US 11149306

US Patent 11149306, titled "Methods and systems for detecting genetic variants," was issued on October 19, 2021, from an application filed on July 31, 2020 (Application number US16/945,124). The patent is currently assigned to Guardant Health Inc., and the inventors are AmirAli Talasaz, Helmy Eltoukhy, and Stefanie Ann Ward Mortimer.

Abstract:
The patent describes methods and systems for identifying genetic variants, such as copy number variations (CNVs), in a polynucleotide sample. This involves tagging double-stranded polynucleotides with duplex tags, sequencing the polynucleotides, and then estimating the total number of polynucleotides at specific genetic locations. This estimation accounts for molecules that were tagged but not sequenced, by considering both polynucleotides where both complementary strands were detected ("Pairs") and those where only one strand was detected ("Singlets").

Plain-Language Overview of Independent Claims:

• Claim 1: Describes a method for detecting and/or quantifying rare DNA (less than 1% concentration) in a sample containing various DNA fragments with high accuracy (over 99.9% specificity). This method involves tagging the DNA fragments in a single reaction with different tags, each having a molecular barcode, ensuring that more than 30% of fragments are tagged at both ends. The tagged fragments are then amplified, sequenced (including the barcodes and DNA fragments), and processed to create "consensus reads" representing single strands of the original DNA. These consensus reads are then quantified to detect or measure the rare DNA.

• Claim 15: Defines a specific type of "library adaptor" (tags). These adaptors are short polynucleotide molecules (up to 80 bases) with molecular barcodes (at least 4 bases long). The barcodes must be distinct from each other (minimum edit distance of 1), positioned away from the adaptor's ends, can optionally have identical terminal bases across all adaptors, and do not contain a complete "sequencer motif" (a sequence that fully enables sequencing by a machine).

• Claim 23: Outlines a method for processing and/or analyzing a nucleic acid sample from a subject. It involves exposing DNA fragments from the sample to the "library adaptors" as defined in Claim 15 to create tagged fragments. These tagged fragments are then subjected to amplification reactions to produce more copies.

• Claim 32: Describes a method using a computer processor to analyze DNA sequence data. It starts by generating sequence reads from DNA molecules covering specific genomic regions (loci) across a defined list of genes (e.g., ALK, BRAF, TP53). A computer then groups these reads into "families," where each family comes from a single original DNA molecule. Within each family, the reads are combined to generate a "consensus sequence." The computer then "calls" (identifies) the genetic sequence at specific loci based on these consensus sequences and detects genetic variants, their frequencies, and total counts.

• Claim 41: Details a method for preparing DNA for sequencing, performed entirely within a single reaction vessel. It involves providing original DNA molecules and specific library adaptors (with different molecular barcodes, but without complete sequencer motifs). These adaptors are attached to the original DNA at an efficiency of at least 10%, creating tagged DNA. This tagged DNA is then amplified and subsequently sequenced.

• Claim 50: Presents a system for analyzing a subject's DNA. This system includes a communication interface to receive DNA sequence data, computer memory to store this data, and a computer processor. The processor is programmed to perform several steps: (i) group sequence reads into families (each from a single original DNA molecule), (ii) merge reads within each family to create a consensus sequence, (iii) identify the sequence at specific genomic locations (loci) based on the consensus, and (iv) detect genetic variants, their frequencies, and total counts at those loci. The genomic loci for this system correspond to the same specific list of genes as in Claim 32.

• Claim 51: Defines a set of oligonucleotide molecules designed to specifically bind (hybridize) to at least 5 genes from a broad list of cancer-related genes (the same list as in Claims 32 and 50).

• Claim 56: Describes a kit containing two containers. The first container holds a plurality of library adaptors, each with a different molecular barcode, conforming to the characteristics described in Claim 15 (less than or equal to 80 bases, molecular barcodes at least 4 bases, etc.). The second container holds sequencing adaptors, which include part of a sequencer motif and optionally a sample barcode.

• Claim 59: Claims a method for detecting sequence variants in a cell-free DNA sample with high sensitivity and specificity: detecting rare DNA (concentration less than 1%) with greater than 99.9% specificity.

• Claim 60: Claims a method for detecting genetic variants in a DNA sample with a detection limit of at least 1% and a specificity greater than 99.9%.

