion(s), and/or substitution(s) such as, e.g., a K4R substitution) (SEQ ID NO: 35)." Claim 10, however, expressly glosses SEQ ID NO:35 as "(CNP22K4R)". The natural reading is that claim 1 requires Arg at position 4. But if a tribunal read the parenthesized (Arg)4 as a variable position (as the EP sibling EP 3,175,863 claim 1 does with (h)10), claim 1 would read directly on native CNP‑53 — a §102 problem, not merely a §103 problem. This is the single most consequential construction in the case and should be pinned down first.
2. "About 2.6 kDa." With (x) mandatory, claim 1 requires an N-terminal extension or PEG mass of roughly ≥0.37 kDa — i.e., (x) of about 4+ residues, or a small PEG. Bare R‑/ER‑CNP22(K4R) fall outside claim 1 but are recaptured by claim 24 via the hydrophilic polymer.

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3. Person of ordinary skill in the art (POSITA)

For a 2007 critical date, the POSITA is a scientist with a Ph.D. (or M.S. plus several years' experience) in peptide chemistry, biochemistry, pharmacology or molecular biology, and 2–5 years' practical experience in one or more of: (i) structure–activity relationship (SAR) mapping of small peptide hormones; (ii) natriuretic peptide receptor biology (NPR-A/B/C, cGMP assays); (iii) peptide pharmacokinetics, including NEP-mediated degradation and renal clearance; and (iv) PEGylation/conjugation chemistry for peptide half-life extension. The POSITA routinely consults the natriuretic-peptide and peptide-PEGylation literature and would treat substitutions among chemically similar residues as routine.

Cross-check: the Ascendis PGR petitions against the sibling '106 patent articulate a POSA definition on this record; that definition should be pulled and harmonized before any invalidity contention is served, since a claim of a higher skill level is a standard patentee counter-move.

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4. The prior art of record (from the Prior-Art section) mapped to claim 1

Two decisive observations about this set.

First, the prior art already contains a species inside the claimed mass range: CNP‑53 at ~5.9 kDa, which sits squarely within "about 2.6 kDa to about 7.0 kDa." Under In re Peterson / In re Woodruff, that overlap makes the claimed range prima facie obvious unless the patentee proves criticality — and the specification supplies no data showing a sharp change at 2.6 kDa (its own rationale is the ~3 kDa NEP ceiling, which is a different number).

Second, claim 1 is, structurally, CNP‑53 with a single Lys→Arg change at position 4, optionally PEGylated, optionally bearing a (z) group. That framing — one conservative substitution away from a reference the applicant itself cited on the face of the patent — is the heart of the §103 case.

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5. Ground A — Claim 1 is obvious over US 6,034,231 + US 5,434,133 + US 5,846,932 + US 5,252,714 (in view of Oefner 2000 and Yeung 1996)

Why a POSITA would combine these references. The '884 specification itself supplies the motivation, and its Background section is an admission of the state of the art:

• The problem was known and pressing. "Therapeutic use of CNP is currently limited by its short plasma half-life, which has been shown to be 2.6 minutes in vivo in humans." The '884 spec also acknowledges that "continuous infusion has been necessary in all human and animal studies." A long-felt need for a longer-acting CNP was therefore well documented and was the explicit objective of the field — this is a motivation, not a patentable contribution.
• The mechanism and its solution were known. The spec acknowledges that CNP's half-life is reduced by "degradation by neutral endopeptidase (NEP) and clearance by natriuretic peptide receptor C (NPR-C)," and cites Oefner for the proposition that NEP "recognizes substrates smaller than about 3 kDa due to the limited size of its active site cavity." A POSITA seeking NEP resistance would therefore, as a matter of routine design, raise the mass above ~3 kDa — and the claimed range (2.6–7.0 kDa) sits on that axis.
• Size extension without activity loss was already demonstrated. Yeung 1996 (cited in the spec) teaches that "Both CNP‑53 and CNP‑22 bind similarly to NPR‑B. Furthermore, they both induce cGMP production in a dose-dependent and similar fashion." US 6,034,231 supplies the CNP‑53 sequence itself. So the art taught that adding a 31‑amino-acid N‑terminal tail — the exact structural motif of claim 1's (x) — preserves function.
• Non-CNP extensions were known. US 5,583,108/WO 94/20534 (vasonatrin) and US 6,407,211 teach chimeric CNP constructs, reaching claim 1's (z) Markush.
• Reduced NPR-C/renal clearance was known. US 5,846,932 and WO 00/61631 teach reducing NPR-C-mediated clearance, and Caliceti teaches anionic-polymer conjugation for the same purpose — reaching claim 1's "moieties that reduce renal clearance."
• PEGylation was known and routine. US 5,252,714 teaches PEG-aldehyde conjugation; WO 2004/047871 expressly teaches PEGylated natriuretic peptides for improved circulatory half-life. Claim 1 recites PEG only optionally, so the PEG element is at most a de minimis addition.

