Gnosis S.p.A.v.South Alabama Medical Science Foundation

Patent Trial and Appeal Board

Jun 20, 2014

10196118 (P.T.A.B. Jun. 20, 2014)

Trials@uspto.gov Paper 64
Tel: 571-272-7822 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)

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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
Basis Claims challenged
Serfontein § 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”)).
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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.
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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
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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”).
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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.

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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.
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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
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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.
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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 N
5
-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.
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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.
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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).
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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
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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.
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(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.”).
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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.
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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.
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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.
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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
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the exquisite control of folate metabolism. Ex. 2064, 157:2-6.
11
Instead, he
states only that administration of 5-methyl-(6S)-THFA would bypass the
inhibition of methylene tetrahydrofolate reductase (the enzyme that forms
5-methyl-(6S)-THFA in vivo). Id. at 157:13-16. Moreover, Dr. Miller does
not express any concern, in the cited testimony, that such bypassing would
have any deranging effect on folate metabolism. And although Dr. Miller
does agree that folate metabolism is complex (see Ex. 2063, 240:2), and
does not deny that disruption of folate metabolism could have serious
adverse effects (see Ex. 2064, 154:7-16), Dr. Miller does not state, in the
cited testimony, that administration of 5-methyl-(6S)-THFA would cause
disruption.
SAMSF also cites deposition testimony of Dr. Ralph Green. Ex. 2075
¶ 113 (citing Ex. 2065, 73:5-9). According to SAMSF, Dr. Green testifies
that administration of a “large or otherwise” bolus of 5-methyl-(6S)-THFA
would “have the propensity, the capacity to disrupt those exquisite controls.”
Id. This evidence is not persuasive because the facts or data underlying it
are not disclosed adequately. Dr. Green’s opinion that a bolus of
5-methyl-(6S)-THFA would have the propensity to disrupt folate
metabolism is premised on his assertion that 5-methyl-(6S)-THFA, itself,
exerts “considerable influence” and “exquisite control” over the “entire
pathways” of folate metabolism. See Ex. 2065, 72:8-14, 22-24. Dr. Green
does not explain the basis for this opinion, such as by reference to some
scientific treatise, peer-reviewed paper, or other authority. Dr. Green refers

11
“Q. And so when you provide large amounts of 5-methyl-THF directly, are
you effectively bypassing this exquisite control? A. No, I wouldn’t say that.”
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to similar views having been expressed by Dr. Barry Shane in a “report of
Dr. Shane,” id. at 72:17, but SAMSF has not identified whether this report is
of record in this proceeding. For these reasons, we accord Dr. Greene’s
testimony on this point little weight.
SAMSF also cites pages 540-51 of Exhibit 2052 as expressing
“concern.” This exhibit is a review article by Pietrzik et al. discussing the
pharmacokinetics and pharmacodynamics of folic acid compared to
5-methyl-(6S)-THFA. Ex. 2052, 535. The portion of this article that
SAMSF cites describes how 5-methyl-(6S)-THFA is synthesized in vivo and
indicates that an inadequate level of 5-methyl-(6S)-THFA results in an
elevated plasma homocysteine level. Id. at 540-41. The cited portion of the
article neither refers to administration of 5-methyl-(6S)-THFA nor expresses
concern that excess 5-methyl-(6S)-THFA would derange feedback loops.
(d) Stability
SAMSF argues that folic acid was known, at the time of invention, to
be “highly stable” and therefore “considered superior” to reduced folates,
and that reduced folates were known to be less resistant to oxidation than
folic acid. Resp. 11 (citing Ex. 2075 ¶ 37). SAMSF, through Dr. Gregory,
cites testimony of Dr. Miller in support of this argument. Ex. 2075 ¶ 37
(citing Ex. 2063, 100:10–104:9, 256:13-16; Ex. 2064, 59:9-18, 130:3-16).
12

Dr. Miller testifies that (a) folic acid was considered stable (Ex. 2063,

12
Dr. Gregory also cites the ’381 patent itself in support of this argument.
The patent is admissible, however, only as evidence of what it describes.
37 C.F.R. § 42.61(c). To the extent the ’381 patent includes data upon
which SAMSF relies to prove the truth of the data, Dr. Gregory’s declaration
is insufficient to authenticate the data, because Dr. Gregory does not state
that he has first-hand knowledge of how the data was generated. See id.
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101:23-25), (b) reduced folates are less stable than folic acid (Ex. 2064,
59:9-18), (c) reduced folates were considered by some to be unstable (Ex.
2063, 256:13-16), and (d) the limited stability of reduced and methylated
folates requires cold storage conditions (Ex. 2064, 130:3-18).
13

SAMSF argues that the lower stability of reduced folates was one
reason why they were not considered suitable for therapeutic use prior to
1996. Resp. 11-12 (citing Ex. 2075 ¶¶ 38-39). SAMSF cites further
testimony of Dr. Miller in support of this argument. Ex. 2075 ¶ 38 (citing
Ex. 2063, 102:12–103:10, 103:23–104:9). Dr. Miller’s testimony, however,
is given in the context of his consideration of the “Report of Dr. Barry
Shane.” Ex. 2063, 102:12–103:10, 103:23–104:9. We accord that testimony
little weight, for the reasons given above in section II.B.2.c(2)(b).
SAMSF also cites five scientific papers, Buehring (Ex. 2030),
Harpey I (Ex. 1031), Harpey II (Ex. 1032), Etienne (Ex. 2032), and Stout
(Ex. 2054), as evidence that reduced folates are less stable than folic acid.
Ex. 2075 ¶¶ 38-39. In particular, SAMSF highlights Harpey I (published in
1981) for expressing doubts about the therapeutic usefulness of 5-methyl-
THF due to its instability, and Harpey II (published in 1983) for indicating
that 5-methyl-THF therapy was attempted but withdrawn due to instability.
Id. ¶ 38; Tr. 102:16-18.