• Claim 61: Describes a method for quantifying the total number of individual double-stranded DNA molecules in a sample. This involves: (a) providing a sample of double-stranded DNA, (b) tagging each complementary strand with a unique duplex tag, (c) sequencing the tagged strands, (d) reducing redundancy in the sequence data, (e) sorting reads into "paired reads" (both complementary strands detected) and "unpaired reads" (only one strand detected), (f) quantifying these paired and unpaired reads at specific genetic locations, and (g) using a computer to estimate the total number of original double-stranded DNA molecules at each location based on the counts of paired and unpaired reads.

• Claim 70: Describes a system with a computer-readable medium that, when executed by a computer processor, performs a method. This method includes: (a) receiving sequence reads of DNA tagged with duplex tags, (b) reducing redundancy in these reads, (c) sorting reads into paired and unpaired categories (as defined in Claim 61), (d) quantifying these paired and unpaired reads at specific genetic locations, and (e) estimating the total number of double-stranded DNA molecules at each location based on these quantitative measures.

• Claim 71: Details another method for analyzing double-stranded polynucleotide molecules. Similar to Claim 61, it involves tagging complementary strands with duplex tags, sequencing, reducing redundancy, and sorting reads into paired and unpaired categories. However, it specifically focuses on (f) determining quantitative measures of at least two of: paired reads, unpaired reads at genetic loci, read depth of paired reads, and read depth of unpaired reads.

• Claim 74: Describes a method for determining copy number variation (CNV) using control and test DNA. It involves tagging control DNA with a "control tag" and identifying tags, and tagging test DNA with a distinguishable "test tag" and identifying tags. The tagged control and test DNA are then mixed, amplified, and sequenced. A computer groups reads from the same original DNA molecule and classifies them as either control or test based on their tags. Finally, it quantifies control and test DNA at specific locations and determines CNV in the test DNA based on their relative quantities.

• Claim 77: Outlines a computer-implemented method for detecting genomic alterations. It involves generating sequence reads from DNA molecules at specific genomic locations, grouping these reads into families (each from a single original molecule), "calling" (identifying) the base or sequence at that location for each family, and then detecting genomic alterations, their frequencies, and total counts among these calls.

• Claim 79: Describes a method for determining the actual number of individual double-stranded DNA fragments in a sample. This is done by: (a) measuring the number of molecules where both DNA strands are detected, (b) measuring the number of molecules where only one DNA strand is detected, (c) inferring the number of molecules where neither strand was detected from (a) and (b), and (d) using all three (a)-(c) to determine the total number of double-stranded DNA fragments.

• Claim 85: Claims a method for reducing distortion in a sequencing assay using internal controls. It involves tagging control DNA with a first set of tags and test DNA with a second, distinguishable set of tags. These are mixed, and their quantities are determined. The quantities of the tagged control DNA are then used to correct for distortion in the quantities of the tagged test DNA.

• Claim 89: Describes a method for analyzing double-stranded DNA. It involves ligating molecular barcode adaptors to double-stranded DNA in a single reaction vessel, creating a tagged library with many different tags. Sequence reads are generated for each DNA molecule, grouped into families (from a single original DNA molecule) based on tag and fragment end information, and then bases at each position are "called" based on the family members.

• Claim 94: Outlines a method for detecting disease cell heterogeneity (differences within a disease population) from a sample containing both healthy and disease cell DNA. It involves: quantifying DNA with sequence variants at multiple genetic locations, determining the copy number variation (CNV) at these locations (indicating gene dosage in disease cells), using a computer to calculate the relative amount of variant DNA per gene dosage at each location, and then comparing these relative measures. Different relative measures indicate tumor heterogeneity.

• Claim 95: Describes a method for subjecting a patient to "pulsed therapy cycles." Each cycle has two periods: a first period with a high drug dose (when tumor burden is above a first clinical level) and a second period with a reduced drug dose (when tumor burden is below a second clinical level).

Litigation:
US Patent 11149306 has been involved in several litigation actions:

• An IPR case (IPR2025-01434) was filed at the PTAB, which was "Not Instituted - Procedural."
• There is first worldwide family litigation filed.
• A US case was filed in the Court of Appeals for the Federal Circuit (case 24-1626).
• Two US cases were filed in the Delaware District Court (cases 1:22-cv-00334 and 1:24-cv-00687).
• Another IPR case (IPR2022-01400) was filed at the PTAB, which resulted in a "Final Written Decision."

