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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`ELYSIUM HEALTH, INC.
`Petitioner,
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`v.
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`TRUSTEES OF DARTMOUTH COLLEGE,
`Patent Owner.
`____________
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`U.S. Patent No. 8,197,807 B2
`____________
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`DECLARATION OF JOSEPH A. BAUR, PH.D.
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`I, Joseph A. Baur, hereby declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I have been retained by Elysium Health, Inc. (“Elysium”). I am being
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`paid for my time regardless of the outcome of this case. Beyond the compensation
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`I received for my time in this matter, I will not be affected in any way, positively
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`or negatively, by the outcome of this case.
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`II. QUALIFICATIONS
`2.
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`I am an Associate Professor of Physiology and the Director of the
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`Mouse Phenotyping, Physiology, and Metabolism Core at the Perelman School of
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`Medicine, the medical school of the University of Pennsylvania.
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`3.
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`I hold a Bachelor’s degree in Chemistry with honors from Acadia
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`University (Wolfville, NS, Canada) and received a Ph.D. from the program in
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`Integrative Physiology at the University of Texas Southwestern Medical Center at
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`Dallas.
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`4. As a postdoctoral researcher, I trained with David Sinclair at Harvard
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`Medical School, who is a world-renowned expert in sirtuins – a class of enzymes
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`that require nicotinamide adenine dinucleotide (NAD+) as a co-substrate. My
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`research particularly focused on strategies to activate these enzymes and the
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`primary research paper resulting from this work is one of the most highly cited in
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`the field, with over 3000 citations to date (Baur et al., “Resveratol improves health
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`and survival of mice on a high-calorie diet,” Nature, 444(7117):337-42 (2006)).
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`5. As an independent researcher, I have won a number of competitive
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`awards, including a New Scholar Award from the Ellison Medical Foundation and
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`the Joseph A. Pignolo, Sr. Award in Aging Research.
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`6. One of my major research interests has been in the metabolism and
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`potential benefits of NAD+ precursors, including nicotinamide riboside. I have
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`received a research grant from the National Institutes of Health to study NAD+
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`metabolism, and have recently published three papers on the subject in top journals
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`(Cell Metabolism, Hepatology, and the Journal of Biological Chemistry), with
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`several more manuscripts in preparation for publication.
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`7. I am regularly invited to give lectures at the national and international
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`level and sought out as a peer reviewer for grant applications and manuscripts
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`related to sirtuins and NAD+. Thus, I believe I am well qualified to evaluate the
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`patents and relevant literature discussed in this Declaration.
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`8. My CV is attached to this Declaration as Appendix A.
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`III. MATERIALS CONSIDERED
`9. I have read U.S. Patent No. 8,197,807 (the “’807 patent”) (Ex. 1001) and
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`reviewed its prosecution history. I have also reviewed pieces of prior art that are
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`relevant in my opinion to the ’807 patent, including the following, which are
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`discussed below:
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`• Joseph Goldberger et al., “A Study of the Blacktongue-Preventative Action
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`of 16 Foodstuffs, with Special Reference to the Identity of Blacktongue of
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`Dogs and Pellagra of Man,” Public Health Reports, 43(23):1385-1454
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`(1928) (“Goldberger et al.”) (Ex. 1005); and
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`• Joseph Goldberger and W.F. Tanner, “A Study of the Treatment and
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`Prevention of Pellagra,” Public Health Reports, 39(3):87-107 (1924)
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`(“Goldberger and Tanner”) (Ex. 1006).
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`I have also reviewed other references that illuminate the inherent properties of the
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`prior art, including the following, which are discussed below:
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`• Samuel A.J. Trammell et al., “Nicotinamide Riboside is a Major NAD+
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`Precursor Vitamin in Cow Milk,” J. of Nutrition, 146(5):965-963 (2016)
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`(“Trammell I”) (Ex. 1007);
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`• Samuel A.J. Trammell et al., “Nicotinamide Riboside is Uniquely and Orally
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`Bioavailable in Mice and Humans,” Nature Communications, Vol. 7, Art.