13
SAMSF also cites a scientific paper dated 2002 as evidence that 5-methyl-
tetrahydrofolate is regarded as less stable than folic acid, even today. Ex.
2075 ¶ 37 (citing Ex. 2075 ¶ 42 (citing Ex. 2023, 734, 740)). We do not
consider this evidence further, because the relevant time period for
obviousness considerations is the time the invention was made.
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Gnosis acknowledges that there were “early concerns expressed in the
prior art regarding the stability” of reduced folates, but argues a preparation
of 5-methyl-THF of adequate stability for therapeutic use had become
available (from Bio-Research, Milan, Italy) after the Harpey papers and
before the time the invention was made. Reply 6; Tr. 136:1-3. In particular,
Gnosis cites three scientific papers as evidence, Reggev (Ex. 1028), Godfrey
(Ex. 1029), and Pattini (Ex. 1077), all published prior to 1996. SAMSF
argues, in reply, that the Reggev, Godfrey, and Pattini papers do not discuss
stability of reduced folates. Tr. 125:21–126:9; Ex. 2327, 24 (citing Ex.
1142, 149:4–153:6, 158:25–159:21, 159:25–160:23).
The evidence on this issue supports Gnosis’s position. Although
Dr. Miller acknowledges that reduced folate stability is less than that of folic
acid, such that even special handling is required to avoid degradation, and
other evidence SAMSF cites supports its argument that reduced folates are
relatively unstable compared to folic acid, SAMSF cites no credible
evidence that 5-methyl-(6S)-THFA was regarded as unsuitable for
therapeutic use, aside from Harpey I and Harpey II. But even Harpey I and
Harpey II do not support SAMSF’s position convincingly when considered
in the context of other evidence of record. The doubt Harpey I expresses
about 5-methyl-THFA was insufficient to discourage an attempt to use it in
Harpey II, and the failure reported in Harpey II was insufficient to
discourage the development of the Bio-Research preparation. The evidence
shows that interest in the use of 5-methyl-THFA for various therapeutic
purposes persisted until the time the invention was made, despite setbacks.
Harpey I and II may reflect the state of the art many years before the
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invention was made, but they do not necessarily reflect the state of the art at
the time of invention.
SAMSF’s argument that the Reggev, Godfrey, and Pattini papers
include essentially no express discussion of stability is also unpersuasive.
These papers show, implicitly, that the Bio-Research preparation of 5-
methyl-THFA had sufficient stability to conduct human testing.
(e) Commercial availability
SAMSF argues that reduced folates had limited commercial
availability at the time the invention was made, because they were difficult
to synthesize. Resp. 12. SAMSF cites testimony of Dr. Miller to the effect
that folic acid was cheaper and more readily available than reduced folates,
for the purpose of folate supplementation, because it was easier to synthesize
folic acid than it was to synthesize and isolate a chirally pure reduced folate.
Id. (citing Ex. 2063, 152:8-17, 104:2-9; Ex. 2064, 19:9-16; Ex. 2075
¶¶ 40-41 (citing same from Exs. 2063-64)). SAMSF argues that the
“impracticability” of synthesizing or obtaining reduced folates would have
discouraged one of ordinary skill from using them and would have, instead,
continued to use folic acid as the “only credible alternative.” Id.; Ex. 2075
¶¶ 40-41.
This argument is not persuasive, because the evidence SAMSF cites
does not show that making or acquiring reduced folates was “impracticable”
or so problematic as to discourage their use. At best, Dr. Miller’s testimony
shows that folic acid was regarded as easier to make or buy than reduced
folates. It does not follow that one of ordinary skill in the art would have
been dissuaded from using reduced folates. See In re Mouttet, 686 F.3d at
1334.
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3. Differences between the claimed subject matter and the
prior art
a. Petitioner’s arguments
Gnosis argues that Serfontein discloses all limitations of claim 32
except the use of substantially chirally pure 5-methyl-(6S)-THFA.
Pet. 10-11, 18-24. Gnosis argues that Marazza discloses substantially
chirally pure 5-methyl-(6S)-THFA. Id. at 18-24.
b. Patent Owner’s arguments
(1) Serfontein
SAMSF argues that a person of ordinary skill in the art would
disregard Serfontein’s reference to “a suitable active metabolite of folate”
because that phrase is so vague, and encompasses so large a class of
compounds, as to be meaningless. Resp. 13-17. SAMSF argues that
Serfontein’s broad and non-specific reference to “a suitable active
metabolite of folate” instead would have driven one of ordinary skill to use
tried-and-true folic acid. Id. at 14 (citing Ex. 2075 ¶ 55). SAMSF points out
that all of Serfontein’s examples use folic acid, not active metabolites of
folate, and that Serfontein suggests no advantages of active metabolites over
folic acid. Id. SAMSF also cites testimony of Dr. Miller, again through
Dr. Gregory. Id. at 14-15 (citing Ex. 2063, 125:10-22; Ex. 2064, 73:25–
74:10, 78:23–81:12; Ex. 2075 ¶¶ 60-61). According to SAMSF, Dr. Miller
acknowledges that the phrase “a suitable active metabolite of folate”
potentially encompasses thousands of permutations of folates in various salt
forms and having various glutamate linkages. Id. at 15. SAMSF argues that
the class of “suitable active metabolites of folate” was effectively undefined,
due to the large number of possible salt forms, as well as the range of
possible crystalline forms, and also due to uncertainty as to which
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compounds would be “suitable” for the uses specified in Serfontein. Id. at
15-16 (citing Ex. 2075 ¶¶ 62-63, 66). SAMSF concludes that the
uncertainty surrounding Serfontein’s disclosure of “a suitable active
metabolite of folate” would simply have led one of ordinary skill away from
reduced folates and toward the conventional folic acid. Id. at 16-17 (citing
Ex. 2075 ¶¶ 67-68).
This argument is unpersuasive because it addresses only what the
Serfontein disclosure, alone, would have conveyed to one of ordinary skill in
the art, not what the combination of the Serfontein and Marazza disclosures
would have conveyed. In the obviousness challenge on which this review
was instituted, Gnosis relies on Serfontein for a general, nonspecific
reference to “a suitable active metabolite of folate” and on Marazza for a
specific identification of 5-methyl-(6S)-THFA as a “natural metabolite” of
folate that may be used “as at least one active compound” in a vitamin
therapy for folate deficiency. See Pet. 18-19 (citing Ex. 1012, 1:21-28).
Whether Serfontein’s reference to “a suitable active metabolite of folate”
was so undefined as to have been meaningless to one of ordinary skill in the
art does not address whether Marazza’s disclosure, of which one of ordinary
skill is presumed to have been aware,
14
would have led one of ordinary skill
to the claimed subject matter when combined with Serfontein.
To the extent SAMSF argues that Serfontein teaches away from the
use of “a suitable active metabolite of folate,” we are unpersuaded. First,
SAMSF cites no legal precedent for the notion that an approving disclosure

