-i-
`
`Smith & Nephew Ex. 1027
`IPR Petition - USP 8,657,827
`
`

`

`The declaration of the inventor X is enclosed
`
`X unsigned.
`
`The fee has been calculated as follows:
`
`A. Basic Application Fee
`
`B. Total Claims 74 - 20 = 54
`
`C. Independent Claims 9 - 3 = 6
`
`D. If multiple dependent claims present, add
`
`E. Total Application Fee (Total of A, B, C, & D)
`
`F. If small entity status is claimed,
`reduce Total Application Fee by 50%
`
`G. Application Fee Due (E — F)
`
`x $18
`
`x $84
`
`$280
`
`=
`
`=
`
`$740
`
`$972
`
`$504
`
`0
`
`$2,216
`
`$1,108
`
`$1,108
`
`H. Assignment Recording Fee of $40.00 if
`assignment document is enclosed
`
`$40
`
`NA
`
`I.TOTALFEE(G+ID
`
`$1,108
`
`Respectfully submitted,
`
`Dahna S. Pasternak
`
`Registration No. 41,41 1
`
`Bar Code:
`
`Datezfimggm
`
`By:
`
`Customer No.: 20855
`ROBINS & PASTERNAK LLP
`
`545 Middlefield Road, Suite 180
`Menlo Park, CA 94025
`Telephone: 650-325-7812
`Facsimile: 650-325-7823
`
`
`
`Page 2/2
`
`-11-
`
`-ii-
`
`

`

`"Express Mail" Mailing Label No. EV 081 925 454 US
`Date of Deposit 28 Max 2002
`
`- I hereby certify that this paper or fee is being deposited with the United States Postal Service "Express Mail Post
`Office to Addressee" service under 37 C.F.R. § 1.10 on the date indicated above and is addressed to the
`'stant Commissioner for Patents, Washington, DC. 20231.
`
`
`
`
`Signture of Person Mailing Paper or Fee
`
`Application for US. Letters Patent Entitled
`
`METHODS AND COMPOSITIONS FOR ARTICULAR RESURFACING
`
`claiming priority to US. Provisional Application
`Serial No. 60/293,488, filed May 25, 2001,
`Serial No. 60/363,527, filed March 12, 2002,
`Serial No. 60/380,695, filed May 14, 2002, and
`Serial No. Unassigned, filed May 14, 2002
`
`
`
`:31-”
`
`
`
`by Inventors:
`
`Philipp Lang
`Barry Linder
`Daniel Steines
`
`Customer No. 20855
`ROBINS & PASTERNAK LLP
`
`545 Middlefield Road, Suite 180
`
`Menlo Park, CA 94025
`Telephone: 650-325-7812
`Facsimile: 650-325—7823
`
`Attorney Docket No. 675 0—0005
`
`411—
`
`-iii-
`
`

`

`6750-0005
`
`METHODS AND COMPOSITIONS FOR ARTICULAR RESURFACING
`
`Cross-Reference to Related Applications
`
`This application claims the benefit of US. Serial Number 60/293,488 entitled
`
`“METHODS To IMPROVE CARTILAGE REPAIR SYSTEMS", filed May 25, 2001, US. Serial
`
`Number 60/363,527, entitled "NOVEL DEVICES FOR CARTILAGE REPAIR, filed March 12,
`
`2002 and US. Serial Numbers 60/380,695 and Unassigned, entitled "METHODS AND
`
`COMPOSITIONS FOR CARTILAGE REPAIR," (Attorney Docket Number 6750—0005p2) and
`
`"METHODS AND COMPOSITIONS FOR JOINT REPAIR," (Attorney Docket Number 6750—
`
`0005p3), filed May 14, 2002, all of which applications are hereby incorporated by
`
`reference in their entireties.
`
`Technical Field
`
`The present invention relates to orthopedic methods, systems and prosthetic
`
`devices and more particularly relates to methods, systems and devices for articular
`
`resurfacing.
`
`Background
`
`There are various types of cartilage, e.g., hyaline cartilage and fibrocartilage.
`
`Hyaline cartilage is found at the articular surfaces of bones, e.g., in the joints, and is
`
`responsible for providing the smooth gliding motion characteristic of moveable joints.
`
`Articular cartilage is firmly attached to the underlying bones and measures typically less
`
`than 5mm in thickness in human joints, with considerable variation depending on joint
`
`and site Within the joint. In addition, articular cartilage is aneural, avascular, and
`
`alymphatic. In adult humans, this cartilage derives its nutrition by a double diffusion
`
`system through the synovial membrane and through the dense matrix of the cartilage to
`
`reach the chondrocyte, the cells that are found in the connective tissue of cartilage.
`
`
`
`20
`
`25
`
`

