UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`THORNE RESEARCH, INC.,
`Petitioner,
`
`v.
`
`TRUSTEES OF DARTMOUTH COLLEGE,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2021-00268
`Patent No. 8,383,086
`_____________________________
`
`DECLARATION OF DR. SAMIE JAFFREY, M.D., Ph.D.
`
`THORNE - EXHIBIT 1002
`
`
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`THORNE RESEARCH, INC.,
`Petitioner,
`
`v.
`
`TRUSTEES OF DARTMOUTH COLLEGE,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2021-00268
`Patent No. 8,383,086
`_____________________________
`
`DECLARATION OF DR. SAMIE JAFFREY, M.D., Ph.D.
`
`THORNE - EXHIBIT 1002
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`QUALIFICATIONS ........................................................................................ 1
`I.
`SCOPE OF WORK.......................................................................................... 3
`II.
`III. LEGAL STANDARDS ................................................................................... 3
`IV. A BRIEF OVERVIEW OF THE ’086 PATENT ............................................ 6
`V.
`BRIEF OVERVIEW OF THE SCOPE AND CONTENT OF THE
`ART ............................................................................................................... 12
`A.
`Stamler ................................................................................................. 15
`B.
`Bieganowski ........................................................................................ 16
`C.
`Brenner ................................................................................................ 17
`VI. BRIEF OVERVIEW OF THE LEVEL OF SKILL ...................................... 17
`VII. CLAIM CONSTRUCTION .......................................................................... 18
`VIII. DETAILED EXPLANATION OF THE GROUNDS OF
`UNPATENTABILITY .................................................................................. 21
`A.
`[Ground 1] Claim 2 is Anticipated by Stamler (EX1006) .................. 21
`i.
`“pharmaceutical composition comprising nicotinamide
`riboside in admixture with a carrier, wherein the
`composition is formulated for oral administration” .................. 21
`“isolated from a natural or synthetic source” ............................ 22
`ii.
`[Ground 2] Claim 2 is Obvious over Stamler ..................................... 25
`i.
`“pharmaceutical composition comprising nicotinamide
`riboside in admixture with a carrier, wherein the
`composition is formulated for oral administration” .................. 25
`“isolated from a natural or synthetic source” ............................ 26
`ii.
`[Ground 3] Claim 2 is Anticipated by Bieganowski (EX1008) .......... 27
`
`C.
`
`B.
`
`-i-
`
`
`
`
`
`i.
`
`D.
`
`“pharmaceutical composition comprising nicotinamide
`riboside in admixture with a carrier, wherein the
`composition is formulated for oral administration” .................. 27
`“isolated from a natural or synthetic source” ............................ 28
`ii.
`[Ground 4] Claim 2 is Obvious over Bieganowski ............................. 32
`i.
`“pharmaceutical composition comprising nicotinamide
`riboside in admixture with a carrier, wherein the
`composition is formulated for oral administration” .................. 32
`“isolated from a natural or synthetic source” ............................ 34
`ii.
`[Ground 5] Claim 2 is Anticipated by Brenner (EX1007) .................. 35
`i.
`“pharmaceutical composition comprising nicotinamide
`riboside in admixture with a carrier, wherein the
`composition is formulated for oral administration” .................. 35
`“isolated from a natural or synthetic source” ............................ 36
`ii.
`IX. CONCLUDING STATEMENTS .................................................................. 40
`X. APPENDIX - LIST OF EXHIBITS .............................................................. 42
`
`
`E.
`
`-ii-
`
`
`
`
`
`I.
`
`I, Dr. Samie Jaffrey, declare as follows:
`
`QUALIFICATIONS
`1.
`I received a Bachelor of Science (B.S.) degree in biology from the
`
`Massachusetts Institute of Technology in 1992. In 1999, I received a Doctor of
`
`Medicine (M.D.) degree and a Doctor of Philosophy (Ph.D.) degree in
`
`neuroscience from the Johns Hopkins University School of Medicine.
`
`2.
