Harvard faculty David Liu, David Weitz, Joseph Italiano, Yoshito Kishi, Clifford Woolf, Kevin Eggan, Brian Wainger, Dan Finley, Randy King, Joseph Mancias, Adam Cohen, Wade Harper, Marko Loncar, Charlie Lieber, Don Ingber, and Eric Mazur are among the inventors issued U.S. patents in July 2019.

The innovations recognized are as follows:

Continuous directed evolution
U.S. Patent 10,336,997 (July 2, 2019)

David R. Liu, Kevin Michael Esvelt, and Jacob Charles Carlson

Abstract: The invention provides systems, methods, reagents, apparatuses, vectors, and host cells for the continuous evolution of nucleic acids. For example, a lagoon is provided in which a population of viral vectors comprising a gene of interest replicates in a stream of host cells, wherein the viral vectors lack a gene encoding a protein required for the generation of infectious viral particles, and wherein that gene is expressed in the host cells under the control of a conditional promoter, the activity of which depends on a function of the gene of interest to be evolved. Some aspects of this invention provide evolved products obtained from continuous evolution procedures described herein. Kits containing materials for continuous evolution are also provided.

System and method for a biomimetic fluid processing
U.S. Patent 10,343,163 (July 9, 2019)

Joseph Italiano, Linas Mazutis, Jonathan N. Thon, and David A. Weitz

Abstract: A system and method are provided for harvesting target biological substances. The system includes a substrate and a first and second channel formed in the substrate. The channels longitudinally extending substantially parallel to each other. A series of gaps extend from the first channel to the second channel to create a fluid communication path passing between a series of columns with the columns being longitudinally separated by a predetermined separation distance. The system also includes a first source configured to selectively introduce into the first channel a first biological composition at a first channel flow rate and a second source configured to selectively introduce into the second channel a second biological composition at a second channel flow rate. The sources are configured to create a differential between the first and second channel flow rates to generate physiological shear rates along the second channel that are bounded within a predetermined range.

Chromium-mediated coupling and application to the synthesis of halichondrins
U.S. Patent 10,344,038 (July 9, 2019)

Yoshito Kishi, Wuming Yan, Jingwei Li, Zhanjie Li, and Kenzo Yahata

Abstract: The present invention provides unified synthesis of the CI-CI 9 building blocks of halichondrins and analogs thereof using selective coupling of poly-halogenated nucleophiles in chromium-mediated coupling reactions. The present invention also provides a practical and efficient synthesis of C20-C38 building blocks of halichondrins and analogs thereof. Also provided herein are general methods of selective activation and coupling of poly-halogenated analogs with an aldehyde. The provided coupling reactions are selective for halo-enone and halo-acetylenic ketal over vinyl halide and halide attached to a sp hydridized carbon. The provided efficient selective coupling reactions can allow easy access to the CI-CI 9 building blocks and C20-C38 building blocks of halichondrins and analogs thereof with limited or no purification or separation of the intermediates.

Quantum processor problem compilation
U.S. Patent 10,346,748 (July 9, 2019)

Alan Aspuru-Guzik, Ryan Babbush, and Bryan O'Gorman

Abstract: Solution of a problem of determining values of a set of N problem variables x, makes use of a quantum processor that has a limited number of hardware elements for representing quantum bits and/or limitations on coupling between quantum bits. A method includes accepting a specification of the problem that includes a specification of a set of terms where each term corresponds to a product of at least three variables and is associated with a non-zero coefficient. A set of ancilla variables, each ancilla variable corresponding to a pair of problem variables, is determined by applying an optimization procedure to the specification of the set of the terms. The accepted problem specification is then transformed according to the determined ancilla variables to form a modified problem specification for use in configuring the quantum processor and solution of problem.

Systems and methods for parallelizing Bayesian optimization
U.S. Patent 10,346,757 (July 9, 2019)

Ryan P. Adams, Roland Jasper Snoek, and Hugo Larochelle

Abstract: Techniques for use in connection with performing optimization using an objective function. The techniques include using at least one computer hardware processor to perform: beginning evaluation of the objective function at a first point; before evaluating the objective function at the first point is completed: identifying, based on likelihoods of potential outcomes of evaluating the objective function at the first point, a second point different from the first point at which to evaluate the objective function; and beginning evaluation of the objective function at the second point.

Soft retractors
U.S. Patent 10,349,927 (July 16, 2019)

Kevin C. Galloway and Joshua Aaron Lessing

Abstract: A soft material retractor includes at least two soft actuators, each actuator having at least one pressurizable interior space, wherein the actuator has a first flexible resting state and a second stiffer pressurized state; and a flexible sheet spanning the actuators such that the actuators can be spaced apart from each other by a distance selected to displace a volume of material of a body cavity. The retractor can be uses for holding open wounds or incisions, with trochars, or to displace anatomical features such as organs within a body cavity.

Methods to treat neurodegenerative diseases
U.S. Patent 10,350,191 (July 16, 2019)

Clifford J. Woolf, Brian J. Wainger, Evangelos Kiskinis, and Kevin Eggan

Abstract: The specification provides compositions and methods to treat neurodegenerative diseases.

Compositions and methods for modulating NCOA4-mediated autophagic targeting of ferritin
U.S. Patent 10,350,264 (July 16, 2019)

Alec C. Kimmelman, Joseph D. Mancias, and Jeffrey Wade Harper

Abstract: Described herein are methods of modulating autophagic targeting of ferritin in a cell, wherein the method comprises modulating the level and/or activity of nuclear receptor coactivator 4 (NCOA4) in the cell. Also provided are related methods of treatment.

