U.S. Serial No. NEW
`Preliminary Amendment
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`Attorney Docket No. 53242-701301
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`AMENDMENTS TO THE CLAIMS
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`This listing of claims replaces all prior versions and listing of claims in the above—
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`referenced patent application. The following amendments do not constitute an admission
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`regarding the patentability of the amended subject matter and should not be so construed.
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`Amendments to the claims were made for purposes of more clearly stating the claimed subject
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`matter and do not add new matter or alter the scope of the claims. Deletions are denoted by
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`[[str—ikethreu-ghfl and additions are denoted by underline.
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`Listing of the Claims
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`1.
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`(Currently Amended) A method for determining a disorder state of brain tissue in a brain
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`of a subject, comprising:
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`(a) obtaining magnetic resonance imaging (MRI) data comprising at least one MRI
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`image of the brain, the MRI image comprising a plurality of voxels, a voxel of the
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`plurality of voxels being associated with the brain tissue of the brain of the subject
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`and comprising one or more measured MRI parameters in the MRI data;
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`(b) for the voxel of the plurality of voxels, using one or more computer processors to
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`process the one or more measured MRI parameters with one or more simulated
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`MRI parameters for the voxel, the one or more simulated MRI parameters being
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`generated from one or more micro structural models at the voxel;
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`(c) for the voxel of the plurality of voxels, selecting a diagnostic model from the one
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`or more microstructural models, the diagnostic model meeting a threshold
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`congruence between the one or more measured MRI parameters and the one or
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`more simulated MRI parameters associated with the diagnostic model; and
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`(d) £9r—thaveaeel—ef—theplu-ralityef—veaeelsrusing the diagnostic model to determine
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`the disorder state of the brain tissue associated with at least the voxel.
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`2.
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`(Canceled)
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`3.
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`(Currently Amended) The method of claim [[2]];, wherein the one or more measured
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`MRI parameters are a plurality of measured MRI parameters.
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`4.
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`(Original) The method of claim 3, wherein the one or more simulated MRI parameters
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`are a plurality of simulated MRI parameters.
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`5 .
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`(Canceled)
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`-3-
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`U.S. Serial No. NEW
`Preliminary Amendment
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`Attorney Docket No. 53242-701301
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`(Currently Amended) The method of claim [[5]];, further comprising repeating (b)—(d)
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`for all other voxels of the plurality of voxels.
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`(Currently Amended) The method of claim [[5]];, further comprising repeating (b)—(d)
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`for all voxels associated with a specified region of the brain to determine disorder states
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`across the brain tissue associated with the specified region of the brain of the subject.
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`(Currently Amended) The method of claim [[5]];, further comprising repeating (b)—(d)
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`for all voxels associated with an entirety of the brain to determine disorder states of the
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`brain tissue associated with the entirety of the brain of the subject.
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`(Currently Amended) The method of claim [[5]];, further comprising repeating (a)—(d)
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`for a plurality of MRI images, each MRI image of the plurality of MRI images associated
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`with a brain selected from a plurality of brains, each brain of the plurality of brains
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`associated with a subject selected from a plurality of subjects to determine disorder states
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`of the brain tissue associated the plurality of subjects.
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`(Currently Amended) The method of an—y—ef—claimfls 6—9]]l, wherein the MRI image is
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`selected from the group consisting of: a longitudinal relaxation time (Tl)—weighted MRI
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`image, a transverse relaxation time (T2)—weighted MRI image, and a diffusion—weighted
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`MRI image.
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`(Currently Amended) The method of claim 10, wherein the measured MRI parameter is
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`selected from the group consisting of: a longitudinal relaxation time (T1), a transverse
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`relaxation time (T2), and a diffusion coefficient.
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`(Canceled)
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`(Currently Amended) The method of claim [[12]];, wherein the one or more
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`microstructural models comprise information regarding a parameter selected from the
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`group consisting of: intracellular content, extracellular content, distribution of
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`extracellular content within interstitial space, distribution of intracellular content within
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`intracellular space, and tissue geometry.
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`(Original) The method of claim 13, wherein the one or more microstructural models
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`comprise measured or predicted values of a parameter selected from the group consisting
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`of: cell density, cell shape, cell geometry, cell size, cell distribution, intercellular spacing,
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`extracellular matrix homogeneity, interstitial tortuo sity, water to protein ratio, water to
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`lipid ratio, water to carbohydrate ratio, protein to lipid ratio, protein to carbohydrate ratio,
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`10.
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`ll.
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`12.
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`13.
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`14.
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`and lipid to carbohydrate ratio.
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`-4-
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`U.S. Serial No. NEW
`Preliminary Amendment
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`Attorney Docket No. 53242-701301
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`15.