14
“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 at 1579.
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of a feature could ever amount to a teaching away of that feature. The case
law concerning teaching away makes clear that “a reference may be said to
teach away when a person of ordinary skill, upon reading the reference,
would be discouraged from following the path set out in the reference, or
would be led in a direction divergent from the path that was taken by the
applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). Implicit in this
rule is that there must be some “teaching” in the reference, other than the
disclosure relied upon to assert obviousness, that would have led the person
of ordinary skill away from using that disclosure.
More importantly, we are unpersuaded because SAMSF does not cite
credible evidence in support of its “teaching away” argument. SAMSF
argues, in effect, that Serfontein teaches away from using “a suitable active
metabolite folate,” despite Serfontein favorably disclosing exactly that,
because the disclosure is discouragingly vague. See Resp. 13-17.
Dr. Gregory echoes this argument, see Ex. 2075 ¶ 67. SAMSF, through
Dr. Gregory, cites numerous portions of Dr. Miller’s testimony but no other
evidence. Id. ¶¶ 54-67 (citing Ex. 2063, 82:24–84:21, 85:10-25, 87:10–
88:17, 122:2-13, 122:21–123:4, 125:10–126:10, 129:24–130:11; Ex. 2064,
59:11–60:6, 62:23–63:7, 71:3–73:20, 73:25–74:10, 74:19-25, 78:15–82:11,
87:12–88:22, 90:4-13, 95:24–98:3, 102:13–103:14, 139:7-22). Dr. Miller’s
relevant testimony can be summarized as follows:
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1. Serfontein’s class of “suitable active metabolites of folate”
includes many variations of eight fundamental compounds (Ex.
2064, 62:23–63:7, 78:23-80:12, 81:5-12);
15

2. The variations stem from choice of salt form and glutamylation
state, among other considerations (Ex. 2063, 125:10-22);
3. The variations can affect a given folate’s chemical, physical, and
biological properties, including stability, absorbability,
bioavailability, and in vivo function (Ex. 2063, 82:24–84:21,
85:10-25, 87:10–88:17; Ex. 2064, 59:11–60:6, 74:19-25, 78:15–
82:11, 87:12–88:22); and
4. Serfontein itself provides little guidance for one of ordinary skill to
select a particular folate from this class (Ex. 2063, 125:23–126:10,
129:24–130:11; Ex. 2064, 71:3–73:20, 73:25–74:10, 90:4-13,
95:24–98:3, 102:13–103:14).
SAMSF argues that Serfontein’s class of “suitable active metabolite[s]
of folate” includes potentially thousands of variations, given that there are
over one hundred suitable salt forms of the reduced folates, as well as
numerous polyglutamate forms. Resp. 15 (citing Ex. 2075 ¶ 61). SAMSF
argues further that Serfontein provides essentially no guidance on
determining which particular variations would have been “suitable.” Id. at