The one limitation requiring separate reasoning: (Arg)4. No recovered front-page reference expressly discloses Arg at position 4 of CNP-22. This — and only this — is where the §103 case must do real work. Four independent, mutually reinforcing rationales make the substitution obvious:

1. It is the textbook conservative substitution. Lys→Arg replaces one basic, positively charged residue with another basic, positively charged residue of nearly identical length and pKa. Under KSR's "predictable variation" and MPEP §2143, a substitution of a known element for a known element to obtain substantially the same result is obvious per se. The applicant has effectively conceded the characterization: the '884 specification describes position 4 as substitutable by "a conservative amino acid substitution or a natural or unnatural amino acid or peptidomimetic that does not have a reactive primary amine on a side chain, including but not limited to Arg…"
2. The prior art teaches position 4 is not activity-critical. US 5,434,133's SAR work located the activity determinants at positions 6, 7, 9, 11 and 22; US 7,276,481 located tolerable positions at 9, 10, 11, 16, 17, 19 and 20. Position 4 is conspicuously absent from both lists — i.e., the art affirmatively identified it as a position where change is tolerated. This is the classic "finite number of identified, predictable solutions" situation.
3. Functional rationale in the art. The '884 specification's own stated purpose for the K4R change — eliminating a reactive primary amine so as to avoid unwanted internal-site PEGylation and to reduce serum-albumin binding while retaining an alkaline pI (CNP-22 has pI 8.9) — is a design incentive that a POSITA would have had independently. Substituting Arg for Lys achieves exactly that: it removes the nucleophilic side-chain amine while preserving the +1 charge and the diffuse cationic character needed for interaction with NPR-B.
4. Range overlap. Whatever residue is at position 4, the claimed 2.6–7.0 kDa mass band is disclosed by CNP-53 (~5.9 kDa). Absent criticality data, the range is obvious. In re Peterson.

Dependent claims 2–9 are each independently obvious: claim 2 (bisphosphonates, polyAsp, polyGlu, osteopontin/osteocalcin/sialoprotein domains) reflects the well-developed bone-targeting conjugate art; claim 3 (negatively charged hydrophilic polymers) is taught by Caliceti; claims 4–6 (natriuretic/non-natriuretic sequence extensions from CNP-22, CNP-53, NPPC, ANP, BNP, albumin, IgG, HRGP, fibronectin, fibrinogen, zinc-finger proteins, FGF-2, BMPs) is a compilation of the exact fusion partners disclosed in US 6,407,211, WO 94/20534, US 7,256,253 and US 6,034,231; claim 7 (1–40 aa) is a routine range; claim 8 (C5–C12 carboxylic acids, fatty acids) reflects standard albumin-binding lipidation; claim 9 (an Arg immediately preceding Gly1) is the express teaching of the specification's own PEG-CNP27(Arg4) design.

Predicted outcome: high likelihood of a §103 invalidity finding on claim 1, subject to (a) the (Arg)4 construction and (b) whether the patentee can muster a criticality showing for the 2.6 kDa floor — and, per the spec, that data appears to be absent (the stated threshold is ~3 kDa).

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6. Ground B — Claim 1 is alternatively obvious over US 7,276,481 + US 6,034,231 + US 5,252,714

An independent route that does not depend on US 5,434,133's SAR argument:

• US 7,276,481 teaches directly that the active principle of CNP resides in the cyclic core (Cys6–Cys22) and that CNP-17 variants retain utility, including for elongating abnormal bone in skeletal dysplasia — i.e., it supplies the therapeutic motivation that the '884 asserts.
• US 6,034,231 teaches that a 31-residue N-terminal tail is compatible with NPR-B binding and cGMP induction (via Yeung 1996), giving both the structural element (x) and the claimed mass.
• A POSITA combining them would, with a reasonable expectation of success, arrive at a CNP peptide bearing a long N-terminal extension within the claimed mass range; the additional Lys→Arg change at position 4 is the routine conservative substitution discussed above.
• US 5,252,714 supplies the optional PEG conjugation.