`
`I am currently the Greenberg-Star Professor in the Department of
`
`Pharmacology at Weill Medical College at Cornell University. I joined the faculty
`
`of Weill Medical College in 2001 as an Assistant Professor of Pharmacology,
`
`where I received tenure beginning in 2006. Prior to that, I was a postdoctoral
`
`fellow in Dr. Solomon H. Snyder’s laboratory at JHU researching the chemical
`
`biology of protein modifications by nitric oxide and proteomic characterization of
`
`nitric oxide signaling.
`
`3.
`
`I have extensive expertise in neuroscience and molecular biology, as
`
`well as novel proteomic and computational techniques, chemical biology tools for
`
`imaging RNA and RNA biology in cells, and epitranscriptomic regulation of gene
`
`expression. My current research interests focus on identifying RNA regulatory
`
`pathways that control protein expression, especially in neurodevelopmental
`
`disorders such as mental retardation and autism. My laboratory’s work involves
`
`exploring RNA modifications in gene regulation, using synthetic and chemical
`
`1
`
`
`
`
`
`biology approaches to developing RNAs with novel functions, and developing
`
`novel RNA-fluorophore complexes with novel spectral properties for studying
`
`RNA trafficking and imaging RNA processing events in living cells.
`
`4. My past research has included studies of axon degeneration and the
`
`role of nicotinamide riboside in preventing axonal degeneration, including in
`
`animal models of axon injury. I have studied how nicotinamide riboside functions
`
`in mammalian cells and in animals, including how it affects SIRT3, a major
`
`cellular target of nicotinamide riboside and its downstream metabolite NAD+. I
`
`have explored how nicotinamide riboside can be administered to mice that are used
`
`in an animal model of an axonal injury disease (noise-induced hearing loss). Thus,
`
`I have experience with the pharmacology and pharmacokinetics of nicotinamide
`
`riboside. I have also studied how NAD+ and nicotinamide riboside affects
`
`intracellular biology and how it affects cellular responses to chemotherapeutic
`
`agents.
`
`5.
`
`A copy of my curriculum vitae, attached as Exhibit 1003, contains
`
`further details on my education, experience, publications, patents, and other
`
`qualifications to render an expert opinion in this matter.
`
`-2-
`
`
`
`
`
`II.
`
`SCOPE OF WORK
`6.
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office for Inter Partes Review (“IPR”) of U.S. Patent No.
`
`8,383,086 (“the ’086 patent,” EX1001).
`
`7.
`
`I have been retained by Petitioner, Thorne Research, Inc. (“Thorne”),
`
`as a technical expert to provide analysis and opinions regarding claim 2 of the ʼ086
`
`patent. I have reviewed the ʼ086 patent. I have also reviewed and considered
`
`various other documents in arriving at my opinions and cite them in this
`
`declaration. For convenience, documents cited in this declaration are listed in the
`
`Appendix in Section X.
`
`8.
`
`I am compensated at the rate of $1000 per hour for my services. No
`
`part of my compensation is dependent on my opinions or the outcome of this
`
`proceeding and I have no other financial interest in the outcome of this matter.
`
`III. LEGAL STANDARDS
`9.
`I have been advised that the burden in this proceeding is on Petitioner
`
`to demonstrate the unpatentability of the challenged claims.
`
`10.
`
`I have been advised that anticipation under 35 U.S.C. § 102 occurs
`
`when a single prior art reference discloses all of the elements of the claimed
`
`invention, as they are arranged in the claim. I have been further advised that it is
`
`not enough that the prior art reference includes multiple, distinct teachings that
`
`-3-
`
`
`
`
`
`may somehow be combined to achieve the claimed invention. Rather, it is my
`
`understanding that the reference must clearly and unequivocally disclose the
`
`claimed invention or direct a person of ordinary skill in the art to the claimed
`
`invention without any need for picking, choosing, or combining various
`
`disclosures that are not directly related to each other in the reference.
`
`11.
`
`I understand that a claimed invention is not patentable under 35
`
`U.S.C. § 103, for obviousness, if the differences between the invention and the
`
`prior art are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to a person having ordinary skill in the art to which
`
`the subject matter pertains.
`
`12.
`
`It is further my understanding that a determination of obviousness
`
`requires inquiries into: (1) the scope and content of the art when the invention was
`
`made; (2) the differences between the art and the claims at issue; (3) the level of
`
`ordinary skill in the pertinent art when the invention was made; and, to the extent
`
`they exist, (4) secondary indicia of obviousness.
