US 12152262

US patent 12152262 is titled "PH20 polypeptide variants, formulations and uses thereof".

• Assignee: The original assignee was Halozyme Inc, and the current assignee is Halozyme Therapeutics Inc.
• Inventors: Ge Wei, H. Michael Shepard, Qiping Zhao, and Robert James Connor.
• Filing Date: June 23, 2023.
• Issue Date: November 26, 2024.

Abstract:
The patent describes modified PH20 hyaluronidase polypeptides, particularly those engineered to exhibit increased stability and/or activity. The invention also encompasses compositions, formulations, and uses of these modified polypeptides. The modifications primarily involve amino acid replacements, deletions, or insertions, with detailed information provided for residues that affect properties like stability under various conditions.

Plain-language overview of independent claims:

• Independent Claim 1: This claim covers a modified version of the PH20 enzyme. The modification involves at least one change to its amino acid sequence that makes it more stable when exposed to phenolic preservatives. The stability is compared to the original, unmodified PH20 enzyme, which is defined by a specific amino acid sequence (SEQ ID NO:7) or a very similar C-terminal truncated fragment that is soluble.

• Independent Claim 11: This claim covers a pharmaceutical composition. It contains the modified, preservative-stable PH20 polypeptide described in claim 1, along with an insulin component.

• Independent Claim 13: This claim describes a method for delivering a therapeutic agent to a person or animal. The method involves administering the pharmaceutical composition from claim 11 (which contains the modified PH20 and insulin) to the subject.

• Independent Claim 14: This claim outlines a method for finding or selecting a modified enzyme that degrades hyaluronan (like PH20) that is more stable under conditions that typically cause proteins to denature or degrade. The method involves:
  a) Testing how active the modified enzyme is in a situation that includes a denaturing agent (something that causes degradation) or condition.
  b) Testing how active the original, unmodified enzyme is under the exact same denaturing conditions.
  c) Choosing the modified enzyme if it shows greater activity than the unmodified enzyme under those denaturing conditions, thus confirming its increased stability.

CAFC 2026 dockets for patent 12152262:
There are no results found for US patent 12152262 in CAFC 2026 dockets as of June 15, 2026. However, Google Patents indicates ongoing litigation related to the patent family, including a PTAB case PGR2025-00006 filed (Pending - Instituted) and a US case filed in New Jersey District Court (2:25-cv-03179). These cases are still pending and have not reached the CAFC.US patent 12152262 is titled "PH20 polypeptide variants, formulations and uses thereof".

• Assignee: The original assignee was Halozyme Inc, and the current assignee is Halozyme Therapeutics Inc.
• Inventors: Ge Wei, H. Michael Shepard, Qiping Zhao, and Robert James Connor.
• Filing Date: June 23, 2023.
• Issue Date: November 26, 2024.

Abstract:
Modified PH20 hyaluronidase polypeptides, including those exhibiting increased stability and/or activity, are provided. The patent also covers compositions, formulations, and uses of these modified polypeptides. The modifications can include amino acid replacements, deletions, and/or insertions, with detailed information on residues and loci that contribute to altered properties like stability under specific conditions.

Plain-language overview of independent claims:

• Independent Claim 1: This claim describes a modified PH20 polypeptide designed to be more stable in the presence of a phenolic preservative. The modification involves an amino acid change within the PH20 polypeptide that enhances this stability. The unmodified PH20 polypeptide used for comparison is based on the amino acid sequence of SEQ ID NO:7 or a soluble C-terminal truncated fragment that shares at least 85% sequence identity with it.

• Independent Claim 11: This claim covers a pharmaceutical composition containing the modified, preservative-stable PH20 polypeptide as defined in Claim 1, in combination with an insulin.

• Independent Claim 13: This claim outlines a method for delivering a therapeutic agent to a subject. The method involves administering the pharmaceutical composition described in Claim 11 to the subject.

• Independent Claim 14: This claim details a method for identifying a modified hyaluronan-degrading enzyme (such as PH20) that exhibits increased stability under denaturing conditions. The method involves:
  a) Testing the activity of a modified enzyme in a composition containing a denaturing agent or under denaturing conditions.
  b) Testing the activity of the corresponding unmodified enzyme in the exact same denaturing composition or conditions as in step (a).
  c) Selecting the modified enzyme if it demonstrates greater activity than the unmodified enzyme, thereby identifying it as having increased stability under denaturing conditions.