`

`6750-0005
`
`Adult cartilage has a limited ability of repair; thus, damage to cartilage produced
`
`by disease, such as rheumatoid and/or osteoarthritis, or trauma can lead to serious
`
`physical deformity and debilitation. Furthermore, as human articular cartilage ages, its
`
`tensile properties change. The superficial zone of the knee articular cartilage exhibits an
`
`increase in tensile strength up to the third decade of life, after which it decreases
`
`markedly with age as detectable damage to type II collagen occurs at the articular
`
`surface. The deep zone cartilage also exhibits a progressive decrease in tensile strength
`
`with increasing age, although collagen content does not appear to decrease. These
`
`observations indicate that there are changes in mechanical and, hence, structural
`
`organization of cartilage with aging that, if sufficiently developed, can predispose
`
`cartilage to traumatic damage.
`
`Usually, severe damage or loss of cartilage is treated by replacement of the joint
`
`with a prosthetic material, for example, silicone, e. g. for cosmetic repairs, or metal alloys.
`
`See, e.g., US. Patent No. 6,383,228, issued May 7, 2002; US. Patent No. 6,203,576,
`
`issued March 20, 2001; US. Patent No. 6,126,690, issued October 3, 2000. Implantation
`
`of prosthetic devices is usually associated with loss of underlying tissue and bone without
`
`recovery of the full function allowed by the original cartilage. Serious long-term
`
`complications associated with the presence of a permanent foreign body can include
`
`infection, osteolysis and also loosening of the implant.
`
`Further, joint arthroplasties are highly invasive and require surgical resection of
`
`the entire or the majority of the articular surface of one or more bones. With these
`
`procedures, the marrow space is reamed in order to fit the stem of the prosthesis. The
`
`reaming results in a loss of the patient’s bone stock.
`
`Osteolysis will frequently lead to loosening of the prosthesis. The prosthesis will
`
`subsequently have to be replaced. Since the patient’s bone stock is limited, the number of
`
`possible replacement surgeries is also limited for joint arthroplasty. In short, over the
`
`course of 15 to 20 years, and in some cases shorter time periods, the patients may run out
`
`of therapeutic options resulting in a very painful, non-fianctional joint.
`
`
`
`10
`
`15
`
`20
`
`25
`
`

