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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. 8,383,086 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.
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`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.
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`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.
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`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.
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`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.
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`I have read U.S. Patent No. 8,383,086 (the “’086 patent”) (Ex. 1001)
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`and reviewed its prosecution history. I have also reviewed pieces of prior art that
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`are relevant in my opinion to the ’086 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
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`Action of 16 Foodstuffs, with Special Reference to the Identity of
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`Blacktongue of Dogs and Pellagra of Man,” Public Health Reports,
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`43(23):1385-1454 (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
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`Orally Bioavailable in Mice and Humans,” Nature Communications,
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`Vol. 7, Art. 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,”
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`Public Health Reports, 43(12):657-694 (1928) (“A Further Study of
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`Experimental 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.,
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`48(4):397-408 (2013) (“Mouchiroud et al.”) (Ex. 1010);
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`• Texas Agricultural Extension Service, “Good Milk for Good Meals,”
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`Texas Agricultural Experiment Station, Bulletin No. 807 (1956) (“Good
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`Milk”) (Ex. 1011);
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`• William Douglas McFarlane and Hugh Lehman Fulmer, “The
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`Colorimetric Determination of the Tyrosine and Tryptophan Content of
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`Various Crude Protein Concentrates,” Biochemical Journal, 24(6):1601-
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`1610 (1930) (Ex. 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
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`Enhances Oxidative Metabolism and Protects against High-Fat Diet-
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`Induced Obesity,” Cell Metabolism, 15:838-847 (2012) (“Cantó”) (Ex.
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`1018);
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`5
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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
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`β-secretase 1 degradation and mitochondrial gene expression in
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`Alzheimer’s mouse models,” Neurobiol. Aging, 34:1581-1588 (2013)
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`(“Gong”) (Ex. 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
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`1916,” Public Health Report, 35(12):648-713 (1920) (“Relation of Diet
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`to Pellagra 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 claim 1 of the ’086 patent is an “independent” claim
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`and claims 2-5 are “dependent” claims that depend from claim 1. Dependent
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`claims include all of the elements of the claims upon which they depend.
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`Likewise, an independent claim encompasses the subject matter of its dependent
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`claims. Accordingly, I understand that the term “pharmaceutical composition” in
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`independent claim 1 of the ’086 patent encompasses the formulations specified in
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`dependent claim 3, including food.
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`27.
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`I understand that the ’086 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, ’086 patent, at 9:3-9:10.) Accordingly, I understand the phrase “is
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`isolated” as used in claim 2 should be understood to mean “is separated or
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`substantially free from at least some of the other components of the naturally
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`occurring organism.”
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`28.
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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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`29. 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 ’086 Patent
`30. Claim 1 claims a pharmaceutical composition comprising
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`nicotinamide riboside in admixture with a carrier, wherein said composition is
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`formulated for oral administration. In claim 2, the NR is isolated from a natural or
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`synthetic source. Claim 3 specifies different forms the NR-containing formulation
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`can take, including an elixir, suspension, or food. Claim 4 requires that the
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`composition also contain tryptophan, nicotinic acid, and/or nicotinamide. Finally,
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`claim 5 specifies that the pharmaceutical composition increases NAD+
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`biosynthesis upon oral administration.
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`B. Disclosures by Goldberger et. al
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`1.
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`Claim 1
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`31. 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 pharmaceutical
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`composition (which is understood to include food, based on the legal standard
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`outlined above in paragraph 26) to prevent blacktongue. While it was not known at
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`the time that Goldberger and colleagues performed their work that cow’s milk
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`inherently contained NR, that fact is mentioned in the ’086 patent and later
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`described in detail, including with respect to skim milk, in Trammell I. (Ex. 1005,
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`Goldberger et al., at 1402-05; Ex. 1001, ’086 patent, at 3:9-12; Ex. 1007, Trammell
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`I, at 3, 5, 6.)
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`32. The NR in skim milk is in admixture with other components of the
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`milk, including components that are demonstrated in Trammell I to bind and
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`stabilize the compound. (Ex. 1007, Trammell I, at 5-6.) The skim milk in
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`Goldberger et al. was administered orally. (Ex. 1005, Goldberger et al., at 1403.)