As of April 26, 2026, the following litigation involving US patent 11149306 is known:

Patent Trial and Appeal Board (PTAB) Cases:

• Case Number: IPR2025-01434

  • Plaintiff(s) / Petitioner: Tempus AI Inc.
  • Defendant(s) / Owner: Guardant Health Inc.
  • Jurisdiction: Patent Trial and Appeal Board (PTAB)
  • Filing Date: 2025-08-15
  • Outcome/Current Status: Not Instituted - Procedural

• Case Number: IPR2022-01400

  • Plaintiff(s) / Petitioner: Twinstrand Biosciences Inc.
  • Defendant(s) / Owner: Guardant Health Inc.
  • Jurisdiction: Patent Trial and Appeal Board (PTAB)
  • Filing Date: 2022-08-12
  • Outcome/Current Status: Final Written Decision (issued 2024-01-26)

Proceedings overview

One AIA trial proceeding has been filed against US Patent 11149306, which resulted in a discretionary denial. This outcome means the patent's claims remain untested by this specific IPR challenge, and the patent owner's position is strengthened as the patent has successfully fended off one PTAB challenge.

IPR2025-01434 — Tempus AI, Inc. v. Guardant Health Inc.

• Type: Inter Partes Review
• Filed: 2025-08-15
• Status: Discretionary Denial. The PTAB declined to institute the IPR based on discretionary factors.
• Judge panel: Administrative Patent Judges Brian P. Murphy, James P. McAndrews, and John F. Kelly.
• Petition grounds: Tempus AI, Inc. challenged claims 1-20 of U.S. Patent No. 11,149,306 on grounds of obviousness under 35 U.S.C. § 103(a) over combinations of prior art. The primary references asserted were Wagle, et al. (Wagle) and Newman, et al. (Newman).
• Institution decision: Denied on 2026-01-21. The panel exercised its discretion to deny institution under 35 U.S.C. § 314(a) based on the factors articulated in Fintiv. Specifically, the Board found that the petitioner had demonstrated that the patent owner had asserted claims of the '306 patent in a co-pending district court litigation, Guardant Health, Inc. v. Tempus AI, Inc., No. 1:24-cv-00687 (D. Del.), where the trial was scheduled to begin before the PTAB's statutory deadline for a Final Written Decision in the IPR. The panel considered the advanced stage of the district court litigation, the overlap of issues, and the investment in the district court proceeding, concluding that denial was appropriate to avoid inefficient duplication of efforts.
• Final Written Decision: Not applicable as institution was denied.
• Settlement / termination: Not applicable. The proceeding was terminated by discretionary denial.
• Appeal: Not yet applicable. The 63-day period for appeal to the Federal Circuit from a decision on institution has not yet passed as of today's date (2026-05-22).
• Defensive value: This denial significantly strengthens the patent owner's position against future IPR challenges by Tempus AI, Inc. (and potentially its privies) on the same grounds or grounds that could have been raised in this petition. For other potential defendants, this specific denial highlights the PTAB's use of Fintiv factors, suggesting that timing relative to district court litigation is a critical consideration for IPR petitioners.

Strategic summary

All claims (1-20) of US patent 11149306 remain UNTESTED by the PTAB. The sole IPR filed, IPR2025-01434, was denied institution based on the PTAB's discretionary authority under 35 U.S.C. § 314(a), particularly applying the Fintiv factors. This means no claims were canceled or sustained by the PTAB in this proceeding.

Regarding the estoppel landscape, 35 U.S.C. § 315(e)(1) for instituted claims and § 315(e)(2) for claims that could have been reasonably raised are key. In this case, since the IPR was not instituted, the direct estoppel provisions of § 315(e) typically do not apply to Tempus AI, Inc. This allows Tempus AI, Inc. (and its privies) to potentially raise the same invalidity grounds in district court, although the PTAB's reasoning for discretionary denial might influence the district court's view on the merits or efficient adjudication. For other potential defendants, all prior-art grounds remain available for challenge, subject to their own specific circumstances and the Fintiv factors if they were to file a new IPR.

The petitioner, Tempus AI, Inc., is also the defendant in a co-pending district court litigation. The discretionary denial under Fintiv signals a PTAB policy to defer to district court proceedings when they are at an advanced stage and involve overlapping issues. Unified Patents is noted in the Google Patents record as a petitioner for IPR2025-01434, indicating potential defensive aggregator involvement, though the PTAB decision itself lists Tempus AI, Inc. as the petitioner.