`

`6750-0005
`
`The use of matrices, tissue scaffolds or other carriers implanted with cells (e.g.,
`
`chrondrocytes, chondrocyte progenitors, stromal cells, mesenchymal stem cells, etc.) has
`
`also been described as a potential treatment for cartilage repair. See, also, International
`
`Publications WO; 99/51719; WO 01/91672 and W0 01/17463;U.S. Patent No. 5,283,980
`
`B1, issued September 4, 2001; US. Patent No. 5,842,477, issued December 1, 1998; US.
`
`Patent No. 5,769,899, issued June 23, 1998; US. Patent No. 4,609,551, issued Sep. 2,
`
`1986; US. Patent No. 5,041,138, issued Aug. 20, 199; US. Patent No. 5,197,985, issued
`
`March 30, 1993; US. Patent No. 5,226,914, issued July13, 1993; US. Patent No.
`
`6,328,765, issued December 1 1, 2001; US. Patent No. 6,281,195, issued August 28,
`
`2001; and US Patent No. 4,846,835, issued July 11, 1989. However, clinical outcomes
`
`with biologic replacement materials such as allograft and autograft systems and tissue
`
`scaffolds have been uncertain since most of these materials cannot achieve a morphologic
`
`arrangement or structure similar to or identical to that of normal, disease-free human
`
`tissue. Moreover, the mechanical durability of these biologic replacement materials is
`
`not certain.
`
`Despite the large number of studies in the area of cartilage repair, the integration
`
`of the cartilage replacement material with the surrounding cartilage of the patient has
`
`proven difficult. In particular, integration can be extremely difficult due to differences in
`
`
`
`thickness and curvature between the surrounding cartilage and/or the underlying
`
`20
`
`subchondral bone and the cartilage replacement material.
`
`Thus, there remains a need for methods and compositions for joint repair,
`
`including methods and compositions that facilitate the integration between the cartilage
`
`replacement system and the surrounding cartilage.
`
`25
`
`Summary
`
`The present invention provides novel devices and methods for replacing a portion
`
`(e.g., diseased area and/or area slightly larger than the diseased area) of a joint (e.g.,
`
`cartilage and/or bone) with a non-pliable, non-liquid (e.g., hard) implant material, where
`
`the implant_achieves a near anatomic fit with the surrounding structures and tissues. In
`
`

`

`675 0—0005
`
`cases Where the devices and/or methods include an element associated with the
`
`underlying articular bone, the invention also provides that the bone-associated
`
`element achieves a near anatomic alignment with the subchondral bone. The invention
`
`also provides for the preparation of an implantation site a single cut.
`
`In one aspect, the invention includes a method for providing articular replacement
`
`material, the method comprising the step of producing articular replacement (e.g.,
`
`cartilage replacement material) of selected dimensions (e.g., size, thickness and/or
`
`curvature).
`
`In another aspect, the invention includes a method of making cartilage repair
`
`material, the method comprising the steps of (a) measuring the dimensions (e.g.,
`
`thickness, curvature and/or size) of the intended implantation site or the dimensions of
`
`the area surrounding the intended implantation site; and (b) providing cartilage
`
`replacement material that conforms to the measurements obtained in step (a). In certain
`
`aspects, step (b) comprises measuring the thickness of the cartilage surrounding the
`
`intended implantation site and measuring the curvature of the cartilage surrounding the
`
`intended implantation site. In other embodiments, step (a) comprises measuring the size
`
`of the intended implantation site and measuring the curvature of the cartilage surrounding
`
`the intended implantation site. In other embodiments, step (a) comprises measuring the
`
`thickness of the cartilage surrounding the intended implantation site, measuring the size
`
`of the intended implantation site, and measuring the curvature of the cartilage
`
`surrounding the intended implantation site.
`
`In any of the methods described herein, or more components of the articular
`
`replacement material (e.g., the cartilage replacement material) is non-pliable, non-liquid,
`
`solid or hard. The dimensions of the replacement material may be selected following
`
`intraoperative measurements, for example measurements made using imaging techniques
`
`such as ultrasound, MRI, CT scan, X-ray imaging obtained with X-ray dye and
`
`fluoroscopic imaging. A mechanical probe (with or Without imaging capabilities) may
`
`also be used to selected dimensions, for example an ultrasound probe, a laser, an optical
`
`probe and a deformable material.
`
`
`
`20
`
`25
`
`