`
`13.
`
`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art and one of ordinary skill could have
`
`combined the elements as claimed by known methods with no change in their
`
`respective functions, and the combination would have yielded nothing more than
`
`predictable results to one of ordinary skill in the art.
`
`-4-
`
`
`
`
`
`14.
`
`I understand that hindsight must not be used when comparing the
`
`prior art to the invention for obviousness. Thus, a conclusion of obviousness must
`
`be firmly based on the knowledge and skill of a person of ordinary skill in the art at
`
`the time the invention was made, without the use of post-filing knowledge.
`
`15.
`
`I understand that in order for a claimed invention to be considered
`
`obvious, there must be some rational underpinning for combining cited references
`
`as proposed.
`
`16.
`
`I understand that obviousness may also be shown by demonstrating
`
`that it would have been obvious to modify what is taught in a single piece of prior
`
`art to create the patented invention. Obviousness may be shown by demonstrating
`
`that it would have been obvious to combine the teachings of more than one
`
`element disclosed by prior art. In determining whether a piece of prior art could
`
`have been combined with other prior art or with other information within the
`
`knowledge of one of ordinary skill in the art, the following are examples of
`
`approaches and rationales that may be considered:
`
`(a)
`
`combining prior art elements according to known methods to yield
`
`predictable results;
`
`(b)
`
`substituting one known element for another to obtain predictable
`
`results;
`
`(c)
`
`using a known technique to improve similar devices (methods, or
`
`-5-
`
`
`
`
`
`products) in the same way;
`
`(d)
`
`applying a known technique to a known device (method, or product)
`
`that was ready for improvement to yield predictable results;
`
`(e)
`
`applying a technique or approach that would have been “obvious to
`
`try” (i.e., choosing something from a finite number of identified, predictable
`
`solutions, with a reasonable expectation of success);
`
`(f)
`
`applying variations based on known work in one field of endeavor for
`
`use in either the same field or a different one, based on design incentives or
`
`other market forces, if the variations would have been predictable to one of
`
`ordinary skill in the art; or
`
`(g)
`
`acting upon some teaching, suggestion, or motivation in the prior art
`
`to modify the prior art reference or to combine prior art reference teachings
`
`thereby arriving at the claimed invention.
`
`IV. A BRIEF OVERVIEW OF THE ’086 PATENT
`17. The ’086 patent is entitled “Nicotinamide Riboside Kinase
`
`Compositions and Methods for Using the Same,” with Charles M. Brenner being
`
`the sole named inventor.
`
`18. The claims of the ’086 patent relate to pharmaceutical compositions of
`
`nicotinamide riboside (“NR”) formulated for oral administration. I understand that
`
`claims 1 and 3-5 were invalidated in a previous IPR. I specifically discuss
`
`-6-
`
`
`
`
`
`challenged claim 2 below. The disclosure of the ’086 patent, however, goes well
`
`beyond discussion of the NR pharmaceutical composition of the claims.
`
`19. The ’086 patent discloses that nicotinic acid and nicotinamide
`
`(collectively, niacins), are the vitamin forms of nicotinamide adenine dinucleotide
`
`(“NAD+”). EX1001, 1:20-23. According to the ’086 patent, one known
`
`biosynthetic pathway of NAD+ synthesis uses tryptophan, and supplementation
`
`with niacins prevents pellagra in populations with tryptophan-poor diets. Id., 1:23-
`
`27.
`
`20. The ’086 patent notes that NR was known to be a precursor to NAD+
`
`in bacteria, but states that it has also been found to be a precursor to NAD+ in a
`
`eukaryotic biosynthetic pathway. Id., 2:62-64, 3:1-3. The ’086 patent thus discloses
`
`yeast and human nicotinamide riboside kinase enzymes (“Nrk”), which have
`
`specific functions in NAD+ metabolism. Id., 3:3-6. The ’086 patent also discloses,
`
`inter alia, isolated nucleic acids encoding the same, expression vectors and
`
`cultured cells containing the nucleic acids, as well as an isolated eukaryotic
`
`nicotinamide riboside kinase polypeptide. Id., 3:13-48.
