Fact-checked by Grok 2 weeks ago

Markush structure

A Markush structure is a generic representation of a chemical compound or class of compounds used primarily in patent claims to encompass a range of related molecules sharing a common core scaffold but varying in specific substituents or functional groups, typically denoted by placeholders such as "R" groups or enumerated alternatives.^[1]^[2] This notation allows inventors to claim broad protection for chemical inventions without enumerating every possible variant, streamlining patent applications in fields like pharmaceuticals, agrochemicals, and materials science.^[3]^[1] The concept originated in 1923 when American chemist Eugene A. Markush filed U.S. Patent Application No. 611,637 for a process to produce pyrazolone dyes, in which he claimed a method involving coupling a halogen-substituted pyrazolone with "a diazotized unsulphonated material selected from the group consisting of aniline, homologues of aniline and halogen substitution products of aniline."^[4] This innovative claim format, approved in the 1924 decision Ex parte Markush (1925 Dec. Comm'r Pat. 126), marked the first judicial acceptance of such generic groupings in U.S. patent law, enabling the protection of multiple related inventions in a single claim.^[3] The structure's name derives from this case, and it has since become a cornerstone of chemical patent drafting worldwide.^[3] In modern practice, Markush structures must meet strict criteria for validity, particularly under U.S. Patent and Trademark Office (USPTO) guidelines, where a proper Markush grouping requires that the alternatives share a "single structural similarity" and a "common use," such as belonging to a recognized chemical class or possessing a substantial structural feature essential to their function.^[3] For instance, claims to fluoroaliphatic radical-containing anionic sulfonamido compounds sharing a common structural feature essential to their surfactant utility have been deemed proper, while disparate herbicides lacking such unity may be rejected as improper.^[3] Beyond patents, these structures facilitate cheminformatics tasks like database searching, virtual screening, and enumeration of compound libraries in drug discovery, often represented using specialized software that expands the generic form into specific instantiations.^[1]^[2]

Fundamentals

Definition

A Markush structure is a condensed chemical representation that depicts a genus of related compounds through the use of variables, such as R groups, to encompass multiple alternatives without enumerating each individual molecule.^[3] This approach allows for the depiction of a family of structures sharing a common core while varying in substituents or functional groups.^[5] The primary purpose of a Markush structure in patent claims is to simplify the description of homologous series, substituents, or functional groups, enabling efficient coverage of potential inventions that share similar chemical or physical properties and utility.^[3] By grouping alternatives within a single claim, it avoids the need for lengthy lists, which would be impractical for large sets of related compounds in fields like chemistry and pharmacology.^[6] Basic components of a Markush structure include a core scaffold—the invariant central framework—and enumerated or nested variables, such as R1 denoting alternatives like hydrogen (H), methyl (CH₃), or phenyl (C₆H₅), attached at specific positions.^[7] These variables define the permissible variations, often listed explicitly to form a closed group of alternatives.^[3] Unlike a specific chemical structure, which represents a single, discrete molecule, a Markush structure claims an entire family or genus of compounds, providing broader protection for innovations involving structural analogs.^[5] This distinction is crucial in patent practice, as it focuses on shared structural similarities and common applications rather than isolated embodiments.^[3]

Notation and Representation

Markush structures employ a standardized notation that utilizes R-group variables to denote variable substituents or fragments within a core chemical scaffold. These R-groups, typically labeled as R¹, R², and so on, represent positions where multiple alternatives can attach, allowing for the concise depiction of a genus of compounds. Alternatives for each R-group are often specified using phrases such as "selected from the group consisting of" followed by a list, or in structural contexts, enclosed in brackets like R = [A, B, C] to indicate enumerated options.^[3]^[8] For more complex genera, nested structures are used, where one R-group definition incorporates further variables, such as R¹ being a substructure itself with its own R² alternatives, enabling hierarchical representation of multifaceted chemical diversity.^[1] Graphically, Markush structures are rendered in chemical diagrams where the invariant core is drawn with standard bonds (solid lines for single bonds, double lines for double bonds), and variable positions are marked by attachment points leading to R-group labels or substructures. Radicals or fragments for alternatives are depicted as separate diagrams linked to the core via dashed or specialized Markush bonds, which may include visual cues like shadows for positional variations. Atom lists within the structure, such as variable elements at a site, are shown in bracketed notation directly on atoms, e.g., [C,N,O], to specify permissible substitutions without expanding to full molecules.^[1]^[8] In patent specifications, Markush structures appear in two primary formats: textual descriptions, which detail variables linguistically in claims (e.g., "wherein R is hydrogen, alkyl, or aryl"), and structural formulas, which combine diagrams with annotations for alternatives. Textual formats prioritize clarity for legal scope, listing options exhaustively to define the claimed genus, while structural formulas integrate visuals for precision, often accompanying textual explanations to illustrate the core and substituents. This dual approach ensures both readability and exactness in describing chemical inventions.^[3]^[9] A simple example of a Markush diagram is a benzene ring with three substituents: positions 1, 3, and 4 attached to R¹, R², and R³, respectively, where the core is a hexagonal ring with alternating double bonds, and each R attachment is a single bond line ending in the variable label. Here, R¹ might be defined as [H, CH₃, OH], R² as [Cl, Br, F], and R³ as [NH₂, NO₂, COOH], representing a family of trisubstituted benzenes such as 1-methyl-3-chloro-4-aminobenzene among others. This notation captures positional isomerism and substituent variety without enumerating each member individually.^[1]^[9]