15
The fundamental compounds are those identified in Dr. Miller’s
declaration: (1) 7,8 dihydrofolic acid; (2) (6S)-tetrahydrofolic acid; (3)
5-methyl-(6S)-tetrahydrofolic acid; (4) 5-formyl-(6S)-tetrahydrofolic acid;
(5) 10-formyl-(6R)-tetrahydrofolic acid; (6) 5,10-methylene-(6R)-
tetrahydrofolic acid; (7) 5,10-methenyl-(6R)-tetrahydrofolic acid; and (8)
5-formimino-(6S)-tetrahydrofolic acid. Ex. 1005 ¶¶ 18-20; Dec. 10;
Ex. 2075 ¶ 53; Tr. 25:1-21.
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16 (citing Ex. 2075 ¶ 63). SAMSF argues, through Dr. Gregory, that the
many considerations that figure in determining what compounds fall within
the class require “a considerable amount of experimentation” to sort out.
Ex. 2075 ¶65. The need for experimentation, says Dr. Gregory, would have
made it “impossible” for a person of ordinary skill in the art to know all of
the compounds that make up Serfontein’s class. Id.
SAMSF concludes that a person of ordinary skill, confronted by
Serfontein’s vague and directionless disclosure about “suitable active
metabolite[s] of folate,” compared to its specific reference to, and numerous
examples including, folic acid, would have selected folic acid and avoided
the reduced folates. Resp. 16-17 (citing Ex. 2075 ¶¶ 67-68).
SAMSF’s evidence does not credibly support this conclusion.
Dr. Miller does not express an opinion, in the cited testimony, that a person
of ordinary skill would have been discouraged by Serfontein from using
reduced folates. It is Dr. Gregory who concludes this, but he cites only
Dr. Miller’s testimony as support for it. Dr. Gregory does not explain how
Dr. Miller’s testimony leads Dr. Gregory to his conclusion. For example,
Dr. Gregory does not address why the level of skill in the art is such that one
of ordinary skill would be so utterly unable to navigate a class of closely-
related compounds.
16

Moreover, Dr. Gregory’s deposition evidence casts some doubt on his
conclusion. Dr. Gregory testified that one of ordinary skill in the art would
not have considered seriously salt forms that were not in “common

16
According to Dr. Gregory, persons of ordinary skill in the art may be
“researchers and/or medical practitioners that conduct research on, or
possess sufficient knowledge about, folate metabolism.” Ex. 2075 ¶ 11 n.3.
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understanding or consideration.” See Reply 8 (citing Ex. 1135, 191:17–
193:5) (quotation at 192:3-4).
17
Dr. Gregory did not specify how many of
the hundred-or-more salts one of ordinary skill would have been considered,
though he named only four—calcium, barium, sodium, and potassium—as
ones commercially available at the time. See Ex. 1135, 192:20–193:2. It is
not clear, then, on the evidence of record, whether the class of “suitable
active metabolite[s] of folate” would encompass thousands of compounds,
based on many possible salts, or some significantly smaller number, based
on salts one of ordinary skill in the art would have seriously considered. For
these reasons, we determine that Dr. Gregory’s opinion is not supported by
credible facts or underlying data, and we give it little weight.
SAMSF cites In re Bell, 991 F.2d 781 (Fed. Cir. 1993) and In re
Baird, 16 F.3d 380, 382 (Fed. Cir. 1994), in support of its teaching away
argument. Tr. 24:23-24, 85:20-21. These cases stand for the
uncontroversial proposition that disclosure of a large genus does not, by
itself, render obvious individual species within that genus. In re Bell, 991
F.2d at 784 (amino acid sequence does not render obvious one particular
nucleic acid sequence among the undecillion-odd (10
36
) sequences that could
encode the amino acid); In re Baird, 16 F.3d at 382 (generic chemical
formula does not, by itself, render obvious one particular compound out of
about one hundred million compounds). SAMSF does not explain the
relevance of these cases to the selection of a species from a far smaller set,

