U.S. Patent No. 8,197,807 B2
`Petition for Inter Partes Review
`
`Filed on behalf of Elysium Health, Inc.
`
`By: Brendan T. Jones, Reg. No. 65,077 (Lead Counsel)
`Foley Hoag, LLP
`155 Seaport Boulevard
`Boston, MA 02210
`Tel: (617) 832-1000
`Email: bjones@foleyhoag.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ELYSIUM HEALTH, INC.
`Petitioner,
`
`v.
`
`TRUSTEES OF DARTMOUTH COLLEGE,
`Patent Owner.
`____________
`
`Case No.: IPR2017-01796
`U.S. Patent No. 8,197,807 B2
`____________
`
`PETITION
`for Inter Partes Review
`
`THORNE - EXHIBIT 1025
`
`
`Petition for Inter Partes Review
`
`Filed on behalf of Elysium Health, Inc.
`
`By: Brendan T. Jones, Reg. No. 65,077 (Lead Counsel)
`Foley Hoag, LLP
`155 Seaport Boulevard
`Boston, MA 02210
`Tel: (617) 832-1000
`Email: bjones@foleyhoag.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ELYSIUM HEALTH, INC.
`Petitioner,
`
`v.
`
`TRUSTEES OF DARTMOUTH COLLEGE,
`Patent Owner.
`____________
`
`Case No.: IPR2017-01796
`U.S. Patent No. 8,197,807 B2
`____________
`
`PETITION
`for Inter Partes Review
`
`THORNE - EXHIBIT 1025
`
`
`
`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
`
`I.
`II.
`
`III.
`IV.
`V.
`VI.
`
`TABLE OF CONTENTS
`INTRODUCTION................................................................................ 1
`BACKGROUND.................................................................................. 1
`A.
`The ’807 Patent ...........................................................................1
`B.
`Prosecution History of the ’807 Patent .......................................2
`SUMMARY OF CHALLENGES AND RELIEF REQUESTED ....... 5
`PERSON OF ORDINARY SKILL IN THE ART............................... 6
`CLAIM CONSTRUCTION ................................................................. 6
`SPECIFIC GROUNDS FOR PETITION............................................. 7
`A.
`Ground I: Goldberger et al. Anticipates Claims 1-3...................7
`1.
`Independent Claim 1...................................................... 11
`2.
`Dependent Claim 2 ........................................................ 15
`3.
`Dependent Claim 3 ........................................................ 16
`4.
`Conclusion ..................................................................... 17
`Ground II: Goldberger and Tanner Anticipates Claims 1-3 .... 18
`1.
`Independent Claim 1...................................................... 21
`2.
`Dependent Claim 2 ........................................................ 27
`3.
`Dependent Claim 3 ........................................................ 28
`4.
`Conclusion ..................................................................... 28
`VII. CONCLUSION .................................................................................. 29
`VIII. CERTIFICATION OF GROUND FOR STANDING ....................... 29
`IX. MANDATORY NOTICES ................................................................ 29
`A.
`Real Party in Interest................................................................ 29
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`B.
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`
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
`
`B.
`C.
`D.
`
`Related Matters ........................................................................ 29
`Lead and Back-up Counsel ...................................................... 30
`Service Information.................................................................. 30
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`TABLE OF AUTHORITIES
`
`Cases
`
`Brassica Protection Prods. LLC v. Sunrise Farms (In re Cruciferous Sprout
`Litig.),
`301 F.3d 1343 (Fed. Cir. 2002).............................................. 12, 17, 22, 29
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ............................................................................... 6
`
`SmithKline Beecham Corp. v. Apotex Corp.,
`403 F.3d 1331 (Fed. Cir. 2005).......................................................... 12, 22
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007).................................................................. 7
`
`Upsher-Smith Labs v. Pamlab, L.L.C.,
`412 F.3d 1319 (Fed. Cir. 2005).......................................................... 17, 29
`
`ChromaDex, Inc. v. Elysium Health, Inc.,
`Case No. 16-cv-02277-KES (C.D. Cal.)....................................................... 29
`
`Statutory Authorities
`
`35 U.S.C. § 102........................................................................................... 1, 5
`
`35 U.S.C. § 102(b)................................................................................ 7, 8, 18
`
`35 U.S.C. § 103(a)............................................................................................. 4
`
`Rules and Regulations
`
`37 C.F.R. § 42.100(b) ..................................................................................... 6
`
`37 C.F.R. § 42.104(a) ................................................................................... 32
`
`- iii -
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`
`
`Exhibit No.
