Document ID: FDA-2009-Q-0301-0011
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Posted Date: 2009-12-08T05:00Z

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<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:72.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 13.02pt">Section C:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:114.40pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 13.02pt">ANALYTICAL DATA REGARDING THE SUBSTANCE</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:176.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">S</FONT></FONT></u><u><FONT COLOR="000000"><FONT STYLE="font-size: 9.48pt">ECTION </FONT></FONT></u><u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">C</FONT></FONT></u><u><FONT COLOR="000000"><FONT STYLE="font-size: 9.48pt">ONTENTS</FONT></FONT></u></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:486.00pt;top:176.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Page</FONT></FONT></u></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:204.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Introduction............................................................................................................................2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:231.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Analytical Attributes of the Substance ..................................................................................3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:259.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Protein................................................................................................................................4</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:273.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Process ...............................................................................................................................5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:286.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Finished Product Characteristics........................................................................................6</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:300.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Preclinical Indicators of Functionality...............................................................................8</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:314.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Clinical Evidence of Functionality ..................................................................................11</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:342.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Section Appendices..............................................................................................................12</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:397.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C-I:  21 CFR 184.1979c - Whey Protein Concentrate</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:429.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C-II:  TNBS Method for Alpha amino-Nitrogen/Total Nitrogen</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:458.20pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C-III:  2006 Directive of the Commission of European Communities</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:472.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on infant formulae and follow-on formulae</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:507.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C-IV:  BLG ELISA Method</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:542.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C-V:  Molecular Weight Graphs</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:577.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C-VI:  Method for Peptide Profiling by SE-HPLC</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:612.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C-VII:  Method for SDS-PAGE</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:84.00pt;top:646.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C- VIII:  Preclinical Indicators Graphs</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:792.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:1534.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:864.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Introduction</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:890.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Section 101.70(f) provides that a health claim petition should contain analytical data that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:917.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">show the amount of the substance that is present “in representative foods that would be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:945.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">candidates to bear the claim” and that such data “should be obtained from the representative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:972.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">samples using methods from the Association of Official Analytical Chemists (AOAC), where</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1000.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">available.”  The section goes on to provide that if no AOAC method is available, the petition</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1028.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">must contain the assay method used and data establishing the validity of the method for assaying</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1055.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the substance in food.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1095.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Although critical to both establishing and policing many health claims, the analytical data</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1122.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">requirement in the context of this Petition is somewhat anomalous in light of the fact that only</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1150.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">one food, infant formula, is at issue – and the amount of protein in that food is restricted within a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1178.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">statutorily prescribed range (1.8 – 4.5 g/100 kcal).  In practice, this range is further narrowed by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1205.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the downward trend in current recommendations from the expert medical community.  The 1998</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1233.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommendations from an expert panel under the auspices of the Life Sciences Research</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1260.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Organization were for no more than 3.4 g/100 kcal, and the international CODEX Alimentarius</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1288.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“Standard for Infant Formulas and Formulas for Special Medical Purposes Intended for Infants”</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1316.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(revised in 2007) allows a maximum of only 3.0 g/100 kcal.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1355.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">More relevant to the claim in question is the need to assure that any 100% whey-protein</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1383.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">partially hydrolyzed infant formula (PHF-W), for which such a claim may be made, is consistent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1410.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">with the analytical attributes of the PHF-W used in the clinical studies that support this proposed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1438.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">claim. The following section discusses all those analytical attributes, as well as describing the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1466.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analytical method relied upon by Nestlé to determine the precise amount of protein.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:1584.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:2326.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1656.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Analytical Attributes of the Substance</FONT></FONT></i></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1682.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">As discussed in Section B: Summary and Systematic Evaluation of Scientific Data, a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1709.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">large body of evidence supports the proposed claim regarding the link between infants’ diets</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1737.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">containing 100% whey-protein partially hydrolyzed infant formula and a reduction in the risk of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1764.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">atopic dermatitis.  Should FDA authorize a health claim regarding this link, it goes without</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1792.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">saying that only formulas for which the extensive information required by FDA has been</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1820.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">submitted to establish their adequacy to substitute for breastmilk – and for which the agency has</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1847.