17
Exhibit 1135 presents excerpts of Dr. Gregory’s deposition transcript. A
complete transcript was filed as Exhibit 1142.
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nor how these cases support its argument that Serfontein’s generic disclosure
teaches away.
(2) Marazza
SAMSF argues that Marazza does not (a) suggest that a reduced folate
is better than folic acid; (b) disclose using folates for lowering serum
homocysteine levels; nor (c) explain the role of the unnatural isomer.
Resp. 17-22 (citing Ex. 2075 ¶¶ 81-88). These arguments are unpersuasive,
because Gnosis does not rely on Marazza for any of these disclosures.
Gnosis relies on Marazza simply for the precise identification of chirally-
pure 5-methyl-(6S)-THFA as an active metabolite of folate suitable for oral
administration to increase folate levels. See Pet. 18-20.
SAMSF argues also that it would not have been obvious to combine
chirally-pure 5-methyl-(6S)-THFA with vitamin B12 because
5-methyl-(6S)-THFA, unlike folic acid, does not mask vitamin B12
deficiency. Resp. 21 (citing Ex. 2075 ¶¶ 89-92). SAMSF offers no
evidence, other than a bare assertion by Dr. Gregory, that
5-methyl-(6S)-THFA does not mask vitamin B12 deficiency. See Ex. 2075
¶ 90. Dr. Gregory does not identify facts or data that lead him to this
conclusion. We give it, therefore, little weight.
4. Objective indicia of non-obviousness
SAMSF argues that several lines of objective evidence (or “secondary
considerations”) demonstrate the non-obviousness of claim 32. Resp. 22-60.
In particular, SAMSF argues commercial success (id. at 23-34), licensing
(id. at 34-38), copying (id. at 38-43), long-felt but unmet need (id. at 44-49),
discovering and solving an unrecognized problem (id. at 49-52), unexpected
results (id. at 52-55), skepticism (id. at 55-56), and praise (id. at 57-60).
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In this case, SAMSF cites evidence stemming from five products.
Resp. 24. The five products are:
1. Metanx® medical food, which contains 5-methyl-(6S)-THFA,
methylcobalamin (a form of vitamin B12), and pyridoxal 5´-
phosphate (a form of vitamin B6), for treating diabetic peripheral
neuropathy (Resp. 27-28 (citing Ex. 2008 ¶ 32; Ex. 2013 ¶ 32;
Ex. 2022 ¶ 37; Ex. 2075 ¶ 128); Ex. 2078);
2. Cerefolin® medical food, which contains 5-methyl-(6S)-THFA,
riboflavin (vitamin B2), cyanocobalamin (another form of vitamin
B12), and pyridoxine hydrochloride (another form of vitamin B6),
for mild cognitive impairment and vascular dementia (Resp. 27-28
(citing Ex. 2011 ¶¶ 29-30, 42-43; Ex. 2022 ¶¶ 46-47; Ex. 2075
¶ 141); Ex. 2251);
3. CerefolinNAC® medical food, which contains
5-methyl-(6S)-THFA, methylcobalamin, and N-acetylcystine, for
mild cognitive impairment and vascular dementia (Resp. 27-28
(citing Ex. 2011 ¶¶ 29-30, 42-43; Ex. 2022 ¶¶ 46-47; Ex. 2075
¶ 141); Ex. 2085);
4. Néevo® prescription prenatal vitamins, which contains
5-methyl-(6S)-THFA and a range of vitamins and minerals,
including the cyanocobalamin form of vitamin B12 and the
pyridoxine hydrochloride form of vitamin B6, for nutritional
supplementation during pregnancy and pre- and post-natal periods
(Resp. 28 (citing Ex. 2022 ¶¶ 60-63; Ex. 2075 ¶¶ 153-60); Ex.
2079); and
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5. NeevoDHA® prescription prenatal vitamins, which contains
5-methyl-(6S)-THFA, methylcobalamin, pyridoxine hydrochloride,
algal oil (a source of docosahexaenoic acid (“DHA”)), and a range
of vitamins and minerals, for nutritional supplementation during
pregnancy and pre- and post-natal periods (Resp. 28 (citing
Ex. 2022 ¶¶ 60-63; Ex. 2075 ¶¶ 153-60); Ex. 2080).
Each of the products is manufactured and sold by Pamlab, under
sublicense from Merck & Cie, a licensee of the ’381 patent. Resp. 24. Each
of the five products includes substantially chirally-pure Metafolin®
5-methyl-(6S)-THFA as an active ingredient,
18
in combination with other
active and inactive ingredients. Id. at 24, 28-30.
a. Commercial success
SAMSF offers evidence that the Pamlab products have had annual
sales over the past several years measured in the millions of dollars, with
revenue and profit growth year-to-year. Resp. 24-26. SAMSF argues that
the commercial success of the products is attributable to the claimed features
of claim 32. Id. at 27-31. In particular, SAMSF argues that the indicated
uses for the products (noted above) “align” with the claimed use of
“increasing a human subject’s dietary intake of folate,” and that the products
are prescribed by clinicians because their specific combinations of active
ingredients (also noted above) are effective for treating those particular uses.
Id. at 28-31. SAMSF also argues that Pamlab’s sales figures understate the