`1001
`1002
`1003
`1004
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
`
`PETITIONER’S LIST OF EXHIBITS
`Description
`U.S. Patent No. 8,197,807 B2
`Declaration of Joseph A. Baur, Ph.D.
`Excerpts from Prosecution History of Serial No. 11/912,400
`Exhibit number not used
`Joseph Goldberger et al., “A Study of the Blacktongue-
`Preventative Action of 16 Foodstuffs, with Special Reference
`to the Identity of Blacktongue of Dogs and Pellagra of Man,”
`Public Health Reports, 43(23):1385-1454 (1928)
`(“Goldberger et al.”)
`Joseph Goldberger and W.F. Tanner, “A Study of the
`Treatment and Prevention of Pellagra,” Public Health
`Reports, 39(3):87-107 (1924) (“Goldberger and Tanner”)
`Samuel A.J. Trammell et al., “Nicotinamide Riboside is a
`Major NAD+ Precursor Vitamin in Cow Milk,” J. of
`Nutrition, 146(5):965-963 (2016) (“Trammell I”)
`Samuel AJ Trammell et al., “Nicotinamide Riboside is
`Uniquely and Orally Bioavailable in Mice and Humans,”
`Nature Communications, Vol. 7, Art. No. 12948 (2016)
`(“Trammell II”)
`Joseph Goldberger et al., “A Further Study of Experimental
`Blacktongue with Special Reference to the Blacktongue
`Preventative in Yeast,” Public Health Reports, 43(12):657-
`694 (1928)
`Laurent Mouchiroud et al., “NAD+ Metabolism, a
`Therapeutic Target for Age-Related Metabolic Disease,”
`Crit. Rev. Biochem. Mol. Biol., 48(4):397-408 (2013)
`(“Mouchiroud et al.”)
`Texas Agricultural Extension Service, “Good Milk for Good
`Meals,” Texas Agricultural Experiment Station, Bulletin No.
`807 (1956) (“Good Milk”)
`William Douglas McFarlane and Hugh Lehman Fulmer,
`“The Colorimetric Determination of the Tyrosine and
`Tryptophan Content of Various Crude Protein Concentrates,”
`Biochemical Journal, 24(6):1601-1610 (1930)
`- iv -
`
`
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
`
`Library of Congress copy of Joseph Goldberger et al., “A
`Further Study of Experimental Blacktongue with Special
`Reference to the Blacktongue Preventative in Yeast,” Public
`Health Reports, 43(12):657-694 (1928)
`Library of Congress copy of Joseph Goldberger and W.F.
`Tanner, “A Study of the Treatment and Prevention of
`Pellagra,” Public Health Reports, 39(3):87-107 (Jan. 18,
`1924)
`Library of Congress copy of Joseph Goldberger et al., “A
`Study of the Blacktongue-Preventative Action of 16
`Foodstuffs, with Special Reference to the Identity of
`Blacktongue of Dogs and Pellagra of Man,” Public Health
`Reports, 43(23):1385-1454 (1928)
`Texas A&M University Library catalogue webpage showing
`Good Milk’s publication details and call number at the
`library of Texas A&M University obtained from
`https://libcat.tamu.edu/vwebv/holdingsInfo?searchId=73&rec
`Count=50&recPointer=2&bibId=1216980 as of July 13,
`2017
`Krishna S. Tummala, et al., “Inhibition of De Novo NAD+
`Synthesis by Oncogenic URI Causes Liver Tumorigenesis
`through DNA Damage,” Cancer Cell, 26:826-839 (2014)
`(“Tummala”)
`Carles Cantó et al., “The NAD+ Precursor Nicotinamide
`Riboside Enhances Oxidative Metabolism and Protects
`against High-Fat Diet-Induced Obesity,” Cell Metabolism,
`15:838-847 (2012) (“Cantó”)
`Bing Gong et al., “Nicotinamide riboside restores cognition
`through an upregulation of proliferator-activated receptor-y
`coactivator 1α regulated β-secretase 1 degradation and
`mitochondrial gene expression in Alzheimer’s mouse
`models,” Neurobiol. Aging, 34:1581-1588 (2013) (“Gong”)
`Joseph Goldberger et al., “The Prevention of Pellagra: A Test
`of Diet Among Institutional Inmates,” Public Health
`Reports, 30(43):3117-3131 (1915) (“The Prevention of
`Pellagra”)
`Joseph Goldberger et al., “A Study of the Relation of Diet to
`Pellagra Incidence in Seven Textile-Mill Communities of
`
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`South Carolina in 1916,” Public Health Report, 35(12):648-
`713 (1920) (“Relation of Diet to Pellagra Incidence”)
`Declaration of Brendan T. Jones
`
`1022
`
`- vi -
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
`
`I.
