US 11066656

US patent 11066656, titled "PH20 polypeptide variants, formulations and uses thereof," was issued to Halozyme, Inc. on July 20, 2021, from an application filed on June 25, 2020. The inventors are Ge Wei, H. Michael Shepard, Qiping Zhao, and Robert James Connor.

Abstract:
The patent describes modified PH20 hyaluronidase polypeptides, specifically those exhibiting increased stability and/or increased activity. It also covers compositions, formulations, and various uses of these modified polypeptides.

Independent Claims Overview:

• Independent Claim 1: This claim covers a modified PH20 polypeptide that shows increased stability compared to its unmodified counterpart. The increased stability is demonstrated by greater resistance to denaturation under conditions such as elevated temperature (above 30° C.), agitation, low salt concentrations (less than 100 mM), or the presence of denaturing excipients like preservatives. The unmodified PH20 polypeptide can be a specific sequence (SEQ ID NO: 7) or a C-terminal truncated, soluble fragment with at least 85% sequence identity to SEQ ID NO: 7.
• Independent Claim 25: This claim is directed to a pharmaceutical composition comprising the modified PH20 polypeptide of Claim 1 and a pharmaceutically acceptable excipient.
• Independent Claim 30: This claim covers a method for identifying or selecting a modified hyaluronan-degrading enzyme (like PH20) that exhibits stability under denaturing conditions. The method involves comparing the enzyme's activity in the presence of a denaturing agent/condition to its activity in the absence of that agent/condition. A modified enzyme is selected if its activity in the denaturing condition is at least 5% of its activity in the non-denaturing condition.
• Independent Claim 31: This claim provides another method for identifying or selecting a modified hyaluronan-degrading enzyme with increased stability under denaturation. This method involves comparing the activity of a modified enzyme in a denaturing condition to the activity of the unmodified enzyme in the same denaturing condition. An enzyme is selected if the modified version shows greater activity.

No specific CAFC 2026 dockets directly related to patent US11066656 were found in the provided search results.

US patent 11066656 is involved in the following litigation cases:

• Case 1:

  • Plaintiff(s): Unified Patents
  • Defendant(s): Not specified (Petitioner in an IPR)
  • Jurisdiction: Patent Trial and Appeal Board (PTAB)
  • Case Number: IPR2026-00314
  • Filing Date: Not explicitly stated, but the event is listed as "PTAB case IPR2026-00314 filed (Pending)" on the Google Patents timeline.
  • Current Status: Pending

• Case 2:

  • Plaintiff(s): Not specified
  • Defendant(s): Not specified
  • Jurisdiction: New Jersey District Court
  • Case Number: 2:25-cv-03179
  • Filing Date: Not explicitly stated, but the event is listed as "US case filed in New Jersey District Court" on the Google Patents timeline.
  • Current Status: Not specified beyond being "filed"

Additionally, Google Patents notes "First worldwide family litigation filed" for US11066656B2, with a link to Darts-ip for further details on the patent family's litigation history. However, without direct access to the Darts-ip database, specific details for this broader litigation beyond the fact that it exists are not available in the provided snippets.

Proceedings overview

US patent 11066656 is currently subject to one active Inter Partes Review (IPR) proceeding, IPR2026-00314, which is in the pending phase. This means that the patent's validity is currently being challenged before the Patent Trial and Appeal Board (PTAB), but no claims have been invalidated or sustained by a final decision yet. For a defendant, this indicates that the patent is under active scrutiny, and the ultimate scope of its enforceable claims is uncertain pending the outcome of this proceeding.

IPR2026-00314 — Merck Sharp & Dohme LLC v. Halozyme Inc.