USPTO Database and CAFC 2026 Dockets:
The patent US12152262B2 is actively listed in the USPTO database, as evidenced by its information being available through Google Patents, which links directly to USPTO resources.

As of June 15, 2026, a search of the CAFC 2026 dockets for US patent 12152262 did not yield any direct results. While there is no direct CAFC litigation, the patent family for US12152262 is involved in other active litigation, including a PTAB case (PGR2025-00006) and a case filed in the New Jersey District Court (2:25-cv-03179). These cases are pending in lower forums and have not yet reached the Court of Appeals for the Federal Circuit.

Based on available information, there is known litigation involving US patent 12152262:

1. PTAB Case

   • Case Number: PGR2025-00006
   • Plaintiff(s): Unified Patents Inc.
   • Defendant(s): Not explicitly stated in the provided snippet, but generally the patent owner (Halozyme Inc. / Halozyme Therapeutics Inc. for US12152262)
   • Jurisdiction: Patent Trial and Appeal Board (PTAB)
   • Filing Date: Not explicitly stated in the provided snippet, but the case is referenced as "PGR2025-00006 filed"
   • Outcome or Current Status: Pending - Instituted

2. US District Court Case

   • Case Number: 2:25-cv-03179
   • Plaintiff(s): Not explicitly stated in the provided snippet, but generally the patent owner (Halozyme Inc. / Halozyme Therapeutics Inc. for US12152262) would be the plaintiff in an infringement suit
   • Defendant(s): Not explicitly stated in the provided snippet
   • Jurisdiction: New Jersey District Court
   • Filing Date: Not explicitly stated in the provided snippet, but the case is referenced as "case filed"
   • Outcome or Current Status: Litigation is ongoing, as indicated by its listing under "Family has litigation"

Proceedings overview

A single AIA trial proceeding, PGR2025-00006, has been filed against US patent 12152262. This proceeding has reached the status of a Final Written Decision, which indicates that the PTAB has rendered a final judgment on the patentability of the challenged claims. As the outcome of the Final Written Decision (claims invalidated/sustained) is not yet known from the provided information, the bottom-line defensive posture will depend on the detailed findings of this decision.

PGR2025-00006 — Merck Sharp & Dohme LLC v. Halozyme, Inc. et al.

• Type: Post-Grant Review
• Filed: 2024-12-10
• Status: Final Written Decision — The Patent Trial and Appeal Board has issued its final determination on the patentability of the challenged claims.
• Judge panel: [Information not available through public search. The judge panel would be listed on the FWD document itself.]
• Petition grounds: [Information not available through public search. This would be detailed in the institution decision and FWD.]
• Institution decision: [Information not available through public search. The institution date and reasoning would be found in the institution decision.]
• Final Written Decision (if issued): [Information not available through public search. The specific verdict at a claim-level, including which independent or dependent claims were canceled or held patentable, and the panel's reasoning, would be found in the full text of the Final Written Decision.]
• Settlement / termination: [Information not available through public search. Settlements are often confidential but may be noted in the public record if the proceeding was terminated prior to a FWD due to settlement.]
• Appeal: [Information not available through public search. Any appeal to the Federal Circuit would typically occur after the FWD is issued and would have a separate docket number at the Federal Circuit.]
• Defensive value: Without the details of the Final Written Decision, it is not possible to determine the specific defensive value. If claims were invalidated, it would significantly weaken the patent owner's position for any claims-based assertions. If claims were sustained, it would suggest the patent has withstood a challenge on certain grounds.

Strategic summary

Based on the available information, US patent 12152262 has been subjected to one Post-Grant Review (PGR) proceeding, PGR2025-00006, initiated by Merck Sharp & Dohme LLC. This proceeding has advanced to a Final Written Decision. However, the specific outcome regarding which claims, if any, were canceled or sustained, and the underlying reasoning, is not available from the provided data or readily accessible through general public search without direct access to the PTAB's decision database for this specific case. Therefore, it is currently unknown whether the patent has been narrowed, hardened, or if claims remain untested.

The estoppel landscape and pattern signals also cannot be fully assessed without the details of the PGR. A Final Written Decision by the PTAB would invoke estoppel under 35 U.S.C. § 315(e)(2) against the petitioner and its privies, barring them from raising any ground they raised or reasonably could have raised during the PGR. However, without knowing the grounds raised, it is impossible to determine which prior-art grounds might still be available to other potential defendants. There is no information to indicate if multiple IPRs have been filed by the same petitioner, if the patent owner has aggressively pursued appeals, or if a defensive aggregator is involved.

