Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-10-24
2002-09-03
Carlson, Karen Cochrane (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S381000, C530S412000, C530S350000, C514S012200, C514S912000, C424S078040, C424S094640, C424S094650, C424S094660, C424S094670, C424S450000, C424S489000
Reexamination Certificate
active
06444791
ABSTRACT:
BACKGROUND OF THE INVENTION
Keratoconus is a bilateral ocular disorder that progressively thins and distorts the central portion of the cornea toward a conic shape, typically leading to substantial visual impairment and corneal scarring. Distortion of the cornea in keratoconus results from decreased resilience and low mechanical strength of the corneal tissues (Wollensak et al.,
Fortschr. Ophthalmol
. 84:28-32, 1987, incorporated herein by reference). These structural defects represent important pathogenetic factors in the disease (Edmund,
Acta Ophthalmol
. 66:134-140, 1988, incorporated herein by reference), however the mechanisms that cause these structural changes remain undefined.
To date, no specific tools have been developed to treat or prevent keratoconus. In the mildest cases, management involves the use of spectacles or soft contact lenses. More commonly, early stage management of keratoconus requires specially designed contact lenses that compensate visual defects and provide some structural support to correct corneal distortion. More advanced presentations are managed with rigid gas-permeable (RGP) contact lenses to minimize corneal distortion and correct irregular astigmatism (Koliopoulos et al.,
Ann. Ophthalmol
. 13(7):835-7, 1981, incorporated herein by reference). If satisfactory wearing time is not achieved with contact lens, or if the contact lens-corrected vision is not adequate (which may result from corneal scarring or poor fitting of the steeply sloped cone) keratoplasty is indicated.
Even with the aid of the foregoing management tools, the vision of patients with keratoconus often deteriorates beyond correction. At this point the replacement of corneal tissue by transplantation becomes the indicated treatment option. Corneal transplantation is necessary for 10% to 20% of patients with keratoconus (Kennedy et al.,
Am. J. Ophthalmol
. 101(3):267-73, 1986; and Smiddy et al.,
Ophthalmology
95:487-92, 1988, each incorporated herein by reference). However, corneal transplantation is attended by high costs, limitation of the supply of suitable corneas, and substantial risks, including risks of adverse sequelae from anesthesia, transplant failure, and transmission of tissue-borne pathogens (e.g., HIV virus) from donor tissue to the transplant recipient.
In addition to visual defects, the medical history of keratoconus patients often elicits allergic or systemic conditions. Atopic disease (allergy) is present in approximately 35% of cases (Rahi et al.,
Br. J. Ophthalmol
. 61:761-4, 1977, incorporated herein by reference). Eye rubbing, possibly a response to allergic discomfort, is reported by 20% of patients with keratoconus (Ridley,
Br. J. Ophthalmol
. 45:631, 1961, incorporated herein by reference). In addition, keratoconus has been associated with inherited systemic diseases such as Down syndrome, Lebers congenital amaurosis, osteogenesis imperfecta, and connective tissue disorders such as Ehier-Danlos syndrome.
Despite extensive clinical and research efforts, no definitive etiology has emerged for patients presenting with a diagnosis of keratoconus. Some evidence suggests that a genetic component is involved (Rabinowitz et al.,
Arch. Ophthalmol
. 108:365-371, 1990; and Jacobs et al.,
Int. Ophthalmol. Clin
. 33:249-260, 1993, each incorporated herein by reference). Other reports suggest that environmental conditions, such as excessive eye rubbing or contact lens wearing, contribute to the disease (Coyle,
Am. J. Ophthalmol
. 97:527-528, 1984; and Macsai et al.,
Arch. Ophthalmol
. 108:534-538, 1990, each incorporated herein by reference). Yet additional causes have been proposed, including atopic disease and systemic conditions.