The "reasonable expectation of success" is unusually well supported here because the combination's predictability was expressly documented: the art knew (i) exactly where NEP cleaves CNP, (ii) that NEP cannot process substrates above ~3 kDa, and (iii) that large N-terminal extensions of CNP retain full NPR-B potency. Claims to predictable solutions to a known problem are obvious even if the specific combination had not been physically made. KSR; In re O'Farrell (predictability defeats "obvious to try" objections).

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7. Ground C — Claim 10 is obvious over US 6,034,231 + US 6,407,211 + US 7,256,253 + US 5,846,932

Claim 10 is a closed Markush over twelve species, each of which is CNP22(K4R) bearing a known N-terminal or C-terminal fusion partner:

Motivation to make the GANXX variants. The '884 specification states that "(x) and/or (z) do not contain two adjacent basic natural or unnatural amino acids (e.g., Lys-Lys or Arg-Arg), designed to reduce susceptibility to cleavage by the protease furin," and the specification itself recites that pro-CNP "is secreted and cleaved again by an unknown enzyme" and that furin generates the active 53-mer. Because the native CNP-53 tail ends in the dibasic -Lys-Lys- immediately preceding Gly1, a POSITA seeking a stable construct would predictably eliminate that dibasic furin site — e.g., by substituting Gln (GANQQ) or Ser (GANSS). That is a one-step modification of a known sequence to remove a known protease site, for a known purpose, with a predictable result.

Motivation to make the R/ER variants. Shortening the native tail to the minimum while retaining a positively charged residue at the −1 position immediately N-terminal to Gly1 is the design principle the specification itself articulates for retaining CNP functionality with a PEG attached.

Motivation to make the IgG/HSA/fibronectin/fibrinogen/zinc-finger chimeras. Fusing peptides to serum-protein fragments to alter half-life and plasma-protein binding was a mature technology by 2007 (US 7,256,253; US 6,407,211). There are only a handful of well-characterized serum-protein fragments, making this the paradigm KSR "finite number of identified, predictable solutions." The rationale the '884 offers — reduced albumin binding so the peptide can diffuse through cartilage to growth-plate chondrocytes — is a result a POSITA would expect from choosing small, hydrophilic, non-lipophilic fragments.

Vulnerability note. The weakest element of Ground C is the "reduced binding to serum albumin" rationale, because the specification does not corroborate it with data for the IgG/HSA/fibronectin/fibrinogen/zinc-finger species, and one could argue the art would have expected serum-protein fragments to increase albumin binding. Even so, the claim is a closed Markush with no functional requirement attached to the fragments, so the patentee cannot escape on motivation alone if the POSITA would have selected a finite set of serum-protein fragments for half-life modulation generally. This ground is moderate-to-high confidence.

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8. Ground D — Claim 24 is obvious over US 6,034,231 + US 5,252,714 + WO 2004/047871, in view of the furin-site teaching

Claim 24 = a hydrophilic polymer + one of {ER-CNP22(K4R), R-CNP22(K4R), GANQQ-CNP22(K4R)} + total mass 2.6–7.0 kDa, with the polymer at the N-terminus, C-terminus or an internal site.

• The hydrophilic polymer element is squarely taught by US 5,252,714 (PEG-aldehyde conjugation) and WO 2004/047871 (PEG-BNP conjugates for improved circulatory half-life). The specification also cites "the polymer addition method of Bednarsaki" and Altus cross-linking for "improving stability and protease resistance and reducing immunogenicity" — i.e., the motivation and the techniques were already in the literature.
• Attachment-site flexibility ("N-terminus, the C-terminus or an internal site") is inherent in the cited conjugation chemistry: NHS chemistry targets Lys ε-amines and N-terminal amines; aldehyde chemistry targets N-terminal amines. A POSITA would recognize the choice of site as a routine optimization. Note that the site is unconstrained, which removes any argument that a particular attachment point was inventive.
• The specific peptides are, as in Ground C, trivially derived from the CNP-53 tail (US 6,034,231) by (i) truncation and (ii) removal of the Lys-Lys furin site.
• The mass limitation is met by the PEG itself: R-CNP22(K4R) is ~2.38 kDa before conjugation and ~2.98 kDa with a 0.6 kDa PEG — i.e., the very polymer the specification identifies as PEO12. The claim's numerical floor is thus satisfied by a routine conjugation, and its satisfaction is a mathematical consequence, not a technical achievement. In re Peterson applies with particular force: the applicant cannot claim credit for the arithmetic.

Predicted outcome: high likelihood of invalidity on claim 24, because the claim recites a naked combination of two known elements (a CNP peptide and a PEG), with no functional limitation tying the combination to a result.