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thoroughly reviewed that information and found it sufficient – would be eligible to make the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1875.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">claim. It is also essential that the claim be applied only to formulas that comprise the studied</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1902.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">substance.  The main purpose of this section of the Petition is to characterize this substance in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1930.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">such a way that FDA, and manufacturers who wish to make use of such a claim, may determine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1958.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">whether a given product comprises the eligible substance.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1991.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">It should be noted, first of all, that all hydrolyzed formulas are not the same.  For</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2019.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">example, a considerable amount of data support the use of extensively hydrolyzed cow’s milk</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2046.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">protein in formulas (EHF) to reduce the risk of allergic disease, in addition to the therapeutic use</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2074.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for which they were designed.  And, although the body of evidence on EHF for use in primary</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2102.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">prevention is smaller than that collected on PHF-W, EHF are already considered useful by the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2129.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">medical community in reducing the risk of allergic disease in those infants identified as being at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2157.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“high risk”, based on their family history of atopic disease.  EHF formulas are, however,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2184.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“exempt” or “specialty” infant formulas, designed for use by infants having a diagnosed allergy</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2212.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to cow’s milk.  As such, they are not intended for use in the general/healthy infant population –</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2240.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and the much greater expense of these formulas, in addition to their lack of palatability, further</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2267.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">limits their use in the general population.  Since FDA-authorized health claims are intended for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:2376.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:3118.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2448.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the general population, this Petition is not intended to cover extensively hydrolyzed cow’s milk</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2475.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">protein in infant formulas.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2509.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Partially hydrolyzed casein/whey protein blends in infant formula (PHF-C/W) have also</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2537.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">been studied for use in primary prevention (Szajewska 2004, Han 2003, Oldaeus 1997).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2564.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">However, only one study to date has shown a statistically significant effect on allergy prevention</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2592.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(Han 2003), and the interpretation of these results is limited by the study’s short-term follow-up</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2619.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(6 months).  Consequently, this Petition is not intended to cover partially hydrolyzed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2647.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">casein/whey protein blends in infant formulas.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2681.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Of the total of 12 study cohorts in which data on PHF-W in atopic dermatitis prevention</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2708.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">have been collected, only one (Chirico 1997) used a PHF-W from another manufacturer.  All</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2736.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">other studies of PHF-W used Nestlé formulations.  In spite of slight variations over the years in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2763.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">levels and sources of protein, processing conditions, etc., these formulations have consistently</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2791.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">been shown to reduce the risk of atopic dermatitis.  Thus, Nestlé proposes that the characteristics</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2819.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of the substance eligible to carry the proposed claim be defined in terms of the functional</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2846.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">substance common to all of the Nestlé PHF-W formulations tested – i.e., a 100% whey-protein</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2874.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">partially hydrolyzed infant formula that is characterized by meeting all of the technical criteria</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2901.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">detailed in the following pages.  These criteria are discussed in order of their ease of use in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2929.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">eliminating products that are not sufficiently similar to the studied formulas to justify their</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2957.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">carrying the proposed claim.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2996.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Protein</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3036.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The first criterion for identifying an eligible infant formula product should be a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3063.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determination of the type of protein used.  The protein component in an eligible formula would</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:3168.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:3910.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3240.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consist of 100% Whey Protein in accordance with the description of "Whey protein concentrate"</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3267.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">at 21CFR 184.1979c (attached at Appendix C-I), which may or may not be further isolated (e.g.,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3295.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to reduce mineral or lactose content) and which may or may not be fortified with additional</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3323.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">amino acids.  The analytical method relied upon by Nestlé to determine the amount of protein</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3350.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(via total nitrogen) is equivalent to AOAC method #991.21.  However, as noted above, the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3378.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">amount of protein in infant formula is already sufficiently constrained by statute and by current</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3405.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">medical recommendations.  What is important from the point of view of determining eligibility</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3433.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for the proposed claim is that only protein in compliance with the 21CFR 184.1979c definition</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3461.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be used in the manufacture of the formula. If this criterion were not met in a given product, there</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3488.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">would be no basis for associating that product with the clinical substantiation for this claim, and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3516.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">so no additional criteria would need to be considered.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3556.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Process</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3595.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Any further examination of potential eligibility should focus on the hydrolysis process.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3623.