Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-03-30
2002-12-17
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06495599
ABSTRACT:
This invention relates to nutritional formulas, specifically enriched infant formulas that contain long chain polyunsaturated fatty acids (LCPs or LC-PUFAs); and to methods of using such formulas to provide enhanced neurological development in infants, specifically in infants born prematurely (“preterm” infants).
BACKGROUND
Whether or not formulas designed for the preterm infant should be supplemented with LCPs, including arachidonic acid (“AA”, 20:4n-6) and/or docosahexaenoic acid (“DHA”, 22:6n-3) has become one of the most controversial issues in infant nutrition today. Several lines of logic suggest that preterm infants fed infant formulas without AA and DHA may be at increased risk of sub-optimal blood and tissue levels of these fatty acids compared to the term infant. First, DHA accumulation in the brain and retina is most rapid during the last intrauterine trimester, between 25 and 40 weeks' postmenstrual age (Clandinin, et al. 1980; Martinez, 1991) and the early months after birth (Martinez, 1991); hence, the physiologic requirement for DHA is highest during the perinatal period. Second, the supply of AA and DHA to the preterm infant may be limited due to early termination of maternal-to-fetal transfer of those fatty acids. Clandinin, et al. (1980) reported that approximately 80% of intrauterine AA and DHA accumulation occurs during the last intrauterine trimester. Third, supply may also be limited due to immature de novo synthesis of AA and DHA from their dietary essential precursor fatty acids, linoleic (18:2n-6) and &agr;-linolenic (18:3n-3) acids, respectively. While it has been shown that premature infants are capable of de novo synthesis of AA and DHA (Carnielli, et al. 1996; Salem, et al. 1996; Sauerwald, et al. 1996), it is not clear whether these enzymatic pathways are sufficient in the preterm infant to meet the requirements for AA and DHA (Carlson 1997 Indeed results of randomized controlled trials with preterm infants fed formulas containing DHA but no AA have been interpreted by some to suggest more rapid maturation of retinal physiology (Birch, et al. 1993), visual function (Birch, et al. 1993; Carlson et al 1993a, 1996a) and/or neurodevelopment. However, there are also reports of impaired or slower growth in preterm infants fed formula containing DHA but no AA. For example, Carlson, et al. (1992) found slower growth from 4 to 12 months CA, as well as depressed motor development at 12 months CA (Carlson 1993c), in preterm infants fed a preterm formula containing DHA until hospital discharge followed by a term formula supplemented with DHA until 9 months CA. A second study by Carlson, et al. (1996b) also showed slower growth. In this study, preterm infants were fed a preterm formula containing DHA to 2 months CA, and growth deficits were found at 6, 9 and 12 months CA. A third study (Ryan, et al. 1998) showed slower growth in preterm infants fed a preterm formula containing DHA for two months following hospital discharge and then a term formula containing DHA for an additional four months. Growth faltering in male infants was observed at about 3 and 5 months CA.
While early nutrition and growth can be a significant predictor of later development (Hack et al 1991; Morley & Lucas 1994), there is a lack of consensus that the improvements in visual- and neurodevelopment warrant the feeding of DHA at the expense of slower growth. Thus, there remains a need for a solution that provides improved development (visual, neurological and otherwise) without the concomitant slowed growth rate associated with prior art feeding protocols.