`
`INTRODUCTION
`Elysium Health, Inc. petitions for inter partes review of claims 1–3 of
`
`U.S. Patent No. 8,197,807 B2 (Ex. 1001) (the “’807 patent”). For the
`
`reasons set forth below, there is a reasonable likelihood that the claims are
`
`unpatentable as anticipated under 35 U.S.C. § 102 in view of the references
`
`submitted by Petitioner.
`
`II.
`
`BACKGROUND
`A.
`The ’807 Patent
`The ’807 patent is directed to pharmaceutical compositions
`
`comprising nicotinamide riboside. Nicotinamide riboside is a form of
`
`vitamin B3 that is found in nature (e.g., in milk). (Ex. 1002, Declaration of
`
`Joseph A. Baur, Ph.D. (“Baur Baur Decl.,”) ¶11.) Nicotinamide riboside is a
`
`precursor of nicotinamide adenine dinucleotide (NAD+), a coenzyme
`
`associated with a variety of biological activities. (Id. ¶10.) Other NAD+
`
`precursors include nicotinic acid and tryptophan. (Id.) NAD+ deficiency
`
`can cause pellagra, a disease whose symptoms in humans include dermatitis,
`
`diarrhea, and dementia, and death if untreated. (Id. ¶15)
`
`The ’807 patent purports to disclose the discovery of a biosynthetic
`
`pathway that is naturally present in eukaryotic cells and converts
`
`nicotinamide riboside to NAD+. (Ex. 1001, ’807 patent at 3:3-3:11.) Based
`
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`on the discovery of this natural phenomenon, the ’807 patent claims
`
`compositions comprising nicotinamide riboside. (Ex. 1001, ’807 patent at
`
`53:59-54:43.)
`
`Independent claim 1 is indicative of the broad subject matter claimed
`
`and is reproduced below.
`
`1. A composition comprising isolated nicotinamide riboside in
`combination with one or more of tryptophan, nicotinic acid, or
`nicotinamide, wherein said combination is in admixture with a
`carrier comprising a sugar, starch, cellulose, powdered
`tragacanth, malt, gelatin, talc, cocoa butter, suppository wax,
`oil, glycol, polyol, ester, agar, buffering agent, alginic acid,
`isotonic saline, Ringer’s solution, ethyl alcohol, polyester,
`polycarbonate, or polyanhydride, wherein said composition is
`formulated for oral administration and increases NAD+
`biosynthesis upon oral administration.
`
`Dependent claim 2 confirms that the nicotinamide riboside of claim 1 may
`
`be naturally occurring:
`
`2. The composition of claim 1, wherein the nicotinamide
`riboside is isolated from a natural or synthetic source.
`
`Prosecution History of the ’807 Patent
`B.
`The ’807 patent issued from Serial No. 11/912,400 (the “’400
`
`application). In the ’400 application, the applicant initially sought an
`
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`independent claim drawn to a composition comprising isolated nicotinamide
`
`riboside in admixture with a carrier (then pending as claim 30), and
`
`dependent claims specifying that the nicotinamide riboside is isolated from a
`
`natural or synthetic source (claim 31) and that the composition is formulated
`
`for oral administration (claim 32). (Exhibit 1003, Excerpts from Prosecution
`
`History of Serial No. 11/912,400, at 3.)
`
`All three claims were rejected as anticipated by two references by
`
`Saunders et al. which, the Examiner found, disclose the preparation of a
`
`composition comprising isolated nicotinamide riboside in water. (Id. at 16.)
`
`All three claims were also rejected as anticipated by Tanimori, which, the
`
`Examiner found, teaches the production of a syrup and solid form
`
`comprising nicotinamide riboside. (Id. at 17-18.) In explaining why these
`
`disclosures anticipate claim 32—the dependent claim requiring that the
`
`composition is formulated for oral administration—the Examiner noted that
`
`the claim does not specify the dose or application of the claimed
`
`formulation. (Id.) As explained below, the applicant never amended the
`
`claims to specify the does or application of the claimed formulation and
`
`instead overcame the Examiner’s rejections by adding other limitations.