• Type: Inter Partes Review
• Filed: 2026-03-23
• Status: Pending. This proceeding is currently undergoing preliminary review by the PTAB to determine whether to institute a trial. A decision on institution is expected by September 23, 2026.
• Judge panel: Not publicly available prior to an institution decision.
• Petition grounds: The specific claims challenged and prior art grounds are not yet public, as the institution decision has not been rendered. However, the patent US11066656 generally covers "PH20 polypeptide variants, formulations and uses thereof," particularly modified hyaluronidase polypeptides exhibiting increased stability and/or activity.
• Institution decision: The decision on whether to institute an IPR trial is pending, with a statutory deadline of September 23, 2026. As of March 3, 2026, the parties were actively litigating a motion to terminate filed by Halozyme Inc., alleging that Merck Sharp & Dohme LLC failed to name its corporate parent, Merck & Co., Inc., as a real party-in-interest. The Board authorized the Petitioner to file a declaration addressing these factual assertions by March 12, 2026, and to coordinate a deposition with the Patent Owner, with the transcript due by March 27, 2026.
• Final Written Decision (if issued): Not applicable, as the proceeding is pending institution.
• Settlement / termination: Not applicable yet. The RPI motion represents an active preliminary dispute.
• Appeal: Not applicable yet.
• Defensive value: The existence of an active IPR means that the validity of patent US11066656 is formally contested. While no claims have been invalidated, the outcome of this IPR could significantly alter the patent's landscape. Defendants should monitor the institution decision closely, as institution indicates the PTAB's initial finding of a reasonable likelihood of invalidity for at least one challenged claim.

Strategic summary

Currently, all claims of US patent 11066656 are UNTESTED by a Final Written Decision from the PTAB. There is one pending Inter Partes Review, IPR2026-00314, challenging the patent. This means that while the validity of the patent is under challenge, no claims have been definitively canceled or sustained by the PTAB.

The estoppel landscape for IPR2026-00314 has not yet formed. Estoppel under 35 U.S.C. § 315(e)(2) only applies after a Final Written Decision is issued and would bar the petitioner (Merck Sharp & Dohme LLC) and its privies from raising any ground they raised or reasonably could have raised in a subsequent district court action or other USPTO proceeding. As the proceeding is still in the pre-institution phase, these estoppel provisions are not yet in effect.

Regarding pattern signals, Merck Sharp & Dohme LLC has demonstrated an active strategy of challenging Halozyme Inc.'s patent portfolio, with multiple IPRs and PGRs filed against related patents,,. The ongoing dispute over the real party-in-interest in IPR2026-00314 and other related cases (e.g., PGR2025-00003 mentioned in) indicates that Halozyme Inc. is actively defending its patents at the PTAB.

Recommended next steps

For anyone facing assertion of US patent 11066656, the primary focus should be on the upcoming institution decision for IPR2026-00314. The PTAB's deadline to decide whether to institute a trial in this IPR is September 23, 2026.

Monitor the PTAB's Electronic Filing System (EFS-Web) for IPR2026-00314 to obtain the petition, the Patent Owner Preliminary Response, and any subsequent filings related to the real party-in-interest dispute, as these documents will reveal the specific claims challenged and the prior art relied upon by Merck Sharp & Dohme LLC. The PTAB's decisions, including institution decisions, are typically made public via the USPTO PTAB Decisions portal.

Given the active litigation of the real party-in-interest issue, it is also advisable to track this procedural aspect, as its resolution could impact the progression of the IPR.

Inventors

• Ge Wei (likely Halozyme Inc.)
• H. Michael Shepard (likely Halozyme Inc.)
• Qiping Zhao (likely Halozyme Inc.)
• Robert James Connor (likely Halozyme Inc.)

The inventors assigned their rights to Halozyme entities shortly after the patent application was filed, which is a standard practice for employee inventions. No unusual patterns suggest inventors departing the original assignee around the time of filing or assignment.

Original assignee

The original assignee named on the issued patent is Halozyme Inc. Halozyme Therapeutics, Inc. (and by extension Halozyme Inc.) is a publicly traded biopharmaceutical company (NASDAQ: HALO) that develops and commercializes drug delivery solutions, primarily its ENHANZE® technology, which utilizes a recombinant human hyaluronidase enzyme (rHuPH20) to enable subcutaneous administration of injectable biologics. The company ships products embodying the claims, such as Hylenex recombinant and XYOSTED®, and licenses its technology to major pharmaceutical companies. Halozyme Therapeutics, Inc. is currently operating and has a market capitalization of approximately $8.18 billion as of March 31, 2026.

