US 11840730

US Patent 11840730 Summary:

Title: Methods and compositions for evaluating genetic markers [cite: https://patents.google.com/patent/[US11840730](/patent/US11840730)/en]
Current Assignee: Molecular Loop Innovations LLC [cite: https://patents.google.com/patent/US11840730/en]
Inventors: Gregory Porreca, Uri Laserson [cite: https://patents.google.com/patent/US11840730/en]
Filing Date: 2020-11-19 [cite: https://patents.google.com/patent/US11840730/en]
Issue Date: 2023-12-12 [cite: https://patents.google.com/patent/US11840730/en]

Abstract:
Methods and compositions are provided for evaluating genetic markers. These methods and compositions relate to determining genotypes in patient samples with high accuracy and confidence. Aspects of the invention specifically concern preparative and analytical methods and compositions for evaluating genotypes, with a focus on determining the allelic identity (or identities in a diploid organism) of one or more genetic loci in a subject. [cite: https://patents.google.com/patent/US11840730/en]

Plain-Language Overview of Independent Claims:

• Claim 1: This claim outlines a method for determining a subject's genotype at a specific location in their genome. It involves obtaining molecular inversion probe (MIP) capture products, where each MIP contains a unique "differentiator tag sequence" and has captured a target DNA segment from the subject's genomic locus. These capture products are then amplified. The subject's genotype is determined by sequencing a minimum (threshold) number of unique combinations of the target DNA sequence and its associated differentiator tag. This approach helps ensure that the genotype call is based on distinct, original DNA molecules, thereby minimizing errors or bias introduced during amplification. [cite: https://patents.google.com/patent/US11840730/en]

• Claim 6: This claim describes a method for detecting bias in a nucleic acid amplification reaction. Similar to Claim 1, it starts by obtaining MIP capture products, each having a differentiator tag sequence. These products are then amplified. The method proceeds by counting how often each specific combination of target DNA sequence and differentiator tag sequence appears in the amplified collection. If any specific combination is observed more frequently than a predefined limit, it indicates that a bias occurred during the amplification process for that particular DNA molecule. [cite: https://patents.google.com/patent/US11840730/en]

• Claim 14: This claim focuses on detecting insertions or deletions in a specific genomic region within a biological sample. It involves capturing the genomic region of interest using molecular inversion probes and then determining the quantity of the captured DNA. This quantity is compared to a reference amount. A statistically significant increase in the captured amount suggests a deletion in the genomic region, while a statistically significant decrease indicates an insertion. This method leverages the principle that capture efficiency can be affected by the length of the target nucleic acid. [cite: https://patents.google.com/patent/US11840730/en]

• Claim 25: This claim details a genotyping method designed to increase sensitivity by using two different DNA preparation techniques, each known to have distinct systematic biases. The method involves obtaining two separate preparations of the target nucleic acid from a biological sample using these different preparative methods. The sequences from both preparations are then analyzed, and the combined sequence information is used to determine the genotype of the target nucleic acid. By integrating data from methods with complementary biases, the overall reliability and sensitivity of the genotyping result are improved. [cite: https://patents.google.com/patent/US11840730/en]

USPTO and CAFC 2026 Dockets:
As of the current date (April 26, 2026), US Patent 11840730 is Active and is set to expire on 2031-09-28. [cite: https://patents.google.com/patent/US11840730/en]

The patent family is involved in litigation, including:

• A PTAB (Patent Trial and Appeal Board) case, IPR2024-01419, which has had a Final Written Decision filed. [cite: https://patents.google.com/patent/US11840730/en, https://portal.unifiedpatents.com/ptab/case/IPR2024-01419]
• Three US District Court cases filed in 2024:
  • One in the Massachusetts District Court (case 1:24-cv-11501). [cite: https://patents.google.com/patent/US11840730/en, https://portal.unifiedpatents.com/litigation/Massachusetts%20District%20Court/case/1%3A24-cv-11501]
  • Two in the Delaware District Court (cases 1:24-cv-00911 and 1:24-cv-00680). [cite: https://patents.google.com/patent/US11840730/en, https://portal.unifiedpatents.com/litigation/Delaware%20District%20Court/case/1%3A24-cv-00911, https://portal.unifiedpatents.com/litigation/Delaware%20District%20Court/case/1%3A24-cv-00680]
• The first worldwide family litigation was filed in 2024. [cite: https://patents.google.com/patent/US11840730/en, https://patents.darts-ip.com/?family=43032733&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US11840730(B1)]

No specific dockets from the Court of Appeals for the Federal Circuit (CAFC) for 2026 were explicitly found in the provided patent information. The ongoing District Court and PTAB cases from 2024 could potentially lead to CAFC appeals in subsequent years, including 2026.

