Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`
`Paper 64
`Entered: June 20, 2014
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`GNOSIS S.P.A., GNOSIS BIORESEARCH S.A.,
`and GNOSIS U.S.A., INC.
`Petitioners
`
`v.
`
`SOUTH ALABAMA MEDICAL SCIENCE FOUNDATION
`Patent Owner
`_______________
`
`Case IPR2013-00118
`Patent 6,673,381 B2
`_______________
`
`
`Before JACQUELINE WRIGHT BONILLA, SCOTT E. KAMHOLZ, and
`SHERIDAN K. SNEDDEN, Administrative Patent Judges.
`
`
`KAMHOLZ, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73(b)
`
`
`
`
`
`Tel: 571-272-7822
`
`
`
`
`
`Paper 64
`Entered: June 20, 2014
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`GNOSIS S.P.A., GNOSIS BIORESEARCH S.A.,
`and GNOSIS U.S.A., INC.
`Petitioners
`
`v.
`
`SOUTH ALABAMA MEDICAL SCIENCE FOUNDATION
`Patent Owner
`_______________
`
`Case IPR2013-00118
`Patent 6,673,381 B2
`_______________
`
`
`Before JACQUELINE WRIGHT BONILLA, SCOTT E. KAMHOLZ, and
`SHERIDAN K. SNEDDEN, Administrative Patent Judges.
`
`
`KAMHOLZ, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73(b)
`
`
`
`
`
`
`IPR2013-00118
`Patent 6,673,381 B2
`
`
`I.
`
`INTRODUCTION
`
`A. Background
`
`Petitioner Gnosis S.p.A., Gnosis Bioresearch S.A., and Gnosis U.S.A.,
`
`Inc. (collectively, “Gnosis”) filed a Petition (Paper 2 (“Pet.”)) to institute an
`
`inter partes review of claims 22, 26, and 32-38 (“the challenged claims”) of
`
`U.S. Patent No. 6,673,381 B2 (Ex. 1002 (“the ’381 patent”)). The Board
`
`instituted trial for the challenged claims on the following grounds of
`
`unpatentability asserted by Gnosis:
`
`Reference(s)1
`Serfontein
`
`Basis Claims challenged
`§ 102
`22, 26, and 33-38
`
`Serfontein and Marazza
`
`§ 103
`
`22, 26, and 32-38
`
`Decision to Institute 2 (Paper 6 (“Dec.”)).
`
`After institution of trial, South Alabama Medical Science Foundation
`
`(“SAMSF”) filed a Patent Owner Response in redacted form (Paper 20) and
`
`unredacted form (Paper 21). With our authorization (Paper 26), SAMSF
`
`filed a replacement Patent Owner Response in redacted form (Paper 31
`
`(“Resp.”)) and unredacted form (Paper 30). Gnosis filed a Reply to the
`
`Patent Owner Response in redacted (Paper 38 (“Reply”)) and unredacted
`
`(Paper 37) forms.
`
`SAMSF also filed a Motion to Amend (Paper 22). In it, SAMSF
`
`proposed canceling claims 22, 26, and 33-38, i.e., all challenged claims
`
`except claim 32. Paper 22, 1.
`
`
`1 The references are: European Patent Application EP 0 595 005 A1
`(Ex. 1009 (“Serfontein”)) and U.S. Patent No. 5,194,611 (Ex. 1012
`(“Marazza”)).
`
`2
`
`
`
`IPR2013-00118
`Patent 6,673,381 B2
`
`SAMSF also filed a Motion to Exclude certain of Gnosis’s evidence
`
`(Paper 46 (“PO Motion to Exclude”)). Gnosis filed an Opposition (Paper
`
`48), and SAMSF filed a Reply (Paper 55). Gnosis filed a Motion to Exclude
`
`certain of SAMSF’s evidence (Paper 44 (“Pet. Motion to Exclude”)).
`
`SAMSF filed an Opposition (Paper 50), and Gnosis filed a Reply (Paper 54).
`
`Gnosis relies upon a declaration of Dr. Joshua W. Miller (Ex. 1005) in
`
`support of its Petition. SAMSF relies upon declarations of Dr. Vivian A.
`
`Fonseca (Ex. 2013), Dr. Jesse F. Gregory (Ex. 2075), Ivan T. Hofmann
`
`(Ex. 2017), Dr. Allen M. Jacobs (Ex. 2008), Dr. Vera A. Katz (Ex. 2016),
`
`Dr. Andrew C. Kerr (Ex. 2011), Audy Kent Ladner (Ex. 2022), Dr. Brian C.