Historical Development

Invention by Eugene Markush

Eugene A. Markush was a chemist born in Budapest, Hungary, who immigrated to the United States in 1913 after earning a Ph.D. from various Hungarian universities.^[10] In 1919, he founded the Pharma Chemical Corporation in New Jersey, focusing on the development and production of dyestuffs.^[11] On January 3, 1923, Markush filed U.S. Patent Application Serial No. 611,637 for a process to manufacture pyrazolone dyes suitable for dyeing wool or silk in an acid bath.^[4] The invention centered on coupling a halogen-substituted pyrazolone, such as dichlor-sulpho-phenyl-methyl pyrazolone, with a diazotized unsulphonated material to produce dyestuffs with enhanced fastness properties.^[4] To claim the invention efficiently, Markush employed a generic formula in his claims, specifying variable components such as the diazotized material selected from a related set of aryl amines.^[4] Specifically, Claim 1 read: "The process for the manufacture of dyes which comprises coupling with a halogen-substituted pyrazolone, a diazotized unsulphonated material selected from the group consisting of aniline, homologues of aniline and halogen substitution products of aniline."^[4] This phrasing allowed coverage of multiple analogous compounds without enumerating each one individually, addressing the practical challenge of claiming families of similar chemical structures in dyestuff inventions.^[11] The U.S. Patent and Trademark Office (USPTO) examiner initially rejected the claims as indefinite and lacking specificity, arguing that the generic group format did not clearly define the invention.^[12] Markush appealed the rejection, leading to review by higher authorities within the USPTO.^[3] The appeal reached the Commissioner of Patents, who ruled that such generic claims were permissible when the alternatives shared a common property and were equivalent in function, thereby upholding the validity of Markush's approach.^[12] This decision established a precedent for claiming groups of related chemical entities.^[3] The patent, titled "Pyrazolone Dye and Process of Making the Same," was ultimately issued on August 26, 1924, as U.S. Patent No. 1,506,316, assigned to Pharma Chemical Corporation.^[4] The approval of these claims introduced what became known as "Markush claims," named after the inventor, revolutionizing the drafting of chemical patents by enabling concise representation of compound families.^[11]

Evolution in Patent Practice

Following the initial allowance of alternative chemical claims in the 1925 Ex parte Markush decision, which built on Eugene Markush's 1923 patent application for dye compounds, the United States Patent and Trademark Office (USPTO) began formalizing their use in the 1930s.^[13] Early guidelines emphasized substitutability among alternatives, but concerns arose over overuse, as noted in a 1935 analysis by V.I. Richard, who highlighted how such claims could encompass unrelated substances and complicate prior art searches.^[13] By the late 1930s, USPTO examiners increasingly permitted "alternative" language in chemical patents under strict conditions of equivalence, marking a shift toward standardized practice while addressing potential abuse, as evidenced in the 1934 Ex parte Dahlen decision.^[14] The 1950s represented a key period of liberalization and codification in USPTO guidelines for Markush claims. The second edition of the Manual of Patent Examining Procedure (MPEP), published in 1953, incorporated detailed provisions in section 706.03(d) for examining alternative claims, requiring members of a group to share common utility or obviousness rather than presumed equivalence.^[13] This update was reinforced by the 1958 Court of Customs and Patent Appeals decision in In re Ruff, which clarified that proper Markush groupings no longer needed to assume all alternatives were patentably indistinct, provided they met enablement standards under 35 U.S.C. § 112.^[13] The USPTO's 1958 Training Manual further solidified this by treating members of proper Markush groups as generally patentably indistinct, facilitating broader adoption in chemical patent applications and establishing examples for examiners.^[13] By the 1970s and 1980s, advances in chemical informatics enabled the expansion of Markush claims to encompass larger genera, particularly in pharmaceutical patents where combinatorial chemistry allowed for vast libraries of potential compounds.^[14] The 1980 In re Harnisch decision emphasized "unity of invention" requirements for such expansive chemical claims, ensuring that alternatives shared a common inventive concept while accommodating the growing complexity of drug discovery.^[13] This era saw Markush structures evolve from simple lists to graphical representations with variable substituents, driven by informatics tools that supported the claiming of enormous compound sets—for instance, some patents covered over 10^{24} potential molecules—reflecting the standardization of generic claiming in response to pharmaceutical innovation.^[14]