The prevalence of atopic disease, such as hay fever and asthma, is approximately three times more common for patients with keratoconus when compared with a matched control group (Rahi et al.,
Br. J. Ophthalmol
. 61:761-4, 1977, incorporated herein by reference). Eye rubbing, perhaps a response related to the allergy, is also more frequently exhibited by patients with keratoconus (Ridley,
Br. J. Ophthalmol.
45:631, 1961, incorporated herein by reference). However, a causal association between allergy and/or eye rubbing, and the onset or progression of keratoconus, has not been established.
Other reports in the literature suggest that rigid contact lens wear is a causal factor in some cases of keratoconus (Macsai et al.,
Arch. Ophthalmol
. 108:534-8, 1990, incorporated herein by reference). This finding is difficult to substantiate, because keratoconus patients may self-select contact lens wear due to their refractive error or patient dissatisfaction with spectacles.
A variety of systemic conditions have also been associated with keratoconus. Exemplary conditions include connective tissue disease, such as Ehlers-Danlos Rieger's, Crouzon's, and Marfan's syndromes. In addition, keratoconus has been diagnosed in up to 6% of patients with Down syndrome (Skeller et al.,
Acta. Ophthalmol.
29:149-61, 1951, incorporated herein by reference).
With regard to possible genetic factors, keratoconus has been shown to carry a hereditary component in approximately 6% to 8% of patients (Kennedy et al.,
Am. J. Ophthalmol
. 101(3):267-73, 1986, incorporated herein by reference). In this context, Rabinowitz et al. (
Arch. Ophthalmol
. 108:365-71, 1990, incorporated herein by reference), have used videokeratographs to construct family pedigrees to determine modes of keratoconus heredity. The genetic component of keratoconus can be either dominant or recessive. However, the genotype of autosomal dominant is most common.
Despite the puzzling etiology of keratoconus, researchers continue to seek answers regarding the basic mechanisms underlying the onset and progression of this disease. However, to date most studies have focused on the morphological, i.e., histological and ultrastructural, changes associated with keratoconus. In this regard, it has long been noted that keratoconic corneas exhibit various ultrastructural defects, including fragmentation of Bowman's layer, fragmentation of the epithelial cell basement membrane, and fibrillation of the anterior stroma (Teng,
Am. J. Ophthalmol
. 55:1847, 1963; Chi et al.,
Am. J. Ophthalmol
. 42:847-60, 1956; and Bron et al.,
Trans. Ophthalmol. Soc. UK
98:393-6, 1978, each incorporated herein by reference). Possible causes of these defects have been suggested to include changes in the metabolism and composition of extracellular matrix materials (ECMs).
Bowman's layer is an acellular matrix at the interface between the corneal epithelium and the stroma. It links the epithelial basement membrane and the stroma proper and may be crucial for epithelial attachment and function. During human corneal epithelial development, a distinct Bowman's layer is formed at 19 weeks (Tisdale et al.,
Invest. Ophthalmol. Vis. Sci
. 29:727-736, 1988, incorporated herein by reference). After birth, the thickness of Bowman's layer remains unchanged. Components of Bowman's layer are believed to be synthesized by both corneal epithelial and stromal cells, and an epithelial-stromal interaction is suggested to be a major factor in the formation of Bowman's layer (Hay,
Int. Rev. Cytol
. 63:263-322, 1980, incorporated herein by reference).
Several years after radial keratotomy in human corneas, a Bowman's layer-like structure is formed underneath epithelial plugs that extend into the stroma (Melles et al.,
Arch. Ophthalmol
. 113:1124-1130, 1995, incorporated herein by reference). The collagen fibrils in Bowman's layer are of relatively small diameter and are randomly arranged. In the underlying corneal stroma, the resident stromal cells are responsible for the maintenance and organization of the collagens. However, considering that Bowman's layer is acellular, the organization and maintenance of collagens at this site remains unexplained. One possibility is that these functions are performed by the sparse stromal cells that transverse into Bowman's layer. Cy
Carlson Karen Cochrane
K-Quay Enterprises LLC
Kam Chih-Min
Woodcock & Washburn LLP
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