`
`In response to the Examiner’s initial rejection of all three claims, the
`
`applicant amended the independent claim by specifying that the carrier
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`comprises several common carriers (e.g., sugar, starch, cellulose) but not
`
`including water, which is the carrier the Examiner found was disclosed in
`
`the Saunders et al. references. (Id. at 34.) The applicant also added a new
`
`dependent claim (claim 33) specifying that “the formulation comprises a
`
`tablet, troche, capsule, elixir, suspension, syrup, wafer, chewing gum, or
`
`food.” (Id.)
`
`The Examiner rejected the amended claims under 35 U.S.C. § 103(a).
`
`(Id. at 46-50.) To overcome this rejection, the applicant amended the
`
`independent claim again, this time to require that the nicotinamide riboside
`
`is “in combination with one or more of tryptophan, nicotinic acid, or
`
`nicotinamide.” (Id. at 79.) The Examiner concluded that the claims were
`
`obvious even with this additional limitation. (Id. at 90-94; see also id. at
`
`113-17.)
`
`In response, the applicant amended the independent claim to require
`
`that the claimed composition “is formulated for oral administration,” and
`
`relied upon a Declaration from the sole named inventor, Charles Brenner, to
`
`argue that nicotinamide riboside was orally bioavailable in unexpectedly
`
`high levels. (Id. at 121-24, 132-35.) The Examiner found that this
`
`amendment did not overcome the obviousness rejection and noted that one
`
`of ordinary skill in the art would have been motivated to provide an oral
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`formulation because nicotinamide riboside is present in milk. (Id. at 138-
`
`39.) The applicant then amended the independent claim to require that the
`
`composition “increases NAD+ biosynthesis upon oral administration.” (Id.
`
`at 142-47.) The Examiner thereafter allowed the claims as claims 1-3 of the
`
`’807 patent. (Id. at 159-61.) Although the Examiner acknowledged that
`
`nicotinamide riboside is present in milk, the Examiner did not recognize that
`
`the administration of milk in the prior art therefore inherently anticipates the
`
`claims.
`
`III.
`
`SUMMARY OF CHALLENGES AND RELIEF REQUESTED
`Petitioner asserts the following challenges, supported by expert
`
`testimony of Joseph A. Baur, Ph.D., a professor and researcher at the
`
`University of Pennsylvania School of Medicine (Ex. 1002):
`
`Ground
`
`Reference
`
`I
`
`II
`
`Goldberger et al.
`
`Goldberger and Tanner
`
`Basis
`
`§ 102
`
`§ 102
`
`Claims Challenged
`
`1-3
`
`1-3
`
`Petitioner requests that the Board cancel claims 1-3 of the ’807 patent
`
`because they are unpatentable under 35 U.S.C. § 102.
`
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`IV. PERSON OF ORDINARY SKILL IN THE ART
`A person of ordinary skill in the relevant timeframe (i.e., the mid-
`
`2000s) would have had a Ph.D. in biology, biochemistry, or a similar field.
`
`(Ex. 1002, Baur Decl., ¶24.)
`
`V.
`
`CLAIM CONSTRUCTION
`In an inter partes review, claim terms in an unexpired patent are given
`
`their broadest reasonable construction in light of the specification of the
`
`patent in which they appear. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs.,
`
`LLC v. Lee, 136 S. Ct. 2131, 2144 (2016).
`
`Independent claim 1 is directed to a composition comprising
`
`“isolated” nicotinamide riboside. Dependent claim 2 requires that the
`
`nicotinamide riboside “is isolated” from a natural or synthetic source. The
`
`specification states:
`
`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.
`
`(Ex. 1001, ’807 patent at 9:23-9:30.) Accordingly, “isolated” in claim 1
`
`should be understood to mean “separated or substantially free from at least
`
`some of the other components of the naturally occurring organism” and
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`“is isolated” in claim 2 should be understood to mean “is separated or
`
`substantially free from at least some of the other components of the naturally
`
`occurring organism.”
`
`All other terms in the challenged claims are given their ordinary and
`
`customary meaning, as would be understood by one of ordinary skill in the
`
`art in the context of the entire disclosure. See In re Translogic Tech., Inc.,
`
`504 F.3d 1249, 1257 (Fed. Cir. 2007).
`
`VI.
`
`SPECIFIC GROUNDS FOR PETITION
`A.