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The protein in the studied formulas was hydrolyzed by a process that includes hydrolysis of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3650.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">whey protein described above with a proteolytic enzyme to provide a first enzymatic</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3678.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hydrolysate; heating the first hydrolysate for 3 to 10 minutes at a temperature of 80 degrees C to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3705.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">100 degrees C at pH 6 to 8 to denature proteins remaining intact after the first hydrolysis;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3733.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cooling the heated first hydrolysate to a temperature of 40 degrees C to 60 degrees C; subjecting</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3761.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the cooled first hydrolysate to hydrolysis with a proteolytic enzyme to hydrolyze the intact</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3788.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">denatured proteins in the first hydrolysate for providing a second hydrolysate significantly</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:3816.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reduced in allergens of protein origin; and then heating the second hydrolysate to thermally</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:3960.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:4702.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">6</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4032.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">inactivate the enzyme for providing a hydrolysate product significantly reduced in allergenic</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4059.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">potential.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:117.00pt;top:4058.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4099.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Finished Product Characteristics</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4133.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Only if a product met the first two criteria for eligibility, would it be necessary to go on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4160.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to confirm their similarity to the studied formulas through analysis of the end product of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4188.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">formula’s manufacture.  The typical end product resulting from this process can be described as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4215.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">falling within the following ranges on the following indicators of appropriate hydrolysis:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4263.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">NPN/TN %</FONT></FONT></u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">: Non-Protein Nitrogen over Total Nitrogen is widely used as a measure of</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4290.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">soluble protein created by enzyme hydrolysis.  In the 100% whey-protein partially hydrolyzed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4318.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">infant formulas (PHF-W) used in the clinical trials discussed in this Petition, NPN/TN typically</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4346.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ranges between 71 – 93%.  The analytical method used to measure NPN is equivalent to AOAC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4373.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">method #991.20.  TN is determined by the method referred to above for the measurement of total</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4401.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">protein.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4434.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Alpha amino-N/TN %</FONT></FONT></u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">:  Alpha amino-Nitrogen over Total Nitrogen is another ratio widely</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4462.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">used as a measure of what is commonly referred to as “degree of hydrolysis”.  As late as 1990,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4490.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Nestlé shared with FDA its observations that its Good Start infant formula was 17.5%</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4517.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hydrolyzed.  Similarly, a European patent owned by Nestlé (filed in 1996) describes the Nestlé</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4545.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">PHF-W formulations as 15-19% hydrolyzed.  The values seen currently in these formulas are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4572.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">typically between 9 – 14 %.  The difference between the earlier values and the current ones is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4600.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">due to the fact that the earlier values were measured by the “ninhydrin” method.  This same</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4628.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">degree of hydrolysis, as currently measured by Nestlé worldwide using the newer TNBS method,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:72pt;top:4658pt;width:144pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4663.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">1</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:4664.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">This process description is adapted from Claim 1 of United States Patent Number 5,039,532 dated August 13,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4675.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">1991, which expired in 2008.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:4752.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:5494.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">7</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4824.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">results in a lower numerical range.  The TNBS method for measuring Alpha amino-Nitrogen</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4851.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">over Total Nitrogen may be found under Appendix C-II.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:342.90pt;top:4850.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:352.90pt;top:4851.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">It should be noted here that, according</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4879.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to the European patent, in order to induce “oral tolerance” – which is theorized to be the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4907.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mechanism by which the Nestlé PHF-W formulations reduce the risk of atopic dermatitis – it is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4934.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as important for the degree of hydrolysis not to be too high, as it is for it not to be too low.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:4968.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">BLG</FONT></FONT></u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">:  Nestlé tests Beta-lactoglobulin (BLG) on a regular basis, using the ELISA method,</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:4995.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as an indicator of total immunoreactive material. BLG constitutes somewhere between 30% -</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5023.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">50% of the total immunoreactive material in whey.  Thus a BLG level below 3 mg/g protein,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5051.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">which is typical of the Nestlé PHF-W formulations, indicates that the product has no more than</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5078.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1% immunoreactive protein.  Such a level is consistent with Annex IV of European Commission</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5106.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Directive 2006/141/EC of 22 December 2006 on Infant Formulae and Follow-On Formulae</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5133.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(attached at Appendix C-III, see item 2.1), which sets forth certain conditions for an infant</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5161.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">formula claiming to reduce the risk of allergy to milk proteins.  The second listed condition (item</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5189.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(b)) is that the maximum for immunoreactive protein would be 1% of nitrogen containing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5216.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">substances in the formula.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:197.35pt;top:5214.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">3</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.35pt;top:5216.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">That is equivalent to a total of 10 mg of immunoreactive protein (as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5244.