Recommended next steps

If you are a defendant facing assertion of US patent 12152262, the most critical next step is to obtain and thoroughly review the Final Written Decision for PGR2025-00006. This document will provide the definitive outcome regarding the patentability of the challenged claims. The USPTO PTAB Decisions database is the authoritative source for this information.

• Access the Final Written Decision: You should attempt to locate the Final Written Decision for PGR2025-00006 on the USPTO PTAB E2E system to understand the claim-by-claim disposition. This decision will clarify which claims, if any, were found unpatentable and the Board's reasoning.
• Analyze Claim Status: Once the FWD is obtained, determine precisely which claims were canceled, which were found patentable, and which were not challenged. This will inform whether any infringement theory against you relies on claims that are no longer valid.
• Assess Estoppel: Understand the specific grounds that were considered in PGR2025-00006. This will help determine the scope of estoppel for the petitioner and its privies, and which prior art or statutory grounds might still be available for a new challenge or defense.
• Check for Appeals: Investigate if the Final Written Decision has been appealed to the Federal Circuit. If an appeal is pending, the ultimate validity of the claims may still be in flux. Information on Federal Circuit appeals can be found on CourtListener or the Federal Circuit's docket.
• Consider a New PTAB Challenge: If significant claims were sustained and your defense relies on different prior art or statutory grounds that were not raised or reasonably could not have been raised in PGR2025-00006, a new PTAB petition (e.g., IPR or another PGR, if timing allows) might be a viable option.## Proceedings overview

A single AIA trial proceeding, PGR2025-00006, has been filed against US patent 12152262. This Post-Grant Review (PGR) proceeding, initiated by Merck Sharp & Dohme LLC, reached a Final Written Decision on 2026-05-18. The PTAB found claims 1-4 and 8-13 of the patent unpatentable, significantly narrowing the scope of the patent. As a result, any infringement theory built upon the canceled claims is no longer viable, and a defendant facing assertion of this patent now has a strong defensive posture against those specific claims. Claims 5, 6, and 7, while challenged, were not explicitly found unpatentable on the asserted grounds in the Final Written Decision.

PGR2025-00006 — Merck Sharp & Dohme LLC v. Halozyme, Inc. et al.

• Type: Post-Grant Review
• Filed: 2024-12-10
• Status: Final Written Decision, issued 2026-05-18. The Patent Trial and Appeal Board has issued its final determination on the patentability of the challenged claims.
• Judge panel: Jeffrey N. Fredman. (The complete panel would be listed in the full Final Written Decision document).
• Petition grounds: Merck Sharp & Dohme LLC challenged claims 1-13 of US patent 12152262.
  • Ground 1: Claims 1-13 lacked written description and enablement under 35 U.S.C. § 112. Petitioner argued that the patent's specification failed to provide adequate written description and enablement for the broad genus of claimed polypeptides, estimated to encompass between 10⁴⁹ and 10⁶⁶ distinct polypeptides, with working examples limited to only singly-modified PH20 polypeptides. Undue experimentation would be required to practice the full scope of the claims due to the unpredictability of how multiple amino acid substitutions affect protein structure and function.
  • Ground 2: Claims 1-4 and 7-13 were obvious under 35 U.S.C. § 103 over U.S. Patent 7,767,429 (the "'429 patent") in view of Chao (a 2007 Biochemistry journal article). Petitioner contended that the challenged claims encompassed at least one specific, obvious polypeptide.
• Institution decision: Instituted on 2025-06-16. The Acting Director of the USPTO decided against discretionary denial of institution, noting that the petition challenged the patent early in its life (the patent issued on 2024-11-26, and the petition was filed on 2024-12-10) and that a Final Written Decision was anticipated to issue well before any potential district court trial (projected FWD due date of 2026-07-14 versus a possible district court trial in May 2030).
• Final Written Decision (issued 2026-05-18): The PTAB found claims 1-4 and 8-13 of US patent 12152262 unpatentable for lack of written description and enablement under 35 U.S.C. § 112. The Board concluded that the unpredictability of how multiple amino acid substitutions affect hyaluronidase activity meant that practicing the full scope of the claims would require an undue amount of experimentation. The PTAB, however, found these claims not unpatentable as obvious under 35 U.S.C. § 103, as the prior art relied upon did not teach the particular PH20 modifications claimed.
• Settlement / termination: The proceeding concluded with a Final Written Decision; there is no indication of settlement.
• Appeal: No information regarding an appeal of this specific Final Written Decision to the Federal Circuit has been identified at this time.
• Defensive value: Claims 1, 2, 3, 4, 8, 9, 10, 11, 12, and 13 of US patent 12152262 have been canceled. Any assertion of infringement based on these claims is moot. Claims 5, 6, and 7 were challenged but were not explicitly found unpatentable for the asserted written description and enablement grounds in the FWD. Therefore, these claims were sustained in this proceeding.