`

`6750-0005
`
`In any of the methods described herein, the replacement material may be selected
`
`(for example, from a pre-existing library of repair systems), grown from cells and/or
`
`hardened from various materials. Thus, the material can be produced pre- or post-
`
`operatively. Furthermore, in any of the methods described herein the repair material may
`
`also be shaped (e.g., manually, automatically or by machine), for example using
`
`mechanical abrasion, laser ablation, radiofrequency ablation, cryoablation and/or
`
`enzymatic digestion.
`
`In any of the methods described herein, the articular replacement material may
`
`comprise synthetic materials (e.g., metals, polymers, alloys or combinations thereof) or
`
`biological materials such as stem cells, fetal cells or chondrocyte cells.
`
`In another aspect, the invention includes a method of repairing a cartilage in a
`
`subject, the method of comprising the step of implantating cartilage repair material
`
`prepared according to any of the methods described herein.
`
`In yet another aspect, the invention provides a method of determining the
`
`curvature of an articular surface, the method comprising the step of (a) intraoperatively
`
`measuring the curvature of the articular surface using a mechanical probe. The articular
`
`surface may comprise cartilage and/or subchondral bone. The mechanical probe (with or
`
`Without imaging capabilities) may include, for example an ultrasound probe, a laser, an
`
`optical probe and/or a deformable material.
`
`In a still further aspect, the invention provides a method of producing an articular
`
`replacement material comprising the step of providing an articular replacement material
`
`that conforms to the measurements obtained by any of the methods of described herein.
`
`In a still further aspect, the invention includes a partial articular prosthesis
`
`comprising a first component comprising a cartilage replacement material; and a second
`
`component comprising one or more metals, wherein said second component has a
`
`curvature similar to subchondral bone, wherein said prosthesis comprises less than about
`
`80% of the articular surface. In certain embodiments, the first and/or second component
`
`comprises a non—pliable material (e.g., a metal, a polymer, a metal allow, a solid
`
`biological material). Other materials that may be included in the first and/or second
`
`
`
`20
`
`25
`
`

`

`6750—0005
`
`components include polymers, biological materials, metals, metal alloys or combinations
`
`thereof. Furthermore, one or both components may be smooth or porous (or porous
`
`coated). In certain embodiments, the first component exhibits biomechanical properties
`
`(e.g., elasticity, resistance to axial loading or shear forces) similar to articular cartilage.
`
`The first and/or second component can be bioresorbable and, in addition, the first or
`
`second components may be adapted to receive injections.
`
`In another aspect, a partial articular prosthesis comprising an external surface
`
`located in the load bearing area of an articular surface, wherein the dimensions of said
`
`external surface achieve a near anatomic fit with the adjacent cartilage is provided. The
`
`prosthesis of may further comprise one or more metals or metal alloys.
`
`In yet another aspect, an articular repair system comprising (a) cartilage
`
`replacement material, wherein said cartilage replacement material has a curvature similar
`
`to surrounding or adjacent cartilage; and (b) at least one non-biologic material, wherein
`
`said articular surface repair system comprises a portion of the articular surface equal to or
`
`smaller than the weight-bearing surface is provided. In certain embodiments, the
`
`cartilage replacement material is non—pliable (e.g., hard hydroxyapatite, etc.). In certain
`
`embodiments, the system exhibits biomechanical (e.g, elasticity, resistance to axial
`
`loading or shear forces) and/or biochemical properties similar to articular cartilage. The
`
`first and/or second component can be bioresorbable and, in addition, the first or second
`
`
`
`20
`
`components may be adapted to receive injections.
`
`In a still further aspect of the invention, an articular surface repair system
`
`comprising a first component comprising a cartilage replacement material, wherein said
`
`first component has dimensions similar to that of adjacent or surrounding cartilage; and a
`
`second component, wherein said second component has a curvature similar to
`
`25
`
`subchondral bone, wherein said articular surface repair system comprises less than about
`
`80% of the articular surface (e.g., a single femoral condyle, tibia, etc.) is provided. In
`
`certain embodiments, the first component is non—pliable (e.g., hard hydroxyapatite, etc.).
`
`In certain embodiments, the system exhibits biomechanical (e.g., elasticity, resistance to
`
`axial loading or shear forces) and/or biochemical properties similar to articular cartilage.
`
`