Applications in Patents

Claiming Chemical Inventions

Markush structures play a crucial role in patent claims for chemical inventions by enabling the coverage of lead compounds, their analogs, and metabolites through a single generic representation, avoiding the need for exhaustive enumeration of each variant. This approach allows inventors to claim a genus of related molecules sharing a common structural core and functional properties, such as in pharmaceutical compositions where variations in substituents do not alter the core activity.^[3]^[15] In drafting strategies, patentees often employ a single Markush claim to encompass a broad class of compounds, particularly when the alternatives share a substantial structural similarity and common utility, such as reactivity or therapeutic effect. Alternatively, multiple dependent claims may be used to narrow the scope for specific sub-groups, reducing vulnerability to rejection during examination. Combining Markush structures with functional language, like "pharmaceutically active" or "selected from the group consisting of... wherein said group provides antibacterial activity," further defines the claim's boundaries while maintaining breadth, ensuring the alternatives are linked by shared performance characteristics.^[3]^[3]^[16] The primary advantages of Markush structures include providing broad protection against design-arounds, where competitors might attempt minor modifications to evade infringement, and enhancing efficiency in patent prosecution by consolidating multiple embodiments into fewer claims, thereby streamlining review and reducing costs. This method is particularly valuable in fields like organic chemistry, where synthesizing and testing every possible analog is impractical.^[16]^[17]^[3] In drug discovery patents, Markush structures are commonly used to claim variable side chains in antibiotic molecules. A representative example appears in international patent applications for novel antimicrobials, where Formula I structures specify variable A (C1-10 hydrocarbyl) and X (-NHR, -NHOR, etc.) positions to encompass a family of organophosphorus or organosulfur compounds effective against resistant strains without listing each derivative individually.^[18]

International Variations

The European Patent Office (EPO) permits Markush structures in claims but enforces a strict unity of invention requirement under Rule 44(1) of the European Patent Convention, which is fulfilled only if the alternatives share the same or corresponding special technical features, assessed based on structural similarity.^[19] Markush claims are allowable for chemical compounds provided that all alternatives exhibit a common property or activity and either share a significant structural element—defined as a large common structure or a distinctive portion contributing technically over the prior art—or belong to a recognized class in the art where substitutability yields similar results.^[19] However, if substituents are unrelated or lack these common technical features, the scope may be limited, potentially leading to a lack of unity; for instance, if one alternative lacks novelty, the entire grouping must be reconsidered for unity.^[19] In contrast, the Japan Patent Office (JPO) accepts broad Markush claims for chemical substances and compositions expressed in alternative form, provided they demonstrate a common property or activity along with either a shared significant structural element or membership in a recognized class, ensuring clarity under Article 36(6)(ii) of the Patent Act.^[20] To meet enablement requirements under Article 36(4)(i), the description must allow a skilled person to implement all alternatives without undue experimentation, typically necessitating working examples for each alternative group in chemical or use inventions, such as specific pharmacological tests for medicinal applications.^[20] Insufficient disclosure for some alternatives, like providing examples for only a subset of substituents (e.g., methyl and hydroxy but not carboxylic acid groups), can violate enablement if the others require excessive trials.^[20] The China National Intellectual Property Administration (CNIPA) has shown increasing acceptance of Markush structures since the 2010s, particularly following revisions to examination guidelines and key judicial rulings that treat them as integral technical solutions generalizing classes of compounds with shared functions, rather than mere lists of independent alternatives.^[21] This shift resolved prior inconsistencies in court interpretations, with the Supreme People's Court in 2017 (Retrial Verdict No. 41) affirming Markush claims as unified wholes, limiting amendments like substituent deletions unless they do not expand scope.^[21] Enablement remains a core emphasis, requiring the specification to support all claimed variants through sufficient disclosure, as highlighted in CNIPA's 2021 guiding cases (e.g., Invalidation Decision No. 48183), where priority and support for the full genus must be evident from the priority document or description to avoid invalidation for lack of inventive step or unity.^[22] As of 2024, CNIPA and IP courts have further tightened rules on Markush claim amendments and inventive step assessments in pharmaceutical patents, emphasizing stricter support for broad genera.^[23]^[24] Key differences among these jurisdictions lie in their assessment frameworks: the EPO applies a rigorous "same or corresponding special technical features" test focused on structural and functional relatedness to ensure unity, often narrowing unrelated substituents, whereas the JPO and CNIPA adopt more flexible approaches centered on enablement, mandating comprehensive working examples or disclosures for all alternatives to confirm reproducibility across the claimed scope.^[19]^[20]^[22] This enables broader initial filings in Asia but subjects them to stricter post-grant scrutiny on support.^[21]