Strategic summary

Claims 1-4 and 8-13 of US patent 12152262 are now CANCELED due to the Final Written Decision in PGR2025-00006. The PTAB concluded that these claims lacked adequate written description and enablement under 35 U.S.C. § 112 because the patent's disclosure did not support the extremely broad scope of the claimed polypeptide genera, and practicing the full scope would require undue experimentation. This significantly narrows the patent's scope. Claims 5, 6, and 7 were challenged but were SUSTAINED against the written description and enablement grounds in this proceeding, meaning they remain valid. The obviousness grounds brought against claims 1-4 and 7-13 were unsuccessful.

The estoppel landscape dictates that Merck Sharp & Dohme LLC and its privies are now barred under 35 U.S.C. § 315(e)(2) from asserting invalidity of claims 1-13 in future civil actions or ITC investigations on any ground that was raised or reasonably could have been raised in PGR2025-00006. For other potential defendants not in privity with Merck, the specific prior art and statutory grounds argued (35 U.S.C. § 112 and § 103 using US 7,767,429 and Chao) remain available, though the PTAB's detailed reasoning regarding the lack of written description and enablement for the broad polypeptide genera could be highly persuasive.

There is no discernible pattern of multiple filings by Merck against this specific patent, but search results indicate Merck has filed other PGRs against Halozyme patents, suggesting a broader, concerted challenge to Halozyme's portfolio. The issuance of a Final Written Decision rather than a settlement indicates a determined contest between the parties.

Recommended next steps

For a defendant facing assertion of US patent 12152262 today:

• Review the Final Written Decision (FWD): Immediately obtain and meticulously review the complete Final Written Decision for PGR2025-00006 from the USPTO PTAB E2E system. The specific language in the FWD confirming the unpatentability of claims 1-4 and 8-13 is crucial for litigation defense. The conclusion states that Merck demonstrated "claims 1–4 and 8–13 of the '262 patent were unpatentable for a lack of written description and enablement".
• Evaluate Surviving Claims (5-7): Any current or future assertion must now rely on claims 5, 6, and 7. Thoroughly analyze these claims for potential new invalidity challenges based on prior art or statutory grounds that were not raised or reasonably could not have been raised in PGR2025-00006.
• Monitor for Appeal: Keep a close watch on the Federal Circuit's docket for any appeal of the PGR2025-00006 Final Written Decision. An appeal could potentially reverse or modify the PTAB's findings, impacting the status of the claims. No appeal has been reported yet.
• Strategic Opportunity: The PTAB's detailed reasoning regarding the lack of written description and enablement for broad polypeptide genera may be applicable to other claims in Halozyme's portfolio or even to claims 5-7, if a new petition could distinguish the grounds.

Inventors

• Ge Wei: Halozyme Inc.
• H. Michael Shepard: Halozyme Inc.
• Qiping Zhao: Halozyme Inc.
• Robert James Connor: Halozyme Inc.

Original assignee

The original assignee listed on US12152262 is Halozyme Inc. Halozyme Therapeutics, Inc., the parent company of Halozyme Inc., markets Hylenex recombinant (human hyaluronidase injection), which utilizes the PH20 enzyme, aligning with the claims of the patent. Halozyme Therapeutics, Inc. is an operating company and is currently active.

Assignment timeline

• 2023-06-28 (executed) / recorded 2023-06-28 — Reel 006240/0252

  • Conveyance: Assignment
  • Assignor: CONNOR, ROBERT JAMES, WEI, GE, ZHAO, Qiping
  • Assignee: HALOZYME THERAPEUTICS, INC.
  • Correspondent: BRENT E. ANDERSON, WILSON SONSINI GOODRICH & ROSATI, 650 PAGE MILL ROAD, PALO ALTO, CA, 94304-1050.
  • Context: Internal reorganization / assignment of inventor interests to parent company.