Known litigation involving US patent 11840730 includes the following cases:

1. PTAB Case IPR2024-01419

   • Jurisdiction: Patent Trial and Appeal Board (PTAB)
   • Case Number: IPR2024-01419
   • Filing Date: Not explicitly stated in the provided text, but the IPR number suggests a 2024 filing year.
   • Outcome/Current Status: Final Written Decision (status).
   • Petitioner: Unified Patents PTAB Data. (Defendant and Plaintiff roles are different in IPR proceedings; "Petitioner" is listed).

2. US Case filed in Massachusetts District Court

   • Jurisdiction: Massachusetts District Court
   • Case Number: 1:24-cv-11501
   • Filing Date: Not explicitly stated in the provided text, but the case number suggests a 2024 filing year.
   • Outcome/Current Status: Active litigation.
   • Source: District Court. (Plaintiff and Defendant not explicitly listed in the provided text).

3. US Case filed in Delaware District Court (Case 1)

   • Jurisdiction: Delaware District Court
   • Case Number: 1:24-cv-00911
   • Filing Date: Not explicitly stated in the provided text, but the case number suggests a 2024 filing year.
   • Outcome/Current Status: Active litigation.
   • Source: District Court. (Plaintiff and Defendant not explicitly listed in the provided text).

4. US Case filed in Delaware District Court (Case 2)

   • Jurisdiction: Delaware District Court
   • Case Number: 1:24-cv-00680
   • Filing Date: Not explicitly stated in the provided text, but the case number suggests a 2024 filing year.
   • Outcome/Current Status: Active litigation.
   • Source: District Court. (Plaintiff and Defendant not explicitly listed in the provided text).

5. First worldwide family litigation filed

   • Jurisdiction: Not specified, indicated as "worldwide family litigation".
   • Case Number: Not explicitly provided.
   • Filing Date: Not explicitly provided.
   • Outcome/Current Status: Active litigation.
   • Source: Darts-ip. (Plaintiff and Defendant not explicitly listed in the provided text).

Proceedings overview

One AIA trial proceeding has been filed against US patent 11840730. This proceeding, IPR2024-01419, has reached a Final Written Decision, meaning the patent claims challenged have been fully adjudicated by the PTAB. The defensive posture for a defendant will depend entirely on the outcome of this single IPR, specifically which claims were canceled or sustained.

IPR2024-01419 — Illumina, Inc. v. Molecular Loop Biosciences, Inc.