United States Specifics

In the United States, the United States Patent and Trademark Office (USPTO) provides specific guidance on Markush claims through the Manual of Patent Examining Procedure (MPEP) Section 2173.05(h), which outlines criteria for a proper Markush grouping.^[25] A Markush claim is considered proper if the alternatives share a "single structural similarity," such as a common chemical core or backbone structure, and exhibit substantially the same or similar properties or uses, ensuring related utilities.^[25] For instance, alternatives must demonstrate unity of invention under 35 U.S.C. § 101 and § 112, avoiding groupings where members are unrelated in structure or function, which could lead to a rejection for improper Markush grouping.^[3] This standard, rooted in judicial precedents like In re Harnisch, 631 F.2d 716 (CCPA 1980), emphasizes that the common core must be sufficient to predict the properties of all embraced species without undue experimentation.^[25] The acceptance of Markush claims in U.S. patent practice has evolved significantly since their inception. In the 1920s, following Ex parte Markush (1925 Dec. Comm. Pat. 126), the USPTO initially adopted a narrow approach, permitting such claims only when no suitable generic term existed and the alternatives were closely related, primarily in the chemical arts to describe dyestuffs.^[26] By the 1980s, amid advancements in biotechnology, allowances broadened considerably; decisions like In re Harnisch refined the criteria to focus on structural similarity and common utility, enabling more expansive claims for complex biological and chemical genera without requiring exhaustive enumeration. This shift facilitated the use of Markush structures in biotech patents, where they could encompass large families of compounds with predictable variations, reflecting the growing complexity of inventions in that field.^[26] U.S. filing requirements for Markush claims emphasize enablement under 35 U.S.C. § 112(a), mandating disclosure of a representative number of species to support the full scope of the claimed genus.^[27] Applicants need not disclose every alternative within the Markush group; instead, providing working examples of representative species suffices if one of ordinary skill in the art can make and use the entire genus without undue experimentation, based on the predictability of the field.^[28] For chemical inventions, this often involves describing a sufficient number of embodiments to illustrate the common core and variations, ensuring the specification teaches how to select and combine alternatives effectively.^[27] Markush claims are prevalent in U.S. chemical and pharmaceutical patents, underscoring their role in claiming broad classes of related compounds efficiently. This usage highlights their importance in protecting innovations in drug discovery, where they allow coverage of structurally similar molecules without individual claims for each.

Legal Considerations

Validity and Enablement Requirements

In the United States, the enablement requirement under 35 U.S.C. § 112(a) mandates that a patent specification must disclose the invention in sufficient detail to enable a person skilled in the art to make and use the full scope of the claimed invention without undue experimentation.^[28] For Markush claims, which define a genus of chemical compounds or substituents, this requires the specification to provide adequate support for the entire claimed group, ensuring that variations within the Markush structure—such as different substituents—can be synthesized and utilized predictably.^[28] Failure to enable the full genus renders the claim invalid, as the disclosure must be commensurate in scope with the claims.^[28] A key challenge in validating Markush claims arises when the genus is overly broad, potentially requiring undue experimentation to practice the invention across its full range; this is assessed using the "Wands factors" from In re Wands, which include the breadth of the claims relative to the disclosure, the nature of the invention, the state of the prior art, the level of ordinary skill, the predictability of the art, the amount of direction provided, the presence of working examples, and the quantity of experimentation needed. In the unpredictable field of chemistry, a Markush claim may be deemed invalid if the specification lacks support across the genus—such as for extreme or disparate substituents—without demonstrating common structural or functional properties that bridge the group, thereby imposing undue burden on the skilled artisan. These factors ensure that broad genera do not overreach beyond what the disclosure reasonably supports, particularly where structural similarities do not guarantee uniform operability. Improper Markush groupings with unrelated alternatives may also be rejected as indefinite under 35 U.S.C. § 112(b) if they fail to provide clear boundaries.^[29] Internationally, the European Patent Office (EPO) imposes a parallel requirement under Article 83 of the European Patent Convention, which demands that the patent application disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art.^[30] For Markush structures, this sufficiency of disclosure necessitates enabling the skilled person to produce and apply the claimed genus without inventive effort, often requiring representative examples or structural generalizations that cover the full scope; claims encompassing vast, unpredictable chemical variations may fail if the description does not plausibly extend to the entire group.^[30] A seminal case illustrating valid enablement for a Markush claim is In re Hogan, where the Court of Customs and Patent Appeals upheld a genus claim to chromium-based olefin polymerization catalysts with alternative substituents, finding the specification sufficient because the members shared structural similarities and the art's predictability allowed extension from working examples without undue experimentation.^[31] This decision emphasized that related substituents in a Markush group can support enablement when the disclosure demonstrates common utility across the genus.^[31]