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9. Consolidated KSR rationale table

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10. Anticipated nonobviousness arguments and how they fare

(a) Unexpected results — retention of activity with a small PEG requires a bulky, positively charged residue immediately N-terminal to Gly1. The specification asserts — and would be the patentee's primary Graham factor (4) evidence — that PEGylation of wtCNP-22 at ≥0.6 kDa reduces cGMP activity, and that activity is retained only when the PEG is ~0.6–1.2 kDa and is attached to a variant bearing a positively charged residue immediately preceding Gly1.

Assessment: Weak as a defense of these claims. Under In re Kao and the "commensurate in scope" line of authority, unexpected results must cover the full scope of the claim. Claim 1, however, requires Arg at position 4 — an internal residue — while the proffered "surprising" result concerns the residue immediately preceding Gly1, i.e., the C-terminal residue of (x). These are different positions, and claim 1 does not require an Arg immediately preceding Gly1. Claim 1 also permits (x) of any length from 1 to 40 residues, any (z) from a broad functional Markush, and PEG optionally. The narrow PEO24-GANRR-CNP22(K4R) result therefore does not establish nonobviousness across the claim. Similarly, the in vivo half-life data (CNP37 T½ ≈ 49.5 min vs. CNP-22 ≈ 1.42 min; PEO24-CNP27(Arg4) ≈ 22.3 min) is not commensurate with claim 1's scope and, in any event, shows only a predictable prolongation.

(b) Criticality of the 2.6 kDa lower bound. The patentee would need to show a sharp, unexpected change in NEP resistance at 2.6 kDa. The specification instead invokes a ~3 kDa ceiling, and the experimental support (e.g., the Analog L data showing that removing three of six NEP sites still yielded a short half-life) does not establish criticality at 2.6 kDa. This argument likely fails. Note also that claim 1's lower bound extends below the art's own NEP ceiling — a POSITA would not even expect NEP resistance in the 2.6–3.0 kDa sub-range, further eroding any "criticality" theory.

(c) Long-felt need and failure of others. The '884 Background candidly states that "there have been no published reports… on a successful strategy for making CNP resistant to NEP while retaining its functionality." This is the patentee's best Graham factor (4) argument. It is met, not overcome, by Grounds A–D: the asserted failure is with respect to peptide-bond isostere/backbone approaches; the claim at issue covers ordinary N- and C-terminal extensions and PEGylation, which the art taught as routine. A long-felt need satisfied by obvious means is still obvious.

(d) Commercial success (VOXZOGO®/vosoritide). No nexus. Vosoritide is Pro-Gly-wtCNP37, which retains Lys4. Claims 1, 10 and 24 all require the K4R change (SEQ ID NO: 35). The commercial product therefore does not embody the claims, and any secondary-considerations argument built on VOXZOGO fails the nexus requirement. (This is internally consistent with BioMarin's ITC position that "the claims of the '884 patent do not recite … CNP‑38.")

(e) Teaching away. None of the recovered references criticizes the claimed modifications. US 7,276,481's report of diminished activity concerns substitutions at activity-critical positions within CNP-17 — the very positions US 5,434,133 identified — and does not teach away from N-terminal extension or from substitution at position 4.

(f) Enablement/utility counterweights. The patentee might argue that the sheer breadth of (x) (1–40 amino acids) and (z) makes the claim a research plan rather than an invention. That argument is a sword for the challenger (§112), not a shield against §103 — breadth of an obvious genus is not a saving grace.

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11. Practical posture (cross-referencing the earlier sections)

• No PTAB proceeding exists on the '884 patent, so an IPR is unavailable in practice: the patent is pre-AIA (no PGR), any served defendant would be time-barred under §315(b) after one year, and the patent is recorded as "Expired – Fee Related" with anticipated expiration 2028‑11‑21. Verify the maintenance-fee history for application 12/744,079 in USPTO PatentCenter before spending money on any invalidity theory — a genuine, unremedied lapse ends the inquiry.
• The '884 patent has been used as a sword against BioMarin's own later patent, not as a cause of action. In N.D. Cal. the record states that Ascendis "pin[s] its hopes in the ITC primarily on the argument that the RE'267 patent is anticipated under 35 U.S.C. §102(e) by BioMarin's own U.S. Patent No. 8,377,884 ('884) and its WO counterpart (WO 2009/067639)." There is an important asymmetry that the §103 analysis above sharpens: the broader the '884 disclosure is read for §102(e) purposes against RE'267, the more one is also characterizing the '884 claims as narrow (they require K4R and an (x) tail). The two positions are reconcilable — disclosure breadth and claim scope are different things — but a party taking both positions should brief that distinction explicitly to avoid an estoppel-flavored inconsistency.
• Every claim of the '884 patent remains untested — as the earlier PTAB section concluded. This analysis is therefore hypothetical/defensive work product, not a response to any Board record.