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`Thus, Goldberger et al. teaches the administration of a pharmaceutical composition
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`that inherently contains NR in admixture with a carrier and is suitably formulated
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`for oral administration.
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`2.
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`Claim 2
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`33. Given the understanding of the term “is isolated” described above in
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`paragraph 27, the element added by claim 2 is disclosed in Goldberger et al.
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`because the NR in skim milk is isolated from a natural source, first, from the cow
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`and later from the whole milk when the fat elements of whole milk are separated
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`from the non-fat elements, including the NR. (Ex. 1005, Goldberger et al., at 1403;
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`Ex. 1011, Good Milk, at 6.)
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`3.
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`
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`Claim 3
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`34. Goldberger et al. discloses the element added in claim 3 because milk
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`is a food.
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`4.
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`
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`Claim 4
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`35. 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, satisfying the requirement added in
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`claim 4.
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`5.
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`
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`Claim 5
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`36. 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
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`above in paragraphs 13-14, directly demonstrating that oral intake of NR increases
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`NAD+ concentration in multiple tissues. Thus, Goldberger et al. teaches the oral
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`administration of a composition containing NR that necessarily increases NAD+
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`biosynthesis upon oral administration, as required by claim 5.
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`C. Disclosures by Goldberger and Tanner
`
`1.
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`
`
`Claim 1
`
`37. All of the elements of claim 1 are disclosed in Goldberger and Tanner.
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`Goldberger and Tanner teaches the administration of a pharmaceutical composition
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`(which is understood to include food, based on the legal standard outlined above in
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`paragraph 26) to prevent pellagra. While it was not known at the time that
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`Goldberger and Tanner performed their work that buttermilk contained NR and
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`buttermilk was not the form of milk in which NR was directly assayed in Trammell
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`I, it is my opinion that NR is present in buttermilk, for the reasons given above in
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`paragraph 12. The NR in buttermilk is in admixture with other soluble components
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`of the milk, including components that are demonstrated in Trammell I to bind and
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`stabilize the compound. (Ex. 1007, Trammell I, at 5-6.) The buttermilk in
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`Goldberger and Tanner was administered orally. (Ex. 1006, Goldberger and
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`Tanner, at 93.) Thus, Goldberger and Tanner teaches the administration of a
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`pharmaceutical composition that inherently contains NR in admixture with a
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`carrier that is suitably formulated for oral administration.
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`2.
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`
`
`Claim 2
`
`38. Given the understanding of the term “is isolated” described above in
`
`paragraph 27, the element added by claim 2 is disclosed in Goldberger and Tanner
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`because the NR in buttermilk is isolated from a natural source, first, from the cow,
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`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. (Ex. 1006,
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`Goldberger and Tanner, at 93; Ex. 1011, Good Milk, at 6.)
`
`3.
`
`
`
`Claim 3
`
`39. Goldberger and Tanner discloses the element added in claim 3
`
`because milk is a food.
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`4.
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`
`
`Claim 4
`
`40. As explained above in paragraph 35, 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
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`when the butter is removed.
`
`41. 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.
`
`42. Thus, the buttermilk in Goldberger and Tanner is a composition
`
`containing nicotinamide and tryptophan, satisfying the requirement added by claim
`
`4.
`
`5.
`
`
`
`Claim 5
`
`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 NR increases
`
`NAD+ concentration in multiple tissues. Thus, although the authors did not know
`
`
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`it at the time, Goldberger and Tanner inherently discloses an NR-containing
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`composition that can be orally administered and increases NAD+ biosynthesis
`
`upon oral administration.
`
`44.
`
`I hereby declare that all statements made herein of my own
`
`knowledge are true and that all statements made on information and belief are
`
`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
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`imprisonment, or both, under Section 1001 of Title XVII of the United States
`
`Code.
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`July 16, 2017
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`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 Foundation
`Breast Cancer Research Program Pre-doctoral Fellowship DAMD17-01-1-0419, US
`Department of Defense
`Sigma Xi and GSO Poster Awards
`Finalist for the Nominata Award (top UTSW Graduate Student)
`Post-doctoral Fellowship 0425834T, American Heart A