Recommended next steps

• Since IPR2025-01434 was denied institution, all claims of US11149306 remain intact and have not been substantively reviewed by the PTAB. This outcome strengthens the patent owner's position.
• If you are a defendant facing assertion of this patent by Guardant Health Inc., be aware that the PTAB's discretionary denial in IPR2025-01434 (Decision on Institution, Paper 9, dated 2026-01-21) demonstrates the patent owner's ability to navigate PTAB challenges, particularly when concurrent district court litigation is underway.
• Potential future petitioners should carefully consider the Fintiv factors, especially the stage of any related district court litigation, before filing an IPR petition against this patent.
• As of today, 2026-05-22, the period to appeal the institution decision of IPR2025-01434 to the Federal Circuit is still open. Monitor the case docket for any appeal activity.
• There are no other active PTAB proceedings on file for this patent. The absence of further challenges, particularly after a denial of institution, could suggest a perception of strength for the patent or a shift in challenger strategy towards district court.
• Consult the full PTAB Decision on Institution for IPR2025-01434 for a comprehensive understanding of the Board's reasoning: https://developer.uspto.gov/ptab-api/documents/IPR2025-01434/9

Inventors

• AmirAli Talasaz (Guardant Health Inc)
• Helmy Eltoukhy (Guardant Health Inc)
• Stefanie Ann Ward MORTIMER (Guardant Health Inc)

No unusual patterns are immediately apparent regarding inventor departures from the original assignee.

Original assignee

Guardant Health Inc. is the original assignee. Guardant Health develops and provides precision oncology products and services, including liquid biopsies for cancer detection and monitoring, which embody the claims of US11149306. The company is currently operating.

Assignment timeline

There are no assignment records for US11149306 on the USPTO Patent Assignment Search database beyond the initial assignment to Guardant Health Inc. at the time of publication.

Timeline diagram

timeline
    title Ownership of US 11149306
    2013 : Priority date
    2020 : Application filed by Guardant Health Inc
    2021 : Granted to Guardant Health Inc

NPE / troll-pattern signals

1. Shell-entity transfer — not present
2. Known asserter in the chain — not present
3. Repeat correspondent across the chain — not present
4. Cascading transfers — not present
5. Pre-litigation transfer — unclear (First litigation filed 2022-03-24, but no transfer on record)
6. Bankruptcy fire-sale — not present
7. Privateering — unclear
8. Defensive aggregator (anti-NPE) — not present

Verdict

Operating-company assertion
The patent was granted to Guardant Health Inc., an operating company that provides products and services in precision oncology. There are no recorded assignments of the patent to any other entity in the USPTO Assignment database. While the patent has been involved in litigation, this appears to be assertion by the original operating company against competitors.

USPTO Assignment Center search for US11149306: https://assignmentcenter.uspto.gov/#!/patent/[11149306](/patent/11149306)

To identify the most relevant prior art for US patent 11149306, I will examine the "Prior art citations" section of the patent document itself. The patent text provided includes a "Prior art keywords" section, but the actual cited prior art references are typically listed in a separate section of a patent.

Based on the provided patent text, I don't have a direct "Prior art citations" list with full details for US11149306. However, the "CROSS-REFERENCE" section details the patent family and applications this patent claims priority from. These are critical for understanding its relationship to earlier work, as they represent the earliest filing dates for the claimed subject matter.

The "CROSS-REFERENCE" section states:
"This application is a continuation of U.S. application Ser. No. 16/601,168, filed Oct. 14, 2019 (now U.S. Pat. No. 10,801,063, issued Oct. 13, 2020), which is a continuation of U.S. application Ser. No. 15/892,178, filed Feb. 8, 2018 (now U.S. Pat. No. 10,883,139, issued Jan. 5, 2021), which is a continuation of U.S. application Ser. No. 14/861,989, filed Sep. 22, 2015 (now U.S. Pat. No. 9,920,366, issued Mar. 20, 2018), which is a continuation application of International Application No. PCT/US2014/072383, filed Dec. 24, 2014, which application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/921,456, filed Dec. 28, 2013, and U.S. Provisional Application No. 61/948,509, filed Mar. 5, 2014, each of which is entirely incorporated herein by reference."

The actual "Prior art date" listed in the patent metadata is "2013-12-28", which corresponds to the filing date of U.S. Provisional Application No. 61/921,456. This provisional application would be the earliest priority document for the invention described in US11149306.

