-i-
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`Smith & Nephew Ex. 1016
`IPR Petition - USP 8,657,827
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`

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`WoO 02/22014 Ad
`
`—_MIUIIIITIIIITTATINATATOVRATAMTMA
`
`Published:
`—
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`bor two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations" appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`-ii-
`
`-ii-
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`

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`WO 02/22014
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`PCT/US01/28680
`
`ASSESSING THE CONDITION OF A JOINT AND
`
`DEVISING TREATMENT
`
`This invention was supported in part by a National Institute of Health Grant No. PAR-97-
`
`014, and the government may haverights in this invention.
`
`BACKGROUND OF THE INVENTION
`
`FIELD OF INVENTION
`
`This invention relates to assessing the condition of a joint and the use of the assessment in
`
`aiding in prevention of damage to the joint or treatment of diseased cartilage in the joint.
`
`BACKGROUND
`
`10
`
`15
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`Osteoarthritis is the most common condition to affect human joints as well as a
`
`frequent cause of locomotor pain and disability. More particularly, osteoarthritis (OA) of
`
`20
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`the knee occurs in a substantial portion of the population overthe age offifty.
`In spite of its societal
`impact and prevalence, however,
`there is a paucity of
`
`information on the factors that cause osteoarthritis to progress more rapidly in some
`
`individuals and not in others. Previously considered a “wear and tear” degenerative disease
`
`with little opportunity for therapeutic intervention, osteoarthritis is now increasingly viewed
`
`25
`
`as a dynamic process with potential for new pharmacologic and surgical
`
`treatment
`
`modalites such as cartilage transplantation, osteochondral allo- or autografting, osteotomies
`
`and tibial corticotomies with angular distraction.
`
`However, the appropriate deployment and selection of treatment interventions for
`
`OA is dependent on the development of better methods for the assessment of the condition
`
`30
`
`of a patient’s joint and the degeneration process.
`
`There is, therefore, a need for improved methods for examining the factors that
`
`influence as well as quantification of the progression of the disease.
`Magnetic resonance imaging (MRI) is an accurate non-invasive imaging technique
`for visualization of articular cartilage in osteoarthritis, particularly in knees. However,
`
`