`Ground I: Goldberger et al. Anticipates Claims 1-3
`Claims 1-3 are unpatentable under 35 U.S.C. § 102(b) as anticipated
`
`by Joseph Goldberger et al., “A Study of the Blacktongue-Preventative
`
`Action of 16 Foodstuffs, with Special Reference to the Identity of
`
`Blacktongue of Dogs and Pellagra of Man,” Public Health Reports,
`
`43(23):1385-1454 (1928) (“Goldberger et al.”) (Ex. 1006)1, as evidenced by
`
`Samuel A.J. Trammell et al., “Nicotinamide Riboside is a Major NAD+
`
`Precursor Vitamin in Cow Milk,” J. of Nutrition, 146(5):965-963 (2016)
`
`(“Trammell I”) (Ex. 1007) and Samuel A.J. Trammell et al., “Nicotinamide
`
`1 A copy of Goldberger et al. from the Library of Congress’s collection is
`
`submitted as Exhibit 1015.
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`Riboside is Uniquely and Orally Bioavailable in Mice and Humans,” Nature
`
`Communications, Vol. 7, Art. No. 12948 (2016) (“Trammell II”) (Ex. 1008).
`
`Goldberger et al. qualifies as prior art under 35 U.S.C. § 102(b)
`
`because it was published in 1928, more than one year before the earliest
`
`possible priority date. Goldberger et al. was not cited during prosecution of
`
`the ’807 patent.
`
`Cow milk has been consumed throughout history. One example of
`
`milk consumption in the prior art is Goldberger et al., a 1928 article
`
`examining a variety of different foods, including skim milk, administered to
`
`dogs to prevent the onset of what Goldberger et al. refers to as
`
`“blacktongue.” (Ex. 1005, Goldberger et al. at 1385-86; Ex. 1002, Baur
`
`Decl., ¶¶20-21.) Blacktongue, which is also known as black tongue disease
`
`and various other names, is a canine disease caused by NAD+ deficiency
`
`and is identical to pellagra in humans. (Ex. 1005, Goldberger et al. at 1385-
`
`86, 1446-47; Laurent Mouchiroud et al., “NAD+ Metabolism, a Therapeutic
`
`Target for Age-Related Metabolic Disease,” Crit. Rev. Biochem. Mol. Biol.,
`
`48(4):397-408 (2013) (“Mouchiroud et al.”) at 2; Ex. 1002, Baur Decl.,
`
`¶¶15, 20, 36.)
`
`Goldberger et al. discloses an experiment in which five dogs were fed
`
`a base diet, designated “Diet No. 123,” which was known to induce
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`blacktongue.2 (Ex. 1005, Goldberger et al. at 1403; Ex. 1002, Baur Decl.,
`
`¶¶20-21.) This base diet was supplemented with a daily dose of skim milk
`
`administered “by drench” (i.e., orally). (Ex. 1005, Goldberger et al. at 1402-
`
`1403; Ex. 1002, Baur Decl., ¶20.) Three of the five dogs showed no
`
`evidence of blacktongue over the course of the study; one developed slight
`
`transient evidence of an attack after one year; and one developed a “well
`
`marked attack” after a period of 37 days. (Ex. 1005, Goldberger et al. at
`
`1403-1404; Ex. 1002, Baur Decl., ¶21.) Goldberger noted that the diet fed
`
`2 In “A Further Study of Experimental Blacktongue with Special Reference
`
`to the Blacktongue Preventative in Yeast,” Public Health Reports,
`
`43(12):657-694 (1928) (Ex. 1009), Goldberger and his co-authors report that
`
`they fed diet No. 123 to 14 dogs and observed “all 14 of the test animals
`
`developed blacktongue, the first distinctive signs of which appeared within
`
`not to exceed 53 days after beginning the test diet.” Id. at 661. The authors
`
`also note that blacktongue was “[a]llowed to take its course without
`
`therapeutic interference in two of the dogs, and it ended in the death of both
`
`animals.” Id. A copy of this article from the Library of Congress’s
`
`collection is submitted as Exhibit 1013.
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`to the dogs, when not supplemented by milk, “has regularly resulted in an
`
`attack of blacktongue within a period only exceptionally longer than about
`
`two months.” (Id.) Based on these results, Goldberger et al. concluded that
`
`milk “contains the blacktongue preventative.” (Id.)