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">BLG) per g nitrogen containing substance (as protein).  The analytical method Nestlé uses to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5271.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">measure BLG may be found under Appendix C-IV.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5305.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Molecular Weight & Peptide Profile</FONT></FONT></u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">:  The median molecular weight of 100% whey-</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5333.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">protein partially hydrolyzed infant formulas (PHF-W) is typically between 1000 – 1350 Daltons.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:72pt;top:5369pt;width:144pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5374.65pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:5376.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">The method for TN in this Nestlé laboratory instruction is referenced as LI-00.556-2, which is equivalent to AOAC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5387.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">991.21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5409.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt">3</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.75pt;top:5410.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">The second criterion requires that the product label indicate that it is not intended for use in infants allergic to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5422.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">cow’s milk unless the product has been clinically proven to be tolerated by 90% of such infants.  This level of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5433.45pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">tolerance is roughly equivalent to the AAP criterion for use of the term “hypoallergenic”.  Accordingly, any product</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5445.00pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">meeting the substance definition for this claim must be labeled as not for use in infants allergic to cow’s milk.  The</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5456.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">final two criteria are discussed below.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:5544.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:6286.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">8</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5616.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Attached at Appendix C-V is a graphic illustration of how PHF-W compare on this parameter</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5643.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">with a standard intact cow’s milk formula.  Also under Appendix C-V is a typical mean</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5671.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">molecular weight distribution for these PHF-W. 50% or more of the peptides have a mean</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5699.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">molecular weight of less than 1,500 daltons, and less than 5% of the peptides greater than 5,000</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5726.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">daltons.  Nestlé’s method for peptide profiling by size exclusion chromatography is enclosed at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5754.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix C-VI.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5787.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Release Criteria</FONT></FONT></u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">: While the above criteria are useful in determining the general</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5815.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">similarity to the studied formulas, only one specific release criterion has been deemed reliable</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5843.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">enough to remain in effect, both globally and from the time these formulas were introduced,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5870.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">among the Nestlé PHF-W demonstrated as effective in the clinical trials described in Section B:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5898.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Summary and Systematic Evaluation of Scientific Data.  This criterion requires performance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5925.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consistent with a control on a test of hydrolysis called SDS-Polyacrylamide Gel Electrophoresis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5953.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(SDS-PAGE).  This test requires a semi-quantitative visual comparison, not subject to numerical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:5981.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">description.  The analytical method for this test may be found under Appendix C-VII.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:6020.80pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Preclinical Indicators of Functionality</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:6060.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Even where a potentially eligible formula has met all the preceding criteria, the agency</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6087.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">may wish to further ensure its protective effect against allergic disease through the use of some</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6115.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indicator of clinical functionality.  Nestlé has found the following preclinical testing methods</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6143.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">useful in this regard.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:6182.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">As mentioned in the section above on BLG, the protein hydrolysis process used in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6210.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">manufacturing PHF-W significantly reduces the immunoreactive protein content (>99%</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6237.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">compared to intact protein) without eliminating it completely.  And, in addition to the BLG</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:6336.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:303.00pt;top:7078.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">9</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6408.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testing described above, the residual BLG-specific allergenicity has also been determined</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6435.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">functionally by tritiated serotonin (3H serotonin) release assay.</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:6475.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The level of BLG-specific IgE mediated allergenicity of PHF-W has been determined by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6503.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">evaluating the capacity of this formula to trigger the release of serotonin (an allergic mediator)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6530.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">from sensitized mast cells. To test this, peritoneal mast cells from normal rats were labeled with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6558.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3H serotonin and sensitized passively in vitro with a pool of rat sera containing specific IgE anti-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6585.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">BLG. Then, 3H serotonin release was triggered with increasing concentrations of bovine BLG</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6613.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(as a standard) or with PHF-W or intact cows’ milk protein infant formula (CMF).  The dose-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6641.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">dependent response in 3H serotonin release (shown in Fig. I at Appendix C-VIII) has been</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6668.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">previously documented.  Significantly more PHF-W is required, on a protein equivalent basis, to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6696.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">trigger similar amounts of 3H serotonin compared to CMF (Fritsché 1997).  The residual BLG-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6723.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">specific allergenicity calculated based on this functional assay is 0.39% to 0.5% of that found in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6751.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">CMF.  These values are consistent with the corresponding values of BLG as determined by the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6779.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ELISA method.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:6818.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Using a similar animal model, consumption of PHF-W have also been demonstrated to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6846.