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`No. 12948 (2016) (“Trammell II”) (Ex. 1008);
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`• Joseph Goldberger et al., “A Further Study of Experimental Blacktongue
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`with Special Reference to the Blacktongue Preventative in Yeast,” Public
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`Health Reports, 43(12):657-694 (1928) (“A Further Study of Experimental
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`Blacktongue”) (Ex. 1009);
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`• Laurent Mouchiroud et al., “NAD+ Metabolism, a Therapeutic Target for
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`Age-Related Metabolic Disease,” Crit. Rev. Biochem Mol Biol., 48(4):397-
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`408 (2013) (“Mouchiroud et al.”) (Ex. 1010);
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`• Texas Agricultural Extension Service, “Good Milk for Good Meals,” Texas
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`Agricultural Experiment Station, Bulletin No. 807 (1956) (“Good Milk”)
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`(Ex. 1011);
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`• William Douglas McFarlane and Hugh Lehman Fulmer, “The Colorimetric
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`Determination of the Tyrosine and Tryptophan Content of Various Crude
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`Protein Concentrates,” Biochemical Journal, 24(6):1601-1610 (1930) (Ex.
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`1012);
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`• Krishna S. Tummala, et al., “Inhibition of De Novo NAD+ Synthesis by
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`Oncogenic URI Causes Liver Tumorigenesis through DNA Damage,”
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`Cancer Cell, 26:826-839 (2014) (“Tummala”) (Ex. 1017);
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`• Carles Cantó et al., “The NAD+ Precursor Nicotinamide Riboside Enhances
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`Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity,”
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`Cell Metabolism, 15:838-847 (2012) (“Cantó”) (Ex. 1018);
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`• Bing Gong et al., “Nicotinamide riboside restores cognition through an
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`upregulation of proliferator-activated receptor-y coactivator 1α regulated β-
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`secretase 1 degradation and mitochondrial gene expression in Alzheimer’s
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`mouse models,” Neurobiol. Aging, 34:1581-1588 (2013) (“Gong”) (Ex.
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`1019);
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`• Joseph Goldberger et al., “The Prevention of Pellagra: A Test of Diet
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`Among Institutional Inmates,” Public Health Reports, 30(43):3117-3131
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`(1915) (“The Prevention of Pellagra”) (Ex. 1020); and
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`• Joseph Goldberger et al., “A Study of the Relation of Diet to Pellagra
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`Incidence in Seven Textile-Mill Communities of South Carolina in 1916,”
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`Public Health Report, 35(12):648-713 (1920) (“Relation of Diet to Pellagra
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`Incidence”) (Ex. 1021).
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`IV. BACKGROUND
`A. NAD+ Biosynthesis
`10. NAD+ is a coenzyme associated with various biological activities. It
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`is synthesized in eukaryotes through four major pathways: 1) Nicotinamide is
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`phosphoribosylated by the enzyme nicotinamide phosphoribosyltransferase
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`(NAMPT) to generate nicotinamide mononucleotide, which is subsequently
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`converted to NAD+ by the action of nicotinamide mononucleotide
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`adenylyltransferases (NMNATs). 2) Nicotinic acid is phosphoribosylated by a
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`distinct phosphoribosyltransferase (NAPRT) to generate nicotinic acid
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`mononucleotide, which is subsequently converted to nicotinic acid adenine
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`dinucleotide by the action of NMNATs, and finally, is converted to NAD+ by
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`NAD synthase. This is known as the Preiss-Handler pathway. 3) Tryptophan is
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`converted to NAD+ through a complex, but well-defined series of enzymatic
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`reactions known as the de novo (kynurenine) pathway. 4) Nicotinamide riboside
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`and nicotinic acid riboside are incorporated into NAD+ synthesis pathways by the
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`action of nicotinamide riboside kinases (NRKs), which convert them to the
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`corresponding mononucleotides.