`
`Reisetter (Ex. 2020), and Dr. Samuel Strada (Ex. 2019) in its Response,
`
`along with a deposition of Dr. Miller (Ex. 2064).2 Gnosis relies upon
`
`depositions of Dr. Fonseca (Ex. 1143), Dr. Gregory (Ex. 1142),
`
`Mr. Hofmann (Ex. 1146), Dr. Jacobs (Ex. 1144), Dr. Katz (Ex. 1145), and
`
`Mr. Ladner (Ex. 1147) in its Reply.
`
`Oral argument was conducted on March 20, 2014. A corrected
`
`transcript is entered as Paper 62 (“Tr.”).
`
`The Board has jurisdiction under 35 U.S.C. § 6(c). This final written
`
`decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`
`SAMSF’s Motion to Amend is granted. As such, only the
`
`obviousness challenge to claim 32 remains at issue in this proceeding.
`
`Gnosis has proved that claim 32 is unpatentable.
`
`SAMSF’s Motion to Exclude Evidence is dismissed as moot.
`
`2 SAMSF also relies on a deposition of Dr. Miller from ITC Investigation
`No. 337-TA-857 (Ex. 2063), as well as depositions of several other
`individuals who were not produced by Gnosis in this proceeding.
`
`3
`
`
`
`IPR2013-00118
`Patent 6,673,381 B2
`
`Gnosis’s Motion to Exclude Evidence is denied.
`
`B. The ’381 Patent
`
`The ’381 patent is titled “Uses for Food and Vitamin Preparations
`
`Containing the Natural Isomer of Reduced Folates,” and generally relates to
`
`dietary folate supplementation. Ex. 1002, 1:17-19. The patent background
`
`explains that folate deficiency has been linked to various birth defects as
`
`well as to peripheral vascular disease and other disorders. Id. at 1:37-53.
`
`The background notes that individuals with peripheral vascular disease often
`
`have “abnormal blood levels of homocysteine, a precursor to methionine in
`
`the folate dependent step of the S-adenosylmeth[i]onine cycle.” Id. at
`
`1:47-49. The background explains that folate is added to commercial
`
`preparations (sometimes in combination with other vitamins, id. at 2:10-11)
`
`in the form of folic acid (id. at 2:32-33), a form which some individuals
`
`reportedly do not absorb readily from the intestine upon oral administration.
`
`Id. at 4:11-12. The background states that “there is reason to believe” that
`
`those with poor oral response to folic acid nevertheless will “possess[]
`
`adequate oral response to reduced folates.” Id. at 4:18-20.
`
`The background section of the ’381 patent further explains that “the
`
`reduced folates found in nature” include compounds such as tetrahydrofolic
`
`acid (“THFA” or “THF”), 5-methyl-tetrahydrofolic acid, 5-formyl-
`
`tetrahydrofolic, each “having the same L-configuration at carbon-6.” Id. at
`
`4:38-41 (referring to compounds (II) – (VIII) shown in col. 3, ll. 1-65).
`
`Thus, the ’381 patent identifies (6S)-THFA, 5-methyl-(6S)-THFA, and
`
`4
`
`
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`IPR2013-00118
`Patent 6,673,381 B2
`
`5-formyl-(6S)-THFA among the “reduced folates found in nature.” Id.3 The
`
`background notes that recent concerns about adverse effects of the
`
`“unnatural isomer component” (i.e., the (6R) stereoisomer of 5-formyl-
`
`THFA) has led to commercial production of chirally-pure 5-formyl-(6S)-
`
`THFA for disease therapy. Ex. 1002, 4:43-46. The ’381 patent proposes the
`
`use of natural isomers of reduced folates in dietary vitamin preparations.
`
`Id. at 4:59-63.
`
`The detailed description section of the ’381 patent specification
`
`describes the formulation of dietary vitamin preparations that include natural
`
`isomers of reduced folate. It discloses the amounts of one or more natural
`
`isomers of reduced folate that are to be included in preparations and
`
`expresses those amounts as percentages of the recommended dietary
`
`allowance (“RDA”) or the reference daily intake (“RDI”). Id. at cols. 6-7.
`
`Inclusion of other nutrients is discussed, along with relative amounts of such
`
`other nutrients compared to the natural isomers of reduced folate. Id. at
`
`cols. 8-9. Various considerations for the manufacture of preparations are
`
`addressed. Id. at cols. 10-12. The specification of the ’381 patent concludes
`
`with a listing of several example preparations. Id. at cols. 13-15. Among
`
`the other nutrients contemplated for inclusion in reduced folate preparations
`
`are pyridoxine hydrochloride (vitamin B6) (id. at 13:52) and cyanocobalamin
`
`(vitamin B12) (id. at 13:57, 14:58-59).