18
I.e., the products contain the (6S) diastereoisomer nearly or entirely free of
the unnatural (6R) diastereoisomer. See Resp. 24.
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commercial success, because some sales are lost to copycat products by
other companies. Id. at 31-34.
b. Licensing
SAMSF offers evidence that Merck first licensed the ’381 patent in
2000, after prevailing over competitors for the license, and has since sought
to expand both the term and scope of its license. Id. at 34-36, 38. Merck, in
turn, sub-licensed the patent to Pamlab in 2002, as well as to other
companies, and Pamlab itself has sub-licensed the patent further. Id. at
36-37. SAMSF argues that the royalty stream from the licenses is
“substantial,” measured in millions of dollars. Id. at 37. SAMSF argues that
Merck still receives weekly requests to sublicense the patent. Id. at 38.
c. Copying
SAMSF offers evidence that six companies have made and sold
copies of one or more of the Pamlab products listed above and that those
copies contain the same active ingredients, in the same dosages and for the
same purposes, as the Pamlab products. Id. at 39-43.
d. Long-felt need
SAMSF offers evidence that claim 32 satisfied a long-felt, but
unsatisfied, need to treat diabetic peripheral neuropathy. Id. at 44-49.
e. Unrecognized problem
SAMSF offers evidence that the inventors of the ’381 patent
recognized that there exists a sub-population of individuals for whom folic
acid has poor bioavailability due to variations in the activity of the enzyme
dihydrofolate reductase. Id. at 49-50. According to SAMSF, the inventors
realized that administration of 5-methyl-(6S)-THFA would alleviate this
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problem by providing a more uniformly bioavailable form of folate than
folic acid. Id. at 49-52.
f. Unexpected results
SAMSF offers evidence purporting to show that 5-methyl-(6S)-THFA
has unexpectedly greater potency than racemic 5-methyl-THFA. Id. at
52-54. SAMSF cites a paper by Venn et al. (Ex. 2058), which reports that
administration of 5-methyl-(6S)-THFA at a dose of 113 μg/day for 24 weeks
lowered plasma homocysteine by 14.6%. Resp. 53. SAMSF cites a second
paper, by Fohr et al. (Ex. 2034), which reports that administration of racemic
5-methyl-THFA at a dose of 480 μg/day for 8 weeks lowered plasma
homocysteine by 3%. Resp. 53. Venn et al. cite the Fohr paper, and note
that the Venn dose of 5-methyl-(6S)-THFA was less than half of the half of
Fohr’s racemic dose of 5-methyl-THFA that was the (6S) diastereoisomer.
Id. at 54 (citing Ex. 2058, 660-61). SAMSF argues that this result was
unexpected, because chirally-pure 5-methyl-(6S)-THFA was more effective
at lowering plasma homocysteine than more than double the dose of
5-methyl-(6S)-THFA mixed with its (6R) partner. Id. Dr. Gregory
characterizes the potency of 5-methyl-(6S)-THFA as “much greater” than
5-methyl-THFA on this basis and opines that the magnitude of the increased
potency was unexpected. Ex. 2075 ¶¶ 104-107. Dr. Gregory also cites a
study by Akoglu et al. (Ex. 2027), which reports that administration of
5-methyl-(6S)-THFA at a dose of 1 mg/day for 8 weeks lowered plasma
homocysteine by 37%, whereas administration of 1 mg/day of folic acid
lowered plasma homocysteine by 24% at 8 weeks. Ex. 2075 ¶ 108.
SAMSF also argues that a paper by Willems et al. (Ex. 2062),
published in 2004, shows that reduced folates, particularly
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5-methyl-(6S)-THFA, are significantly more bioavailable that folic acid.
Resp. 54-55 (citing Ex. 2075 ¶ 109). SAMSF argues that, taken together,
the evidence from the papers summarized above demonstrates unexpectedly
superior properties of 5-methyl-(6S)-THFA. Id. (citing Ex. 2075 ¶ 110).
g. Skepticism
SAMSF argues that one of ordinary skill in the art would have been
skeptical of using 5-methyl-(6S)-THFA therapeutically, due to concerns
about disrupting folate metabolism, stability, and bioavailability.
Resp. 55-56 (citing Ex. 2075 ¶¶ 111-118). SAMSF also relies on the
portions of Dr. Miller’s testimony addressed above in section II.B.2.c(2)(c).
Finally, SAMSF refers to recommendations by the Food and Drug
Administration and by the Centers for Disease Control regarding folate
fortification of the U.S. food supply. Resp. 56 (citing Ex. 2075 ¶ 118).
SAMSF represents these recommendations as having not considered
5-methyl-(6S)-THFA a sound option. Id. (citing Ex. 2075 ¶ 118). SAMSF
does not further identify the recommendations, nor does it indicate that the
recommendations have been made of record in this proceeding.
h. Praise
SAMSF argues that several of its witnesses praise various Pamlab
products and also testify to praise by others in the medical community.
Id. at 57-58. SAMSF offers evidence that Merck was given the “Product
Differentiation Innovation Award” by Frost & Sullivan for Metafolin brand
5-methyl-(6S)-THF. Id. at 58. Finally, SAMSF offers evidence that Gnosis
intentionally mislabeled racemic 5-methyl-THF as substantially chirally pure
5-methyl-(6S)-THF. Id. at 59.
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5. Analysis
One of ordinary skill in the art is presumed to have been aware of both
Serfontein and Marazza. See In re GPAC Inc., 57 F.3d at 1579. Serfontein
calls for a “suitable active metabolite of folate” in oral preparations to