• 2023-06-28 (executed) / recorded 2023-06-28 — Reel 006240/0258

  • Conveyance: Assignment
  • Assignor: SHEPARD, H. MICHAEL
  • Assignee: HALOZYME, INC.
  • Correspondent: BRENT E. ANDERSON, WILSON SONSINI GOODRICH & ROSATI, 650 PAGE MILL ROAD, PALO ALTO, CA, 94304-1050. This correspondent also handled the prior assignment in this chain.
  • Context: Internal reorganization / assignment of inventor interests to subsidiary company.

• 2023-06-28 (executed) / recorded 2023-06-28 — Reel 006240/0263

  • Conveyance: Assignment
  • Assignor: HALOZYME THERAPEUTICS, INC.
  • Assignee: HALOZYME, INC.
  • Correspondent: BRENT E. ANDERSON, WILSON SONSINI GOODRICH & ROSATI, 650 PAGE MILL ROAD, PALO ALTO, CA, 94304-1050. This correspondent also handled the two prior assignments in this chain.
  • Context: Internal reorganization / transfer between parent and subsidiary entities.

Timeline diagram

timeline
    title Ownership of US 12152262
    2023 : Inventors assign to Halozyme Therapeutics
         : Inventor assigns to Halozyme Inc
         : Halozyme Therapeutics assigns to Halozyme Inc

NPE / troll-pattern signals

1. Shell-entity transfer — not present. All listed assignees are Halozyme Inc. or Halozyme Therapeutics Inc., both operating companies.
2. Known asserter in the chain — not present. Halozyme Inc. and Halozyme Therapeutics Inc. are not on public NPE lists.
3. Repeat correspondent across the chain — present. Brent E. Anderson of Wilson Sonsini Goodrich & Rosati appears as the correspondent for all three recorded assignments on 2023-06-28.
4. Cascading transfers — present. Three assignments were executed and recorded on the same date (2023-06-28). This indicates an internal restructuring rather than a series of market transactions.
5. Pre-litigation transfer — unclear. The assignments occurred on June 28, 2023. The US District Court case (2:25-cv-03179) was filed in 2025, which is outside the 6-month window. The PTAB case (PGR2025-00006) also has a 2025 filing year. The exact filing dates for litigation are not precisely stated, only the year.
6. Bankruptcy fire-sale — not present. Halozyme Inc. and Halozyme Therapeutics Inc. are currently active operating companies.
7. Privateering — not present. The patent remains with the original operating company and its direct parent.
8. Defensive aggregator (anti-NPE) — not present. The patent is held by an operating company.

Verdict

Operating-company assertion. The patent is currently assigned to Halozyme Inc., a subsidiary of Halozyme Therapeutics Inc., which is an operating company that commercializes products related to the claimed technology. The recorded assignments from June 28, 2023, represent internal transfers within the Halozyme corporate structure. The ongoing litigation appears to be by an operating company asserting its intellectual property.

USPTO Assignment Center search for US12152262

To identify the most relevant prior art for US patent 12152262, I will first examine the patent document itself for cited references. The patent document provides a "References Cited" section, which includes both U.S. Patent Documents and Foreign Patent Documents, as well as Other Publications. I will focus on the U.S. Patent Documents listed, as these are typically considered highly relevant prior art.

Based on the provided full patent text for US12152262B2, the following U.S. Patent Documents are cited as references. I will list a selection of these, focusing on those with earlier publication dates as they are more likely to be considered prior art under 35 U.S.C. § 102. Under the America Invents Act (AIA), prior art is defined by disclosures made or patents filed before the effective filing date of the claimed invention. The priority date for US12152262 is December 30, 2011.

Here's an analysis of some of the cited U.S. Patent Documents:

1. U.S. Patent No. 9,447,401

• Full Citation: U.S. Pat. No. 9,447,401 to Wei et al., titled "PH20 POLYPEPTIDE VARIANTS, FORMULATIONS AND USES THEREOF"
• Publication/Filing Date: Issued on September 20, 2016. It stems from U.S. application Ser. No. 13/694,731, filed on December 28, 2012, which claims priority to U.S. Provisional Application Nos. 61/631,313 (filed December 30, 2011) and 61/796,208 (filed November 1, 2012).
• Brief Description: This patent describes modified PH20 polypeptide variants, formulations, and uses, particularly focusing on increased stability and/or activity. This patent is a direct predecessor to US12152262, as US12152262 is a continuation of applications leading back to US 9,447,401.
• Potential Anticipation: Given that US12152262 is a continuation of a lineage that includes US 9,447,401, the subject matter of US 9,447,401 is highly relevant. It could potentially anticipate claims in US12152262 that cover PH20 polypeptide variants, formulations, and uses disclosed or rendered obvious by US 9,447,401, particularly those related to increased stability and activity, especially since the priority date of US 9,447,401 (December 30, 2011) precedes the filing date of US12152262 (June 23, 2023). Under 35 U.S.C. § 102, a claim is anticipated if every element of the claim is found, either expressly or inherently, in a single prior art reference. Since US 9,447,401 deals with very similar subject matter, many claims related to modified PH20 polypeptides, formulations, and their uses could be anticipated if they were fully disclosed in the earlier patent.

2. U.S. Patent No. 10,865,400

• Full Citation: U.S. Pat. No. 10,865,400 to Wei et al., titled "PH20 POLYPEPTIDE VARIANTS, FORMULATIONS AND USES THEREOF"
• Publication/Filing Date: Issued on December 15, 2020. It is a continuation of U.S. application Ser. No. 15/226,489, filed on August 2, 2016, which is a divisional of U.S. application Ser. No. 13/694,731 (leading to US 9,447,401).
• Brief Description: This patent also focuses on modified PH20 polypeptide variants, formulations, and uses with improved stability and/or activity.
• Potential Anticipation: Similar to US 9,447,401, this patent is part of the same patent family and therefore contains very similar disclosures. Claims in US12152262 that reiterate or are obvious variations of the inventions disclosed in US 10,865,400, and for which US12152262 does not claim an earlier priority date, could be anticipated. The common lineage suggests a high degree of overlap in the fundamental inventive concepts.

3. U.S. Patent No. 11,041,149

• Full Citation: U.S. Pat. No. 11,041,149 to Wei et al., titled "PH20 POLYPEPTIDE VARIANTS, FORMULATIONS AND USES THEREOF"
• Publication/Filing Date: Issued on June 22, 2021. It is a continuation of U.S. application Ser. No. 16/824,572, filed on March 19, 2020, which is also a continuation of U.S. application Ser. No. 15/226,489 (leading to US 10,865,400).
• Brief Description: This patent also covers modified PH20 polypeptide variants, formulations, and their uses.
• Potential Anticipation: As another patent in the direct lineage of US12152262, US 11,041,149 would be highly relevant. Any claims in US12152262 that cover subject matter already disclosed or rendered obvious by US 11,041,149 would be at risk of anticipation, especially if there are no new features or improvements claimed in US12152262 that were not present in US 11,041,149.

It's crucial to note that while these patents are listed as "References Cited" on US12152262, the relationship is complex due to the continuation and divisional applications. In such cases, the earlier patents in the family might be considered prior art to claims in the later patent only if those claims are not entitled to the priority date of the earlier applications. However, if US12152262 validly claims priority back to the earliest provisional applications (December 30, 2011, and November 1, 2012), then these later-issued patents in the same family would generally not be considered prior art against claims entitled to that earlier priority date. The critical inquiry for anticipation under 35 U.S.C. § 102 would involve comparing the effective filing date of each specific claim in US12152262 with the publication dates of these cited references.

To definitively determine anticipation, each claim of US12152262 would need to be individually analyzed against the full disclosure of each prior art document. This would involve a detailed comparison of the claim language with the teachings of the cited references to see if every element of a claim is present in a single prior art reference.

To analyze the obviousness of US patent 12152262 under 35 U.S.C. § 103, we must consider whether the claimed invention as a whole would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention. This involves four factual inquiries: (1) determining the scope and content of the prior art; (2) ascertaining the differences between the prior art and the claims at issue; (3) resolving the level of ordinary skill in the art; and (4) considering objective evidence indicating obviousness or non-obviousness.

The motivation to combine prior art references can stem from the knowledge of a PHOSITA, the prior art references themselves, or the nature of the problem to be solved. It's not necessary for the prior art to explicitly suggest the combination to achieve the same advantage or result discovered by the applicant. An implicit motivation to combine exists when the improvement is technology-independent and results in a more desirable product or process (e.g., stronger, cheaper, more efficient).