`
`Claim 32, along with its parent claim 22, are reproduced below:
`
`
`3 The ’381 patent refers to these compounds in their acid forms but also
`refers generally to them as “folates,” i.e., in their conjugate base forms. We
`consider these references synonymous for purposes of this decision. Accord
`Ex. 1012, 1:21-22 (“tetrahydrofolic acid” abbreviated as “THF”).
`
`5
`
`
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`IPR2013-00118
`Patent 6,673,381 B2
`
`
`22. A method for treating and/or preventing
`vascular disease in a subject, said method
`comprising administering, to the subject,
`a composition which comprises:
`one or more natural isomers of reduced
`folate selected from the group consisting
`of (6S)-tetrahydrofolic acid, 5-methyl-
`(6S)-tetrahydrofolic acid, 5-formyl-(6S)-
`tetrahydrofolic
`acid, 10-formyl-(6R)-
`tetrahydrofolic
`acid, 5,10-methylene-
`(6R)-tetrahydrofolic acid, 5,10-methenyl-
`(6R)-tetrahydrofolic acid, 5-formimino-
`(6S)-tetrahydrofolic acid, and poly-
`glutamyl derivatives thereof; and
`a nutritional substance selected from the
`group consisting of a food preparation,
`an essential nutrient preparation, and
`combinations thereof;
`wherein, when the nutritional substance is a
`food preparation, the food preparation
`comprises two or more food components
`and each gram of said food preparation
`has a natural molar amount, N, of said
`one or more natural isomers of reduced
`folate, wherein N is greater or equal to
`zero and wherein each gram of said
`composition has a total molar amount, T,
`of said one or more natural isomers of
`reduced folate greater than N;
`wherein, when the nutritional substance is
`an essential nutrient preparation, the
`essential nutrient preparation comprises a
`vitamin other than ascorbic acid.
`
`
`32. A method according to claim 22, wherein
`each of the one or more natural isomers of
`reduced folate is substantially chirally
`pure.
`
`
`
`6
`
`
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`IPR2013-00118
`Patent 6,673,381 B2
`
`II. DISCUSSION
`
`A. Claim Construction
`
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their broadest reasonable construction in light of the
`
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`
`Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,766 (Aug. 14,
`
`2012). Claim terms are also 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. In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`
`(Fed. Cir. 2007). Any special definition for a claim term must be set forth in
`
`the specification with reasonable clarity, deliberateness, and precision. In re
`
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). In the absence of such a
`
`definition, limitations are not to be read from the specification into the
`
`claims. In re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir. 1993).
`
`We construed the term “substantially chirally pure” to mean, in the
`
`context of the ’381 patent, “nearly or entirely free of unnatural isomers of
`
`reduced folate.” Dec. 13-14. We determined that no other claim terms
`
`required express construction and were to be given their ordinary and
`
`customary meanings. Id. at 7. Neither party contests those determinations,
`
`and we maintain them.
`
`B. Obviousness of claim 32 over Serfontein and Marazza
`
`Gnosis argues that the subject matter of claim 32 would have been
`
`obvious over the combined teachings of Serfontein and Marazza.
`
`Pet. 18-24. SAMSF responds, arguing that Gnosis has not demonstrated the
`
`obviousness of claim 32 (Resp. 1-22), and presenting objective evidence of
`
`nonobviousness. Id. at 22-60.
`
`7
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`
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`IPR2013-00118
`Patent 6,673,381 B2
`
`We undertake the four factual inquiries of an obviousness analysis:
`
`determining the scope and content of the prior art; ascertaining the
`
`differences between the prior art and claim 32; resolving the level of
`
`ordinary skill in the pertinent art; and assessing objective evidence of
`
`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966).
`
`1. The level of skill in the pertinent art
`
`“The person of ordinary skill in the art is a hypothetical person who is
`
`presumed to know the relevant prior art.” In re GPAC Inc., 57 F.3d 1573,
`
`1579 (Fed. Cir. 1995). This person is of ordinary creativity, not merely an
`
`automaton, and is capable of combining teachings of the prior art. KSR Int’l
`
`Co. v. Teleflex Inc., 550 U.S. 398, 420-21 (2007).