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12. Confidence, gaps, and the single highest-value next step

High confidence:

• The claim text of claims 1, 10 and 24, and the count of 24 claims, as retrieved from Google Patents Claims (24) and the Justia mirror.
• That claim 1 requires Arg at position 4 on its face ("(Arg)4" tied to SEQ ID NO: 35, which claim 10 expressly glosses as "CNP22K4R").
• That CNP-53 (US 6,034,231) sits inside the claimed 2.6–7.0 kDa range and differs from claim 1 by a single Lys→Arg change — i.e., claim 1 is one conservative substitution from cited prior art, triggering In re Peterson on the range.
• That no recovered reference expressly discloses Lys4→Arg, and that this substitution is accordingly the load-bearing point of the entire §103 analysis.
• That VOXZOGO/vosoritide (Pro-Gly-wtCNP37) does not embody claims 1, 10 or 24, since it lacks Arg4 — defeating any nexus-based secondary-considerations defense.

Medium confidence:

• The exact dependency structure and full text of claims 11–23 (the Justia/Google renderings elided several).
• My approximate molecular weights (rounded residue masses, ±~1%); the qualitative conclusions (R‑/ER‑CNP22(K4R) fall below 2.6 kDa; GANQQ/GANRR‑CNP22(K4R) exceed it) are robust to the rounding.
• That RE48,267 is a reissue of US 8,598,121 rather than of the '884 patent. The priority-date mismatch and the §102(e) use of '884 against RE'267 are both strongly inconsistent with RE'267 reissuing the '884, but a live PatentCenter reissue-record pull (application 15/646,822, "identification of the patent being reissued") would settle it definitively.

Unconfirmed / gaps:

• Six of the 24 front-page patent citations were never retrieved in the earlier session, including the Yeda US 6,265,632 B1 reference whose subject matter is unverified. One or more of those six could teach Arg at position 4.
• The "Other Publications" (NPL) list for the '884 patent was never retrieved, nor was the file wrapper showing any examiner §102/§103 rejection. Without the prosecution history, we cannot tell whether the K4R limitation was added to overcome a specific reference — which would be highly probative of what the applicant believed the art taught.
• No sequence-based prior-art search has been run. This is the gap that matters most.

Immediate next step (highest expected value): run a sequence homology search against pre-2007-11-21 publications for the exact K4R sequences — GLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO: 35), GANRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO: 36), RGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO: 41), and GANQQGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO: 69) — using NCBI BLAST against patents (PatentScope/Google Patents BigQuery), GenBank, and published CNP-analog SAR papers (Suntory, Mayo, Genentech, Prochon). If any pre-2007 publication discloses CNP‑22 bearing Arg4 or any of the claim-10/claim-24 species, the case converts from §103 to §102, which is substantially easier to prove and immune to the motivation-to-combine arguments a patentee would otherwise press. A second, lower-cost step is to pull the complete "References Cited" face page and NPL list plus the file wrapper from USPTO PatentCenter for application 12/744,079.

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Bottom line. On the present record, claim 1 of US 8,377,884 is likely obvious under pre-AIA §103(a) as CNP-53 (US 6,034,231, ~5.9 kDa, inside the claimed range) modified by the single conservative Lys→Arg substitution at position 4 that the art's own SAR (US 5,434,133; US 7,276,481) taught was tolerated, further in view of the express motivation to exceed NEP's ~3 kDa substrate ceiling (Oefner 2000) and to PEGylate a natriuretic peptide (US 5,252,714; WO 2004/047871). Claim 24 is likely obvious as a naked combination of a known peptide and a known polymer, where the claimed mass floor is satisfied arithmetically by the polymer. Claim 10 is moderately-to-highly likely obvious as a Markush of known peptides fused to known partners. The patentee's best responses — assert the surprise of retaining activity with small PEG, invoke the 2.6 kDa criticality, and point to the long-felt need — are each vulnerable: the surprise data is not commensurate in scope with the claims and concerns a different residue position than claim 1 requires, no criticality data is presented (the spec's own threshold is ~3 kDa), and the long-felt need was met by known means. All conclusions are contingent on (i) the (Arg)4 construction and (ii) the six unretrieved citations and the NPL list, which should be pulled before any contention is finalized.