`
`Later research explains the biological processes underlying the results
`
`reported in Goldberger et al. (Ex. 1002, Baur Decl., ¶¶10-14, 316-36.) As
`
`the ’807 patent states, nicotinamide riboside is an NAD+ precursor in a
`
`eukaryotic NAD+ biosynthetic pathway. (Ex. 1001, ’807 patent, 3:3-3:11;
`
`Ex. 1002, Baur Decl., ¶10.) The Trammell I co-authors, including Charles
`
`Brenner, the named inventor of the ’807 patent, demonstrate that
`
`nicotinamide riboside in high concentration is naturally present in cow milk.
`
`Trammell I examined the NAD+ precursor vitamin concentration in raw cow
`
`milk and in skim cow milk and found that ∼40% is present as nicotinamide
`
`riboside, with the remaining ∼60% present as nicotinamide. (Ex. 1007,
`
`Trammell I at 3 (Table 1), 5 (Table 3), and 6; Ex. 1002, Baur Decl., ¶13.)
`
`Recent scientific studies also confirm that the oral bioavailability of
`
`nicotinamide riboside is as great or greater than that of nicotinamide. For
`
`example, Trammell II (also co-authored by the ’807 patent inventor) reports
`
`that nicotinamide riboside is a more potent booster of NAD+ than
`
`nicotinamide or nicotinic acid. (Ex. 1008, Trammell II at 6-7, 11; Ex. 1002,
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`U.S. Patent No. 8,197,807
`Petition for Inter Partes Review
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`Baur Decl., ¶14.) During prosecution of the application that issued as the
`
`’807 patent, Brenner submitted a sworn Declaration in response to an
`
`obviousness rejection affirming that nicotinamide riboside is more orally
`
`available than nicotinamide to produce NAD+. (Ex. 1003, Excerpts from
`
`Prosecution History of Serial No. 11/912,400, at 132-35; Ex. 1002, Baur
`
`Decl., ¶14.) The two Trammell references (which were not available to the
`
`examiners during prosecution of the ’807 patent) make clear that Goldberger
`
`et al.’s skim milk supplement prevented blacktongue because the naturally
`
`occurring NAD+ precursors in milk, which include nicotinamide riboside,
`
`increased NAD+ biosynthesis. (Ex. 1002, Baur Decl., ¶5.)
`
`Independent Claim 1
`1.
`Claim 1 is anticipated by Goldberger et al.
`
`a.
`
`“A composition comprising isolated
`nicotinamide riboside”
`Goldberger et al. discloses the administration of skim milk to dogs as
`
`a dietary supplement to prevent blacktongue. (Ex. 1005, Goldberger et al. at
`
`1402-1403; Ex. 1002, Baur Decl., ¶30.) Trammell I’s analysis of the NAD+
`
`precursors in milk shows that a significant concentration of nicotinamide
`
`riboside is naturally present in skim milk. (Ex. 1007, Trammell I at 3 (Table
`
`1), 5 (Table 3), and 6; Ex. 1002, Baur Decl., ¶11, 30.) Accordingly, the
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`U.S. Patent No. 8,197,807
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`skim milk disclosed in Goldberger et al. necessarily contained nicotinamide
`
`riboside.3 (Ex. 1002, Baur Decl., ¶11, 30.)
`
`The nicotinamide riboside naturally present in the skim milk
`
`Goldberger et al. administered to dogs is isolated (i.e., separated or
`
`substantially free from at least some of the other components of the naturally
`
`occurring organism) from the cow. The nicotinamide riboside in skim milk
`
`is further isolated during the process of converting whole milk to skim milk
`
`because, during that process, the non-fat elements of whole milk (including
`
`nicotinamide riboside present in skim milk) are separated from the fat. (Ex.
`
`1002, Baur Decl., ¶30.)
`
`3 “Under the principles of inherency, if the prior art necessarily functions in
`
`accordance with, or includes, the claimed limitations, it anticipates.”
`
`Brassica Protection Prods. LLC v. Sunrise Farms (In re Cruciferous Sprout
`
`Litig.), 301 F.3d 1343, 1349 (Fed. Cir. 2002) (internal quotation omitted).
`
`Whether the prior art recognized that nicotinamide riboside is inherent in
`
`milk is irrelevant to the anticipation analysis. See, e.g., SmithKline Beecham
`
`Corp. v. Apotex Corp., 403 F.3d 1331, 1343 (Fed. Cir. 2005) (“[I]nherent
`
`anticipation does not require a person of ordinary skill in the art to recognize
`
`the inherent disclosure in the prior art at the time the art is created.”).
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`U.S. Patent No. 8,197,807
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`b.