`
`21. The ’086 patent also discloses “a dietary supplement composition
`
`comprising nicotinamide riboside identified in accordance with the methods of the
`
`present invention and a carrier.” Id., 4:14-16. The method the ’086 patent teaches
`
`-7-
`
`
`
`
`
`the use of a mutant strain of yeast to identify natural sources of NR, wherein the
`
`yeast has normal growth as long as it is supplied with NR. Id., 7:49-60.
`
`22. The ’086 patent also discloses methods for preventing or treating a
`
`disease or condition associated with the nicotinamide riboside pathway of NAD+
`
`biosynthesis. Id., 4:17-19.
`
`23. As acknowledged by the ’086 patent, NR can be obtained
`
`commercially, isolated from natural sources using standard methods, or
`
`synthesized using established methods. Id., 26:64-67; 27:3-4; 28:16-21.
`
`24. Specifically, the ’086 patent discloses that “[s]ynthetic sources of
`
`nicotinamide riboside can include any library chemicals commercially available
`
`from most large chemical companies including Merck, Glaxo, Bristol Myers
`
`Squibb, Mosanto/Searle, Eli Lilly and Pharmacia.” Id., 26:64-67.
`
`25. The ’086 patent further discloses that “[i]solated extracts of the
`
`natural sources can be prepared using standard methods.” Id., 27:3-4.
`
`26. The ’086 patent also discloses that NR “can be synthesized using
`
`established methods (Tanimori (2002) Bioorg. Med. Chem. Lett. 12:1135-1137;
`
`Franchetti (2004) Bioorg. Med. Chem. Lett. 14:4655-4658).” Id., 28:16-21.
`
`27. The ’086 patent recognizes that “milk is a source of nicotinamide
`
`riboside.” Id., 3:11-12; see also id., 7:49-61 (noting NR was identified in an acid
`
`whey preparation from cow’s milk); 7:57-59 (“As the factor from milk requires
`
`-8-
`
`
`
`
`
`nicotinamide riboside kinase for growth, the nutrient is clearly nicotinamide
`
`riboside and not NMN or NAD+). According to the ’086 patent, NR isolated from
`
`the whey fraction of cow’s milk was sufficient to support growth in the mutant
`
`yeast described above in paragraph 21. Id., 26:32-34, 26:46-48.
`
`28. The ’086 patent discloses:
`
`[A]gents (e.g., nicotinamide riboside) that work through the
`discovered nicotinamide riboside kinase pathway of NAD+
`biosynthesis could have therapeutic value in improving plasma
`lipid profiles, preventing stroke, providing neuroprotection with
`chemotherapy treatment, treating fungal infections, preventing
`or reducing neurodegeneration, or in prolonging health and
`well-being.
`Id., 27:60-66.
`
`29. The ’086 patent notes further that dietary supplements, such as NR,
`
`can be conveniently used or administered in a composition
`containing the active agent in combination with a
`pharmaceutically acceptable carrier. Such compositions can be
`prepared by methods and contain carriers which are well-known
`in the art. A generally recognized compendium of such methods
`and ingredients is Remington: The Science and Practice of
`Pharmacy, Alfonso R. Gennaro, editor, 20th ed. Lippingcott
`Williams & Wilkins: Philadelphia, Pa., 2000.
`Id., 28:52-60.
`
`-9-
`
`
`
`
`
`30. The ’086 patent provides a wide variety of carriers. Specifically, the
`
`’086 patent discloses:
`
`Examples of materials which can serve as carriers include
`sugars, such as lactose, glucose and sucrose; starches, such as
`corn starch and potato starch; cellulose, and its derivatives, such
`as sodium carboxymethyl cellulose, ethyl cellulose and
`cellulose acetate; powdered tragacanth; malt; gelatin; talc;
`excipients, such as cocoa butter and suppository waxes; oils,
`such as peanut oil, cottonseed oil, safflower oil, sesame oil,
`olive oil, corn oil and soybean oil; glycols, such as propylene
`glycol; polyols, such as glycerin, sorbitol, mannitol and
`polyethylene glycol; esters, such as ethyl oleate and ethyl
`laurate; agar; buffering agents, such as magnesium hydroxide
`and aluminum hydroxide; alginic acid; pyrogen-free water;
`isotonic saline; Ringer's solution; ethyl alcohol; pH buffered
`solutions; polyesters, polycarbonates and/or polyanhydrides;
`and other non-toxic compatible substances employed in
`formulations. Wetting agents, emulsifiers and lubricants, such
`as sodium lauryl sulfate and magnesium stearate, as well as
`coloring agents, release agents, coating agents, sweetening,
`flavoring and perfuming agents, preservatives and antioxidants
`can also be present in the compositions.