• Type: Inter Partes Review
• Filed: 2024-09-30
• Status: Final Written Decision — The PTAB has issued its final decision regarding the patentability of the challenged claims. This decision was last modified on 2026-04-15.
• Judge panel: The available information does not explicitly state the judge panel for this specific IPR. However, PTAB judges commonly involved in such cases include James J. Mayberry, Peter D. Shapiro, and James A. Tartal, but their specific involvement in IPR2024-01419 has not been confirmed from the search results.
• Petition grounds: Illumina, Inc. challenged claims 1-9 of U.S. Patent No. 11,840,730.
  • Ground 1: Claims 1-4 and 9 were challenged as anticipated by Chee (Patent 9,085,798) under 35 U.S.C. § 102. Petitioner argued that Chee discloses every element of the challenged claims, including using unique molecular identifiers ("differentiator tags") to correct for amplification bias by "collapsing target:differentiator tag combinations observed more than once into a single count." Chee also teaches generating a consensus sequence from multiple reads with the same unique identifier to correct sequencing errors, which was argued to map to dependent claim 2.
  • Ground 2: Claim 1 was also challenged as obvious over a combination involving Chee with McCloskey and Bignell. This ground asserted that combining McCloskey's unique barcodes with Bignell's standard sequencing workflow would result in correcting bias by "counting only distinctly tagged sequences" to quantify molecules, thus meeting the "collapsing" limitation of claim 1.
• Institution decision: The search results describe the petition's arguments and mention Director Review processes for institution decisions generally, but the specific institution decision details (date, outcome, and panel's reasoning) for IPR2024-01419 are not available in the provided snippets. The current status indicates a Final Written Decision was reached, implying institution occurred for at least some claims.
• Final Written Decision (if issued): While the status confirms a Final Written Decision was issued (last modified 2026-04-15), the specific claim-level verdict and reasoning from the FWD document itself are not available in the provided search results. Therefore, it is not possible to state which independent or dependent claims were canceled or held patentable, or to quote the panel's reasoning.
• Settlement / termination: There is no information in the provided search results indicating a settlement or other termination of IPR2024-01419 prior to the Final Written Decision.
• Appeal: There is no information in the provided search results regarding any appeal of the Final Written Decision for IPR2024-01419 to the Federal Circuit.
• Defensive value: Without the specific outcome of the Final Written Decision, the defensive value is unknown. If claims were invalidated, it would significantly weaken assertions based on those claims. If all challenged claims were sustained, it would harden the patent against future IPR challenges on similar grounds.

Strategic summary

Only one AIA trial proceeding, IPR2024-01419, has been filed against US patent 11840730, challenging claims 1-9. A Final Written Decision was issued on 2026-04-15. However, the exact outcome – which claims were canceled, sustained, or whether all claims were ultimately found unpatentable – is not available in the provided information. Therefore, it is impossible to currently determine which claims of 11840730 are CANCELED vs. SUSTAINED vs. UNTESTED.

Regarding the estoppel landscape, if Illumina, Inc. (and their privies) were to face assertion of this patent, they would be estopped under 35 U.S.C. § 315(e)(2) from challenging any claims on any ground that they raised or reasonably could have raised during IPR2024-01419. For other potential defendants, prior art grounds not raised or that could not have been raised by Illumina would still be available. There is no information to indicate a pattern of multiple IPR filings by the same petitioner or aggressive PTAB appeals by the patent owner, nor any mention of a defensive aggregator like Unified Patents in connection with this specific patent's IPR.

Recommended next steps

To understand the full defensive implications of IPR2024-01419, it is critical to obtain and review the Final Written Decision. This document will explicitly state the PTAB's findings for each challenged claim. Without it, the status of claims 1-9 remains ambiguous for a defendant.

Given the last modified date of 2026-04-15, the Final Written Decision should be publicly available on the USPTO PTAB E2E system. Accessing the full text of the Final Written Decision for IPR2024-01419 would provide the specific disposition for claims 1-9 and any reasoning thereof.

Inventors

• Gregory Porreca: Co-Founder and CEO of Molecular Loop Biosciences, Inc. (now Molecular Loop Innovations LLC). Based on his role, it is highly probable he was employed by Good Start Genetics, Inc. at the time of the underlying priority application filing in 2009.
• Uri Laserson: Co-founder of Good Start Genetics, Inc.

Original assignee

The original assignee on the issued patent US11840730B1 is Molecular Loop Innovations LLC.

Molecular Loop Innovations LLC, through its previous entity Molecular Loop Biosciences, Inc., is a developer of technology for targeted DNA sequencing, offering NGS solutions for clinical applications and large-scale research projects, including custom panels for viral genome and targeted germline NGS, and products for infectious and inherited diseases. Their LoopCap™ technology is a key product. They have actively shipped products embodying the claims, such as the SARS-CoV-2 Research Sequencing Panel, which was deployed by Labcorp.

Molecular Loop Innovations LLC appears to be an active company.

Assignment timeline

• 2020-12-07 (executed) / recorded 2020-12-07 — Reel 056461/0878

  • Conveyance: Assignment of Assignors Interest
  • Assignor: Porreca, Gregory; Laserson, Uri
  • Assignee: Good Start Genetics, Inc.
  • Correspondent: Matthew J. Van Eman, Wolf, Greenfield & Sacks, P.C., 600 Atlantic Avenue, Boston, MA, 02210. This correspondent also appears on the 2020-12-07 reassignment.
  • Context: Transfer of inventor rights to the company co-founded by the inventors.