`
`Neither party directly addresses the level of skill in the pertinent art
`
`with evidence, beyond opinions given by their respective experts as to the
`
`education and experience of a person of ordinary skill in the art. See
`
`Ex. 1005 ¶ 9; Ex. 2075 ¶ 11 n.3. The parties do not dispute, however, that
`
`one of ordinary skill would have had knowledge of Serfontein and Marazza.
`
`We need not resolve the level of skill further, for purposes of this decision.
`
`2. Scope and content of the prior art
`
`a. Overview of prior art references
`
`(1) Serfontein
`
`Serfontein discloses “a pharmaceutical preparation for lowering levels
`
`of homocysteine or for the prophylaxis or treatment of elevated levels of
`
`homocysteine in a patient.” Ex. 1009, 4:37-39. This preparation includes
`
`“folate or a suitable active metabolite of folate or a substance which releases
`
`folate in vivo,” vitamin B6, and vitamin B12. Id. at 4:40-42. One example
`
`preparation contains 5 mg of vitamin B6 (“PL” or “pyridoxal”) and 0.5 mg
`
`8
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`IPR2013-00118
`Patent 6,673,381 B2
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`of vitamin B12. Id. at 8:6, 8:19-49. The preparation may additionally
`
`include an antioxidant. Id. at Abstr., 6:58–7:2. Serfontein identifies
`
`“elevated plasma homocysteine” as a “widely accepted” risk factor for
`
`“generalised arteriosclerotic disease.” Id. at 3:1-3. Serfontein also states
`
`that “several hereditary enzyme defects” are known to cause high levels of
`
`homocysteine, resulting in various “clinical defects” including “[p]recocious
`
`occlusive vascular disease frequently manifested clinically as . . . peripheral
`
`vascular occlusion.” Id. at 2:34-36, 2:47-48. Serfontein discloses
`
`administering preparations to “human infants.” Id. at 4:25. Serfontein also
`
`describes optimizing use of the invention by monitoring homocysteine levels
`
`“in human plasma.” Id. at 12:32-33. Such teachings indicate that the
`
`preparations are to be administered to human patients. Serfontein discloses
`
`various dosage regimens, including once-daily dosing. Id. at 8:19.
`
`Serfontein discloses that preparations may be suitable for various routes of
`
`administration, including injectable, infusible, sub-lingual, and transdermal,
`
`as well as oral. Id. at 4:19-21, 5:52-56.
`
`Serfontein neither explains what is meant by “a suitable active
`
`metabolite of folate” nor cites any exemplary preparations that specify the
`
`source of folate activity as anything other than “folate” or folic acid.4
`
`(2) Marazza
`
`Marazza describes methods for the chiral resolution of 5-methyl-THF
`
`into its (6R) and (6S) diastereomers. Ex. 1012, 1:12-16. Marazza
`
`specifically identifies 5-methyl-(6S)-THF, i.e., “5-methyl-(6S)-
`
`
`4 See supra note 3. Like the ’381 patent and Marazza, Serfontein uses the
`terms “folic acid” and “folate” interchangeably. Compare Ex. 1009, Title
`with id. at Abstr.
`
`9
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`IPR2013-00118
`Patent 6,673,381 B2
`
`tetrahydrofolic acid” as recited in claim 37, as a “natural metabolite” of
`
`folate that may be used “as at least one active compound” in a vitamin
`
`therapy for folate deficiency. Id. at 1:21-28, 1:55-67. Marazza cites a
`
`number of earlier studies expressing concern that the unnatural (6R)
`
`diastereomer of 5-methyl-THF interferes with folate uptake in mammalian
`
`cells. Id. at 2:15-32. Marazza thus seeks improved methods for separating
`
`the (6R) and (6S) diastereomers from one another, id. at 3:32-36, and
`
`describes a method that employs fractional crystallization of ammonium
`
`salts of the diastereomers. Id. at 3:37-40. In this regard, Marazza states that
`
`it provides “a simple, cheap and efficient process, by which a mixture of
`
`(6RS)-diastereoisomers of a N5-methyl-THF-derivative may be separated
`
`into the pure, single (6R) and (6S)-di[]astereoisomers.” Id. at 3:32-36.
`
`b. Petitioner’s Case-in-Chief
`
`Gnosis argues that Marazza specifically identifies chirally-pure 5-
`
`methyl-(6S)-THFA as being a naturally-occurring active metabolite of folate
`
`that is suitable for use in vitamin supplements to treat folate deficiency, and
`
`that, consequently, one of ordinary skill in the art would have had reason to
`
`use 5-methyl-(6S)-THFA as the “suitable active metabolite of folate” called
`
`for in Serfontein’s preparations. Pet. 18-20. Therefore, Gnosis concludes, it
`
`would have been obvious to combine Serfontein with Marazza to arrive at
`
`the subject matter of claim 32. Id. at 18-24.