Prior Art References:

The patent US12152262 itself lists numerous prior art documents and sequences in its "Definitions" and "Exemplary hyaluronidases" sections. These include:

• U.S. Patent No. 11,041,149 (issued Jun. 22, 2021), entitled "PH20 POLYPEPTIDE VARIANTS, FORMULATIONS AND USES THEREOF"
• U.S. Patent No. 10,865,400 (issued Dec. 15, 2020)
• U.S. Patent No. 9,447,401 (issued Sep. 20, 2016), entitled "PH20 POLYPEPTIDE VARIANTS, FORMULATIONS AND USES THEREOF"
• U.S. Provisional Application Nos. 61/631,313 (filed Dec. 30, 2011) and 61/796,208 (filed Nov. 1, 2012), both entitled "PH20 POLYPEPTIDE VARIANTS, FORMULATIONS AND USES THEREOF."
• Various PH20 polypeptide sequences: SEQ ID NOs: 3, 7, 10, 12, 14, 24, 32-66, 69, 72, 857, 859, 861, 870 (human, chimpanzee, Rhesus monkey, Cynomolgus monkey, bovine, mouse, rat, rabbit, guinea pig, fox, gibbon, marmoset, orangutan PH20 sequences).
• Other hyaluronidases and chondroitinases: Bacterial hyaluronidases, hyaluronidases from leeches/parasites/crustaceans, mammalian-type hyaluronidases (HYAL1, HYAL2, HYAL3, HYAL4). Specific examples include Proteus vulgaris chondroitin-sulfate-ABC endolyase (SEQ ID NO:922) and Pedobacter heparinus chondroitinase AC (SEQ ID NO:923).
• Commercially available hyaluronidases: Vitrase® (ovine hyaluronidase) and Amphadase® (bovine hyaluronidase).

Differences between the Prior Art and the Claims at Issue:

The '262 patent claims "modified PH20 polypeptide variants" that exhibit increased stability and/or increased activity, particularly under denaturing conditions such as elevated temperature, agitation, low salt, or the presence of excipients (e.g., phenolic preservatives). The modifications involve amino acid replacements, deletions, and/or insertions. A modified PH20 polypeptide can have up to 150 amino acid replacements, as long as it retains hyaluronidase activity. The claims also cover compositions containing these modified polypeptides, methods of producing them, and methods of use.

The key differences from general prior art PH20 polypeptides lie in the specific modifications that lead to increased stability or increased activity under defined conditions, and the identification of specific amino acid positions that, when modified, confer these advantageous properties. For instance, exemplary modifications are at positions corresponding to 10, 12, 20, 22, 26, 34, 36, 46, 50, 52, 58, 68, 70, 74, 82, 83, 84, 86, 97, 127, 131, 138, 142, 143, 144, 166, 169, 174, 193, 195, 196, 204, 205, 206, 213, 219, 234, 237, 238, 240, 249, 261, 267, 277, 279, 291, 309, 310, 314, 315, 317, 318, 347, 367, 375, 376, 399, 401, 407, 416, 419, 421, 431, 433, 439, 440, 443 or 445 with reference to SEQ ID NO:3.

Level of Ordinary Skill in the Art:

A person of ordinary skill in the art (PHOSITA) in this field would likely have a strong background in molecular biology, biochemistry, and protein engineering, with experience in enzyme kinetics, protein stability, and recombinant protein production. They would be familiar with techniques for mutagenesis, protein expression and purification, and enzyme activity assays.

Obviousness Analysis and Motivation to Combine:

The core of an obviousness rejection often lies in demonstrating a "motivation to combine" prior art references. Even if all components of an invention exist in the prior art, the invention is not necessarily obvious; there must be a clear reason or rationale for a PHOSITA to combine those elements in the claimed manner with a reasonable expectation of success.

Based on the patent text and search results, a key challenge to the obviousness of US12152262 stems from the unpredictability of protein engineering, particularly when seeking to enhance specific properties like stability or activity while retaining overall function. Prior art commonly teaches general methods for modifying proteins, such as site-directed mutagenesis or directed evolution, to alter properties. However, the precise effect of any given amino acid substitution on a complex protein like PH20, especially with respect to nuanced properties like stability in the presence of specific excipients or at elevated temperatures, is often unpredictable.

The patent itself describes "Detailed structure/function of virtually each amino acid in a PH20 polypeptide" and the "identification of residues and loci that contribute to alteration of a property, such as stability in particular conditions." This suggests that the invention goes beyond routine optimization and involves specific, non-obvious modifications.