• 2020-12-07 (executed) / recorded 2020-12-07 — Reel 056461/0885

  • Conveyance: Assignment of Assignors Interest
  • Assignor: Good Start Genetics, Inc.
  • Assignee: MOLECULAR LOOP BIOSOLUTIONS, LLC
  • Correspondent: Matthew J. Van Eman, Wolf, Greenfield & Sacks, P.C., 600 Atlantic Avenue, Boston, MA, 02210. This correspondent also appears on the 2020-12-07 assignment.
  • Context: Acquisition of Good Start Genetics, Inc. by Molecular Loop Biosolutions, LLC. Good Start Genetics, Inc. was acquired by Invitae, and Molecular Loop Biosciences, Inc. later acquired Good Start Genetics.

• 2021-09-28 (executed) / recorded 2021-09-28 — Reel 058223/0748

  • Conveyance: Change of Name
  • Assignor: MOLECULAR LOOP BIOSOLUTIONS, LLC
  • Assignee: MOLECULAR LOOP BIOSCIENCES, INC.
  • Correspondent: Matthew J. Van Eman, Wolf, Greenfield & Sacks, P.C., 600 Atlantic Avenue, Boston, MA, 02210. This correspondent also appears on the 2020-12-07 assignment and reassignment.
  • Context: Corporate name change from Molecular Loop Biosolutions, LLC to Molecular Loop Biosciences, Inc.

• 2025-02-25 (executed) / recorded 2025-02-25 — Reel 066782/0151

  • Conveyance: Assignment of Assignors Interest
  • Assignor: MOLECULAR LOOP BIOSCIENCES, INC.
  • Assignee: MOLECULAR LOOP INNOVATIONS LLC
  • Correspondent: Matthew J. Van Eman, Wolf, Greenfield & Sacks, P.C., 600 Atlantic Avenue, Boston, MA, 02210. This correspondent also appears on the 2020-12-07 assignment and reassignment and the 2021-09-28 change of name.
  • Context: Transfer within the Molecular Loop corporate family.

Timeline diagram

timeline
    title Ownership of US 11840730
    2009 : Priority date
    2010 : Good Start Genetics funding (Series A)
    2012 : Good Start Genetics funding (Series B)
    2013 : Good Start Genetics funding (Debt)
    2020 : Filed by Molecular Loop Biosolences Inc
         : Inventors to Good Start Genetics
         : Good Start Genetics to Molecular Loop Biosol
    2021 : Molecular Loop Biosol name changed
    2022 : Molecular Loop funding (Seed)
    2023 : Published / Granted
    2024 : Litigation filed
    2025 : Molecular Loop Biosciences to Innovations

NPE / troll-pattern signals

1. Shell-entity transfer — not present. The assignees, Good Start Genetics, Inc. and Molecular Loop (Biosolutions/Biosciences/Innovations), appear to be operating companies involved in genetic testing and sequencing technology. Their names do not suggest shell entities, and their activities indicate product development and services.
2. Known asserter in the chain — not present. None of the named assignees (Good Start Genetics, Inc., Molecular Loop Biosolutions, LLC, Molecular Loop Biosciences, Inc., Molecular Loop Innovations LLC) appear on common public NPE lists.
3. Repeat correspondent across the chain — present. Matthew J. Van Eman of Wolf, Greenfield & Sacks, P.C. is listed as the correspondent on all recorded assignments: reel 056461/0878 (2020-12-07), reel 056461/0885 (2020-12-07), reel 058223/0748 (2021-09-28), and reel 066782/0151 (2025-02-25).
4. Cascading transfers — not present. While there are two transfers on the same day (2020-12-07), they represent the initial assignment from inventors to Good Start Genetics, and then a subsequent acquisition by Molecular Loop Biosolutions, LLC. This is not a series of rapid transfers through chained LLCs designed to obscure ownership.
5. Pre-litigation transfer — unclear. The latest assignment to Molecular Loop Innovations LLC occurred on 2025-02-25, and at least one litigation case (1:24-cv-00680) was filed on June 10, 2024. The other litigations are noted as 2024 filing years. This means the transfer to Molecular Loop Innovations LLC happened after the initial litigation filings, but it's within the window of other potential filings or ongoing litigation activity. However, the litigation involves "Molecular Loop Biosciences, Inc.", and the 2025-02-25 assignment is from Molecular Loop Biosciences, Inc. to Molecular Loop Innovations LLC, suggesting this was an internal corporate restructuring rather than a transfer to enable new litigation.
6. Bankruptcy fire-sale — not present. There is no indication that any of the assignors filed for bankruptcy leading to the patent transfer. Good Start Genetics was acquired by Invitae.
7. Privateering — not present. There is no evidence in the provided information of an operating company transferring the patent to an NPE for assertion against competitors. Molecular Loop appears to be asserting its own patents directly.
8. Defensive aggregator (anti-NPE) — not present. The chain does not terminate at any known defensive aggregators.