`
`c. Patent Owner’s Response
`
`SAMSF presents many arguments in response to Gnosis’s challenge.
`
`We address them in turn.
`
`10
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`IPR2013-00118
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`
`(1) The widespread use of folic acid for folate
`deficiency
`
`SAMSF argues that as of the time of invention, around 1996, folic
`
`acid was regarded as the gold standard for folate supplementation in food
`
`and vitamins, due to its safety, efficacy, bioavailability, and chemical
`
`stability. Resp. 2 (citing Ex. 2075 ¶ 13). SAMSF notes that folic acid had
`
`been recognized, by then, as a therapeutic or preventative agent for neural
`
`tube defects, vascular disease, hyperhomocysteinemia, and megaloblastic
`
`anemia. Id. at 2-3 (citing Ex. 2075 ¶¶ 14-15). SAMSF argues that, given
`
`the wide acceptance of folic acid for these purposes, one of ordinary skill
`
`would not have looked to other forms of folate, including natural isomers of
`
`reduced folate. Id. at 3 (citing Ex. 2075 ¶ 13).
`
`SAMSF cites paragraphs 13-15 from Dr. Gregory’s declaration in
`
`support of this argument. Id. at 2-3. In these paragraphs, Dr. Gregory cites
`
`deposition testimony of Dr. Miller, as well as scholarly publications,
`
`supporting SAMSF’s contention that folic acid was a primary source of
`
`folate for nutrition and treatment of certain diseases. Ex. 2075 ¶ 13 (citing
`
`Ex. 2063, 101:1–103:10, 256:13-16; Ex. 2064, 18:9-13; 59-18); ¶ 14 (citing
`
`Ex. 1019, 135; Ex. 2026, 765; Ex. 2051, 210, 216; ¶ 15 (citing Ex. 2031;
`
`Ex. 2051, 210, 216). But as to whether this general acceptance of folic acid
`
`would have discouraged one of ordinary skill from considering other forms
`
`of folate, Dr. Gregory states only: “Throughout this declaration, I highlight
`
`these and other benefits of folic acid in order to exemplify that the [person of
`
`ordinary skill in the art] at the time did not consider natural isomers of
`
`reduced folate as a credible source of folate supplementation.” Ex. 2075
`
`¶ 13.
`
`11
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`This argument is unpersuasive, because it does not follow that a
`
`person of ordinary skill would have avoided alternatives simply because a
`
`standard is known to be suitable and to work well. The evidence SAMSF
`
`cites here shows that folate has several accepted therapeutic and preventative
`
`uses, but none of it credibly shows that other forms of folate were
`
`unaccepted or unsuitable. Dr. Gregory does not explain the factual basis for
`
`his conclusion that one of ordinary skill did not consider natural isomers of
`
`reduced folate as a source of folate supplementation. Consequently, we give
`
`this opinion little weight. See 37 C.F.R. § 42.65(a). SAMSF’s argument
`
`does not persuade us that one with ordinary skill in the art would not have
`
`considered reduced and polyglutamylated variants of folic acid for the uses
`
`to which folic acid was put.
`
`(2) The prior art would have discouraged use of 5-
`methyl-(6S)-THFA to treat deficiency
`
`SAMSF argues that the state of the art, as of 1996, would have
`
`discouraged one of ordinary skill from using natural isomers of reduced
`
`folate for treating folate deficiency. Resp. 5. SAMSF relies principally on a
`
`statement in the Goodman & Gilman pharmacology textbook that folinic
`
`acid,5 while indicated for use in cancer treatment, is “not indicated for use in
`
`the treatment of folic acid deficiency.” Id. (quoting Ex. 2036, 1304)
`
`(emphasis and internal quotation marks omitted).6 According to SAMSF,
`
`this statement indicates that folinic acid is “not suitable” for treating folate
`
`deficiency. Id. (citing Ex. 2075 ¶ 29). SAMSF argues that Dr. Miller
`
`
`5 Folinic acid is a synonym for 5-formyl-THFA. E.g. Ex. 1002, 4:21-22.
`6 Exhibit 2036 is an excerpt from GOODMAN AND GILMAN, THE
`PHARMACOLOGICAL BASIS OF THERAPEUTICS (8th ed. 1990).