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">induce suppression of IgE antibody as well as suppression of mast cell serotonin release, as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6873.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indicators of allergic response. In other words, intake of PHF-W leads to immunomodulatory</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6901.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mechanisms, which can decrease the allergic response to cow milk proteins (such as BLG) by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6929.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">inducing immunologic “tolerance” to these proteins.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:6968.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In these experiments, rats were orally fed either PHF-W or water (as placebo) as part of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6996.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">their diet for a period of time.  Then they were sensitized, by subcutaneous administration, with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7023.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">BLG, or with ovalbumin (a different unrelated protein, to assess the specificity of any</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:7128.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:7870.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">10</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7200.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">immunomodulation associated to the oral intake of PHF-W).  Two weeks later, specific IgE and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7227.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IgG to BLG and ovalbumin were determined by ELISA.  Fig. II (also at Appendix C-VIII) shows</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7255.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that preventive oral administration of PHF-W suppresses production of anti-BLG IgE and IgG in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7283.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">animals that were sensitized to BLG by injection.  Specific serum IgE and IgG antibody</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7310.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">production was suppressed by a factor of at least 25 (2 log5 ELISA antibody titers) compared to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7338.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IgE secretion in the control rats that were fed placebo (water) (Fritsché 1990).  In contrast,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7365.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">antibody responses to ovalbumin remained unchanged when compared to the control group given</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7393.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">water, indicating that the suppressive, or “tolerizing” mechanism is antigen specific.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:7433.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Using the same animal model, suppression of in vitro mast cell serotonin secretion has</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7460.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">also been studied as another way to evaluate the tolerizing capacity of PHF-W (Fritsché 1997).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7488.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Normal peritoneal mast cells were labeled with 3H serotonin and passively sensitized with the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7515.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sera of rats that had orally consumed PHF-W or water.  Then, 3H serotonin release was triggered</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7543.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">using increasing amounts of BLG. As expected, the mast cells from rats given water show a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7571.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">dose-dependent curve of serotonin release when exposed to increasing amounts of BLG,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7598.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consistent with an allergic response.  On the other hand, the serotonin release from mast cells</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7626.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sensitized with sera from rats fed PHF-W was completely blunted (see Fig. III, Appendix C-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7653.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">VIII).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:7693.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In summary, PHF-W not only has reduced antigenicity, as demonstrated by a reduction in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7721.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">immunoreactive protein content; but in in vivo animal experiments, PHF-W leads to functional</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7748.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">suppression of allergic response as measured by lower IgE antibody production and suppression</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7776.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of release of allergic reaction mediator (serotonin) from mast cells.  These studies suggest that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7803.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the consumption of PHF-W not only decreases the chances of allergic reaction by providing a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:7920.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:8662.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">11</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:7992.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lower antigenic load, but potentially also by promoting immunologic tolerance to cow’s milk</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8019.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">antigens.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:8059.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">This data satisfies the fourth criterion (item (d)) under the EC Directive described earlier</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8087.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for formulas that claim to reduce the risk of allergy to milk proteins: “the formulae administered</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8114.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">orally must not induce sensitization, in animals, to the intact proteins from which the infant</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8142.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">formulae are manufactured.”</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:8182.05pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Clinical Evidence of Functionality</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:8221.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The first and most important criterion (item (a)) under the EC Directive is that “Objective</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8249.15pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and scientifically verified data as proof to the claimed properties must be available.”  By analogy</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8276.75pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to the EC format, any product making this claim would – at a minimum – have to be shown by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8304.35pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“objective and scientifically verified data” to meet all of the technical characteristics described in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8331.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">this Section C: Analytical Data Regarding the Substance.  In most cases, that data would</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8359.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">demonstrate that the formula in question was equivalent to the formulas used in the body of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8387.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">scientific evidence described in Section B: Summary and Systematic Evaluation of Scientific</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8414.70pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Data.  Since a U.S. health claim (qualified or not) must rely directly on a body of clinical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8442.30pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">evidence such as this, the best and most direct evidence of eligibility to make this claim would,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8469.90pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of course, be accumulated data from several clinical trials using the potentially eligible formula -</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8497.50pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">- just as have been presented in Section B for the Nestlé PHF-W formulations described here in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8525.10pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Section C.</FONT></FONT></FONT></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:9454.55pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">12</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:245.90pt;top:9088.95pt;z-index:3;"><FONT FACE ="Times New Roman" style = "font-size: 12.00pt"><b><u><FONT COLOR="000000"><FONT STYLE="font-size: 13.02pt">S</FONT></FONT></u><u><FONT COLOR="000000"><FONT STYLE="font-size: 10.50pt">ECTION </FONT></FONT></u><u><FONT COLOR="000000"><FONT STYLE="font-size: 13.02pt">A</FONT></FONT></u><u><FONT COLOR="000000"><FONT STYLE="font-size: 10.50pt">PPENDICES</FONT></FONT></u></b></FONT></SPAN>
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