Infringement and Scope Interpretation

In determining whether a product infringes a Markush claim, courts apply standard patent infringement analysis under U.S. law, assessing literal infringement first. Literal infringement occurs if every limitation of the claim is found in the accused product, which for a Markush claim means the accused structure must correspond to at least one alternative within the claimed group or genus. If the accused substituent matches one of the listed alternatives or falls within the described class, the claim is literally infringed, provided all other claim elements are met. However, if the accused product incorporates a combination of substituents that mixes elements from unrelated alternatives in a manner that does not align with any single embodiment encompassed by the claim, it does not literally infringe.^[3]^[32] The doctrine of equivalents provides an additional avenue for finding infringement when there is no literal infringement but the accused structure performs substantially the same function in substantially the same way to achieve substantially the same result as one of the claimed alternatives in the Markush group. This doctrine applies on an element-by-element basis, allowing courts to extend protection to insubstantially different structures that are equivalent to a specific alternative, provided there is no clear surrender of subject matter during prosecution. For example, if an accused substituent is not listed but is chemically and functionally equivalent to a claimed one, infringement under the doctrine may be found, subject to defenses like prosecution history estoppel. The doctrine thus helps prevent accused products from avoiding infringement through minor variations outside the literal scope of the Markush alternatives.^[33]^[34] Courts have narrowed the scope of Markush claims involving unrelated substituents to avoid overbroad protection, particularly when the alternatives lack a common structural similarity or shared utility, emphasizing that the scope must reflect the invention's enablement and avoid undue breadth. Similarly, in In re Harnisch, 631 F.2d 716 (CCPA 1980), the Court of Customs and Patent Appeals addressed Markush practice in restriction context, holding that groupings of related, analogous alternatives are proper and do not warrant rejection. These rulings ensure that the claim's boundaries are tied to the patent's disclosure, preventing coverage of unpredictable variants.^[3] Claim construction plays a central role in resolving infringement disputes involving Markush claims, as the interpretation of the group's scope directly affects whether an accused product falls within its boundaries. Under Markman v. Westview Instruments, Inc., 517 U.S. 370 (1996), claim construction is a question of law for the judge, often addressed through a dedicated hearing (Markman hearing) where evidence such as the specification, prosecution history, and expert testimony is considered to define terms like the Markush alternatives. This process can narrow or expand the perceived scope; for instance, if the specification describes the Markush group as limited to functionally similar substituents, courts will construe it accordingly to avoid encompassing non-equivalent structures. Remedies for infringement, including injunctions or damages, follow from this construction if the accused product is found to infringe either literally or under the doctrine of equivalents.^[35]^[36]

Modern Developments

Computational Tools and Analysis

Computational tools for Markush structures have advanced significantly, enabling the efficient generation, searching, and analysis of generic chemical claims in patent databases. These tools address the combinatorial complexity of Markush representations by automating enumeration and substructure matching, which is essential for handling vast libraries of potential compounds without manual expansion.^[37] The Derwent Chemical Patents Index (DCPI), part of the Derwent World Patents Index (DWPI), standardizes and redraws Markush structures according to predefined rules to ensure consistency across patents, facilitating the enumeration of virtual compound libraries from generic topologies. By extracting structural information from Markush claims, DCPI generates explicit compound instances, allowing researchers to explore expansive chemical spaces derived from a single generic structure. This capability streamlines the identification of novel variants while integrating with broader patent indexing in the DWPI.^[37] Specialized search engines like CAS SciFinder and Reaxys provide robust substructure matching for Markush structures in patent literature. In CAS SciFinder, the MARPAT database contains over 1.3 million searchable Markush structures from patents dating back to 1988, with selective coverage from earlier years in key languages and regions. Users can perform substructure searches that match query structures against generic claims, retrieving relevant citations without needing to enumerate all possibilities; this is particularly useful for identifying broad patent coverage in chemical inventions. Daily updates ensure access to the latest filings, excluding non-organic materials like polymers. Similarly, Reaxys supports Markush-related searches by allowing users to draw base structures and retrieve associated generic schemes, including options to find related Markush structures with adjustments for tautomers, stereochemistry, and ring variations. Its database spans over 121 million documents as of 2025, enabling precise navigation of patent and journal data for chemical analogs.^[38]^[39]^[40] Algorithms underlying these tools often employ graph-based parsing to manage the hierarchical and nested nature of R-groups in Markush structures. For instance, graph representations model the core scaffold and variable substituents as nodes and edges, enabling recursive decomposition of nested groups—such as R1 containing further R2 variables—through autoregressive generation sequences. Methods like those in MarkushGrapher integrate multi-modal inputs (text, images, layouts) via vision-text encoders to produce sequential graph outputs and substitution tables, outperforming prior models on benchmarks for real-world patent figures. This graph-centric approach handles combinatorial explosion by focusing on topological relationships rather than full enumeration.^[41] Machine learning techniques further enhance analysis by predicting bioactivity across Markush genera, reducing the need for exhaustive synthesis and testing. Systems like BioMiner leverage multi-modal ML to extract and enumerate bioactivity data from literature descriptions of generic structures, inferring protein-ligand interactions and potency metrics for untested variants within a claim. These models train on annotated datasets to forecast properties like binding affinity, aiding in the prioritization of promising sub-libraries from broad Markush definitions. Such predictions integrate chemical language models with graph neural networks to embed and classify substituent effects, improving accuracy in virtual screening.^[42] In pharmaceutical R&D, these computational tools are applied to prior art searches and infringement mapping. For prior art, substructure queries in SciFinder or Reaxys identify overlapping Markush claims that could invalidate novelty, allowing teams to refine inventions around existing generics. Infringement analysis uses enumeration tools like DCPI to map target compounds against patent libraries, assessing coverage risks—e.g., determining if a lead molecule falls within a competitor's R-group variations. This supports strategic decisions in drug development, such as library design for hit optimization, by quantifying white spaces in chemical space and minimizing litigation exposure.^[38]^[37]^[43]