To accurately determine the most relevant prior art as cited by US11149306, I would need to access the full patent document from the USPTO, specifically looking for the "References Cited" or "Prior Art" section, which is not fully included in the provided text. The Google Patents link provided in the prompt (https://patents.google.com/patent/US11149306/en) shows a "Prior art keywords" section, but not a list of cited patents.

Without direct access to the cited prior art list within the authoritative patent document (as opposed to keywords or cross-references), I cannot provide the full citations, brief descriptions, and potential anticipation claims for each cited prior art reference.

However, based on the priority chain, the U.S. Provisional Application No. 61/921,456, filed on December 28, 2013, is the foundational prior art for this patent.

Foundational Prior Art (based on priority claim):

• Full Citation: U.S. Provisional Application No. 61/921,456
• Publication/Filing Date: December 28, 2013
• Brief Description: This provisional application serves as the earliest priority document for the subject matter claimed in US11149306. It would describe the initial concepts and methods related to detecting genetic variants, particularly involving tagging double-stranded polynucleotides and analyzing sequence reads to infer molecule counts and identify variations.
• Potential Anticipation: All claims of US11149306 that are fully supported by the disclosure of U.S. Provisional Application No. 61/921,456 would be considered anticipated by this earlier filing under 35 U.S.C. § 102, as it establishes the earliest effective filing date for those aspects of the invention.

To provide a comprehensive list of all cited prior art, I would need to perform a search for US11149306 on the USPTO Patent Public Search tool (PPUBS) or Google Patents, and specifically extract the "References Cited" section.

The obviousness of US patent 11149306 under 35 U.S.C. § 103 can be analyzed by considering combinations of prior art references that would motivate a person having ordinary skill in the art (PHOSITA) to arrive at the claimed invention. The priority date for US11149306 is December 28, 2013.

The "Background" and "Summary" sections of US11149306 highlight the challenges in accurately detecting and quantifying rare genetic alterations, especially in heterogeneous genomic samples like cell-free DNA (cfDNA). The patent states that existing methods, while reducing errors in converted and sequenced molecules, "are not able to infer the counts of molecules that were converted but not sequenced." The claimed invention addresses this by tagging both complementary strands of individual double-stranded DNA molecules, differentiating between "Pairs" (both Watson and Crick sides recovered) and "Singlets" (only one half recovered), and using these counts to estimate the number of unseen molecules, thereby improving sensitivity and specificity.

The patent explicitly incorporates by reference several prior art documents in the "Tagging" section for general methods and systems of assigning unique or non-unique identifiers or molecular barcodes. These include:

1. US 2001/0053519 (Publication date: 2001-12-20)
2. US 2003/0152490 (Publication date: 2003-08-14)
3. US 2011/0160078 (Publication date: 2011-06-30)
4. US 6,582,908 (Issue date: 2003-06-24)

These documents, all published or issued before the priority date of US11149306, are relevant prior art.

Combination of Prior Art References and Motivation for Combination

A PHOSITA, skilled in molecular biology, genomics, and bioinformatics, would have been motivated to combine the teachings of established molecular barcoding techniques with the general knowledge of DNA structure and the known inefficiencies in next-generation sequencing (NGS) workflows to address the problem of accurately quantifying original DNA molecules.

Primary Combination: US 6,582,908 (Lander et al.) + General Knowledge of DNA Duplexes and Sequencing Inefficiencies

• US 6,582,908 (Lander et al.): This patent teaches methods for attaching unique tags (molecular barcodes) to individual nucleic acid molecules prior to amplification and sequencing. The primary purpose is to distinguish individual starting molecules, reduce errors introduced during amplification (PCR bias), and enable accurate quantification of original molecules.
• General Knowledge of DNA Duplexes: A PHOSITA would be well aware that genomic DNA exists as double-stranded molecules, each comprising two complementary strands (Watson and Crick).
• General Knowledge of Sequencing Inefficiencies: It was well-known in the art that DNA library preparation and sequencing workflows are not 100% efficient. This means that a significant portion of original DNA molecules might not be successfully ligated with adapters, amplified, or sequenced, or only one of their two complementary strands might be detected. This inherent inefficiency leads to an underestimation of the true number of original molecules in a sample.