`

`6750-0005
`
`The first and/or second component can be bioresorbable and, in addition, the first or
`
`second components may be adapted to receive injections. In certain embodiments, the
`
`first component has a curvature and thickness similar to that of adjacent or surrounding
`
`cartilage. The thickness and/or curvature may vary across the implant material.
`
`In a still further embodiment, a partial articular prosthesis comprising (a) a metal
`
`or metal alloy; and (b) an external surface located in the load bearing area of an articular
`
`surface, wherein the external surface designed to achieve a near anatomic fit with the
`
`_ adjacent cartilage is provided.
`
`Any of the repair systems or prostheses described herein (e.g., the external
`
`surface) may comprise a polymeric material, for example attached to said metal or metal
`
`alloy. Further, any of the systems or prostheses described herein can be adapted to
`
`receive injections, for example, through an opening in the external surface of said
`
`cartilage replacement material (e.g., an opening in the external surface terminates in a
`
`plurality of openings on the bone surface). Bone cement, therapeutics, and/or other
`
`bioactive substances may be injected through the opening(s). In certain embodiments,
`
`bone cement is injected under pressure in order to achieve permeation of portions of the
`
`marrow space with bone cement.
`
`These and other embodiments of the subject invention will readily occur to those
`
`of skill in the art in light of the disclosure herein.
`
`Brief Description of the Figures
`
`The file of this patent contains at least one drawing executed in color. Copies of
`
`this patent with color drawing(s) will be provided by the Patent and Trademark Office
`
`upon request and payment of the necessary fee.
`
`FIG. 1 is a flowchart depicting various methods of the present invention
`
`including, measuring the size of an area of diseased cartilage or cartilage loss, measuring
`
`the thickness of the adjacent cartilage, and measuring the curvature of the articular
`
`surface and/or subchondral bone. Based on this information, a best fitting implant can be
`
`
`
`20
`
`25
`
`

`

`6750—0005
`
`selected from a library of implants or a patient specific custom implant can be generated.
`
`The implantation site is subsequently prepared and the implantation is performed.
`
`FIG. 2 is a color reproduction of a three-dimensional thickness map of the
`
`articular cartilage of the distal femur. Three-dimensional thickness maps can be
`
`generated, for example, from ultrasound, CT or MRI data. Dark holes within the
`
`substances of the cartilage indicate areas of full thickness cartilage loss.
`
`FIG. 3 shows an example of a Placido disc of concentrically arranged circles of
`
`light.
`
`FIG. 4 shows an example of a projected Placido disc on a surface of fixed
`
`lO
`
`curvature.
`
`FIG. 5 shows an example of a 2D color-coded topographical map of an
`
`irregularly curved surface.
`
`FIG. 6 shows an example of a 3D color-coded topographical map of an
`
`irregularly curved surface.
`
`FIG. 7 shows a reflection resulting from a projection of concentric circles of light
`
`(Placido Disk) on each femoral condyle, demonstrating the effect of variation in surface
`
`contour on the reflected circles.
`
`FIG. 8A—H are schematics of various stages of knee resurfacing. FIG. 8A shows
`
`an example of normal thickness cartilage in the anterior, central and posterior portion of a
`
`femoral condyle 800 and a cartilage defect 805 in the posterior portion of the femoral
`
`condyle. FIG. 8B shows an imaging technique or a mechanical, optical, laser or
`
`ultrasound device measuring the thickness and detecting a sudden change in thickness
`
`indicating the margins of a cartilage defect 810. FIG. 8C shows a weight-bearing surface
`
`815 mapped onto the articular cartilage. Cartilage defect 805 is located within the weight-
`
`bearing surface 815. FIG. 8D shows an intended implantation site (stippled line) 820 and
`
`cartilage defect 805. The implantation site 820 is slightly larger than the area of diseased
`
`cartilage 805. FIG. 8E depicts placement of a single component articular surface repair
`
`system 825. The external surface of the articular surface repair system 826 has a
`
`curvature similar to that of the surrounding cartilage 800 resulting in good postoperative
`
`
`
`20
`
`25
`
`