`Id., 29:1-20.
`
`31. As for a therapeutically effective amount, the ’086 patent notes
`
`generally it is the amount of NR that “ prevents, reduces, alleviates or eliminates
`
`-10-
`
`
`
`
`
`the signs or symptoms of the disease or condition being prevented or treated.” Id.,
`
`28:36-38. The patent states that the effective amount will vary with the disease or
`
`condition being addressed, and that the skilled clinician can evaluate the disease or
`
`condition after treatment and adjust the amount of NR as needed. Id., 28:36-43.
`
`The ’086 patent teaches further that a patient can include any mammal. Id., 23:8-
`
`10.
`
`32. The ’086 patent provides five examples, only one of which is relevant
`
`to the claimed pharmaceutical composition. Specifically, Example 2 teaches
`
`preparation of a vitamin fraction from whey. Id., 32:55-33:2.
`
`33. Example 1 teaches generation of yeast strains. Id., 31:50. Example 3
`
`teaches generation of a fusion protein library, and assaying pools for Nrk activity.
`
`Id., 33:5. Example 4 discusses NR phosphorylation assays. Id., 33:15. Example 5
`
`discusses cloning of the Nrk gene. Id., 33:30.
`
`34.
`
`I have been informed by counsel that claim 1 of the ’086 patent has
`
`already been found to be unpatentable. I have also been informed by counsel that
`
`claim 2 is dependent claim 1 and incorporates all of the limitations of claim 1.
`
`35. Claim 1 of the ’086 patent recites:
`
`A pharmaceutical composition comprising nicotinamide riboside in
`
`admixture with a carrier, wherein said composition is formulated for oral
`
`administration.
`
`-11-
`
`
`
`
`
`36. Claim 2 recites:
`
`The pharmaceutical composition of claim 1, wherein the nicotinamide
`
`riboside is isolated from a natural or synthetic source.
`
`V. BRIEF OVERVIEW OF THE SCOPE AND CONTENT OF THE ART
`37. NAD+ is essential for life of all organisms. It serves as a coenzyme
`
`for oxidoreductases, a source for ADPribosyl groups used by ADP
`
`ribosyltransferases, as well as a co-substrate for sirtuin deacetylase and deacylases,
`
`including those that retard aging in experimental systems. EX1008 (Bieganowski),
`
`Abstract.
`
`38.
`
`In 1924, Goldberger and Tanner demonstrated a treatment and
`
`prevention of pellegra, caused by a deficiency in NAD+ (EX1013 (Mouchiroud),
`
`2) in humans, in which 29 subjects were provided a diet that included 1,200 grams
`
`of buttermilk a day for up to a year. EX1012 (Goldberger and Tanner), 93. I have
`
`been informed by counsel that the Board concluded the Goldberger and Tanner
`
`reference anticipated claim 1 of the ’086 patent (EX1018 (FWD), 32).
`
`39.
`
`In 1928, Goldberger demonstrated that skim milk exercised a
`
`preventative action against black-tongue (EX1011 (Goldberger), 1402-5), which is
`
`caused by a deficiency of NAD+ (EX1013 (Mouchiroud), 2). I have been informed
`
`by counsel that the Board concluded the Goldberger reference anticipated claim 1
`
`of the ’086 patent (EX1018 (FWD), 25).
`
`-12-
`
`
`
`
`
`40.