`
`12
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`IPR2013-00118
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`conceded that this statement would have “dissuaded” a person of ordinary
`
`skill from using folinic acid to treat folate deficiency. Id. (citing Ex. 2063,
`
`157:3-6); Ex. 2327, 15. SAMSF argues that the caution directed to folinic
`
`acid would have dissuaded one of ordinary skill from using any reduced
`
`folate. Id. at 5-6 (citing Ex. 2075 ¶ 29).
`
`This argument is not persuasive, because the evidence does not bear
`
`out SAMSF’s contentions. Goodman & Gilman states simply that folinic
`
`acid is not indicated for treating folate deficiency. See Ex. 2036, 1304. It
`
`does not follow from this statement that folinic acid is not suitable for
`
`treating deficiency, because there may be reasons other than suitability to
`
`explain why folinic acid is not indicated for that purpose. See, e.g., Ex.
`
`2063, 152:8–153:3 (Dr. Miller opining that the basis for the “not indicated”
`
`statement may be the higher cost or lower availability of folinic acid
`
`compared to folic acid).
`
`Moreover, SAMSF provides no credible explanation for why
`
`Goodman & Gilman’s statement concerning folinic acid (5-formyl-THFA) is
`
`relevant to the issue of whether one of ordinary skill would have considered
`
`the use of other reduced folates, particularly 5-methyl-THFA, for treating
`
`folate deficiency. SAMSF cites paragraph 29 of Dr. Gregory’s declaration,
`
`but Dr. Gregory’s testimony merely echoes the argument, without providing
`
`underlying facts or data to support his opinion. We give his opinion on this
`
`point little weight as a result.
`
`SAMSF argues further that one of ordinary skill, in 1996, would have
`
`been dissuaded from using reduced folates for treating folate deficiency,
`
`because the prior art indicated that reduced folates were inferior to folic acid
`
`in several properties, including, bioavailability, substrate activity, disruption
`
`13
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`IPR2013-00118
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`of folate metabolism, stability, and commercial availability. Resp. 6 (citing
`
`Ex. 2075 ¶ 30).
`
`(a) Bioavailability
`
`SAMSF argues that data concerning bioavailability of 5-methyl-(6S)-
`
`THFA, in 1996, was inconsistent but suggested that 5-methyl-(6S)-THFA
`
`was less bioavailable than folic acid.7 Resp. 6-7 (citing Ex. 1033; Ex. 2075
`
`¶¶ 31-32 (citing Ex. 2035, 777S; Ex. 2048, 474)). SAMSF argues that
`
`persons of ordinary skill “overlooked” using reduced folates because they
`
`were less bioavailable than folic acid. Id. at 7.
`
`This argument is unpersuasive, because SAMSF does not explain
`
`credibly why the bioavailability of reduced folates was considered to be so
`
`low as to discourage one of ordinary skill from using it for dietary purposes.
`
`The evidence SAMSF puts forward indicates, at most, that the
`
`bioavailability of reduced folates was less than that of folic acid. The
`
`evidence does not indicate that the bioavailability of reduced folates was too
`
`low to be useful, or otherwise of such a character as to render reduced
`
`folates unsatisfactory for the purpose of folate supplementation. Mere
`
`inferiority of a modification does not make that modification unobvious. In
`
`re Mouttet, 686 F.3d 1322, 1334 (Fed. Cir. 2012) (“[J]ust because better
`
`alternatives exist in the prior art does not mean that an inferior combination
`
`is inapt for obviousness purposes.”).
`
`
`7 Bioavailability, in the context of dietary intake (i.e., oral administration), is
`usually expressed as a percentage and reflects the portion of the
`administered dose that reaches the systemic circulation.
`
`14
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`IPR2013-00118
`Patent 6,673,381 B2
`
`
`(b) Substrate activity
`
`SAMSF argues that one of ordinary skill would not have considered
`
`using 5-methyl-(6S)-THFA instead of folic acid for dietary folate
`
`supplementation because 5-methyl-(6S)-THFA is a poor substrate for
`
`polyglutamation. Resp. 7-10. According to SAMSF, 5-methyl-(6S)-THFA
`
`inhibits the ability of human tissue to store folate, because it is a poor
`
`substrate for polyglutamation. Id. at 7 (citing Ex. 2075 ¶¶ 33-34).8 SAMSF
`
`argues that a person to whom 5-methyl-(6S)-THFA is administered would
`
`experience a “folate-deficient” state, even though the person’s system is
`
`“awash” with nonglutamylated 5-methyl-(6S)-THFA, because cells cannot
`
`retain it. Id.; Ex. 2075 ¶¶ 33-34.