Recent Case Law and Trends

In the United States, the Supreme Court's 2014 decision in Alice Corp. v. CLS Bank International heightened scrutiny of patent claims directed to abstract ideas, particularly affecting software-related inventions where Markush structures are used to claim chemical variants generated or analyzed computationally. This post-Alice framework requires that claims involving software-enabled chemical modeling or design demonstrate an inventive concept beyond mere abstraction, prompting patent drafters to integrate specific technical improvements, such as enhanced algorithms for Markush enumeration, to establish eligibility under 35 U.S.C. § 101.^[44] For instance, broad Markush claims in patents for software tools simulating molecular structures must avoid reciting generic computer implementation to survive eligibility challenges.^[45] A landmark development occurred in 2023 with the U.S. Supreme Court's unanimous decision in Amgen Inc. v. Sanofi, which invalidated Amgen's patents claiming a broad functional genus of antibodies targeting PCSK9 for cholesterol reduction due to insufficient enablement under 35 U.S.C. § 112(a).^[46] The Court emphasized that the specification must enable a person skilled in the art to make and use the full scope of the claimed genus without undue experimentation, rejecting Amgen's reliance on 26 exemplary antibodies and a "roadmap" approach as inadequate for the vast number of potential embodiments—potentially millions—within the functional definition.^[46] This ruling has profound implications for Markush-like genus claims in biologics patents, requiring more comprehensive disclosure of structural representatives or predictive methods to support broad protection, thereby narrowing the viable scope for antibody and protein inventions.^[28] However, this trend faces emerging challenges from AI-generated compounds, as machine learning models can produce novel molecules that inadvertently infringe existing Markush claims, complicating freedom-to-operate analyses and infringement determinations.^[47] For example, AI tools trained on patent data may output structures falling within a Markush genus, raising risks of unintentional overlap and necessitating advanced similarity algorithms, such as Tanimoto-based matching, to assess infringement.^[47] These developments underscore the growing role of computational aids in navigating Markush-related disputes in AI-driven biologics research.^[48] In Europe, the establishment of the Unified Patent Court (UPC) in June 2023 has begun standardizing the interpretation and enforcement of Markush claims across participating member states, aligning with European Patent Office (EPO) practices on alternatives in claims.^[49] The UPC's centralized jurisdiction facilitates consistent application of EPO Guidelines, which permit Markush groupings where alternatives share structural similarity and common utility, but require unity of invention to avoid overbroad claims.^[50] Early UPC decisions emphasize claim construction starting from the wording while consulting the description, promoting uniformity in assessing Markush scope and reducing forum-shopping divergences previously seen in national courts.^[51] This harmonization supports broader protection for pharmaceutical genera in the post-UPC era, particularly for new chemical entities.^[52]