`
`In 1935, Booher looked at a “vitamin G” concentrate as a preventative
`
`for black-tongue. EX1009 (Booher), 429, 435. The vitamin concentrate was
`
`prepared by a preliminary extraction of low-lactose whey powder, followed by
`
`concentration and drying. Id. The concentrate was then reextracted, and again
`
`concentrated and dried. Id., 429-430. Dogs were given black-tongue producing
`
`diets, and subsequently developed symptoms of black-tongue, such as lesions and
`
`gastro-intestinal symptoms. Id., 430-431. Dogs that then received the vitamin
`
`concentrate recovered. Id., 431-432 (“dog was in buoyant spirits and in excellent
`
`physical condition at the end of the test.”). Booher concluded that the vitamin G
`
`concentrate carries in addition to vitamin G (lactoflavin) another heat-stable
`
`vitamin that is effective for the prevention or cure of black-tongue. Id., 435.
`
`41.
`
`In a 2004 paper, Bieganowski and Brenner demonstrated that
`
`nicotinamide riboside is a NAD+ precursor, and thus is a useful compound for
`
`elevating NAD+ levels in humans. EX1008 (Bieganowski), 495.
`
`42. Bieganowski teaches further that nicotinamide riboside is a nutrient
`
`found in milk. Id., Abstract. NR is thus not produced by the body, but is obtained
`
`as part of the diet. Bieganowski teaches that ingestion of NR would result in its
`
`conversion to NMN as a result of interacting with NRK enzymes in the human
`
`body, and NMN is then converted to NAD+. Bieganowski specifically teaches a
`
`method of isolating NR from whey powder. Id., 500. Accordingly, the ordinary
`
`-13-
`
`
`
`
`
`artisan would understand that the normal route of administration of NR is orally, as
`
`part of the diet.
`
`43. Moreover, as acknowledged by the ’086 patent, methods of isolating
`
`or synthesizing NR were known to the ordinary artisan. EX1001, 27:3-4.
`
`44. For example, Tanimori discloses a simple and efficient method of
`
`synthesizing NR. EX1014 (Tanimori), Abstract. According to Tanimori, NR is a
`
`precursor in the chemical synthesis of nicotinamide mononucleotide, which is a
`
`precursor in both chemical and enzymatic preparation of NAD+. Id., 1135.
`
`45. Franchetti discloses a stereoselective synthesis of NR. EX1010
`
`(Franchetti), Abstract. Franchetti discloses that NR is an intermediate in a bacterial
`
`biosynthetic pathway in which nicotinamide is converted to NAD+. Id., 4655. In
`
`addition, Franchetti notes that “NAD is a co-factor in numerous enzyme-catalyzed
`
`redox reactions in all living organisms and plays a fundamental role in cellular
`
`metabolic processes,” and it is “crucial … that proper levels of NAD are regulated
`
`and maintained for cellular survival.” Id.
`
`46. Additionally, in 2002, Stamler disclosed a pharmaceutical
`
`composition of NR for treatment of a variety of conditions. EX1006 (Stamler), 4,
`
`13-14.
`
`47.
`
`I discuss the disclosures of Stamler and Bieganowski below, which
`
`are relied upon to demonstrate the unpatentability of claim 2 of the ’086 patent.
`
`-14-
`
`
`
`
`
`A.
`Stamler
`48. Stamler is drawn to methods of modulating nitric oxide (NO)
`
`bioactivity to obtain a therapeutic effect. Id., 1. Stamler discloses that inhibiting the
`
`enzyme glutathione-dependent formaldehyde dehydrogenase mediates NO donor
`
`therapy and nitrosative stress and NO bioactivity in vivo. Id., 2. Inhibition of the
`
`enzyme inhibits the proliferation of pathologically proliferating cells and increases
`
`NO bioactivity in diseases where beneficial.
`
`49. Stamler states that patients afflicted with disorders in which an
`
`inhibitor of glutathione-dependent formaldehyde dehydrogenase would benefit
`
`include breathing disorders (e.g., asthma, cystic fibrosis, and ARDS), heart disease,
`
`hypertension, ischemic coronary syndromes, atherosclerosis, glaucoma, diseases
`
`characterized by angiogenesis (e.g., coronary artery disease), disorders where there
`
`is a risk of thrombosis or restenosis occurring, chronic inflammatory diseases (e.g.,
`
`AIDS, dementia and psoriasis), diseases where there is risk of apoptosis occurring
`
`(e.g., heart failure, atherosclerosis, degenerative neurologic disorders, arthritis and
`
`liver injury (ischemic or alcoholic)), impotence, obesity caused by eating in
`
`response to craving for food, stroke, reperfusion injury (e.g., traumatic muscle
`
`injury in heart or lung or crush injury), and disorders where preconditioning of the
`
`heart or brain for NO protection against subsequent ischemic events is beneficial.