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`“in combination with one or more of
`tryptophan, nicotinic acid, or nicotinamide,”
`The milk disclosed in Goldberger et al. inherently comprises a
`
`composition comprising isolated nicotinamide riboside in combination with
`
`tryptophan and nicotinamide. (Ex. 1002, Baur Decl., ¶11, 31.) Trammell I
`
`explains that “[i]t has long been known that the NAD+ precursors in milk
`
`include nicotinamide and tryptophan.” (Ex. 1007, Trammell I at 1, 3; Ex.
`
`1002, Baur Decl., ¶31.) Trammell I also presents data establishing that
`
`nicotinamide is present in skim milk. (Ex. 1007, Trammell I at 5 (Table 3);
`
`Ex. 1002, Baur Decl., ¶31.)
`
`c.
`
`“wherein said combination is in admixture
`with a carrier comprising a sugar, starch,
`cellulose, powdered tragacanth, malt, gelatin,
`talc, cocoa butter, suppository wax, oil, glycol,
`polyol, ester, agar, buffering agent, alginic acid,
`isotonic saline, Ringer’s solution, ethyl alcohol,
`polyester, polycarbonate, or polyanhydride”
`In skim milk, isolated nicotinamide riboside is in combination with
`
`nicotinamide and tryptophan “in admixture” (i.e., in a mixture with) with “a
`
`carrier comprising a sugar” because the combination is in a mixture with
`
`other components of the milk, including at least a sugar (e.g., lactose). (Ex.
`
`1002, Baur Decl., ¶32.)
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`d.
`
`“wherein said composition is formulated for
`oral administration”
`The skim milk in Goldberger et al. was consumed orally. (Ex. 1002,
`
`Baur Decl., ¶33.)
`
`e.
`
`“and increases NAD+ biosynthesis upon oral
`administration. “
`The skim milk disclosed in Goldberger et al. increases NAD+
`
`biosynthesis to test subjects upon oral administration. (Ex. 1002, Baur
`
`Decl., ¶34.) As the ’807 patent acknowledges, nicotinamide riboside is an
`
`NAD+ precursor in a eukaryotic NAD+ biosynthetic pathway. (Ex. 1001,
`
`’807 patent, 3:3-3:11; Ex. 1002, Baur Decl., ¶10.)
`
`Trammell I shows that approximately 40% of the NAD+ precursor
`
`vitamin concentration in milk is present as nicotinamide riboside. (Ex.
`
`1007, Trammell I at 6; Ex. 1002, Baur Decl., ¶4, 30.) Trammell II and the
`
`Brenner Declaration submitted during prosecution of the ’400 application
`
`show that orally consumed nicotinamide riboside is a potent booster of
`
`NAD+. (Ex. 1008, Trammell II at 6-7, 11; Ex. 1003, Prosecution History of
`
`Serial No. 11/912,400, at 132-35; Ex. 1002, Baur Decl., ¶14, 34.)
`
`Accordingly, the consumption of skim milk inherently increases NAD+
`
`biosynthesis. (Ex. 1002, Baur Decl., ¶34.) See, e.g., SmithKline Beecham
`
`Corp. v. Apotex Corp., 403 F.3d 1331, 1343 (Fed. Cir. 2005) (prior art
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`reference inherently anticipates where reference is “sufficient to show that
`
`the natural result flowing from the operation as taught in the prior art would
`
`result in the claimed product”) (internal quotation and citation omitted).
`
`In addition, Goldberger et al. discloses that most of the dogs whose
`
`blacktongue-inducing diets were supplemented with skim milk did not
`
`experience blacktongue. (Ex. 1005, Goldberger et al. at 1403-1404; Ex.
`
`1002, Baur Decl., ¶¶20-21, 36.) As noted above, blacktongue is caused by
`
`deficiency of NAD+. (Ex. 1010, Mouchiroud, at 2; Ex. 1002, Baur Decl.,
`
`¶15.) Accordingly, Goldberger et al.’s results are direct evidence that
`
`NAD+ biosynthesis in the dogs increased upon oral administration of skim
`
`milk. (Ex. 1002, Baur Decl., ¶34.)
`
`Thus, the skim milk disclosed in Goldberger et al. in 1928 was a
`
`composition comprising isolated nicotinamide riboside in combination with
`
`nicotinamide, wherein said combination is in admixture with a carrier
`
`comprising a sugar, is formulated for oral administration, and increases
`
`NAD+ biosynthesis upon oral administration.