Compositions and methods for enhancing proteasome activity
U.S. Patent 10,351,568 (July 16, 2019)

Daniel J. Finley, Randall W. King, Byung-Hoon Lee, Min Jae Lee, and Timothy C. Gahman

Abstract: Proteinopathies result from the proteasome not acting efficiently enough to eliminate harmful proteins and prevent the formation of the pathogenic aggregates. As described herein, inhibition of proteasome-associated deubiquitinase Usp14 results in increased proteasome efficiency. The present invention therefore provides novel compositions and methods for inhibition of Usp14, enhancement of proteasome activity and treatment of proteinopathies.

Optogenetic probes for measuring membrane potential
U.S. Patent 10,352,945 (July 16, 2019)

Adam Ezra Cohen, Joel Kralj, and Adam D. Douglass

Abstract: The invention provides methods, cells and constructs for optical measurement of membrane potential. These methods can be used in cells that are not accessible to presently available methods using electrodes. The methods can be directed to, for example, high-throughput drug screening assays to determine agents that can affect membrane potential of a target cell.

Multi-mode cavities for high-efficiency nonlinear wavelength conversion formed with overlap optimization
U.S. Patent 10,353,269 (July 16, 2019)

Alejandro Rodriguez, Zin Lin, Steven G. Johnson, Marko Loncar, and Xiangdong Liang

Abstract: A fully confined dual frequency optical resonator configured for optical coupling to light having a first frequency ω1. The dual frequency optical resonator includes a plurality of alternating layer pairs configured in a grating configuration, each layer pair having a first layer formed of a first material and a second layer formed of a second material, the first material and second material being different materials. Each layer having a thickness different than a thickness of an adjacent layer to provide thereby aperiodic layer pairs, the thicknesses of adjacent layers being selected to create, via wave interference with each layer, optical resonances at the first frequency ω1 and a second frequency ω2 which is a harmonic of ω1, and to ensure a maximum spatial overlap between confined modes over the materials such that an overall quality factor Q of at least 1000 is achieved.

Methods and systems for scaffolds comprising nanoelectronic components
U.S. Patent 10,355,229 (July 16, 2019)

Charles M. Lieber, Bozhi Tian, and Jia Liu

Abstract: The present invention generally relates to nanoscale wires and tissue engineering. Systems and methods are provided in various embodiments for preparing cell scaffolds that can be used for growing cells or tissues, where the cell scaffolds comprise nanoscale wires. In some cases, the nanoscale wires can be connected to electronic circuits extending externally of the cell scaffold. Such cell scaffolds can be used to grow cells or tissues which can be determined and/or controlled at very high resolutions, due to the presence of the nanoscale wires, and such cell scaffolds will find use in a wide variety of novel applications, including applications in tissue engineering, prosthetics, pacemakers, implants, or the like. This approach thus allows for the creation of fundamentally new types of functionalized cells and tissues, due to the high degree of electronic control offered by the nanoscale wires and electronic circuits.

Manipulation of fluids, fluid components and reactions in microfluidic systems
U.S. Patent 10,357,772 (July 23, 2019)

Seth Fraden, Hakim Boukellal, Yanwei Jia, Seila Selimovic, Amy Rowat, Jeremy Agresti, and David A. Weitz

Abstract: Microfluidic structures and methods for manipulating fluids, fluid components, and reactions are provided. In one aspect, such structures and methods can allow production of droplets of a precise volume, which can be stored/maintained at precise regions of the device. In another aspect, microfluidic structures and methods described herein are designed for containing and positioning components in an arrangement such that the components can be manipulated and then tracked even after manipulation. For example, cells may be constrained in an arrangement in microfluidic structures described herein to facilitate tracking during their growth and/or after they multiply.

Magnetic capture of a target from a fluid
U.S. Patent 10,357,780 (July 23, 2019)

Joo Hun Kang, Donald E. Ingber, and Michael Super

Abstract: Disclosed herein is an improved method for magnetic capture of target molecules (e.g., microbes) in a fluid. Kits and solid substrates for carrying the method described herein are also provided. In some embodiments, the methods, kits, and solid substrates described herein are optimized for separation and/or detection of microbes and microbe-associated molecular pattern (MAMP) (including, e.g., but not limited to, a cell component of microbes, lipopolysaccharides (LPS), and/or endotoxin).

Optically detected magnetic resonance imaging with an electromagnetic field resonator
U.S. Patent 10,359,480 (July 23, 2019)

Khadijeh Bayat and Marko Loncar

Abstract: Measuring a sample includes providing a magnetic field at the sample using an electromagnetic field resonator. The electromagnetic field resonator includes two or more resonant structures at least partially contained within dielectric material of a substrate, at least a first resonant structure configured to provide the magnetic field at the sample positioned in proximity to the first resonant structure. The sample is characterized by an electron spin resonance frequency. A size of an inner area of the first resonant structure and a number of resonant structures included in the electromagnetic field resonator at least partially determine a range of an operating resonance frequency of the electromagnetic field resonator that includes the electron spin resonance frequency. Measuring the sample also includes receiving an output optical signal from the sample generated based at least in part on a magnetic field generated by the electromagnetic field resonator.

Femtosecond laser-induced formation of submicrometer spikes on a semiconductor substrate
U.S. Patent 10,361,083 (July 23, 2019)

Eric Mazur and Mengyan Shen

Abstract: The present invention generally provides semiconductor substrates having submicron-sized surface features generated by irradiating the surface with ultra short laser pulses. In one aspect, a method of processing a semiconductor substrate is disclosed that includes placing at least a portion of a surface of the substrate in contact with a fluid, and exposing that surface portion to one or more femtosecond pulses so as to modify the topography of that portion. The modification can include, e.g., generating a plurality of submicron-sized spikes in an upper layer of the surface.