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`B. Natural Sources of Nicotinamide Riboside
`11. Nicotinamide riboside (NR) is a form of vitamin B3 that has been
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`carefully and clearly documented to be present at a substantial level in milk.
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`Trammell I determined that the NR concentration in milk typically falls in the
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`range of 4.3 +/- 2.6 micromolar (excluding one atypical sample in which 27
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`micromolar NR was detected) in raw cow’s milk, 1.9 +/- 1.0 micromolar in organic
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`skim milk and 3.1 +/- 1.6 micromolar in conventional skim milk. (Ex. 1007,
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`Trammell I, at 3, 5.) Trammell I states that the data presented in the article show
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`that approximately 40% of niacin equivalents (excluding tryptophan) in cow’s milk
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`are present as NR, with the remainder present as nicotinamide. (Id. at 6.)
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`12. While Trammell I did not directly measure NR in buttermilk, it is my
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`opinion that NR is present in buttermilk. Based on the disclosure of Trammell I, it
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`is clear that raw milk and skim milk both contain NR. Skim milk is the product that
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`remains when almost all of the cream is removed from whole milk. (Ex. 1011,
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`Good Milk, at 6.) Traditional buttermilk, such as that which was consumed by the
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`test subjects in Goldberger and Tanner (discussed below), is the product that
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`remains after butter has been churned from whole milk or cream. (Id.) Because NR
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`is a water-soluble molecule that is stable in milk (Ex. 1007, Trammell I, at 3-5), the
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`majority of NR originally present in the churned whole milk or cream remains in
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`the aqueous buttermilk when the fat-rich butter is removed. Thus, the removal of
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`butter from whole milk or cream to make buttermilk necessarily results in an
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`increase in the concentration of any NR originally present in the whole milk or
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`cream from which it was made. This is consistent with Goldberger and Tanner’s
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`finding that the pellagra-preventing activity of buttermilk is significantly higher
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`than that of butter and with their proposal that “...fresh milk and buttermilk may be
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`assumed to be quantitatively interchangeable”. (Ex. 1006, Goldberger and Tanner,
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`at 95.)
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`C. Oral Bioavailability of Nicotinamide Riboside
`13. Nicotinamide riboside taken orally contributes to NAD+ synthesis.
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`This has been documented in numerous studies, including Tummala (Ex. 1017),
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`Cantó (Ex. 1018), and Gong (Ex. 1019) showing that NR is sufficient to increase
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`the concentration of NAD+ in various mammalian tissues. (Ex. 1017, Tummala, at
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`832-33; Ex. 1018, Cantó, at 842-43; Ex. 1019, Gong, at 1583 and Figure 1.)
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`Moreover, several studies, including Trammell II, have taken the additional step of
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`incorporating stable isotopes into the NR before dosing, allowing a definitive
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`demonstration that the orally administered NR is ultimately incorporated into
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`NAD+ molecules, rather than causing an increase indirectly. (Ex. 1008, Trammell
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`II, at 5-7 and Figure 7.)
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`14. The bioavailability of NR taken orally is as great or greater than that
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`of nicotinic acid or nicotinamide. Trammell II reports the consequences of oral
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`administration of equal molar amounts of each of these precursors. NR
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`administration results in a greater peak concentration of the product, NAD+, in the
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`liver than does either of the other two precursors. (Ex. 1008, Trammell II, at 4-5
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`and Figure 5.) The area under the curve over 12 hours, reflecting the total increase
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`in NAD+ synthesis caused by the administered compound, was greater for NR than
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`for nicotinic acid, with an intermediate value for nicotinamide. (Ex. 1008,
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`Trammell II, at 4-6 and Figure 5.) Similarly, in the declaration of Charles Brenner,
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`dated January 16, 2016, and submitted on January 17, 2016 during prosecution of
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`Application No. 11/912,400, it is disclosed that oral administration of NR to a
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`human subject is more effective than oral administration of an equal molar dose of
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`nicotinamide for increasing white blood cell NAD+ concentration, and these data
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`were later published in Trammell II. (Ex. 1003, Excerpts from Prosecution History
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`of Serial No. 11/912,400, at 132-35.) Thus, NR is orally bioavailable, and its
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`bioavailability appears to be greater than that of other NAD+ precursors.