correct folate deficiency (Ex. 1009, 3:31-32, 4:41, 5:4-5), and Marazza
specifically identifies chirally-pure 5-methyl-(6S)-THFA as an active
metabolite of folate suitable for oral use to increase folate levels. Ex. 1012,
1:21-28, 1:36-37. The close similarity of purpose and disclosure between
these references provides sufficient rationale for one of ordinary skill in the
art to have combined them. See Pet. 43; KSR Int'l Co. v. Teleflex Inc., 550
U.S. at 418. SAMSF’s many arguments against the combination of
Serfontein and Marazza, and against the use of reduced folates before the
date of invention, all fail to persuade us, for the reasons discussed above in
sections II.B.2.c and II.B.3.b.
Set against Gnosis’s evidence is the array of objective evidence
SAMSF puts forward in support of the nonobviousness of claim 32. This
evidence is based on the five products made and sold by Pamlab under
sublicense from Merck. SAMSF argues, and Gnosis does not dispute, that
administration of each of the five Pamlab products to a patient falls within
the scope of claim 32. Resp. 27 (citing Ex. 2075 ¶¶ 133, 147, 160).
It is not sufficient, however, that a product or its use merely be within
the scope of a claim in order for objective evidence of nonobviousness tied
to that product to be given substantial weight. There must also be a causal
relationship, termed a “nexus,” between the evidence and the claimed
invention. Merck & Co., Inc. v. Teva Pharm. USA, Inc., 395 F.3d 1364,
1376 (Fed. Cir. 2005). A nexus is required in order to establish that the
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evidence relied upon traces its basis to a novel element in the claim, not to
something in the prior art. Institut Pasteur & Universite Pierre Et Marie
Curie v. Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013). Objective
evidence that results from something is not “both claimed and novel in the
claim” lacks a nexus to the merits of the invention. In re Kao, 639 F.3d
1057, 1068 (Fed. Cir. 2011).
All types of objective evidence of nonobviousness must be shown to
have nexus. In re GPAC Inc., 57 F.3d at 1580 (nexus generally); In re
Huang, 100 F.3d 135, 140 (Fed. Cir. 1996) (commercial success); In re
Antor Media Corp., 689 F.3d 1282, 1293 (Fed. Cir. 2012) (licensing); Wm.
Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1364
(Fed. Cir. 2012) (copying); Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299,
1313 (Fed. Cir. 2006) (failure of others); Rambus Inc. v. Rea, 731 F.3d 1248,
1256 (Fed. Cir. 2013) (long-felt need); In re Kao, 639 F.3d at 1069
(unexpected results); Stamps.com Inc. v. Endicia, Inc., 437 F. App’x 897,
905 (Fed. Cir. 2011) (skepticism); Muniauction, Inc. v. Thomson Corp., 532
F.3d 1318, 1328 (Fed. Cir. 2008) (praise). The stronger the showing of
nexus, the greater the weight accorded the objective evidence of
nonobviousness. See Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
776 F.2d 281, 306 (Fed. Cir. 1985), cert. denied, 475 U.S. 1017 (1986).
Objective evidence of nonobviousness must also be reasonably
commensurate in scope with the claim. In re Kao, 639 F.3d at 1068. This
does not mean that the proffered evidence must reach every embodiment
within the scope of the claim, so long as an “adequate basis to support the
conclusion that other embodiments falling within the claim will behave in
the same manner.” Id.
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SAMSF argues that nexus is established when the thing (product or
method) on which the evidence is based is “covered by the patent.”
Resp. 23 (citing Crocs, Inc. v. Int’l Trade Comm’n, 598 F.3d 1294, 1310-11
(Fed. Cir. 2010)). As discussed above, however, a showing of nexus also
involves establishing that novel elements in the claim, not prior-art elements,
account for the objective evidence put forward to show nonobviousness. In
re Kao, 639 F.3d at 1068.
SAMSF does not identify what novel elements in claim 32 anchor its
objective evidence. Instead, it argues that the combinations of active
ingredients in the five products account for the products’ effectiveness in
treating their respective disease targets and, therefore, success. Resp. 29-30
(regarding CerefolinNAC, Néevo and NeevoDHA), 48 (regarding Metanx);
see also Ex. 2022 ¶ 94 (Ladner declaration) (“[W]e sell a unique blend of
ingredients to treat certain conditions.”). SAMSF emphasizes that the
“unique” aspects of the products’ formulations account for their success.
E.g., Resp. 29-30.
The difficulty with this argument is that claim 32 does not recite the
various active ingredient combinations found in the products. The claim
requires administering a composition containing at least chirally-pure
5-methyl-(6S)-THFA (or a polyglutamyl derivative) and a nutritional
substance comprising a vitamin other than ascorbic acid. The nutritional
substance may include any number or combination of vitamins, in any
chemical form, so long as at least one of them is not ascorbic acid and is
provided in the recited amount. The particular combination of active
ingredients in any of the products is not recited as an element (or
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combination of elements) of any claim under review. As such, the objective
evidence for each product lacks a clear nexus with claim 32.
19