`

`675 0-0005
`
`alignment between the surrounding normal cartilage 800 and the articular surface repair
`
`system 825. FIG. 8F shows an exemplary multi-component articular surface repair
`
`system 830. The distal surface of the deep component 832 has a curvature similar to that
`
`of the adjacent subchondral bone 835. The external surface of the superficial component
`
`837 has a thickness and curvature similar to that of the surrounding normal cartilage 800.
`
`FIG. 8G shows an exemplary single component articular surface repair system 840 with
`
`a'peripheral margin 845 substantially non-perpendicular to the surrounding or adjacent
`
`normal cartilage 800. FIG. 8H shows an exemplary multi-component articular surface
`
`repair system 850 With a peripheral margin 845 substantially non-perpendicular to the
`
`surrounding or adjacent normal cartilage 800.
`
`FIG. 9, A through E, are schematics depicting exemplary knee imaging and
`
`resurfacing. FIG. 9A is a schematic depicting a magnified View of an area of diseased
`
`cartilage 905 demonstrating decreased cartilage thickness when compared to the
`
`surrounding normal cartilage 900. The margins 910 of the defect have been determined.
`
`FIG. 9B is a schematic depicting measurement of cartilage thickness 915 adjacent to the
`
`defect 905. FIG. 9C is a schematic depicting placement of a multi-component mini-
`
`prosthesis 915 for articular resurfacing. The thickness 920 of the superficial component
`
`923 closely approximates that of the adjacent normal cartilage 900 and varies in different
`
`regions of the prosthesis. The curvature of the distal portion of the deep component 925 is
`
`similar to that of the adjacent subchondral bone 930. FIG. 9D is a schematic depicting
`
`placement of a single component mini-prosthesis 940 utilizing fixturing stems 945. FIG.
`
`9E depicts placement of a single component mini-prosthesis 940 utilizing fixturing stems
`
`945 and an opening 950 for injection of bone cement 955. The mini~prosthesis has an
`
`opening at the external surface 950 for injecting bone cement 955 or other liquids. The
`
`bone cement 955 can freely extravasate into the adjacent bone and marrow space from
`
`several openings at the undersurface of the mini-prosthesis 960 thereby anchoring the
`
`mini-prosthesis.
`
`FIG. 10A to C, are schematics depicting other exemplary knee resurfacing
`
`devices and methods. FIG 10A is a schematic depicting normal thickness cartilage in the
`
`
`
`20
`
`25
`
`

`

`6750-0005
`
`anterior and central and posterior portion of a femoral condyle 1000 and a large area of
`
`diseased cartilage 1005 in the posterior portion of the femoral condyle. FIG. 10B depicts
`
`placement of a single component articular surface repair system 1010. The implantation
`
`site has been prepared with a single cut. The articular surface repair system is not
`
`perpendicular to the adjacent normal cartilage 1000. FIG. 10C depicts a multi-
`
`component articular surface repair system 1020. The implantation site has been prepared
`
`with a single cut. The deep component 1030 has a curvature similar to that of the adjacent
`
`subchondral bone 1035. The superficial component 1040 has a curvature similar to that of
`
`the adjacent cartilage 1000.
`
`FIG. 11A and B show exemplary single and multiple component devices. FIG
`
`11A shows an exemplary a single component articular surface repair system 1100 with
`
`varying curvature and radii. In this case, the articular surface repair system is chosen to
`
`include convex and concave portions. Such devices can be preferable in a lateral femoral
`
`condyle or small joints such as the elbow joint. FIG. 11B depicts a multi-component
`
`articular surface repair system with a deep component 1110 that mirrors the shape of the
`
`subchondral bone and a superficial component 1105 closely matching the shape and
`
`curvature of the surrounding normal cartilage 1115. The deep component 1110 and the
`
`superficial component 1 105 demonstrate varying curvatures and radii with convex and
`
`concave portions.
`
`Detailed Description of the Invention
`
`The current invention provides for methods and devices for integration of
`
`cartilage replacement or regenerating materials.
`
`Before describing the present invention in detail, it is to be understood that this
`
`invention is not limited to particular formulations or process parameters as such may, of
`
`course, vary. It is also to be understood that the terminology used herein is for the
`
`purpose of describing particular embodiments of the invention only, and is not intended
`
`to be limiting.
`
`15
`
`20
`
`25
`
`
`
`10
`
`