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`D. The Goldberger Studies
`15. The disease pellagra in humans and a similar condition known as
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`blacktongue in dogs are caused by deficiency in NAD+. Pellagra is characterized
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`by dermatitis, diarrhea, and dementia, and is often fatal if untreated. It was
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`prevalent in the American South in the early part of the twentieth century. The
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`primary forms of the disease are curable by provision of any precursor molecule
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`that can be used to synthesize NAD+, i.e., nicotinamide, nicotinic acid, tryptophan,
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`or nicotinamide riboside (or nicotinic acid riboside). Although symptomatic cases
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`today would be treated with purified precursors in addition to diet modification, a
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`diet rich in milk and meat is sufficient to prevent and in many cases treat pellagra,
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`and improvement in diet quality with particular attention to these components is
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`the primary recommendation for at-risk populations.
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`16. The utility of milk as a means to prevent pellagra was demonstrated
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`almost one hundred years ago by the pioneering studies of Goldberger and
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`colleagues. Goldberger, Waring, and Willets published a study in 1915 in which
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`they reported that an improvement in the quality of the diet provided to
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`institutional inmates was sufficient to completely prevent pellagra. (Ex. 1020, The
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`Prevention of Pellagra.) Meat and milk were suspected to be the active
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`ingredients, but the design of the study did not conclusively test this hypothesis.
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`(Id.) A subsequent observational study by Goldberger, Wheeler, and
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`Syndenstricker, which was reported in 1920, revealed that households receiving a
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`pint of milk or 30 grams of fresh meat per adult were at a substantially reduced risk
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`of pellagra, and that the risk further decreased with increased access to either of
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`these foods. (Ex. 1021, Relation of Diet to Pellagra Incidence, at 687-88.)
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`17.
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`In 1924, Goldberger and Tanner reported the outcome of experiments
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`designed specifically to test whether milk could prevent pellagra. (Ex. 1006,
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`Goldberger and Tanner.) Twenty-nine patients from the Georgia State Sanitarium
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`were given a diet supplemented with 40 ounces of buttermilk per day, selected
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`because this was the primary form of milk consumed in the South at the time. (Id.
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`at 93.) (In an article regarding pellagra in South Carolina households, Goldberger
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`noted that “home-churned buttermilk was the predominating form in which milk
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`was used” by the participants in the study. (Ex. 1021, Relation of Diet to Pellagra
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`Incidence, at 681.)) As noted above, buttermilk is the product that remains when
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`butter is removed from milk or cream in the process of churning. (Ex. 1011, Good
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`Milk, at 6.)
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`18. Of these patients, 19 were pellagrins (i.e., known to have periodic
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`episodes of pellagra symptoms) and 16 of those completed a full year of
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`observation. (Ex. 1006, Goldberger and Tanner, at 93.) No patient developed
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`symptoms of pellagra during the observation period. (Id.) Because their prior
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`experience with similar patients suggested that “upward of 40 or 50 per cent of the
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`group would with certainty have developed pellagra within a period of from three
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`to seven or eight months”, the authors concluded that, “…the complete absence of
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`any indication of the disease in any of this group is, in our judgment, conclusive
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`evidence of the preventive action of the buttermilk.” (Id.) The authors further
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`concluded that “milk contains the essential pellagra preventive factor or factors.”
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`(Id.)
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`19.