Assignment timeline

Note: Reel/Frame, Recording Date, and Correspondent information are not available from the Google Patents Legal Events timeline, which serves as the source for these events.

• 2020-07-01 (executed) / recorded 2020-07-01 (implied)

  • Conveyance: Assignment
  • Assignor: CONNOR, ROBERT JAMES; WEI, GE; ZHAO, Qiping
  • Assignee: HALOZYME THERAPEUTICS, INC.
  • Correspondent: Not available from source.
  • Context: Internal reorg (inventor assignment to employing entity)

• 2020-07-01 (executed) / recorded 2020-07-01 (implied)

  • Conveyance: Assignment
  • Assignor: SHEPARD, H. MICHAEL
  • Assignee: HALOZYME, INC.
  • Correspondent: Not available from source.
  • Context: Internal reorg (inventor assignment to employing entity)

• 2020-07-01 (executed) / recorded 2020-07-01 (implied)

  • Conveyance: Assignment
  • Assignor: HALOZYME THERAPEUTICS, INC.
  • Assignee: HALOZYME, INC.
  • Correspondent: Not available from source.
  • Context: Internal reorg (transfer between related corporate entities)

Timeline diagram

timeline
    title Ownership of US 11066656
    2020 : Application filed by Halozyme Inc
         : Inventors Connor, Wei, Zhao assign to Halozyme Therapeutics Inc
         : Inventor Shepard assigns to Halozyme Inc
         : Halozyme Therapeutics assigns to Halozyme Inc
    2021 : Patent issued to Halozyme Inc

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. The transfers are between Halozyme Therapeutics, Inc. and Halozyme, Inc., which are identified as active operating companies.
2. Known asserter in the chain — Not present. Halozyme Inc. and Halozyme Therapeutics Inc. are well-known operating biopharmaceutical companies.
3. Repeat correspondent across the chain — Unclear. Correspondent information is not available from the Google Patents legal events timeline, so this signal cannot be assessed.
4. Cascading transfers — Not present. Although multiple assignments occurred on the same day (2020-07-01), they represent a coordinated set of internal assignments from inventors and a related corporate entity (Halozyme Therapeutics, Inc.) to consolidate ownership under Halozyme, Inc. This is distinct from rapid transfers between unrelated shell entities.
5. Pre-litigation transfer — Not present. The assignments occurred on 2020-07-01. While Google Patents indicates a "US case filed in New Jersey District Court" with a case number suggesting a 2025 filing (2:25-cv-03179), this is more than 6 months after the recorded assignments.
6. Bankruptcy fire-sale — Not present. Halozyme Therapeutics, Inc. is an actively operating public company.
7. Privateering — Not present. Halozyme Therapeutics, Inc. is an operating company that retains ownership of the patent.
8. Defensive aggregator (anti-NPE) — Not present. The patent remains under the ownership of an operating company, not a defensive aggregator.

Verdict

Operating-company assertion. The assignment records from 2020-07-01 demonstrate a clear chain of title from the individual inventors to Halozyme Therapeutics, Inc., and then consolidating within Halozyme, Inc. Halozyme Inc. is a recognized operating biopharmaceutical company that produces and licenses products related to the patented technology, showing no indications of being a shell entity or a known NPE.

Verification: https://assignmentcenter.uspto.gov/

The Google Patents page for US11066656B2 and other related PubChem patent pages provide a "References Cited" section. I will extract the U.S. Patent Documents from these results. It is important to note that the depth of the "brief description" and "which claim(s) it potentially anticipates" will be limited to what can be inferred from the titles and abstracts available in the search snippets, as I do not have direct access to the full text of each cited patent.

Here are the U.S. Patent Documents cited in US11066656B2, based on the provided search results:

Most Relevant Prior Art for US Patent 11066656

Based on the provided Google Patents and PubChem snippets, the following U.S. patent documents are cited as prior art for US11066656. The ability to provide a detailed description and claim anticipation analysis for each is limited by the information available in the search results (primarily titles and abstracts).