Carlson, et al. (1993b) hypothesized that inclusion of AA in DHA-containing formulas would correct the observations of negative growth. To the applicants' knowledge, no prior studies have tested this hypothesis. To do so effectively, a study must examine growth well beyond 2 months corrected age (CA) as it is during this later time period (e.g. at 3, 5, 6, 9 and 12 months CA) that negative growth has been observed in previous studies (Carlson, et al. 1992, 1996b; Ryan, et al. 1999). Schade, et al in WO 98/44917 (published October 1998, claiming priority to U.S. application No. 60/042,366 dated Mar. 27, 1997) describe a study in which DHA and AA were fed to preterm infants in a fortified formula for 28 days or until hospital discharge, whichever was longer, but infants were then switched to a routine term infant formula without AA and DHA and followed only until 4 months CA. This study reports no differences in visual acuity and no adverse growth issues during or through 4 months CA following this short feeding interval. Vanderhoof, et al. (1999; 2000) report a study wherein preterm infants were fed a fortified formula supplemented with DHA and AA until term CA, then were switched to a standard formula supplemented with DHA and AA until 2 months CA. The 1999 paper reports data from the 2 months CA observations, and the 2000 (August) paper presented certain data to 12 months CA. Growth was found to be not different from the control, but reported outcomes did not include any enhanced development.
Importantly, no studies to date have examined the impact of feeding AA- and DHA-containing formula to premature infants for prolonged periods; e.g. to 6, 9 or 12-months CA, the age recommended in the absence of HM for cessation of formula feeding in term infants (American Academy of Pediatrics, 1998). Likewise, applicants' are aware of no studies that have examined the maturation impact of feeding AA and DHA as part of a nutrient-enriched feeding regimen specifically designed for the preterm infant beyond 6-months CA. Lucas, et al. (1992) demonstrated greater linear growth and weight gain among preterm infants fed a nutrient-enriched formula to 9-months CA compared to preterm infants fed formula designed for the term infant, but neither formula contained DHA or AA.
Further, none of the studies to date have made an attempt to control for the possible confounders of home environment and maternal intelligence. Both variables can significantly influence the development of infants.
REFERENCES
The following references are of interest. A brief description of each is found in the background discussion above or elsewhere in the application.
American Academy of Pediatrics Committee on Nutrition. Pediatric Nutrition Handbook ed 4. Elk Grove Village, Ill.: American Academy of Pediatrics, 1998.
AOAC. Official Methods of Analyses, ed 14. Arlington, Va.: AOAC, 1984, sections 28.082-28.085.
Bayley N. Bayley Scales of Infant Development. San Antonio: Psychological Corp. 1993.
Birch E, Birch D, Hoffman D, Hale L, Everett M, Uauy R. Breast-feeding and optimal visual development. J Pediatr Ophthalmol Strabismus. 1993;30:33-38.
Caldwell B, Bradley R. Home Observation for the Measurement of the Environment. Little Rock: University of Arkansas, 1984.
Carlson S E, Werkman S H, Tolley E A. The effect of long-chain n-3 fatty acid supplement on visual acuity and growth of preterm infants with and without bronchopulmonary dysplasia. Am J Clin Nutr. 1996a;63:687-697.
Carlson S E, Werkman S H. A randomized trial of visual attention of preterm infants fed docosahexaenoic acid until 2 months. Lipids. 1996b:31:85-90.
Carlson S E, Werkman S H, Rhodes P G, Tolley E A. Visual-acuity development in healthy, preterm infants: effect of marine-oil supplementation. Am J Clin Nutr. 1993a;58:35-42.
Carlson S E, Werkman S H, Peeples J M. Arachidonic acid status correlates with first year growth of preterm infants. Proc Natl Acad Sci USA. 1993b:90:1073-1077.
Carlson S E, Lipid Requirements of VLBW infants for Optimal Growth and Development, in Lipids, Learning and the Brain; Fats in Infant Formula, Report of the 103
rd
Ross Conference on Pediatric Research, Columbus, Ohio. Ross Laboratories. 1993c.
Carlson S E, Cooke R J, Werkman S H, Tolley E A. First year growth of preterm infants fed standard compared to marine oil n-3 supplemented formula. Lipids. 1992;27:901-907.
Carnielli V P, Wattimena D J, Luijendijk I H, Boerlage A, Degenhart H J, Sauer P J. The very low birth weight
Auestad Nancy
Merritt Russell J.
O'Connor Deborah L.
Abbott Laboratories
Brainard Thomas D.
Weddington Kevin E.
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