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`In their discussion, Goldberger and Tanner raise a number of points
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`that are relevant to their study. First, they describe unpublished work
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`demonstrating that butter is insufficient to prevent pellagra, and therefore conclude
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`that, “as the treatment and prevention of pellagra (in the specific sense) is
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`concerned, fresh milk and buttermilk may be assumed to be quantitatively
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`interchangeable.” (Id. at 95.) They further point out that milk is likely to be more
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`valuable than beef for the treatment of pellagra because it can be taken without
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`chewing or even by tube, and the condition of the mouth can cause eating to
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`become painful or impossible over the course of the disease. (Id. at 96.) The failure
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`of gelatin to prevent pellagra is discussed as evidence that something in milk and
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`meat beyond protein per se is active in the prevention of disease, and the failure of
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`a vitamin and mineral enriched diet led the authors to suggest that the pellagra
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`preventive factor must be an unrecognized vitamin or mineral complex, or might
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`reflect some quality of the specific proteins in milk and meat, such as the specific
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`mix of amino acids. (Id.) These statements proved extremely prescient.
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`20.
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`In a 1928 report, Goldberger, Wheeler, Lillie, and Rogers presented
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`their findings on dietary factors that can ameliorate or prevent blacktongue in dogs,
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`a condition that they correctly believed to be a canine form of pellagra. (Ex. 1005,
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`Goldberger et al., at 1385-86, 1446-47.) Sixteen specific factors, including milk,
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`were tested, with varying degrees of success. (Id. at 1447-48.) In this study, the
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`milk employed was fresh skim milk, given orally at a dose of approximately 30 c.c.
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`per kg of body weight daily along with “diet No. 123,” a diet that otherwise
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`produced blacktongue within approximately two months. (Id. at 1403.)
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`(Goldberger showed that diet No. 123 produced blacktongue in A Further Study of
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`Experimental Blacktongue (Ex. 1009 at 659-61).)
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`21. Five dogs were tested, with one developing a clear attack of
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`blacktongue in 37 days, one developing “slight transient evidence of an attack” at
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`the end of one year, and three others surviving 9-12 months with no evidence of
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`blacktongue. (Ex. 1005, Goldberger et al., at 1404.) The authors noted that
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`“feeding with basic diet No. 123 has regularly resulted in an attack of blacktongue
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`within a period only exceptionally longer than about two months” and summarized
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`their results by stating, “It may be concluded, therefore, that milk contains the
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`blacktongue preventive, but that somewhat more than 30 c.c. daily per kilogram of
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`body weight, at least of skim milk, may be needed to secure complete protection
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`when used to supplement such a basic diet as our No. 123.” (Id.) Thus, in both
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`humans and in dogs, milk alone was established to improve the course of or
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`prevent pellagra through the action of an unknown preventive substance.
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`V. LEGAL STANDARDS
`22.
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`I have been informed of certain legal principles that impact the
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`interpretation and analysis of the claims in this patent. My understanding of these
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`principles is set forth below.
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`23.
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`I understand that, for purposes of forming the opinions expressed in
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`this Declaration, claim terms should be given their broadest reasonable
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`interpretation in light of the specification, as understood by a person of ordinary
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`skill in the art.
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`24.
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`I understand that several factors are to be considered in determining
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`who would have been a person of ordinary skill in the art. These factors include:
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`the type of problems encountered in the art; prior art solutions to those problems;
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`rapidity with which innovations are made; sophistication of the technology; and
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`educational level of active workers in the field. In my opinion, a person of ordinary
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`skill in the art in the relevant timeframe (i.e., the mid-2000s) would have had a
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`Ph.D. in biology, biochemistry, or a similar field.
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`25.
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`I also understand that claim terms generally should be given their
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`ordinary and customary meaning, as would be understood by a person of ordinary
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`skill in the art.
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`26.
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`I understand that the ’807 patent defines “an isolated molecule” as
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`follows:
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`As used herein, an isolated molecule . . . means a molecule separated
`or substantially free from at least some of the other components of the
`naturally occurring organism, such as for example, the cell structural
`components or other polypeptides or nucleic acids commonly found
`associated with the molecule.
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`(Ex. 1001, ’807 patent, at 9:23-9:30.) Accordingly, I understand the term
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`“isolated” in claim 1 should be understood to mean “separated or substantially free
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`from at least some of the other components of the naturally occurring organism”
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`and the term “is isolated” as used in claim 2 should be understood to mean “is
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`separated or substantially free from at least some of the other components of the
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`naturally occurring organism.”