References

[1]
What are Markush structures, and how can I draw them - ACD/Labs
A Markush structure is a chemical structure representation that defines a group of related compounds. The name Markush comes from patent-law history, ...
[2]
Mapping Markush - ScienceDirect.com
Markush structures are molecular skeletons containing not only specific atoms but also placeholders to represent broad sets of chemical (sub)structures.
[3]
2117-Markush Claims - USPTO
A Markush grouping is proper if the members of a group share a single structural similarity and a common use.
[4]
US1506316A - Pyrazolone dye and process of making the same
The process of manufacturing dyes which comprises coupling with dichlorsulpho-phenyl-methyl pyrazolone, in a bath free from inorganic acids.Missing: structure | Show results with:structure
[5]
Editorial. Markush, or Generic Structures
### Summary of Markush Structure from ACS Journal of Chemical Information and Computer Sciences, 1991
[6]
a web-based intelligent system for fast chemical patent claim drafting
Dec 11, 2019 · The scaffold of the initial Markush structure, including the scaffold and collections of R groups attached to the same atoms, is generated by ...
[7]
Barnard and Downs: Markush Techniques for Combinatorial Libraries
Markush structures are essentially structures involving R-groups, where a part of the molecule is defined by a series of alternatives; they thus specify sets of ...
[8]
Markush structures in MarvinSketch | Chemaxon Docs
R-groups, atom lists, position variation and repeating units with repetition ranges are commonly used features in the representation of Markush structures.
[9]
Understanding Markush Structure in Patents - Collier Legal
A Markush structure is a representation of a group of chemical compounds that share a common core but differ in one or more variable groups.
[10]
EUGENE MARKUSH, CHEMIST, 80, DIES; Holder of Dyestuffs Patents
Dr. Markush was born in Budapest and attended various Hungarian universities, culminating his studies with a Ph.D. degree. He came to the United States in 1913 ...Missing: background | Show results with:background
[11]
Eugene Markush, with attributes selected from the group consisting ...
Jun 30, 2023 · Eugene Markush filed a patent application for a pyrazolone dye, and used a particular combination of six words that revolutionised the writing of claims.
[12]
Annex AA - Markush Claims - IPA Manuals
Oct 24, 2025 · In 1923, Dr Markush filed a patent application claiming a method of preparing a generic group of pyrazalone dyes for wool or silk.
[13]
Examination of Patent Applications That Include Claims Containing ...
Aug 10, 2007 · Similarly, in a later case, the Commissioner of Patents determined that if there is an express admission that claimed species would have ...
[14]
[PDF] Million-Card Monte: Reforming the Markush Claim Post-AIA to Save ...
Id. 6 Ex parte Markush, 1925 Dec. Comm'r Pat. 126 (1924). 7 Pyrazolone Dye & Process of Making the Same, U.S. Patent No. 1,506,316 (filed Jan. 9, 1923).
[15]
[PDF] Mapping Markush - EconStor
Jul 11, 2022 · This paper summarizes the ongoing policy debate about Markush structures and provides first empirical insights into how Markush structures are ...
[16]
https://www.drugpatentwatch.com/blog/the-missing-ingredient-why-patent-data-is-the-key-to-unlocking-ai-powered-drug-discovery/
[17]
The Role of Markush Structure Searches in Patent Protection and ...
Markush structures simplify complex chemical compounds by grouping multiple chemical entities into a single structure. Table of Contents. Toggle. The Idea ...
[18]
WO2018005659A1 - Antimicrobial compounds and methods of use
... Markush groups used in the appended claims. [00134] Certain embodiments of this invention are described herein, including the best mode known to the ...
[19]
GL F V 3.2.5 Markush grouping (alternatives in a single claim) | XEPC
... Markush alternative is not novel, unity of invention must be reconsidered. In particular, if the structure of at least one of the compounds covered by a Markush ...
[20]
[PDF] Chapter 1 Requirements for Description and Claims
For example, in a case where a claim includes statements inadequate as Japanese ... working examples supporting the use are usually required. (6). Relation ...
[21]
China: Supreme People's Court Provides Guidance on Amendment ...
Aug 15, 2018 · Under the PRC Patent Law, a Markush claim refers to a single claim defining a plurality of parallel and alternative elements called Markush ...Missing: CNIPA | Show results with:CNIPA
[22]
Discussion on Priority of Markush Claims Based On Several Guiding ...
Jun 30, 2022 · The Reexamination and Invalidation Department of the Chinese patent office (CNIPA) announced the 10 guiding cases of the year 2021.
[23]
2173-Claims Must Particularly Point Out and Distinctly ... - USPTO
See MPEP § 2173.05(h), subsection I., for more information regarding the determination of whether a Markush claim satisfies the requirements of 35 U.S.C. ...
[24]
[PDF] Žs Historic Struggle with Markush Claims: Will the 2011 Guidelines ...
Today, an applicant generally may use any type of language, including alternative expressions to claim his invention, so long as the meaning of the claim is ...Missing: 1930s 1950s
[25]
2163-Guidelines for the Examination of Patent Applications Under ...
The disclosure of only one species encompassed within a genus adequately describes a claim ... Description of a representative number of species does not require ...