`
`To support this argument, SAMSF relies on cross-examination
`
`testimony of Dr. Miller. Ex. 2075 ¶ 33 (citing Ex. 2063, 103:11-22).
`
`Dr. Miller’s testimony is as follows:
`
` Q. And then on page 19, the second full
`
` paragraph, but the very last sentence, he states,
` “As 5-methyltetrahydrofolate is a poor substrate
` for the synthesis of polyglutamates, the ability of
` tissues to accumulate folate is reduced and the
` functional folate deficiency is compounded by a
` reduction in cellular folate levels,” and then he
` goes on, “Paradoxically, this can lead to an
` increase in plasma folate because tissues fail to
` retain folate.”
`
`
` Do you agree with that statement?
`
` A. Yes.
`
`
`
`8 Polyglutamation may be a mechanism by which folate is sequestered
`within cells. E.g., Ex. 2061, 3534 (“[F]ormation of polyglutamates may be
`one mechanism for keeping folate compounds in the cells.”).
`
`15
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`IPR2013-00118
`Patent 6,673,381 B2
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`Ex. 2063, 103:11-22 (emphasis omitted). This testimony forms part of an
`
`exchange in which Dr. Miller was quoted statements from a “Report of
`
`Dr. Barry Shane” and asked whether he agreed with each statement. Id. at
`
`100:20-22; 102:7–104:9; 272:7. The “Report of Dr. Barry Shane” is not
`
`identified further, and SAMSF does not identify whether a copy of this
`
`report is of record in this proceeding.
`
`SAMSF also relies on the following statement from a scientific paper
`
`(Horne et al., Exhibit 2061) concerning 5-methyl-(6S)-THFA transport:
`
`“Thus, under the conditions of the present study, isolated hepatocytes did not
`
`significantly metabolize 5-CH3-H4-PteGlu.” Ex. 2061, 3531.9 Dr. Gregory
`
`cites this statement, as well as the testimony of Dr. Miller, reproduced
`
`above, as evidence that one of ordinary skill in the art would have been
`
`discouraged from using 5-methyl-(6S)-THFA. Ex. 2075 ¶¶ 33-34;
`
`Resp. 7-8.
`
`This argument is not persuasive, because the evidence SAMSF cites
`
`(through Dr. Gregory) does not support it credibly. Dr. Miller was asked:
`
`“Do you agree with that statement?” after being quoted the statement from
`
`the “Report of Dr. Barry Shane.” Ex. 2063, 103:21. The question was
`
`presented in the present tense. Nothing in the relied-upon testimony
`
`indicates that Dr. Miller was told to consider the statement in any context
`
`other than the present day. We take Dr. Miller’s affirmative answer,
`
`therefore, as an indication that he agrees with the statement as of the date of
`
`the deposition: May 6, 2013. Dr. Miller’s answer is not fairly read as an
`
`
`9 The term “5-CH3-H4-PteGlu” is synonymous with 5-methyl-THFA.
`Ex. 2061, 3529 n.1.
`
`16
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`
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`IPR2013-00118
`Patent 6,673,381 B2
`
`indication that Dr. Miller would have agreed with the statement as of the
`
`earliest filing date of which the ’381 patent is accorded benefit (January 31,
`
`1996). Dr. Miller’s testimony, consequently, is not evidence of the content
`
`of the prior art, or of the level of ordinary skill in the pertinent art, at the
`
`time the invention was made. For this reason, we accord Dr. Miller’s
`
`testimony in this regard little weight.
`
`The single sentence SAMSF relies upon from Horne et al. does not
`
`support SAMSF’s argument, because SAMSF does not explain how an
`
`experimental result, obtained under particular conditions in vitro, from cells
`
`isolated from their normal environment, is probative of how 5-methyl-THFA
`
`is processed in vivo. In addition, this single sentence is taken out of context.
`
`SAMSF (through Dr. Gregory) cites this sentence as evidence that
`
`5-methyl-(6S)-THFA would not accumulate in tissues. Ex. 2075 ¶ 34. But
`
`the cited sentence does not indicate what SAMSF proposes; rather, the
`
`sentence indicates that 5-methyl-THFA is not significantly metabolized by
`
`isolated hepatocytes under the particular experimental conditions. See
`
`Ex. 2061, 3531. It does not say that 5-methyl-(6S)-THFA, or
`
`5-methyl-THFA, for that matter, fails to accumulate. Other experiments
`
`reported in this paper demonstrate that 5-methyl-THFA does, in fact,
`
`accumulate in the cells studied. See, e.g., Ex. 2061, 3534 (“In the present
`
`study we have shown that 5-CH3-H4-PteGlu . . . is concentrated by
`
`hepatocytes.”). Moreover, SAMSF cites no credible evidence that other
`
`forms of folate, such as folic acid, reasonably would have been expected to
`
`be polyglutamated, or otherwise metabolized, within the timeframe and
`
`experimental conditions reported in Exhibit 2061.