`

`6750—0005
`
`The practice of the present invention employs, unless otherwise indicated,
`
`conventional methods of x—ray imaging and processing, x—ray tomosynthesis, ultrasound
`
`including A—scan, B—scan and C-scan, computed tomography (CT scan), magnetic
`
`resonance imaging (MRI), optical coherence tomography, single photon emission
`
`tomography (SPECT) and positron emission tomography (PET) within the skill of the art.
`
`Such techniques are explained fully in the literature. See, e.g., X-Ray Structure
`
`Determination: A Practical Guide, 2nd Edition, editors Stout and Jensen, 1989, John
`
`Wiley & Sons, publisher; Body CT: A Practical Approach, editor Slone, 1999, McGraw-
`
`Hill publisher; X—ray Diagnosis: A Physician's Approach, editor Lam, 1998 Springer—
`
`10
`
`Verlag, publisher; and Dental Radiology: Understanding the X—Ray Image, editor Laetitia
`
`Brocklebank 1997, Oxford University Press publisher.
`
`All publications, patents and patent applications cited herein, whether above or
`
`below, are hereby incorporated by reference in their entirety.
`
`It must be noted that, as used in this specification and the appended claims, the
`“ 3’
`CC
`singular forms a , an”, and “the” include plural references unless the content clearly
`
`dictates otherwise. Thus, for example, reference to “an implantation site” includes a one
`
`or more such sites.
`
`Definitions
`
`20
`
`25
`
`Unless defined otherwise, all technical and scientific terms used herein have the
`
`same meaning as commonly understood by one of ordinary skill in the art to which the
`
`invention pertains. Although any methods and materials similar or equivalent to those
`
`described herein can be used in the practice for testing of the present invention, the
`
`preferred materials and methods are described herein.
`
`The term "arthritis" refers to a group of conditions characterized by progressive
`
`deterioration ofjoints. Thus, the term encompasses a group of different diseases
`
`including, but not limited to, osteoarthritis (OA), rheumatoid arthritis, seronegative
`
`spondyloarthropathies and posttraumatic joint deformity.
`
`
`
`11
`
`

`

`6750-0005
`
`The term "articular" refers to any joint. Thus, "articular cartilage" refers to
`
`cartilage in a joint such as a knee, ankle, hip, etc. The term "articular surface" refers to a
`
`surface of an articulating bone that is covered by cartilage. For example, in a knee joint
`
`several different articular surfaces are present, e. g. in the patella, the medial femoral
`
`condyle, the lateral femoral condyle, the medial tibial plateau and the lateral tibial
`
`plateau.
`
`The term “weight-bearing surface” refers to the contact area between two
`
`opposing articular surfaces during activities of normal daily living.
`
`The term "cartilage" or "cartilage tissue" as used herein is generally recognized in
`
`10
`
`the art, and refers to a specialized type of dense connective tissue comprising cells
`
`embedded in an extracellular matrix (ECM) (see, for example, Cormack, 1987, Ham's
`
`Histology, 9th Ed., J. B. Lippincott Co., pp. 266-272). The biochemical composition of
`
`cartilage differs according to type Several types of cartilage are recognized in the art,
`
`including, for example, hyaline cartilage such as that found Within the joints, fibrous
`
`15‘
`
`cartilage such as that found Within the meniscus and costal regions, and elastic cartilage.
`
`Hyaline cartilage, for example, comprises chondrocytes surrounded by a dense ECM
`
`consisting of collagen, proteoglycans and water. Fibrocartilage can form in areas of
`
`hyaline cartilage, for example after an injury or, more typically, after certain types of
`
`surgery. The production of any type of cartilage is intended to fall Within the scope of the
`
`
`
`20
`
`invention.
`
`Furthermore, although described primarily in relation to methods for use in
`
`humans, the invention may also be practiced so as repair cartilage tissue in any mammal
`
`in need thereof, including horses, dogs, cats, sheep, pigs, among others. The treatment of
`
`such animals is intended to fall Within the scope of the invention.
`
`25
`
`The terms "articular repair system" and "articular surface repair system" include
`
`any system (including, for example, compositions, devices and techniques) to repair, to
`
`replace or to regenerate a portion of a joint or an entire joint. The term encompasses
`
`systems that repair articular cartilage, articular bone or both bone and cartilage. Articular
`
`surface repair systems may also include a meniscal repair system (e.g., meniscal repair
`
`12
`
`