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`27.
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`I have been advised by Elysium’s attorneys that a claim is anticipated
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`when a single prior art patent or publication discloses, either expressly or
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`inherently, every limitation of the claim in the claimed arrangement.
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`28.
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`I understand that a prior art reference will anticipate a claim by
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`inherent disclosure only when the reference must necessarily include unstated
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`limitation(s). I have also been advised that with respect to inherent disclosures, it
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`is not necessary that people skilled in the art actually recognized that a reference
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`inherently made such disclosures at the time the reference was created in order to
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`establish anticipation.
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`VI. SPECIFIC ANALYSES OF ANTICIPATION
`A. Overview of the Claims of the ’807 Patent
`29. Claim 1 claims a composition comprising isolated nicotinamide
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`riboside in combination with one or more of tryptophan, nicotinic acid, and/or
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`nicotinamide, wherein the combination is in admixture with a carrier comprising a
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`sugar, starch, cellulose, powdered tragacanth, malt, gelatin, talc, cocoa butter,
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`suppository wax, oil, glycol, polyol, ester, agar, buffering agent, alginic acid,
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`isotonic saline, Ringer’s solution, ethyl alcohol, polyester, polycarbonate, or
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`polyanhydride, wherein said composition is formulated for oral administration and
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`increases NAD+ biosynthesis upon oral administration. In claim 2, the NR is
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`isolated from a natural or synthetic source. Claim 3 specifies different forms the
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`NR-containing formulation can take, including an elixir, suspension, or food.
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`B. Disclosures by Goldberger et al.
`1.
`Claim 1
`30. All of the elements of claim 1 are disclosed in Goldberger et al. (Ex.
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`1005.) Goldberger et al. teaches the administration of a composition to prevent
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`blacktongue. While it was not known at the time that Goldberger and colleagues
`16
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`performed their work that cow’s milk inherently contained NR, that fact is
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`mentioned in the ’807 patent and later described in detail, including with respect to
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`skim milk, in Trammell I. (Ex. 1005, Goldberger et al., at 1402-05; Ex. 1001, ’807
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`patent, at 3:17-20; Ex. 1007, Trammell I at 3, 5, 6.) Given the understanding of the
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`term “isolated” described above in paragraph 26, the NR in the skim milk
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`administrated by Goldberger is isolated, first, from the cow and later from the
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`whole milk when the fat elements of whole milk are separated from the non-fat
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`elements, including the NR. (Ex. 1005, Goldberger et al., at 1403; Ex. 1011, Good
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`Milk, at 6.)
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`31. As is documented in Trammell I, skim milk contains nicotinamide in
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`addition to NR. (Ex. 1007, Trammell I, at 5.) (Trammell I also notes that “[i]t has
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`long been known that the NAD+ precursors in milk include nicotinamide and
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`tryptophan.” Id. at 1.) Thus, the skim milk in Goldberger et al. necessarily is a
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`composition containing NR and nicotinamide.
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`32. The combination of NR and nicotinamide in skim milk is in admixture
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`with other components of the milk, including a sugar (i.e., lactose).
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`33. The skim milk in Goldberger et al. was administered orally.
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`34. As it is now known that blacktongue in dogs is a disease caused by
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`NAD+ deficiency, it follows that the resolution or prevention of blacktongue by
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`milk supplementation, as shown in Goldberger et al., is direct evidence that the
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`milk stimulated greater NAD+ biosynthesis upon oral administration. (Ex. 1005,
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`Goldberger et al., at 1404.) This conclusion is confirmed by later studies,
`
`discussed above in paragraphs 13-14, directly demonstrating that oral intake of NR
`
`increases NAD+ concentration in multiple tissues. Thus, Goldberger et al. teaches
`
`the oral administration of a composition containing NR that necessarily increases
`
`NAD+ biosynthesis upon oral administration, as required by claim 1.