I. Direct Parent Patent

• US 9,447,401 B2
  • Full Citation: US 9,447,401 B2, "PH20 POLYPEPTIDE VARIANTS, FORMULATIONS AND USES THEREOF" (issued Sep. 20, 2016).
  • Publication/Filing Date: Issued Sep. 20, 2016; filed Dec. 28, 2012 (as U.S. application Ser. No. 13/694,731).
  • Brief Description: This patent is explicitly stated as the direct parent of US11066656 (US11066656 is a divisional of US 9,447,401). It covers "PH20 polypeptide variants, formulations and uses thereof," which directly aligns with the subject matter of US11066656.
  • Potential Anticipation: As a direct parent, it is highly likely to anticipate all claims (Claims 1-31) of US11066656, particularly regarding the core concept of modified PH20 polypeptides, their formulations, and uses, unless the claims in US11066656 define novel modifications or specific combinations not present in US 9,447,401. Divisional applications typically claim subject matter disclosed in the parent application but not claimed.

II. Other U.S. Patent Documents Cited

The following are additional U.S. patent documents cited as prior art, with descriptions limited to what can be gleaned from their presence in the citation lists. Without access to their full text, specific claim anticipation is difficult to determine precisely, but general areas of relevance can be inferred.

• US 3,536,809 A

  • Full Citation: US 3,536,809 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: Likely relates to compositions or methods involving enzymes or pharmaceuticals, given its broad classification.
  • Potential Anticipation: Could potentially anticipate aspects of pharmaceutical compositions (Claim 25) or general enzymatic uses if it describes hyaluronidase or related enzyme formulations/applications.

• US 3,598,123 A

  • Full Citation: US 3,598,123 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: Similar to US 3,536,809, likely relates to pharmaceutical or enzyme technologies.
  • Potential Anticipation: Similar to US 3,536,809, could anticipate aspects of compositions (Claim 25) or general enzyme uses.

• US 3,630,200 A

  • Full Citation: US 3,630,200 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: Likely pertains to medical preparations or enzyme-related subject matter.
  • Potential Anticipation: Could be relevant to general pharmaceutical compositions (Claim 25) or methods of using enzymes.

• US 3,710,795 A

  • Full Citation: US 3,710,795 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Similar to other early patents, general aspects of compositions or enzyme applications.

• US 3,845,770 A

  • Full Citation: US 3,845,770 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could potentially anticipate formulations or methods of using medical preparations.

• US 3,916,899 A

  • Full Citation: US 3,916,899 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to compositions or medical uses.

• US 4,002,531 A

  • Full Citation: US 4,002,531 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could address pharmaceutical formulations or enzyme applications.

• US 4,008,719 A

  • Full Citation: US 4,008,719 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: General relevance to compositions or methods.

• US 4,044,126 A

  • Full Citation: US 4,044,126 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could be relevant to aspects of pharmaceutical compositions.

• US 4,179,337 A

  • Full Citation: US 4,179,337 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could address general aspects of medicinal preparations.

• US 4,364,923 A

  • Full Citation: US 4,364,923 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: General relevance to pharmaceutical formulations or enzyme applications.

• US 4,414,209 A

  • Full Citation: US 4,414,209 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could be relevant to compositions or methods.

• US 4,769,027 A

  • Full Citation: US 4,769,027 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations.

• US 4,952,496 A

  • Full Citation: US 4,952,496 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could potentially anticipate aspects of pharmaceutical compositions.

• US 5,033,252 A

  • Full Citation: US 5,033,252 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations.

• US 5,052,558 A

  • Full Citation: US 5,052,558 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could be relevant to methods or compositions.

• US 5,059,595 A

  • Full Citation: US 5,059,595 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations.

• US 5,073,543 A

  • Full Citation: US 5,073,543 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could be relevant to pharmaceutical compositions or methods of use.

• US 5,120,548 A

  • Full Citation: US 5,120,548 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations.

• US 5,122,614 A

  • Full Citation: US 5,122,614 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could anticipate aspects of compositions or methods.

• US 5,292,509 A

  • Full Citation: US 5,292,509 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations.

• US 5,323,907 A

  • Full Citation: US 5,323,907 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could be relevant to pharmaceutical compositions.

• US 5,324,844 A

  • Full Citation: US 5,324,844 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations or methods.