`

`6750—0005
`
`system can be composed of a biologic or non-biologic material), for example a meniscal
`
`repair system having biomechanical and/or biochemical properties similar to that of
`
`healthy menisci. See, for example, U.S. Patent Publication No. US 2002/00228841A1.
`The meniscal repair system can be surgically or arthroscopically attached to the joint
`
`capsule or one or more ligaments. Non-limiting examples of repair systems include
`
`autologous chondrocyte transplantation, osteochondral allografting, osteochondral
`
`autografting, tibial corticotomy, femoral and/or tibial osteotomy. Repair systems also
`
`include treatment with cartilage or bone tissue grown ex vivo, stem cells, cartilage
`
`material grown with use of stem cells, fetal cells or immature or mature cartilage cells, an
`
`artificial non-human material, an agent that stimulates repair of diseased cartilage tissue,
`
`an agent that stimulates growth of cells, an agent that protects diseased cartilage tissue
`
`and that protects adjacent normal cartilage tissue. Articular repair systems include also
`
`treatment with a cartilage tissue transplant, a cartilage tissue graft, a cartilage tissue
`
`implant, a cartilage tissue scaffold, or any other cartilage tissue replacement or
`
`regenerating material. Articular repair systems include also surgical tools that facilitate
`
`the surgical procedure required for articular repair, for example tools that prepare the area
`
`of diseased cartilage tissue and/or subchondral bone for receiving, for example, a
`
`cartilage tissue replacement or regenerating material. The term "non-pliable" refers to
`
`material that cannot be significantly bent but may retain elasticity.
`
`The terms "replacement material" or "regenerating material" include a broad
`
`range of natural and/or synthetic materials used in the methods described herein, for
`
`example, cartilage or bone tissue grown ex vivo, stem cells, cartilage material grown from
`
`stem cells, stem cells, fetal cell, immature or mature cartilage cells, an agent that
`
`stimulates growth of cells, an artificial non-human material, a cartilage tissue transplant,
`
`a cartilage tissue graft, a cartilage tissue implant, a cartilage tissue scaffold, or a cartilage
`
`tissue regenerating material. The term includes biological materials isolated from various
`
`sources (e.g., cells) as well as modified (e.g., genetically modified) materials and/or
`
`combinations of isolated and modified materials.
`
`
`
`20
`
`25
`
`13
`
`

`

`6750-0005
`
`The term "imaging test" includes, but is not limited to, x-ray based techniques
`
`(such as conventional film based x-ray films, digital x-ray images, single and dual x—ray
`
`absorptiometry, radiographic absorptiometry); digital x-ray tomosynthesis, x-ray imaging
`
`including digital x-ray tomosynthesis with use of x—ray contrast agents, for example after
`
`intra—articular injection, ultrasound including broadband ultrasound attenuation
`
`measurement and speed of sound measurements, A—scan, B-scan and C—scan; computed
`
`tomography; nuclear scintigraphy; SPECT; positron emission tomography, optical
`
`coherence tomography and MRI. One or more of these imaging tests may be used in the
`
`methods described herein, for example in order to obtain certain morphological
`
`information about one or several tissues such as bone including bone mineral density and
`
`curvature of the subchondral bone, cartilage including biochemical composition of
`
`cartilage, cartilage thickness, cartilage volume, cartilage curvature, size of an area of
`
`diseased cartilage, severity of cartilage disease or cartilage loss, marrow including
`
`marrow composition, synovium including synovial inflammation, lean and fatty tissue,
`
`and thickness, dimensions and volume of soft and hard tissues. The imaging test can be
`
`performed with use of a contrast agent, such as Gd—DTPA in the case of MRI.
`
`The term “A -— scan ” refers to an ultrasonic technique Where an ultrasonic source
`
`transmits an ultrasonic wave into an object, such as patient's body, and the amplitude of
`
`the returning echoes (signals) are recorded as a function of