`
`35. Thus, Goldberger et al. teaches the administration of a composition
`
`that inherently contains isolated NR in combination with nicotinamide, wherein
`
`said combination is in admixture with a carrier comprising a sugar, is suitably
`
`formulated for oral administration, and increases NAD+ biosynthesis upon oral
`
`administration.
`
`Claim 2
`
`2.
`36. Given the understanding of the term “is isolated” described above in
`
`paragraph 26, the element added by claim 2 is disclosed in Goldberger et al.
`
`because the NR in skim milk is isolated from a natural source, first, from the cow
`
`and later from the whole milk when the fat elements of whole milk are separated
`
`from the non-fat elements, including the NR. (Ex. 1005, Goldberger et al., at 1403;
`
`Ex. 1011, Good Milk, at 6.)
`
`3.
`
`Claim 3
`
`
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`37. Goldberger et al. discloses the element added in claim 3 because milk
`
`is a food.
`
`C. Disclosures by Goldberger and Tanner
`1.
`Claim 1
`38. All of the elements of claim 1 are disclosed in Goldberger and Tanner.
`
`(Ex. 1006.) Goldberger and Tanner teaches the administration of a composition to
`
`prevent pellagra. While it was not known at the time that Goldberger and Tanner
`
`performed their work that buttermilk contained NR and buttermilk was not the
`
`form of milk in which NR was directly assayed in Trammell I, it is my opinion that
`
`NR is present in the buttermilk disclosed in Goldberger and Tanner, for the reasons
`
`given above in paragraph 12. Given the understanding of the term “is isolated”
`
`described above in paragraph 26, the NR in buttermilk is isolated, first, from the
`
`cow, and later from the whole milk or cream, when the fat elements that are
`
`churned into butter are separated from the water-soluble elements, including NR.
`
`39. As explained above in paragraph 31, Trammell I documents that milk
`
`contains nicotinamide in addition to NR and notes that “[i]t has long been known
`
`that the NAD+ precursors in milk include nicotinamide and tryptophan.” (Ex.
`
`1007, Trammell I at 1, 3.) Nicotinamide, like NR, is water soluble and therefore
`
`present in buttermilk, as explained above in paragraph 12. That is, because
`
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`nicotinamide is a water-soluble molecule, it remains in the aqueous buttermilk
`
`when the butter is removed.
`
`40. Moreover, McFarlane and Fulmer’s testing of dried buttermilk
`
`powder, among other proteins, establishes that tryptophan is present in buttermilk
`
`powder. (Ex. 1012, McFarlane and Fulmer, at, e.g., 1602, 1604, 1608-09.) Indeed,
`
`the researchers concluded that “The tyrosine and tryptophan content of buttermilk
`
`powder has been found to be much higher than that of other crude protein materials
`
`investigated.” (Id. at 1609.) Tryptophan must therefore be present in the liquid
`
`buttermilk from which the buttermilk power is directly derived. Thus, the
`
`buttermilk in Goldberger and Tanner necessarily is a composition containing NR,
`
`nicotinamide, and tryptophan.
`
`41. The combination of NR and nicotinamide in buttermilk is in
`
`admixture with other components of the milk, including a sugar (i.e., lactose).
`
`42. The buttermilk in Goldberger and Tanner was administered orally.
`
`43. As it is now known that pellagra is a disease caused by NAD+
`
`deficiency, it follows that the prevention of pellagra by buttermilk supplementation
`
`demonstrated in Goldberger and Tanner is direct evidence that the buttermilk
`
`stimulated greater NAD+ biosynthesis upon oral administration. (Ex. 1006,
`
`Goldberger and Tanner, at 93.) This conclusion is confirmed by later studies,
`
`discussed above in paragraphs 13-14, directly demonstrating that oral intake of NR
`
`
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`increases NAD+ concentration in multiple tissues. Thus, although the authors did
`
`not know it at the time, Goldberger and Tanner inherently discloses an NR-
`
`containing composition that can be orally administered and increases NAD+
`
`biosynthesis upon oral administration.