`
`Id., 13-14.
`
`-15-
`
`
`
`
`
`50. A therapeutically effective amount provides for amelioration or
`
`protects against a risk associated with the disorder, and therapeutically effective
`
`amounts include ranges from 1 µg to 10 g/kg and often ranges from 10 µg to 1
`
`g/kg. or 10 µg to 100 mg/kg body weight of the patient. Id., 15.
`
`51. Stamler teaches that oral administration is preferred. Id.
`
`52. Stamler teaches that one class of compounds that may be used in its
`
`methods as inhibitors of glutathione-dependent formaldehyde dehydrogenase
`
`include NR. Id., 3-4.
`
`B.
`Bieganowski
`53. Bieganowski discloses a new biosynthetic pathway for the production
`
`of NAD+ in eukaryotes using NR as a precursor. EX1008 (Bieganowski), Abstract.
`
`Bieganowski identifies yeast nicotinamide riboside kinase (“Nrk”) enzyme as well
`
`as a human Nrk enzyme. Id., 495.
`
`54. Bieganowski notes that NR is found in natural sources, such as milk,
`
`and specifically demonstrates that a vitamin fraction of whey contains NR. Id.,
`
`Abstract, 499.
`
`55. According to Bieganowski, “[t]he persistence of ‘niacin’ as a mixture
`
`of nicotinamide and nicotinic acid may attest to the utility of utilizing multiple
`
`pathways to generate NAD+ and suggests that supplementation with nicotinamide
`
`-16-
`
`
`
`
`
`riboside as third importable NAD+ precursor may be beneficial for certain
`
`conditions.” Id., 499.
`
`56.
`
`In particular, Bieganowski notes that high doses of nicotinic acid are
`
`effective at reducing levels of cholesterol, as well as effective in controlling low-
`
`density lipoprotein cholesterol, increasing high-density lipoprotein cholesterol, and
`
`reducing triglyceride and lipoprotein levels. Id., 499-500. According to
`
`Bieganowski, although nicotinic acid effects all of the key lipids in a desirable
`
`direction, as well as decreasing mortality in target populations, its use is limited
`
`because of “flushing,” a side effect of heat and redness. Id., 500. Thus,
`
`Bieganowski states that NR may be a preferred route of improving lipid profiles in
`
`humans. Id.
`
`C. Brenner
`57.
` The disclosure of Brenner is essentially the same as that of the ’086
`
`patent, being drawn to, in one aspect, “a dietary supplement composition
`
`containing nicotinamide riboside identified in accordance with the methods of the
`
`present invention and a carrier.” EX1007, 6:23-26.
`
`VI. BRIEF OVERVIEW OF THE LEVEL OF SKILL
`
`58.
`
`I have been informed that the earliest priority date that the ’086 patent
`
`is entitled to is April 20, 2006. My opinions are based on using that date as the
`
`time of invention. I have also been informed that the ’086 patent purports to claim
`
`-17-
`
`
`
`
`
`a benefit of priority to a filing date of April 25, 2005. I note that my opinions
`
`would not change even if this earlier date were applied.
`
`59.
`
`I have also been informed by counsel that Patent Owner, the Trustees
`
`of Dartmouth College defined the level of skill of the ordinary artisan as “someone
`
`with a Ph.D. in biochemistry or similar field in the pharmaceutical sciences, with
`
`familiarity and experience with pharmacokinetics” in the previous IPR. See
`
`EX1017, 6. I have applied this level of skill in my analysis of claim 2.
`
`VII. CLAIM CONSTRUCTION
`60.
`I have been advised that the claims terms of the ’086 patent are to be
`
`given their plain and ordinary meaning, i.e., the meaning that the terms would have
`
`to a person of ordinary skill in the art at the time of the invention.
`
`61.