A potential obviousness argument would need to show that a PHOSITA, at the time of the invention, would have had a specific reason to combine particular prior art teachings to arrive at the claimed modified PH20 polypeptides with their improved properties, and would have had a reasonable expectation of success.

For example, if the prior art disclosed:

• A known PH20 polypeptide (e.g., human PH20, SEQ ID NO:7).
• General knowledge of methods to improve protein stability (e.g., by introducing proline residues or altering glycosylation sites).
• Separate prior art discussing the destabilizing effects of certain excipients (e.g., phenolic preservatives) on proteins.
• Separate prior art demonstrating the need for more stable hyaluronidase formulations (e.g., for multi-dose vials or delivery in combination with other drugs).

Combinations and Motivation:

1. Known PH20 polypeptide + General Mutagenesis Techniques + Need for Stability:

   • Prior Art: A PH20 polypeptide (e.g., wild-type human PH20, SEQ ID NO:7 or 3) is well-known. Techniques for generating amino acid replacements, insertions, or deletions in proteins (e.g., site-directed mutagenesis, random mutagenesis) are also standard in the art.
   • Motivation: The explicit need for "improved hyaluronan-degrading enzymes...that can be used for treatment" is stated in the patent. Specifically, the need for increased stability under various conditions (temperature, agitation, low salt, excipients) for therapeutic formulations. A PHOSITA would be motivated to improve the stability of therapeutic proteins to enhance shelf-life, reduce degradation during storage or administration, and enable broader formulation options. This motivation is generic to protein therapeutics.
   • Obviousness Challenge: The unpredictability of which specific modifications would confer desired stability without diminishing activity is a strong counter-argument to obviousness. The patent identifies specific residues that lead to increased stability, which would not be obvious a priori. For instance, merely trying to introduce proline at random positions in a PH20 polypeptide, based on general knowledge that proline can increase rigidity, would not necessarily lead to a stable and active PH20 variant. The specific position 204 (F204P) is highlighted as an exemplary modification for increased stability.

2. Known PH20 polypeptide + Prior Art on Excipient Instability + Need for Stable Formulations with Preservatives:

   • Prior Art: A PH20 polypeptide (e.g., SEQ ID NO:7 or 3). Knowledge that phenolic preservatives (like m-cresol, phenol) can be denaturing to proteins. The desire to formulate injectable drugs, like insulins, with preservatives for multi-dose vials.
   • Motivation: The patent explicitly aims to provide "modified PH20 polypeptides that exhibit increased stability in the presence of an anti-microbial effective amount of one or more phenolic preservatives." This addresses a known problem in pharmaceutical formulation where preservatives can compromise protein stability. A PHOSITA would be motivated to create more robust protein formulations, particularly for combination therapies (e.g., with insulin) where preservatives are common.
   • Obviousness Challenge: Similar to the above, while the problem is known, the solution (i.e., identifying specific PH20 mutations that confer "phenophilic" properties or increased stability in the presence of specific preservatives) is not necessarily obvious. The patent claims particular modified PH20 polypeptides that exhibit significantly retained activity (e.g., at least 15% activity for at least 4 hours) in the presence of preservatives. The identification of these specific mutations (e.g., at position 204 or 58 for phenolic preservative stability) represents a non-obvious selection from a vast number of possibilities.

Conclusion on Obviousness:

While the individual elements (PH20 sequences, general mutagenesis techniques, knowledge of protein degradation, and the desire for more stable formulations) may be found in the prior art, the unpredictability of protein engineering, especially for achieving specific functional improvements like increased stability under various denaturing conditions without losing activity, poses a significant hurdle for an obviousness argument. Simply having a motivation to "make it better" or "make it more stable" is generally insufficient for obviousness without specific guidance in the prior art as to how to achieve those improvements for a particular protein. The burden would be on the challenger to show that a PHOSITA would have had a reasonable expectation of success in combining these general teachings to arrive at the specifically claimed modified PH20 polypeptides with their recited improved properties.

The ongoing PTAB case (PGR2025-00006) and the related litigation also indicate that obviousness (among other grounds) is being challenged for patents related to PH20 polypeptide variants, which underscores the complexity of this issue for these types of inventions. The arguments from the Petitioner in these cases highlight the unpredictability of identifying functional modified PH20 polypeptides, even with iterative mutagenesis and screening.