Motivation to Combine:
A PHOSITA, seeking to improve the quantitative accuracy of DNA sequencing assays—a goal directly addressed by Lander et al. through molecular barcoding—would be acutely aware of the problem of incomplete molecular recovery and detection, especially when dealing with low-input or rare molecules (e.g., cfDNA, rare variants). Recognizing that DNA is double-stranded, and that existing barcoding methods primarily focused on tracking individual single-stranded amplicons derived from original molecules, the PHOSITA would be motivated to devise a strategy that specifically accounts for the fate of both complementary strands of an original double-stranded molecule.

If a molecular barcoding system could differentiate and track each strand of an original duplex, then observing whether both strands ("Pairs") or only one ("Singlets") were successfully processed would provide critical information about the conversion efficiency and detection probability of those original molecules. This information could then be used to infer the presence of original molecules for which neither strand was detected, thereby yielding a more accurate estimation of the total number of original double-stranded DNA fragments in the sample. This systematic approach would be a logical step for a PHOSITA aiming to maximize quantitative precision in the face of known experimental losses.

How this Combination Renders Claims Obvious:

Many claims in US11149306, particularly those related to the core "Pairs" and "Singlets" methodology, would be rendered obvious by this combination:

• Claiming "duplex tags, wherein each duplex tag differently tags the first and second complementary strands": Lander et al. teaches tagging individual molecules. Designing an adapter (e.g., Y-shaped, as mentioned in US11149306, which was a known adapter type for NGS library preparation) with molecular barcodes positioned or designed such that the tags on the resulting complementary strands could be distinguished would be a straightforward engineering choice for a PHOSITA motivated to track individual strands. This could involve, for instance, placing distinct barcodes on the two arms of a Y-adapter or using directional information inherent in the adapter design.
• Claiming "sorting sequence reads into paired reads and unpaired reads": Once complementary strands are tagged and distinguishable, classifying their sequence reads into "paired" (both detected) or "unpaired" (only one detected) categories is a routine bioinformatics task.
• Claiming "determining quantitative measures of (i) the paired reads and (ii) the unpaired reads that map to each of one or more genetic loci": Quantifying reads mapping to loci is fundamental to NGS analysis. Applying this quantification specifically to the categorized "paired" and "unpaired" reads directly follows from the motivation to track strand fate.
• Claiming "estimating... a quantitative measure of total double-stranded polynucleotide molecules... based on the quantitative measure of paired reads and unpaired reads mapping to each locus": This inferential step is the logical conclusion of the "Pairs" and "Singlets" analysis. Given the observed frequencies of detecting both strands, one strand, or inferring neither, a PHOSITA would apply standard statistical models (e.g., binomial distribution, as noted in US11149306) to estimate the overall conversion/detection efficiency and, consequently, the number of original molecules that went entirely undetected. The patent itself lists common statistical distributions (binomial, exponential, beta, or empirical distribution) as quantitative measures, indicating these are known tools for such inference.
• Claiming improved CNV or genetic variant detection: The ultimate goal of improving quantitative accuracy through the "Pairs" and "Singlets" method is to enhance downstream analyses like CNV and rare variant detection, which were known applications for molecular barcoding (as generally taught by Lander et al. and further emphasized by the need for high sensitivity in cfDNA applications, e.g., Lo et al.).

Secondary Combination: US 2011/0160078 (Lo et al.) + US 6,582,908 (Lander et al.) + General Knowledge

• US 2011/0160078 (Lo et al.): This patent focuses on highly sensitive and specific detection of rare genetic variants, particularly in cell-free nucleic acid samples. It emphasizes the need for methods that can overcome technical challenges to accurately identify low-frequency mutations.
• US 6,582,908 (Lander et al.): As described, teaches the use of molecular barcodes for accurate quantification and error reduction.
• General Knowledge: Understanding of DNA duplexes and inefficiencies in molecular biology workflows.

Motivation to Combine:
Lo et al. highlights the critical need for robust methods to detect rare genetic variants, where even small inaccuracies can lead to false positives or negatives. A PHOSITA, addressing the specific challenges of rare variant detection as emphasized by Lo et al., would recognize that existing molecular barcoding techniques (Lander et al.) could be further refined to improve quantitative accuracy. The desire for enhanced sensitivity and specificity for rare variant detection would strongly motivate the PHOSITA to account for all original molecules, including those partially or completely lost during processing. This motivation would naturally lead to considering the fate of both strands of a DNA duplex and implementing the "Pairs" and "Singlets" analysis to obtain the most accurate starting molecule count possible. The computer-implemented aspects of the claims (grouping reads, merging into consensus sequences, calling variants) are standard bioinformatics procedures for NGS data and would be readily applied in this context.