`
`44. Thus, Goldberger and Tanner teaches the administration of a
`
`composition that inherently contains isolated NR in combination with nicotinamide
`
`and tryptophan in admixture with a carrier comprising a sugar that is suitably
`
`formulated for oral administration and increase NAD+ biosynthesis upon oral
`
`administration.
`
`Claim 2
`
`2.
`45. Given the understanding of the term “is isolated” described above in
`
`paragraph 26, the element added by claim 2 is disclosed in Goldberger and Tanner
`
`because the NR in buttermilk is isolated from a natural source, first, from the cow,
`
`and later from the whole milk or cream, when the fat elements that are churned
`
`into butter are separated from the water-soluble elements, including NR.
`
`Claim 3
`
`3.
`46. Goldberger et al. discloses the element added in claim 3 because milk
`
`is a food.
`
`47.
`
`I hereby declare that all statements made herein of my own
`
`knowledge are true and that all statements made on information and belief are
`
`
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`believed to be true; and further that these statements are made with knowledge that
`
`willful false statements and the like so made are punishable by fine or
`
`imprisonment, or both, under Section 1001 of Title XVII of the United States
`
`Code.
`
`
`July 16, 2017
`
`
` Joseph A. Baur
`
`
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`APPENDIX A
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`CURRICULUM VITAE
`Joseph Anthony Baur, Ph.D.
`July, 2017
`
`Institute for Diabetes, Obesity, and Metabolism, Department of Physiology
`Perelman School of Medicine, University of Pennsylvania
`Smilow Center for Translational Research, 3400 Civic Center Blvd., Room 12-114
`Tel: (215) 746 4585 • Fax: (215) 898 5408
`Baur@mail.med.upenn.edu
`
`Education
`Acadia University, Wolfville, NS, Canada
`UT Southwestern Medical Center, Dallas, TX
`Harvard Medical School, Boston, MA
`
`Professional Experience
`
`B.Sc.H.
`Ph.D.
`Postdoctoral
`Fellow
`
`1998
`2003
`2008
`
`Chemistry
`Integrative Biology
`Molecular Biology
`of Aging
`
`1998-2003
`
`2003-2008
`
`2008-2009
`
`2009-2017
`
`2016-Present
`
`2017-Present
`
`Ph.D. (Integrative Biology), Department of Cell Biology, UT Southwestern Medical
`Center, Dallas, Texas (UTSW)
`Post-Doctoral Fellow, Dr. David Sinclair, Department of Pathology Harvard Medical
`School
`Instructor, Institute for Diabetes, Obesity and Metabolism and Department of
`Physiology, Perelman School of Medicine, University of Pennsylvania
`Assistant Professor, Institute for Diabetes, Obesity and Metabolism and Department of
`Physiology, Perelman School of Medicine at the University of Pennsylvania
`Director, Mouse Phenotyping, Physiology, and Metabolism Core of the Diabetes
`Research Center, Perelman School of Medicine at the University of Pennsylvania
`Associate Professor, Institute for Diabetes, Obesity and Metabolism and Department
`of Physiology, Perelman School of Medicine at the University of Pennsylvania
`
`Honors and Awards
`
`1994
`1995
`1995
`1995
`1996
`1996-1997
`1997
`1997
`1998
`
`1999
`
`2001
`2001-2003
`
`2001
`2003
`2004-2006
`2008-2012
`
`Gold level Duke of Edinburgh’s Award (Citizenship)
`Manning Scholarship, Acadia University
`NSPI Scholarship, Nova Scotia Power Inc.
`Dr. Leverett Chipman Dev. Scholarship, Acadia University
`Chester W. Small Scholarship, Acadia University
`Clarke K. McLeod Scholarship, Acadia University
`Malcolm W. Orchard Memorial Scholarship, Acadia University
`Colville Award/Huggins Scholarship, Acadia University
`NSERC Post-Graduate Fellowship, National Science and Engineering Research Council
`(declined)
`Honorary Mention for the Howard Hughes Fellowship, Howard Hughes Research
`Institute
`New Opportunities Award NO-0005-00, Ellison Medical Fo