[26]
2164-The Enablement Requirement - USPTO
The invention that one skilled in the art must be enabled to make and use is that defined by the claim(s) of the particular application or patent.2164.02 Working And... · 2164.06(c) Examples Of... · 2164.08 Enablement...
[27]
1. Sufficiency of disclosure - European Patent Office
For the requirements of Art. 83 and Rule 42(1)(c) and Rule 42(1)(e) to be fully satisfied, the invention must be described in terms not only of its structure ...
[28]
https://www.uspto.gov/web/offices/pac/mpep/s2164.html
[29]
Markush Madness: Watson Avoids Infringement by Adding an ...
Apr 4, 2017 · Watson's addition of an ingredient (“magnesium stearate”) to the outer layer of its accused product created non-infringement because it was outside the claimed ...
[30]
2186-Relationship to the Doctrine of Equivalents - USPTO
The doctrine of equivalents arises in the context of an infringement action. If an accused product or process does not literally infringe a patented invention,
[31]
[PDF] Selecting C Elements f Selecting Claims and Claim Elements for ...
Infringement of a patent may be either literal or under the Doctrine of Equivalents. In either event, infringement can only be proved if it is shown that ...
[32]
[PDF] The Death of the Genus Claim - Scholarly Commons
Patent lawyers continue to draft genus claims, the USPTO grants them, and patent owners attempt to enforce them in court. Lawyers and scholars sometimes lament ...Missing: 1920s | Show results with:1920s
[33]
Markman v. Westview Instruments, Inc. | 517 U.S. 370 (1996)
The District Court nevertheless directed a verdict for Westview on the ground that its device is unable to track "inventory" as that term is used in the claim.Missing: Markush | Show results with:Markush
[34]
Using an Expert at a Markman Hearing: Practical and Tactical ...
In 1996, the Supreme Court in Markman v. Westview Instruments, Inc.,1 ruled that the interpretation of patent claims is a matter of law to be determined ...Missing: Markush | Show results with:Markush
[35]
Derwent Chemical Patents Index - Clarivate
Search chemical patents including Markush structures redrawn according to standardized rules. Streamline your chemical patent data processes ...Missing: DARC tool enumerating virtual
[36]
Markush - MARPAT - CAS.org
More than 1.3 million searchable Markush structures from patents covered by CAS from 1988 to the present with selected coverage of Japanese patents from 1987.
[37]
CHEM 116BL (Laverman, Spring 2025): Reaxys
Sep 8, 2025 · Searching Reaxys · Find Similar Structures · Find Related Markush structures · Copy to query (copies the structure in the structure window, where ...
[38]
CVPR 2025 Open Access Repository
### Summary of MarkushGrapher: Graph-Based Approach for Parsing Markush Structures
[39]
BioMiner: A Multi-modal System for Automated Mining of Protein-Ligand Bioactivity Data from Literature
**Summary of BioMiner's Use of ML for Extracting and Predicting Bioactivity from Markush Structures:**
[40]
Improving the R&D Efficiency Using Library Selection in Early Drug ...
Sep 18, 2022 · Markush structures stated in the claims part of a product patent delimit the chemical space covered by a patent.2.1. Markush Combinatorial... · Figure 2 · 3. Materials And Methods
[41]
2106-Patent Subject Matter Eligibility - USPTO
... patents that claim laws of nature, natural phenomena, and abstract ideas from those that claim patent-eligible applications of those concepts.” Alice Corp.
[42]
Patent Drafting Post-Alice: Broadly Define the Problem ... - JD Supra
Apr 28, 2016 · The notion of strategic claim drafting, which experienced patent practitioners understand, is all about writing specific, narrowly defined ...
[43]
[PDF] 21-757 Amgen Inc. v. Sanofi (05/18/23) - Supreme Court
May 18, 2023 · This case concerns patents covering antibodies engineered by scientists that help reduce levels of low-density lipoprotein (LDL) cholesterol,.
[44]
Intelligent System for Automated Molecular Patent Infringement ...
Jan 12, 2025 · However, molecules generated by artificial intelligence may unintentionally infringe on existing patents, posing legal and financial risks that ...
[45]
Can AI Handle Generic (Markush) Patent Claims? TPR Assesses ...
Sep 2, 2025 · Markush structures are often used in patents. They define a fixed molecular core and list various possible chemical groups that can be attached, ...<|control11|><|separator|>
[46]
Unified Patent Court
The UPC is a Court common to currently eighteen EU Member States for which the Agreement on a Unified Patent Court (UPCA) has entered into force on 1 June 2023.Court Fees · Patent Mediation and... · Decisions and Orders · Cases
[47]
3.7 Alternatives in a claim - European Patent Office
In the case of a claim defining (chemical or non-chemical) alternatives, i.e. referred to as a "Markush grouping", unity of invention is considered to be ...
[48]
European Patent Office aligns with Unified Patent Court on claim ...
Jun 18, 2025 · The EPO's new standard states claims are the starting point, and description/drawings are always consulted, not just when ambiguous, for ...Missing: Markush trends
[49]
Pharmaceutical NCEs: 5 ways to maximise protection in Europe
Aug 21, 2025 · The European patent landscape has changed significantly since the launch of the Unified Patent Court (UPC) in June 2023. The new system provides ...