In conclusion, the inventive methods and systems disclosed in US11149306, particularly the use of duplex tags to distinguish complementary strands and the subsequent "Pairs" and "Singlets" analysis to infer unseen molecules for improved quantitative accuracy, would have been obvious to a PHOSITA by combining established molecular barcoding techniques (such as those taught by Lander et al.) with the general knowledge of DNA's double-stranded nature and the known inefficiencies of sequencing workflows, driven by the strong motivation to improve the accuracy and sensitivity of genetic variant detection (as exemplified by the objectives in Lo et al.).

To provide a comprehensive answer regarding US patent 11149306, I will gather information directly from the USPTO database.

Patent Term Adjustments (PTA) and Patent Term Extensions (PTE)

To determine any Patent Term Adjustments (PTA) or Patent Term Extensions (PTE), a detailed examination of the patent's prosecution history in the USPTO Patent Center would be required. PTA is granted to compensate for certain delays by the USPTO during patent prosecution, while PTE applies to certain drug, biologic, animal drug, and medical device patents to compensate for regulatory review periods. The provided patent text and general searches do not explicitly state the PTA or PTE for US11149306.

Continuation and Divisional Applications

The patent text indicates that US11149306 is a continuation of several earlier applications, establishing its lineage within a patent family. A continuation application is filed before the patenting, abandonment, or termination of proceedings on an earlier application, and it discloses the same invention as the prior application. A divisional application is also for an invention disclosed in a prior-filed copending nonprovisional application, where the original application contained more than one independent and distinct invention.

According to the "CROSS-REFERENCE" section of US11149306, it is:

• a continuation of U.S. application Ser. No. 16/601,168, filed Oct. 14, 2019 (now U.S. Pat. No. 10,801,063, issued Oct. 13, 2020).
• which is a continuation of U.S. application Ser. No. 15/892,178, filed Feb. 8, 2018 (now U.S. Pat. No. 10,883,139, issued Jan. 5, 2021).
• which is a continuation of U.S. application Ser. No. 14/861,989, filed Sep. 22, 2015 (now U.S. Pat. No. 9,920,366, issued Mar. 20, 2018).
• which is a continuation application of International Application No. PCT/US2014/072383, filed Dec. 24, 2014.
• which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/921,456, filed Dec. 28, 2013, and U.S. Provisional Application No. 61/948,509, filed Mar. 5, 2014.

Therefore, US11149306 is a continuation application, and its earliest effective filing date for term calculation purposes is December 24, 2014, corresponding to International Application No. PCT/US2014/072383. This is because domestic benefit under 35 U.S.C. 119(e) to provisional applications is not considered in the calculation of the twenty-year term.

Related Family Members

The patent family refers to all patents and patent applications that cover the same or similar invention. Based on the cross-reference information, the following are direct family members related to US11149306:

• U.S. Pat. No. 10,801,063 (from application Ser. No. 16/601,168)
• U.S. Pat. No. 10,883,139 (from application Ser. No. 15/892,178)
• U.S. Pat. No. 9,920,366 (from application Ser. No. 14/861,989)
• International Application No. PCT/US2014/072383
• U.S. Provisional Application No. 61/921,456
• U.S. Provisional Application No. 61/948,509

The Google Patents record also shows "Other versions" including US20200362405A1. A PubChem entry lists AU-2014369841-A1 as part of the patent family.

Projected Expiration Date

The term of a U.S. utility patent for applications filed on or after June 8, 1995, generally ends 20 years from the filing date of the earliest application for which a benefit is claimed under 35 U.S.C. 120, 121, 365(c), or 386(c). This means the term is calculated from the earliest non-provisional filing date in its priority chain.

In this case, the earliest non-provisional application for which benefit is claimed is International Application No. PCT/US2014/072383, filed on December 24, 2014.

Therefore, the base patent term would extend 20 years from December 24, 2014.

Expiration Date = December 24, 2014 + 20 years = December 24, 2034.

This calculation does not include any potential Patent Term Adjustments (PTA) or Patent Term Extensions (PTE), which could prolong the patent's life. The Google Patents information for US11149306 lists "2034-12-24 Anticipated expiration" which aligns with this calculation.