`
`(Ex. 1002, Baur Decl., ¶32.)
`
`Dependent Claim 2
`2.
`Claim 2 depends from claim 1, and the analysis for claim 1 in Section
`
`VI.A.1 is incorporated by reference. Further, Goldberger et al. discloses
`
`“wherein the nicotinamide riboside is isolated from a natural or synthetic
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`source.” (Ex. 1002, Baur Decl., ¶36.) Skim milk is the product that remains
`
`when almost all of the cream is removed from whole milk. (Texas
`
`Agricultural Extension Service, “Good Milk for Good Meals,” Texas
`
`Agricultural Experiment Station, Bulletin No. 807 (1956) (“Good Milk”)
`
`(Ex. 1011) at 6; Ex. 1002, Baur Decl., ¶36.4)
`
`The nicotinamide riboside naturally present in the skim milk
`
`Goldberger et al. administered to dogs is isolated (i.e., separated or
`
`substantially free from at least some of the other components of the naturally
`
`occurring organism) from a natural source: the cow. The nicotinamide
`
`riboside in skim milk is further isolated during the process of converting
`
`whole milk to skim milk because, during that process, the non-fat elements
`
`of whole milk (including nicotinamide riboside present in skim milk) are
`
`separated from the fat. (Ex. 1002, Baur Decl., ¶36.)
`
`Dependent Claim 3
`3.
`Claim 3 depends from claim 1, and the analysis for claim 1 in Section
`
`VI.A.1 is incorporated by reference. Further, Goldberger et al. discloses
`
`“wherein the formulation comprises a tablet, troche, capsule, elixir,
`
`4 The Texas A&M University Library catalogue webpage showing Good
`
`Milk’s publication details and call number is provided as Exhibit 1016.
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`suspension, syrup, wafer, chewing gum, or food.” (Ex. 1002, Baur Decl.,
`
`¶37.) The milk disclosed in Goldberger et al. is a food. (Ex. 1002, Baur
`
`Decl., ¶37.)
`
`Conclusion
`4.
`Goldberger et al. discloses, either expressly or inherently, each
`
`element of claims 1-3 of the ’807 patent. The inventors of the ’807 patent
`
`cannot patent the milk disclosed in Goldberger et al. based on the alleged
`
`discovery of properties inherent in milk. See, e.g., Brassica Protection
`
`Prods. LLC v. Sunrise Farms (In re Cruciferous Sprout Litig.), 301 F.3d
`
`1343, 1351-52 (Fed. Cir. 1002).
`
`In Brassica, the Federal Circuit held that claims directed to a method
`
`of preparing a food product rich in glucosinolates, and a method of preparing
`
`a human food product from sprouts, among other claims, were inherently
`
`anticipated by the prior cultivation and consumption of sprouts. The Court
`
`noted that the patent owner “has done nothing more than recognize
`
`properties inherent in certain prior art sprouts.” Id. at 1350. For the same
`
`reason, the prior administration of milk, as disclosed in Goldberger et al.,
`
`inherently anticipates claims 1-3 of the ’807 patent. See also, e.g., Upsher-
`
`Smith Labs v. Pamlab, L.L.C., 412 F.3d 1319, 1323 (Fed. Cir. 2005)
`
`(inventor’s discovery of the scientific principles explaining why prior art
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`vitamin compositions are more effective than other compositions “does not
`
`entitle him to remove the prior art from the public domain by patenting those
`
`compositions”).
`
`Ground II: Goldberger and Tanner Anticipates Claims 1-3
`B.
`Claims 1-3 are unpatentable under 35 U.S.C. § 102(b) as anticipated
`
`by Joseph Goldberger and W.F. Tanner, “A Study of the Treatment and
`
`Prevention of Pellagra,” Public Health Reports, 39(3):87-107 (Jan. 18, 1924)
`
`(“Goldberger and Tanner”) (Ex. 1006)5, as explained by Trammell I and
`
`Trammell II.
`
`Goldberger and Tanner qualifies as prior art under 35 U.S.C. § 102(b)
`
`because it was published in 1924, more than one year before the earliest
`
`possible priority date. Goldberger and Tanner was not cited during
`
`prosecution of the ’807 patent.
`
`In the early 1920s, Goldberger and Tanner studied whether a variety
`
`of different foods could treat and prevent pellagra, a vitamin deficiency
`
`disease that was prevalent in the American South at the time. (Ex. 1002,
`
`Baur Decl., ¶15-21.) Goldberger and Tanner ex
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