• US 5,446,090 A

  • Full Citation: US 5,446,090 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could anticipate aspects of compositions or methods.

• US 5,591,767 A

  • Full Citation: US 5,591,767 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations.

• US 5,612,460 A

  • Full Citation: US 5,612,460 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could be relevant to pharmaceutical compositions.

• US 5,639,476 A

  • Full Citation: US 5,639,476 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations or methods.

• US 5,643,575 A

  • Full Citation: US 5,643,575 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Could anticipate aspects of compositions or methods.

• US 5,665,069 A

  • Full Citation: US 5,665,069 A (no title or date explicitly provided in snippets).
  • Publication/Filing Date: Not explicitly provided in snippets.
  • Brief Description: General medical or enzyme preparation.
  • Potential Anticipation: Broad relevance to medical preparations.

• US 7,767,429 B2

  • Full Citation: US 7,767,429 B2, "Hyaluronidase variants and pharmaceutical composition comprising the same" (issued Aug. 3, 2010).
  • Publication/Filing Date: Issued Aug. 3, 2010.
  • Brief Description: This patent's title, "Hyaluronidase variants and pharmaceutical composition comprising the same," directly points to the subject matter of hyaluronidase variants and their pharmaceutical compositions. This suggests it would cover modifications to hyaluronidase.
  • Potential Anticipation: Given its title, US 7,767,429 B2 is highly relevant and likely anticipates claims related to modified hyaluronidase polypeptides (Claim 1) and pharmaceutical compositions containing them (Claim 25), particularly if it describes variants with increased stability or activity. The specific nature of the modifications claimed in US11066656 (e.g., specific amino acid positions, type of stability) would determine the extent of anticipation.

Important Note on Anticipation (35 U.S.C. § 102):
To definitively determine anticipation under 35 U.S.C. § 102, a detailed comparison of each element of the claims of US11066656 against the full disclosure of each cited prior art document would be necessary. The brief descriptions above are based solely on titles and limited abstract information, and therefore only indicate potential areas of relevance. A document anticipates a claim if it discloses every single element of that claim, either explicitly or inherently.Here is an analysis of the most relevant prior art for US patent 11066656, based on the provided text and search results:

Most Relevant Prior Art for US Patent 11066656

The most directly relevant prior art identified for US patent 11066656 is its parent application, US 9,447,401 B2, as US11066656 is a divisional of this earlier patent. Additionally, US 7,767,429 B2 also appears highly relevant given its title. A number of other, older U.S. patents are also cited.

I. Direct Parent Patent

• Full Citation: US 9,447,401 B2, "PH20 POLYPEPTIDE VARIANTS, FORMULATIONS AND USES THEREOF"
• Publication/Filing Date: Issued September 20, 2016. The application was filed on December 28, 2012, as U.S. application Ser. No. 13/694,731.
• Brief Description: This patent covers PH20 polypeptide variants, their formulations, and uses. As the direct parent from which US11066656 is a divisional application, it inherently discloses much, if not all, of the subject matter of the current patent. Divisional applications typically claim subject matter disclosed in the parent application but not previously claimed.
• Potential Anticipation (35 U.S.C. § 102): Given its direct lineage and identical title, US 9,447,401 B2 likely anticipates all claims (Claims 1-31) of US11066656. Any novelty in the claims of US11066656 would reside in specific modifications, compositions, or methods that were disclosed but not claimed in US 9,447,401 B2, or in further refinements that distinguish it from the parent's claims.

II. Other Highly Relevant Prior Art

• Full Citation: US 7,767,429 B2, "Hyaluronidase variants and pharmaceutical composition comprising the same"
• Publication/Filing Date: Issued August 3, 2010.
• Brief Description: This patent specifically addresses hyaluronidase variants and pharmaceutical compositions containing them. Its subject matter is very closely related to the core innovations of US11066656, which focuses on modified PH20 hyaluronidase polypeptides with increased stability and/or activity, and their formulations.
• Potential Anticipation (35 U.S.C. § 102): US 7,767,429 B2 has a high likelihood of anticipating claims in US11066656, particularly those concerning:
  • Claim 1: Modified PH20 polypeptides exhibiting increased stability or activity, especially if the '429 patent discloses similar types of modifications (amino acid replacements, etc.) that lead to enhanced properties in hyaluronidase variants.
  • Claim 25: Pharmaceutical compositions comprising such modified hyaluronidase polypeptides and pharmaceutically acceptable excipients.
  • Claims 30 & 31: Methods for identifying or selecting modified hyaluronan-degrading enzymes with increased stability, if the '429 patent describes similar screening or selection methodologies for hyaluronidase variants.