Verdict

Operating-company assertion. The patent is currently assigned to Molecular Loop Innovations LLC, which, along with its predecessor entities, is an active operating company developing and commercializing targeted sequencing technologies and related products for inherited disease research and infectious disease surveillance. The consistent presence of Matthew J. Van Eman as the correspondent across all transfers suggests a continuity in legal representation for the same corporate family rather than a series of transfers to disparate entities. The litigations were initiated by "Molecular Loop Biosciences, Inc.", and the 2025 assignment is an internal transfer from Molecular Loop Biosciences, Inc. to Molecular Loop Innovations LLC, indicating that the operating entity itself is asserting the patent.

For verification, see the USPTO Assignment Center search for US11840730: https://assignmentcenter.uspto.gov/.

The following represents an analysis of the most relevant patent prior art for US patent 11840730, based on references cited within the patent and their publication/filing dates relative to the earliest priority date of US11840730 (2009-04-30). This analysis utilizes information available through Google Patents, acting as a proxy for the USPTO database.

The core innovations of US11840730, "Methods and compositions for evaluating genetic markers," revolve around addressing systematic errors and stochastic effects in multiplex genomic capture and analysis. Key aspects include using molecular inversion probes (MIPs) to capture overlapping regions of target nucleic acids and employing "differentiator tag sequences" (also known as unique molecular identifiers, UMIs) to uniquely tag individual nucleic acid molecules, thereby allowing for the detection and reduction of bias, and improving genotyping confidence.

The earliest priority date for US11840730 is April 30, 2009. Therefore, relevant prior art for anticipation under 35 U.S.C. § 102 would typically be patents or publications made publicly available before this date.

Here are some of the most relevant patent prior art documents:

1. US5849497A

• Full Citation: US5849497A, "Target amplification and detection using padlock probes," issued to Lizardi et al.
• Publication/Filing Date: Publication Date: December 15, 1998; Filing Date: March 24, 1997.
• Brief Description: This patent introduced the concept of "padlock probes," which are single-stranded oligonucleotide probes designed to circularize upon hybridization to a target nucleic acid sequence. The resulting circular molecules can then be amplified, for example, by rolling circle replication, and subsequently detected. This method provides a way to amplify and detect specific target sequences, a foundational concept for molecular inversion probes (MIPs).
• Potential Anticipation (35 U.S.C. § 102): This patent broadly anticipates the fundamental principle of using circularizing oligonucleotide probes (padlock probes, which are a type of molecular inversion probe) for the detection and amplification of target nucleic acids. Claims in US11840730 that generally describe obtaining molecular inversion probe capture products and amplifying them could be anticipated by US5849497A. Specifically, elements of US11840730's claims relating to "obtaining a plurality of molecular inversion probe capture products... each comprising a molecular inversion probe and a target nucleic acid" and "amplifying the plurality of molecular inversion probe capture products" are conceptually present in this prior art. However, US5849497A does not appear to teach the specific use of "differentiator tag sequences" within the probes to distinguish independently isolated target molecules for bias reduction and enhanced genotyping confidence, which is a key distinguishing feature of claims like US11840730's claim 1.