`
`I understand that this analysis focuses on intrinsic evidence, including
`
`how the patentee used the claim term in the claims, specification, and prosecution
`
`history. I also understand that dictionaries or other extrinsic sources may assist in
`
`determining the plain and ordinary meaning but cannot override a meaning that is
`
`unambiguous from the intrinsic evidence. I have followed these principles in my
`
`analysis throughout this declaration.
`
`62.
`
`I have been informed by counsel that the Board has construed the
`
`following claim terms in its Final Written Decision (“FWD”) in IPR2017-01795
`
`(“the ’1795 IPR”), filed by Elysium Health Inc. I have also been informed that the
`
`-18-
`
`
`
`
`
`claims were construed under a different standard of “broadest reasonable
`
`interpretation.” It is my view that the previous constructions of the Board also
`
`would have been how the ordinary artisan would have understood the plain and
`
`ordinary meaning of the claims at the time of invention and as consistent with the
`
`’086 patent. I reproduce those previous constructions, as relevant to this
`
`declaration, below.
`
`63. The Board in the ’1795 IPR construed “pharmaceutical composition
`
`comprising nicotinamide riboside” as a “composition where NR is the active
`
`agent” as being consistent with the specification of the ’086 patent, as well as the
`
`wording of the claim itself. EX1018 (FWD), 9. The Board noted further that the
`
`use of the term “comprising” did not exclude the presence of additional active
`
`agents. Id.
`
`64. The Board construed the term “carrier” broadly in the ’1795 IPR.
`
`Specifically, it construed “carrier” to mean:
`
`a liquid or solid filler, diluent, excipient, or solvent
`
`encapsulating material, [that] is involved in carrying or
`
`transporting the subject compound from one organ, or portion
`
`of the body, to another organ, or portion of the body. Each
`
`carrier must be acceptable in the sense of being compatible with
`
`the other ingredients of the formulation and not injurious to the
`
`-19-
`
`
`
`
`
`patient.
`
`Id., 14. That is consistent with the ’086 specification, which defines the term
`
`in the same way. EX1001, 28:61-67.
`
`65. The Board in the ’1795 IPR construed “isolated” as inclusive of “the
`
`nicotinamide riboside … [being] separated or substantially free from at least some
`
`of the other components associated with the source of the molecule such that it
`
`constitutes at least 25% (w/w) of the composition.” EX1018 (FWD), 12. In so
`
`doing, the Board acknowledged that this level of purity was discussed in the
`
`specification only in the context of proteins, but “determined that one skilled in the
`
`art would have understood that this level of purity extends to other types of
`
`‘isolated’ molecules referenced in the Specification, including NR.” Id.
`
`66.
`
`I note that the disclosure of the ’086 patent explicitly discusses
`
`“isolated” NR, referencing “nicotinamide riboside isolated from deproteinized
`
`whey fraction of cow’s milk was sufficient to support NRK1-dependent growth” in
`
`a yeast mutant dependent on NR for growth. EX1001, 26:32-34; see also Example
`
`2, id., 32:5-33:2 (exemplifying isolation of NR from whey and noting that it was
`
`used at 50% by volume).
`
`67.
`
`I have used the constructions above in my analysis of the
`
`unpatentability of challenged claim 2.
`
`-20-
`
`
`
`
`
`VIII. DETAILED EXPLANATION OF THE GROUNDS OF
`UNPATENTABILITY
`A. [Ground 1] Claim 2 is Anticipated by Stamler (EX1006)
`68. Claim 1, from which claim 2 depends, recites a pharmaceutical
`
`composition comprising NR in admixture with a carrier, wherein the composition
`
`is formulated for oral administration.
`
`69. Claim 2 of the ’086 patent merely adds the limitation that the NR is
`
`isolated from a natural or synthetic source.
`
`i. “pharmaceutical composition comprising nicotinamide riboside in
`admixture with a carrier, wherein the composition is formulated
`for oral administration”
`70. Stamler discloses methods of treating a patient by administering a
`
`therapeutically effective amount of an inhibitor of glutathione-dependent
`
`formaldehyde dehydrogenase, wherein the patient is afflicted with a disorder
`
`ameliorated by NO donor therapy or afflicted with pathologically proliferating
`
`cells. EX1006 (Stamler), 2; see also id., 13-17. Such disorders
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