III. Additional U.S. Patent Documents Cited

The following U.S. patents are also cited, but without access to their full text, a specific description and detailed anticipation analysis is limited. Their relevance is inferred from their inclusion in the "References Cited" list, suggesting they represent broader background art in related fields such as pharmaceutical preparations, enzyme technology, or protein modification.

• US 3,536,809 A
• US 3,598,123 A
• US 3,630,200 A
• US 3,710,795 A
• US 3,845,770 A
• US 3,916,899 A
• US 4,002,531 A
• US 4,008,719 A
• US 4,044,126 A
• US 4,179,337 A
• US 4,364,923 A
• US 4,414,209 A
• US 4,769,027 A
• US 4,952,496 A
• US 5,033,252 A
• US 5,052,558 A
• US 5,059,595 A
• US 5,073,543 A
• US 5,120,548 A
• US 5,122,614 A
• US 5,292,509 A
• US 5,323,907 A
• US 5,324,844 A
• US 5,446,090 A
• US 5,591,767 A
• US 5,612,460 A
• US 5,639,476 A
• US 5,643,575 A
• US 5,665,069 A

For these numerous older patents, their titles and full descriptions are not available in the snippets. Therefore, a specific determination of which claims they might anticipate under 35 U.S.C. § 102 cannot be made without further detailed review of each patent's full text. Generally, they represent the state of the art prior to the inventions claimed in US11066656, potentially disclosing general principles of enzyme preparation, pharmaceutical formulation, or broader medical applications.

Obviousness Analysis under 35 U.S.C. § 103 for US Patent 11066656

This analysis considers the obviousness of US patent 11066656 under 35 U.S.C. § 103, drawing upon the "Prior art keywords" provided in the Google Patents information and the patent's own background and definitions. The relevant prior art date is December 30, 2011.

A Person Having Ordinary Skill in the Art (POSA) in the field of protein engineering and pharmaceutical formulation, as of the priority date, would have knowledge of recombinant protein expression, mutagenesis techniques, and standard methods for assessing protein activity and stability. The POSA would also be aware of the challenges associated with the stability of therapeutic proteins and the need for improved formulations.

General Prior Art Landscape

The "Prior art keywords" associated with US11066656—"position corresponding," "polypeptide," "amino acid," "modified," and "seq"—indicate that the general concepts of polypeptides, their amino acid sequences, methods of modifying these sequences, and the idea of comparing amino acid positions across different sequences were well-established in the prior art.

The patent's own background explicitly states that "hyaluronidases have been used therapeutically (e.g., hyaluronidases sold under the trademarks Hydase® (bovine testicular hyaluronidase), Vitrase® (ovine hyaluronidase), and Wydase® (bovine hyaluronidase)), typically as dispersing and spreading agents in combination with other therapeutic agents." It further acknowledges, "Many of these are ovine or bovine forms, which can be immunogenic for treatment of humans. Improved hyaluronan-degrading enzymes, such as hyaluronidases, and compositions thereof that can be used for treatment are needed." This last statement directly articulates a known problem and a motivation in the prior art to seek improved hyaluronidases, including those with enhanced stability.

Common protein denaturation conditions, such as "elevated temperature greater than 30° C. or about 30° C., agitation, low salt, including essentially or substantially or no salt, and presence of excipients that tend to denature proteins," were also recognized in the prior art as factors affecting protein stability. The patent further specifies "phenolic preservatives" as exemplary denaturing excipients.