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`16.
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`17.
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`18.
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`19.
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`20.
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`21.
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`22.
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`23.
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`24.
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`25.
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`26.
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`(Original) The method of claim 14, wherein the one or more microstructural models are
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`selected from a micro structural model library.
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`(Canceled)
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`(Currently Amended) The method of claim [[16]]1_5, wherein the microstructural model
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`library is constructed by:
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`(a) creating a first microstructural model corresponding to a brain state that is not
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`associated with a disorder; and
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`(b) iteratively subjecting the first microstructural model to a perturbation, each
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`iteration producing an additional perturbed micro structural model.
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`(Canceled)
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`(Canceled)
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`(Currently Amended) The method of claim [[19]]1_7, wherein the perturbation comprises
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`an operation selected from the group consisting of: depleting cells, altering cellular
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`morphology or distribution, altering intracellular or interstitial physico—chemical
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`composition or distribution, altering extracellular matrix composition or distribution, and
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`altering intercellular spacing.
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`(Original) The method of claim 20, wherein the perturbation comprises a stochastic
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`procedure.
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`(Original) The method of claim 21, wherein the threshold congruence is determined by
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`computing an objective function between the one or more measured MRI parameters and
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`the one or more simulated MRI parameters.
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`(Original) The method of claim 22, wherein the objective function comprises an L1 norm
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`or an L2 norm.
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`(Currently Amended) The method of claim [[23]]1, wherein determining the disorder
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`state of the brain tissue associated with the voxel is achieved at an accuracy of at least
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`90%.
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`(Currently Amended) The method of claim [[23]]1, wherein determining the disorder
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`states across the brain tissue associated with the specified region of the brain is achieved
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`at an accuracy of at least 90%.
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`(Currently Amended) The method of claim [[23]]§, wherein determining the disorder
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`states of the brain tissue associated with the [[whole]]entirety of the brain of the subject is
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`achieved at an accuracy of at least 90%.
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`-5-
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`U.S. Serial No. NEW
`Preliminary Amendment
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`Attorney Docket No. 53242-701301
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`27.
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`28.
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`29.
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`30.
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`31.
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`32.
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`33.
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`34.
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`35.
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`36.
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`(Currently Amended) The method of claim [[23]]2, wherein determining the disorder
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`states of the brain tissue associated with the plurality of subjects is achieved at an
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`accuracy of at least 90%.
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`(Currently Amended) The method of claim [[23]];, wherein the disorder is a non—
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`neurodegenerative disorder.
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`(Original) The method of claim 28, wherein the disorder is selected from the group
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`consisting of: a primary neoplasm, a metastatic neoplasm, a motor neuron disease, a
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`seizure disorder, a seizure disorder with focal cortical dysplasia, multiple sclerosis, a non—
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`neurodegenerative encephalopathy, and a psychological disorder.
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`(Currently Amended) The method of an—y—eneef—claim [[23]];, wherein the disorder is a
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`neurodegenerative disorder.
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`(Original) The method of claim 30, wherein the method enables diagnosis of a
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`neurodegenerative disorder more than 5 years prior to the development of symptoms
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`associated with the neurodegenerative disorder.
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`(Original) The method of claim 30, wherein the method enables monitoring of the
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`neurodegenerative disorder at a plurality of time points, the plurality of time points
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`separated by a plurality of time intervals.
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`(Currently Amended) The method of an—y—eneef—claim 30, wherein the neurodegenerative
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`disorder is selected from the group consisting of: Alzheimer’s disease, a non—Alzheimer’s
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`dementia disorder, Parkinson’s disease, a Parkinsonism disorder, a motor neuron disease,
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`Huntington’s disease, a Huntington’s disease—like syndrome, transmissible spongiform
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`encephalopathy, chronic traumatic encephalopathy, and a tauopathy.
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`(Currently Amended) The method of claim [[27]];, further comprising constructing a
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`brain map that, for each voxel of the plurality of voxels, indicates the disorder state of the
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`brain tissue associated with the voxel.
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`(Original) The method of claim 34, further comprising displaying the brain map on a
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`graphical user interface of an electronic device of a user.
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`(Currently Amended) The method of claim 34, wherein the brain map eempr—isesis
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`selected from the group consisting of: a qualitative abnormality map: a binary
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`abnormality map: a Quantitative abnormality map: and a percent abnormality map.
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`37.
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`38.
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`(Canceled)
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`(Canceled)
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`U.S. Serial No. NEW
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`Preliminary Amendment
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`39. (Canceled)
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`40. (Canceled)
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`41. (Canceled)
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`Attorney Docket No. 53242-701301
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