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`WO 02/22014
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`PCT/US01/28680
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`current MRI techniques cannot provide information on the relationship between the location
`
`of the cartilage loss and variations in the load bearing areas during the walking cycle. This
`
`information is important since it has been shown that dynamic loads during walking are
`
`related to the progression of knee OA. Thus,the ability to locate cartilage defects or areas of
`
`cartilage thinning relative to the load bearing areas of the knee could be valuable in
`
`evaluating factors influencing the progression of osteoarthritis.
`
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`SUMMARYOF THE INVENTION
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`20
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`This invention relates to assessing the condition of a joint of a mammal, particularly
`
`a human subject, using the assessment to treat and monitor the subject as needed for
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`cartilage degeneration problems. While the numerousaspects of the invention are useful for
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`joints generally, they are particularly suited for dealing with the human knee. Some aspects
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`25
`
`related the static images and degeneration patterns of a cartilage, while others relate to the
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`interaction of such images and patterns to provide a better means of assessing the condition
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`ofa cartilage.
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`Oneaspect of this invention is a method for assessing the condition of a cartilage.
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`The method comprises obtaining an image of a cartilage, (preferably a magnetic resonance
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`30
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`image), converting the image to a three-dimensional degeneration pattern, and evaluating
`
`the degree of degeneration in a volume ofinterest of the cartilage. By performing this
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`method at an initial time T, and a later time T2, one can determine the change in the volume
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`of interest and evaluate what stepsto take for treatment.
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`Another aspect of this invention is a method of estimating the loss of cartilage in a
`
`joint. The method comprises obtaining a three-dimensional map ofthe cartilage at an initial
`
`time and calculating the thickness or regional volume of a region thought to contain
`
`degenerated cartilage so mapped at the initial time, obtaining a three-dimensional map of
`
`the cartilage at a later time, and calculating the thickness or regional volume ofthe region
`
`thought to contain degenerated cartilage so mapped at the later time, and determining the
`
`loss in thickness or regional volumeofthe cartilage between the later and initial times. The
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`3D map maybea thickness map, a biochemical map or a combination.
`
`Another aspect of the invention is a method for assessing the condition of cartilage
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`10
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`in a joint of a human, which method comprises electronically transferring an electronically-
`
`generated imageof a cartilage of the joint from a transferring device to a receiving device
`
`located distant from the transferring device; receiving the transferred image at the distant
`
`location; converting the transferred image to a degeneration pattern of the cartilage; and
`
`transmitting the degeneration pattern to a site for analysis.
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`15
`
`Another aspect of the invention is a method for determining the volumeofcartilage
`
`loss in a region of a cartilage defect of a cartilage in joint of a mammal. The method
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`comprises (a) determining the thickness, Dn, of the normal cartilage near the cartilage
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`defect; (b) obtaining the thickness of the cartilage defect, Dp, of the region; (c) subtracting
`
`Dp from Dn to give the thickness of the cartilage loss, Di; and (d) multiplying the Di value
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`20
`
`times the area of the cartilage defect, Ap, to give the volumeofcartilage loss.
`
`Still another aspect of the invention is a method of estimating the change of a region
`
`of cartilage in a joint of a mammal over time. The method comprises (a) estimating the
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`width or area or volume of a region of cartilage at an initial time T), (b) estimating the
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`width or area or volumeofthe region of cartilage at a later time T2, and (c) determining the
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`25
`
`change in the width or area or volumeofthe region of cartilage between the initial and the
`
`later times.
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`Still another aspect of the invention is a method of estimating the loss of cartilage in
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`a joint. The method comprises (a) defining a 3D object coordinate system of the joint at an
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`30
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`initial time, T,; (b) identifying a region of a cartilage defect within the 3D object coordinate
`system; (c) defining a volume ofinterest around theregion of the cartilage defect whereby
`the volume ofinterest is larger than the region ofcartilage defect, but does not encompass
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`the entire articular cartilage; (d) defining the 3D object coordinate system of the joint at a
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`second timepoint, T2; (e) placing the identically-sized volumeof interest into the 3D object
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`coordinate system at timepoint T, using the object coordinates of the volume of interest at
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`timepoint T,; (f) and measuring any differences in cartilage volume within the volume of
`
`interest between timepoints T; and To.
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`Another aspect of this invention is a method for providing a biochemically-based
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`map of joint cartilage.
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`The method comprises measuring a detectable biochemical
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`component throughout the cartilage, determining the relative amounts of the biochemical
`
`component throughout the cartilage; mapping the amounts of the biochemical component
`
`through the cartilage; and determining the areas of cartilage deficit by identifying the areas
`
`having an altered amount of the biochemical component present.
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`Once a mapis obtained,it can be used in assessing the condition of a cartilage at an
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`10
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`initial time and over a time period. Thus, the biochemical map may be used in the method
`
`aspects of the invention in a manner similar to the cartilage thickness map.
`
`Another aspect of this invention is a method for assessing the condition of cartilage
`
`in a joint from a distant location. The method comprises electronically transferring an
`
`electronically-generated image of a cartilage of the joint from a transferring device to a
`
`15
`
`receiving device located distant from the transferring device;
`
`receiving the transferred
`
`image at the distant location; converting the transferred image to a degeneration pattern of
`
`the cartilage; and transmitting the degeneration pattern to a site for analysis.
`
`Another aspect of the invention is a kit for aiding in assessing the condition of
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`cartilage in a joint of a mammal, which kit comprises a software program, which when
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`20
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`installed and executed on a computer reads a cartilage degeneration pattern presented in a
`
`standard graphics format and produces a computer readout showing a cartilage thickness
`
`map of the degenerated cartilage.
`
`Another aspect of this invention is a method for assessing the condition of a
`
`subject’s cartilage in a joint,
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`the method comprises obtaining a three dimensional
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`25
`
`biochemical representation of the cartilage, obtaining a morphological representation of the
`cartilage, and merging the two representations, and simultaneously displaying the merged
`
`representations on a medium. The merged representations are then used to assess the
`
`condition of a cartilage, estimate the loss of cartilage in a joint, determining the volume of
`
`cartilage loss in a region of cartilage defect, or estimating the changeof a region ofcartilage
`
`30
`
`at a particular point in time or over a period oftime.
`
`A method for correlating cartilage image data, bone image data, and opto-electrical
`
`image data for the assessment of the condition of a joint, which method comprises (a)
`
`obtaining the bone image data of the joint with a set of skin reference markers positioned in
`
`externally near the joint, (b) obtaining the opto-electrical image data of the joint with a set
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`of skin reference markers positioned in the same manner as (a), and (c) using the skin
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`reference markers to correlate the images obtained in (a) and (b) with each other, wherein
`
`each skin reference markeris detectable in the bone data and the opto-electrical data. The
`
`method also can be used to further evaluate cartilage image data that is obtained using a
`
`similarly positioned set of skin reference markers.
`
`Another aspect of the invention is a skin reference marker that comprises (a) a
`
`material detectable by an imaging technique; (b) a container for holding the material, (c) a
`
`material that causes the container to adhere to the skin of a human, and (d) a reflective
`
`material placed on the surface of the container.
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`10
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`Another aspect of the invention is a biochemical map ofa cartilage that comprises a
`
`three-dimensional representation of the distribution of the amount of the biochemical
`
`component throughoutthe cartilage.
`
`Another aspect of the invention is a method for providing a biochemically-based
`
`map of joint cartilage of a mammal, wherein the joint comprises cartilage and associated
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`15
`
`bones on either side of the joint, which method comprises (a) measuring a detectable
`
`biochemical component throughout the cartilage; (b) determining the relative amounts of
`
`the biochemical component throughout the cartilage;
`
`(c) mapping the amounts of the
`
`biochemical compo