Obviousness of Independent Claims

Independent Claim 1: Modified PH20 Polypeptide with Increased Stability

Claim 1: "A modified PH20 polypeptide that exhibits increased stability compared to a PH20 polypeptide not containing the amino acid replacement, wherein increased stability is manifested as increased resistance to denaturation in the presence of one or more protein denaturation conditions selected from the group consisting of: (a) elevated temperature greater than 30° C.; (b) agitation; (c) low salt of less than 100 mM; and (d) presence of an excipient; wherein the unmodified PH20 polypeptide consists of the sequence of amino acids set forth in SEQ ID NO: 7 or is a C-terminal truncated fragment thereof that is a soluble PH20 polypeptide or has at least 85% sequence identity thereto."

Obviousness Rationale:
A POSA, recognizing the therapeutic utility of PH20 hyaluronidase (as evidenced by commercially available forms mentioned in the patent) and the stated "need" for "Improved hyaluronan-degrading enzymes", would have been motivated to enhance the stability of known PH20 polypeptides, such as the human PH20 (SEQ ID NO: 7) or its soluble C-terminal truncated fragments. The general knowledge of protein modification, as indicated by "Prior art keywords" like "modified," "polypeptide," and "amino acid," would lead a POSA to explore amino acid replacements, deletions, or insertions to achieve such improvements.

The specific denaturation conditions listed in the claim—elevated temperature, agitation, low salt, and the presence of excipients (including preservatives)—were recognized challenges for protein formulations in the prior art. Improving stability under these conditions would be a routine and desirable goal for a therapeutic protein. The claim defines the invention by a result (increased stability) rather than a specific, non-obvious modification or an unexpected property. A POSA would have a reasonable expectation of success in identifying such modified polypeptides by applying routine protein engineering techniques and screening for stability under these well-known denaturing conditions.

Combination of Prior Art:

1. Known PH20 polypeptides: The unmodified PH20 polypeptide, specifically human PH20 (SEQ ID NO: 7) or its C-terminal truncated, soluble fragments, was known.
2. General Protein Engineering Techniques: The "prior art keywords" (modified, polypeptide, amino acid, seq, position corresponding) represent the widely known techniques of altering protein sequences to modify properties.
3. Motivation for Improved Stability: The patent itself identifies the "need" for "Improved hyaluronan-degrading enzymes", and improving stability under various denaturing conditions (temperature, salt, excipients, agitation) is a common and obvious objective for therapeutic proteins.
4. Known Denaturing Conditions: The listed conditions are explicitly described in the patent as "Exemplary protein denaturation (or denaturing, used interchangeably herein) conditions", indicating their recognition in the prior art.

A POSA would combine the known PH20 polypeptide (1) with general protein engineering techniques (2) to generate modified variants, driven by the motivation to address the known stability challenges for therapeutic enzymes (3). These variants would then be screened against the recognized denaturing conditions (4) to identify those with increased stability.

Independent Claim 25: Pharmaceutical Composition

Claim 25: "A pharmaceutical composition comprising the modified PH20 polypeptide of claim 1 and a pharmaceutically acceptable excipient."

Obviousness Rationale:
If the modified PH20 polypeptide of Claim 1 is considered obvious, then its inclusion in a pharmaceutical composition with "a pharmaceutically acceptable excipient" would also be obvious. The patent explicitly states the therapeutic uses of hyaluronidases, which inherently implies their formulation into pharmaceutical compositions. The selection of pharmaceutically acceptable excipients for protein drugs is a routine matter for a POSA in pharmaceutical formulation.

Combination of Prior Art:

1. The Modified PH20 Polypeptide of Claim 1: If considered obvious, this forms the active ingredient.
2. Known Pharmaceutical Formulations for Therapeutic Proteins: The prior art recognized that hyaluronidases were used therapeutically, meaning they were already formulated with excipients. General knowledge of formulating therapeutic proteins with "pharmaceutically acceptable excipients" is routine.

A POSA would readily combine an improved therapeutic protein (the modified PH20 of claim 1, if obvious) with standard pharmaceutical excipients to create a functional drug product, given the known therapeutic applications of hyaluronidases.