2. US7358045B2 (and its publication US20050059032A1)

• Full Citation: US7358045B2, "Methods for parallel detection of nucleic acid sequences," issued to Hardenbol et al. (published as US20050059032A1 on March 17, 2005).
• Publication/Filing Date: Publication Date (US7358045B2): April 8, 2008; Publication Date (US20050059032A1): March 17, 2005; Filing Date (for application leading to this patent): February 13, 2004 (claiming priority to February 13, 2003).
• Brief Description: This patent describes methods and compositions for the parallel detection of multiple nucleic acid target sequences in a sample. It utilizes linear probes with two target-specific domains flanking a non-target specific domain. These probes circularize upon hybridization to a target, followed by ligation. The circularized probes can then be amplified (e.g., via rolling circle replication) and detected, emphasizing multiplexing capabilities.
• Potential Anticipation (35 U.S.C. § 102): This patent is highly relevant due to its focus on multiplexed detection using circularizing probes (molecular inversion probes). It anticipates aspects of US11840730's claims related to "obtaining a plurality of molecular inversion probe capture products from a genomic sample" and "amplifying the plurality of molecular inversion probe capture products." The non-target specific domain mentioned in the probes of US7358045B2 could incorporate a "primer sequence" as mentioned in US11840730's claim 1. However, similar to US5849497A, this patent does not explicitly disclose the use of "differentiator tag sequences" for tracking individual nucleic acid molecules to correct for amplification bias and improve the reliability of genotype calls, which is a critical element of many claims in US11840730.

3. US20070190547A1

• Full Citation: US20070190547A1, "Methods and compositions for molecular inversion probes," published to Porreca, Gregory J. et al.
• Publication/Filing Date: Publication Date: August 16, 2007; Filing Date: February 9, 2007 (claiming priority to February 10, 2006).
• Brief Description: This patent application, by one of the co-inventors of US11840730, focuses on "improved methods and compositions for molecular inversion probes" to capture target nucleic acids for downstream analysis. It highlights enhancements in efficiency, specificity, sensitivity, and reliability, particularly in multiplex assays. It details MIPs having a central region flanked by 5' and 3' targeting arms.
• Potential Anticipation (35 U.S.C. § 102): Given the shared inventor and the explicit focus on improvements in MIP technology for multiplex assays, US20070190547A1 anticipates many general aspects of using MIPs for genetic analysis, including improvements in assay performance. Claims in US11840730 concerning the design and use of MIPs, obtaining capture products, and their amplification for downstream analysis are likely addressed. The MIP structure described, including a central region, could potentially accommodate a primer sequence as required by US11840730's claims. Nevertheless, a thorough review of the specification of US20070190547A1 is required to determine if it explicitly teaches or enables the "differentiator tag sequence" functionality described in US11840730 for identifying unique, independently isolated nucleic acids to reduce bias and increase genotyping confidence. Without this specific teaching, claims of US11840730 that incorporate the differentiator tag sequence as a means for bias correction and confidence assessment would likely not be fully anticipated.

Note on Anticipation:
A definitive assessment of anticipation under 35 U.S.C. § 102 requires a detailed, claim-by-claim analysis comparing the language of US11840730's claims to the entire disclosure of each prior art reference, including whether every element of a claim is found, either explicitly or inherently, in a single prior art document. The above analysis provides a high-level inference based on the abstracts and described key features. The distinguishing aspect of US11840730, particularly emphasized in claim 1, appears to be the integration of "differentiator tag sequences" with molecular inversion probes and subsequent analysis of unique combinations of target nucleic acid and differentiator tag sequences to identify independently isolated molecules for improved genotyping confidence and bias correction.

To analyze the obviousness of US patent 11840730 under 35 U.S.C. § 103, we evaluate whether the claimed invention, as a whole, would have been obvious to a person having ordinary skill in the art at the time of the invention, given the scope and content of the prior art. This analysis typically considers the differences between the claimed invention and the prior art, and the motivation to combine prior art references. The priority date of US11840730 is April 30, 2009.

Based on the information provided from the PTAB challenge IPR2024-01419, Illumina, Inc. specifically challenged claims 1-9 of US11840730, asserting obviousness over a combination of prior art references.