The degree to which SAMSF touts the products’ targeting of
particular therapeutic goals with unique formulations underscores its failure
to show that the objective evidence is commensurate with the scope of the
claim. SAMSF ascribes the therapeutic value of each product to its unique
formulation. See Resp. 29-30, 48; see also Ex. 2022 ¶ 94 (quoted supra).
By arguing the special advantages of the unique formulations, SAMSF
implies that other formulations would not necessarily offer the same benefits
for the same therapeutic goals. Consequently, claim 32 encompasses
numerous species for which SAMSF offers not only no objective evidence
of nonobviousness, but also implicitly suggests would not work as the
products work. We are left, then, with no adequate basis on which to
conclude that the other embodiments falling within the claim will behave in
the same manner as the embodiments for which evidence is offered. See In
re Kao, 639 F.3d at 1068.
20

19
To the extent that SAMSF argues that the objective evidence has nexus
with the claims through administration of 5-methyl-(6S)-THFA, without
regard to what other active ingredients accompany it, this is not persuasive,
because Marazza discloses the use of 5-methyl-(6S)-THFA as an oral
vitamin agent for treatment of folate deficiency. See Ex. 1012, 1:21-28,
1:36-37.
20
SAMSF argues that its “long-felt need” evidence concerning Metanx is
reasonably commensurate in scope with the claims, because Dr. Miller
testifies that other reduced folates would be expected to work if
5-methyl-(6S)-THFA works. Resp. 49 n.12 (citing Ex. 2064, 144-146). We
disagree for the reasons given above.
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Gnosis makes a strong argument for obviousness of claim 32. We
agree with Gnosis that the language Marazza uses to describe
5-methyl-(6S)-THFA—“this natural metabolite as at least one active
compound in a therapeutical agent, for example as vitamin in folate
deficiency states” (Ex. 2012, 1:26-28 (emphasis added))—would have
commended 5-methyl-(6S)-THFA to one of ordinary skill in the art as being
one of Serfontein’s “suitable active metabolite[s] of folate.”
SAMSF’s objective evidence is not sufficient to overcome this strong
argument. As noted above, all types of objective evidence cited by SAMSF
require a nexus with the claimed subject matter. But SAMSF’s evidence,
based on the unique formulations of the Pamlab products, is tied to
combinations of elements not found in claim 32. As a result, the causal
relationship between the claimed subject matter and the objective evidence
is tenuous, at best. This is particularly true for the evidence of commercial
success, licensing, copying, and long-felt need, because this evidence is tied
especially intimately to specific Pamlab products.
The evidence of unrecognized problem, unexpected results,
skepticism, and praise also lack nexus because they are tied in particular to
5-methyl-(6S)-THFA. Although use of 5-methyl-(6S)-THFA for dietary
folate supplementation is recited in the claim, it is a prior art element. Supra
note 19. Consequently, it cannot be used to tie the objective evidence to the
claimed subject matter. See Tokai Corp. v. Easton Enterprises, Inc., 632
F.3d 1358, 1369 (Fed. Cir. 2011) (“If commercial success is due to an
element in the prior art, no nexus exists.”).
Because SAMSF has not shown nexus persuasively, and because
SAMSF has not explained how the objective evidence specific to
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“unique[ly]” formulated products supports the conclusion that other
embodiments would perform similarly, the objective evidence does not
persuade us that the apparent success of the Pamlab products can be traced
to the claimed invention. At best, SAMSF’s objective evidence relates to
unclaimed species embodiments. When we balance Gnosis’s strong
evidence of obviousness against the objective evidence of nonobviousness,
we determine that a preponderance of the evidence supports Gnosis’s
argument that it would have been obvious to combine Serfontein and
Marazza to reach the subject matter of claim 32.
Accordingly, we conclude that Gnosis has demonstrated the
unpatentability of claim 32 by a preponderance of the evidence.
III. MOTION TO AMEND
SAMSF moves the cancellation of claims 22, 26, and 33-38. Paper
22, 1. Gnosis does not oppose. The motion is granted.
IV. MOTIONS TO EXCLUDE EVIDENCE
A. SAMSF’s Motion
SAMSF moves to exclude Gnosis Exhibits 1092, 1093, 1095, 1097,
and 1098 as inadmissible hearsay. PO Motion to Exclude 1-2.
We dismiss SAMSF’s motion as moot because we do not rely on any
of the objected-to evidence in our final decision.
B. Gnosis’s Motion
Gnosis moves to exclude Exhibits 2008, 2011, 2013, 2016, 2017,
2020, 2022, 2024, 2039, 2048, 2049, 2050, 2052, 2055, 2063, 2064, 2065,
2073, 2074, 2075, 2082, 2090, 2099, 2134, 2148, 2149, 2180, 2183, 2184,
2185, 2188, 2213, 2214, 2229-2241, 2281, 2296, 2283, and 2284, in whole
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or in part, citing various provisions of the Federal Rules of Evidence.
Pet. Motion to Exclude 1-15.
We deny Gnosis’s motion. Similar to a district court in a bench trial,
the Board, sitting as a non-jury tribunal with administrative expertise, is
well-positioned to determine and assign appropriate weight to evidence
presented. See, e.g., Donnelly Garment Co. v. NLRB, 123 F.2d 215, 224 (8th
Cir. 1941) (“One who is capable of ruling accurately upon the admissibility
of evidence is equally capable of sifting it accurately after it has been
received . . . .”). Thus, in this inter partes review, the better course is to
have a complete record of the evidence to facilitate public access as well as
appellate review. See id. (“If the record on review contains not only all
evidence which was clearly admissible, but also all evidence of doubtful
admissibility, the court which is called upon to review the case can usually
make an end of it, whereas if evidence was excluded which that court
regards as having been admissible, a new trial or rehearing cannot be
avoided.”). We have considered Gnosis’s arguments for excluding the
above-mentioned evidence, but either do not rely on the specific portions of
evidence cited by Gnosis in our Decision, or assign weight to the evidence
as appropriate in view of the entire record before us.
V. CONCLUSION
Gnosis has proved, by a preponderance of the evidence, that the
subject matter of claim 32 would have been obvious over the combined
teachings of Serfontein and Marazza.
VI. ORDER
For the reasons given, it is
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ORDERED that claim 32 of U.S. Patent No. 6,673,381 B2 is
determined to be UNPATENTABLE;
FURTHER ORDERED that SAMSF’s Motion to Amend claims is
granted, and, accordingly, that claims 22, 26, and 33-38 be CANCELED;
FURTHER ORDERED that SAMSF’s Motion to Exclude Evidence is
dismissed as moot;
FURTHER ORDERED that Gnosis’s Motion to Exclude Evidence is
denied; and
FURTHER ORDERED that because this is a final decision, parties to
the proceeding seeking judicial review of the decision must comply with the
notice and service requirements of 37 C.F.R. § 90.2.

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For PETITIONERS:

Jonathan J. Krit
Janine A. Moderson
Amin Talati, LLC

Joseph E. Cwik
Erik B. Flom
Husch Blackwell LLP

For PATENT OWNERS:

Thomas Parker
Jitendra Malik
Alston & Bird, LLP

Peter Rogalskyj
The Law Office of Peter Rogalskyj