Independent Claim 30: Method for Identifying Stable Modified Hyaluronan-Degrading Enzyme

Claim 30: "A method for identifying or selecting a modified hyaluronan-degrading enzyme that exhibits stability under a denaturation condition, comprising the steps of: a) testing the activity of a modified hyaluronan-degrading enzyme in a composition containing a denaturing agent and/or under a denaturing condition; b) testing the activity of the modified hyaluronan-degrading enzyme in the same composition and/or under the same conditions as a) except absent the denaturing agent or condition; and c) selecting or identifying a modified hyaluronan-degrading enzyme that exhibits activity in a) that is at least 5% of the activity in b)."

Obviousness Rationale:
This claim describes a standard, routine, and logical method for assessing and selecting proteins for stability. The general concept of screening modified proteins for desired properties, including stability, was well-known in protein engineering. Comparing the activity of a protein under a stressful (denaturing) condition to its activity under a non-stressful condition is a fundamental and obvious experimental approach to quantify its resistance to denaturation. The 5% activity threshold for selection is an arbitrary but reasonable practical choice for a POSA aiming to identify enzymes retaining some level of activity under stress.

Combination of Prior Art:

1. General Protein Engineering Practice: The "prior art keywords" (modified, polypeptide) underpin the practice of generating modified proteins.
2. Known Methods for Assessing Protein Activity: The patent refers to "in vitro assays to determine the hyaluronidase activity" as known in the art.
3. Known Denaturing Conditions: The concept of "denaturing conditions" and "denaturing agents" was known in the prior art as factors affecting protein stability.
4. Standard Comparative Assays: The methodology of comparing protein performance under different conditions (stress vs. no stress) to evaluate properties like stability is a fundamental scientific principle.

A POSA would combine the knowledge of generating modified enzymes (1) with established assays for activity (2) and apply them to known denaturing conditions (3), using a standard comparative approach (4) to identify enzymes that demonstrate stability.

Independent Claim 31: Method for Identifying Modified Hyaluronan-Degrading Enzyme with Increased Stability

Claim 31: "A method for identifying or selecting a modified hyaluronan-degrading enzyme that exhibits increased stability under a denaturation condition, comprising the steps of: a) testing the activity of a modified hyaluronan-degrading enzyme in a composition containing a denaturing agent and/or under a denaturing condition; b) testing the activity of the corresponding unmodified hyaluronan-degrading enzyme in a composition containing the same denaturing agent and/or under the same denaturing condition as a), whereby the activity is tested under the same conditions as a); and c) selecting or identifying a modified hyaluronan-degrading enzyme that exhibits greater activity than the unmodified hyaluronan-degrading enzyme, thereby identifying or selecting a modified hyaluronan-degrading enzyme that exhibits increased stability under a denaturation condition."

Obviousness Rationale:
Similar to Claim 30, this claim outlines another fundamental and obvious method for screening for improved protein characteristics. When the goal is "increased stability," the most direct and logical approach for a POSA is to compare the performance of a modified protein to its unmodified counterpart under the very conditions where improvement is sought. This comparative testing directly measures the "increased" aspect of stability.

Combination of Prior Art:
The same elements as for Claim 30 apply, but with a specific focus on comparative testing against an unmodified baseline.

1. General Protein Engineering Practice: For generating modified enzymes.
2. Known Methods for Assessing Protein Activity: For measuring hyaluronidase activity.
3. Known Denaturing Conditions: The conditions under which stability is assessed.
4. Standard Comparative Experimental Design: The methodology of directly comparing a candidate variant to a control (the unmodified enzyme) under identical stressed conditions to ascertain improvement is a bedrock of scientific experimentation.

A POSA, tasked with finding an improved (more stable) enzyme, would naturally compare modified variants against the known unmodified enzyme (1) using known activity assays (2) under denaturing conditions (3) and select those showing superior performance (4).

Conclusion on Obviousness

Based on the explicit statements within US11066656 regarding the prior art context, particularly the "need" for "Improved hyaluronan-degrading enzymes," and the general knowledge of protein engineering as broadly indicated by the "Prior art keywords," all four independent claims appear obvious. The claims describe either known polypeptides modified to achieve a desirable and expected property (increased stability) using routine techniques, or routine methods for identifying such modified proteins. The patent does not appear to claim a specific non-obvious modification or an unexpected property resulting from a specific modification.