`
`17
`
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`IPR2013-00118
`Patent 6,673,381 B2
`
`SAMSF also argues that the evidence that 5-methyl-(6S)-THFA is not
`
`retained in cells (Dr. Miller’s testimony and Horne et al.) in turn suggests
`
`that administering 5-methyl-(6S)-THFA would not have been expected to
`
`increase the intracellular pool of folate. Resp. 8-10. According to SAMSF,
`
`folic acid has its beneficial effects by increasing the intracellular pool of
`
`folate. Id. (citing Ex. 1013; Ex. 2075 ¶¶ 70-77). SAMSF reasons that
`
`because Dr. Miller’s testimony and Horne et al. suggest that administration
`
`of 5-methyl-(6S)-THFA would not have the effect of increasing the
`
`intracellular pool of folate, one of ordinary skill would not have considered
`
`using 5-methyl-(6S)-THFA for this purpose. Id. This argument is not
`
`persuasive, because its premise is not credible. Dr. Miller’s testimony and
`
`Horne et al. do not show that 5-methyl-(6S)-THFA fails to accumulate in
`
`cells, as discussed above.
`
`(c) Disruption to folate metabolism
`
`SAMSF argues that one of ordinary skill would not have considered it
`
`obvious to administer 5-methyl-(6S)-THFA for folate supplementation, due
`
`to concerns that direct administration of a particular metabolite of folate
`
`could disrupt the normal folate metabolism, such as by deranging internal
`
`feedback loops. Resp. 10-11 (citing Ex. 2075 ¶¶ 35-36 (citing Ex. 2052,
`
`540-41; Ex. 2063, 240:2-11, 241:20–242:6;10 Ex. 2064, 153:18–154:23,
`
`157:2-22, 163:5-9; Ex. 2065, 73:5-9; Ex. 2081, 23-42)); see also Resp. 3-5
`
`(describing complexity of folate metabolism). SAMSF argues that folic
`
`acid, in contrast, would be subject to normal metabolic regulation and would
`
`
`10 Lines 3-11 on page 240 and lines 1-6 on page 242 are redacted in Exhibit
`2063 as filed by SAMSF.
`
`18
`
`
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`IPR2013-00118
`Patent 6,673,381 B2
`
`have been, therefore, the preferred choice to one of ordinary skill in the art.
`
`Id. at 11.
`
`This argument is not persuasive, because SAMSF does not identify
`
`credibly any portion of the cited evidence that shows that such a concern
`
`about 5-methyl-(6S)-THFA existed at the time the invention was made.
`
`SAMSF (through Dr. Gregory) cites deposition testimony of
`
`Dr. Miller as evidence that there were “concerns” that administration of
`
`5-methyl-(6S)-THFA would bypass normal enzymatic feedback loops.
`
`Ex. 2075 ¶ 35 (citing Ex. 2064, 153:18–154:23, 163:5-9). We disagree with
`
`SAMSF’s characterization of Dr. Miller’s testimony. Dr. Miller states that
`
`the levels of S-adenosyl methionine and S-adenosyl homocysteine (two
`
`compounds involved with folate in methyl group transfers), as well as their
`
`ratio, are under biochemical control (Ex. 2064, 154:7-16), and that
`
`5-methyl-THF bypasses the enzyme methylene tetrahydrofolate reductase,
`
`which produces 5-methyl-THF (id. at 163:5-9). Dr. Miller expresses no
`
`“concern” that anything untoward would result from administration of
`
`5-methyl-(6S)-THFA.
`
`Other testimony of Dr. Miller that SAMSF cites similarly does not
`
`evidence “concern” about administering 5-methyl-(6S)-THFA. SAMSF
`
`points to a statement by Dr. Miller that administering 5-methyl-(6S)-THFA
`
`would be “bypassing [one] aspect of the control mechanisms” as evidence of
`
`concern that “all” of the “exquisite control” of folate metabolism would be
`
`extinguished. Ex. 2075 ¶ 112 (citing Ex. 2064, 157:2-22). This is a
`
`mischaracterization of Dr. Miller’s testimony. Dr. Miller specifically denies
`
`that direct administration of 5-methyl-(6S)-THFA would effectively bypass
`
`19
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`IPR2013-00118
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