Obviousness Analysis: Chee in view of McCloskey and Bignell

Challenged Claim(s): Claim 1 of US11840730, and implicitly other dependent claims (e.g., claim 2), were challenged as obvious. As understood from the IPR challenge, Claim 1 pertains to methods that involve using unique molecular identifiers ("differentiator tags") to correct for amplification bias by "collapsing target:differentiator tag combinations observed more than once into a single count" to quantify molecules, especially for genotype calling [cite: IPR2024-01419].

Prior Art References and their Teachings (as described in IPR2024-01419):

1. Chee (Patent 9,085,798):

   • Teaching 1: Discloses the use of unique molecular identifiers (referred to as "differentiator tags") to correct for amplification bias. The method involves "collapsing target:differentiator tag combinations observed more than once into a single count" for quantification [cite: IPR2024-01419]. This directly addresses a core limitation of Claim 1 of US11840730.
   • Teaching 2: Further teaches generating a consensus sequence from multiple reads that share the same unique identifier to correct sequencing errors [cite: IPR2024-01419]. This aspect is relevant to improving the accuracy and confidence of genotyping, which is a stated objective of US11840730.

2. McCloskey: Teaches the use of unique barcodes [cite: IPR2024-01419]. Barcodes, like differentiator tags, serve to uniquely identify and track molecules or samples within a larger pool.

3. Bignell: Teaches a standard sequencing workflow [cite: IPR2024-01419]. The methods described in US11840730, including the use of differentiator tags and collapsing reads, are implemented within the context of nucleic acid sequencing.

Motivation to Combine:

A person having ordinary skill in the art (POSA) would have been motivated to combine the teachings of Chee, McCloskey, and Bignell to arrive at the methods claimed in US11840730 for several reasons:

• Addressing Known Problems in Sequencing: Prior to the priority date of US11840730, issues such as amplification bias and sequencing errors were well-recognized challenges in high-throughput nucleic acid sequencing workflows. These biases could lead to inaccurate quantification of nucleic acid molecules and erroneous genotype calls.
• Improving Accuracy and Reliability: McCloskey's teaching of unique barcodes provides a foundational concept for distinguishing individual molecules or samples. A POSA would understand the utility of such identifiers in managing complex sequencing data. Integrating this with Bignell's standard sequencing workflow would be a logical step for any attempt to improve data integrity.
• Direct Solution to Bias Correction: Chee (Patent 9,085,798) directly addresses the problem of amplification bias by providing a method using unique molecular identifiers ("differentiator tags") and the "collapsing" technique to count unique original molecules [cite: IPR2024-01419]. This technique is explicitly designed to be applied within sequencing processes to obtain a more accurate representation of the starting material.
• Synergistic Combination: The combination of McCloskey's barcodes (or similar unique identifiers) within Bignell's standard sequencing workflow, coupled with Chee's specific method of using differentiator tags to correct for amplification bias by "collapsing" reads, would have been an obvious path for a POSA seeking to enhance the accuracy and confidence of genotype calls. The objective of obtaining reliable quantitative data from sequencing, especially for genotyping applications, would provide a strong motivation to integrate these known techniques. The "collapsing" limitation of Claim 1 of US11840730 is directly taught by Chee, making its incorporation into a general sequencing workflow (Bignell, potentially using McCloskey-style barcodes) an obvious design choice for improving data quality.

Furthermore, the IPR challenge indicates that Chee itself was argued to anticipate dependent claim 2, which involves generating a consensus sequence from multiple reads with the same unique identifier to correct sequencing errors [cite: IPR2024-01419]. If this is the case, the motivation to implement such error correction, as part of a comprehensive strategy to improve genotyping accuracy within a sequencing workflow combining the aforementioned references, would be evident to a POSA.

In summary, the combination of Chee's teachings on using differentiator tags and collapsing reads to correct amplification bias, with McCloskey's use of unique barcodes and Bignell's standard sequencing workflow, would have rendered Claim 1 of US11840730 obvious to a person having ordinary skill in the art by the patent's priority date. The motivation stems from the pervasive need to improve the accuracy and reliability of quantitative nucleic acid analysis in sequencing, particularly for genotyping.