Ex Parte 6011040 et al

Patent Trial and Appeal Board

Oct 26, 2017

90013445 (P.T.A.B. Oct. 26, 2017)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
90/011,935 10/04/2011 6011040 Re-Exam of USPN
6,011,040
6314
7590 10/26/2017
MILLEN WHITE ZELANO & BRANIGAN
Arlington Courthouse Plaza 1
2200 Clarendon Blvd.
Suite 1400
Arlington, VA 22201
EXAMINER
DIAMOND, ALAN D
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
10/26/2017 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
90/013,445 02/17/2015 6011040 8270
7590 10/26/2017
MILLEN WHITE ZELANO & BRANIGAN
ARLINGTON COURTHOUSE PLAZA I
2200 CLARENDON BOULEVARD
SUITE 1400
ARLINGTON, VA 22201
EXAMINER
DIAMOND, ALAN D
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
10/26/2017 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte HANS RUDOLF MILLER, MARTIN ULMANN, and
RUDOLF MOSER
____________

Appeal 2017-009209
Reexamination Control 90/011,935 and 90/013,445
Reissue Application No. 14/502,489
Patent 6,011,040
Technology Center 3900
____________

Before JEFFREY B. ROBERTSON, SHERIDAN K. SNEDDEN, and
WESLEY B. DERRICK, Administrative Patent Judges.

DERRICK, Administrative Patent Judge.

DECISION ON APPEAL

STATEMENT OF THE CASE1
This merged proceeding arose out of two requests for ex parte
reexamination and reissue examination of U.S. Patent No. 6,011,040 (“the
’040 patent”) to Muller et al., issued January 4, 2000.2

1 Appellants identify Merck & Cie as the real party in interest. Appeal Brief
filed March 6, 2017 (“Appeal Br.”), 2.
2 Ex parte Reexamination Control Nos. 90/011,935 (“REX ’935”) and
90/013,445 (“REX ’445”) were merged in a “Decision Merging
Reexamination Proceedings” mailed May 26, 2015. Subsequently, the
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Patent Owner appeals under 35 U.S.C. § 134 from the Examiner’s
maintained rejection of claims 16 and 158‒177. Final Office Action issued
September 6, 2016 (“Final Act.”); Examiner’s Answer issued April 10, 2017
(“Ans.”). Claims 16 and 158‒177 are pending.3 Amended claim 16 and
new claims 158‒177 stand rejected under reissue.4 Ans. 2‒3, 21‒101.
Related cases, as identified by the Examiner, include IPR 2013-00117
for the ’040 patent. Ans. 9. The Board’s Final Written Decision in IPR
2013-00117, Gnosis S.P.A. v. Merck & CIE, 2014 WL 2875385 (PTAB
2014) (“IPR 2013-00117 Decision”), was affirmed by the Federal Circuit in
Merck & CIE v. Gnosis S.P.A., 808 F.3d 829 (Fed. Cir. 2015) (“Gnosis I”).
The Examiner further identifies IPRs 2013-00116, 2013-00118, and 2013-
0119, reviewing U.S. Patents 5,997,915, 6,673,381, and 7,172,778,
respectively, as related on the basis that our reviewing court identified the
appeal from these reviews as a companion case to the appeal from IPR 2013-
00117. S. Ala. Med. Sci. Found. v. Gnosis S.P.A., 808 F.3d 823, 826 (Fed.
Cir. 2015) (“Gnosis II”). Further reexamination proceedings pertaining to
these patents are also identified as related on this basis. Ans. 9‒10.

examination of Reissue Application No. 14/502,489 for the ’040 patent was
merged with the Reexaminations in a “Decision Granting Petition to Merge
Reissue and Reexamination Proceedings” mailed September 24, 2015.
3 Issued claims 1‒15 and 17‒22 and reissue claims 23‒157 have been
canceled. See Advisory Action dated December 13, 2016.
4 As to claim 16, actions and responses, including amendment, in the merged
proceeding apply to both reissue examination and ex parte reexamination.
37 C.F.R. § 1.565(d).
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THE INVENTION
The disclosed invention relates to the clinical use of tetrahydrofolates
in natural stereoisomeric form. ’040 patent col. 1, ll. 10‒17.
Amended claim 16 and new claims 158 and 164, reproduced from the
Appeal Brief filed March 6, 2017 (“Appeal Br.”) (Claims App.), 84-85, are
representative (with underlining showing additions and bracketing showing
deletions relative to the originally issued claims).
16. A method [according to claim 4,] of preventing prenatal
neural tube deficiencies associated with increased maternal
homocysteine levels comprising
administering at least one tetrahydrofolate in natural
stereoisomeric form to a female human subject,
wherein said increased maternal [levels of] homocysteine
levels [in the human body] are associated with [thermolabile]
methylene tetrahydrofolate reductase deficiency and wherein
said [the] at least one tetrahydrofolate is 5-methyl-(6S)-
tetrahydrofolic acid, or a pharmaceutically compatible salt
thereof.

158. A method of treating a cardiovascular disease associated
with increased levels of homocysteine in the human body
comprising:
administering to a human subject a formulation
comprising a tetrahydrofolate in natural stereoisomeric form,
wherein said tetrahydrofolate consists essentially of 5-methyl-
(6S)-tetrahydrofolic acid or a pharmaceutically compatible salt
thereof, and one or more vitamin B group vitamins selected
from (a) vitamin B12 or (b) vitamin B12 and vitamin B6;
wherein said formulation is in the form of a capsule or
tablet,
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wherein said formulation is administered as a single
administration, and
wherein each said capsule or tablet contains 1 to 15 mg
of said tetrahydrofolate.

164. A method of treating a neurological disease associated
with increased levels of homocysteine in the human body
comprising administering a formulation comprising:
a tetrahydrofolate in natural stereoisomeric form to a
human subject, wherein said tetrahydrofolate consists
essentially of 5-methyl-(6S)-tetrahydrofolic acid or a
pharmaceutically compatible salt thereof, and
said formulation does not contain a B group vitamin;
wherein said formulation is in the form of a capsule or
tablet,
wherein said formulation is administered as a single
administration, and
wherein said each capsule or tablet contains 1 to 15 mg
of said tetrahydrofolate.
Independent claims 161 and 167 mirror independent claim 158 in the
steps recited in the body of the claims, but are directed to “[a] method of
preventing prenatal neural tube deficiencies associated with increased
maternal homocysteine levels” and to “[a] method of decreasing
homocysteine levels in the human body,” respectively. New dependent
claims further limit the administered tetrahydrofolate to its pharmaceutically
compatible salts, including particularly the calcium salt, and to consisting of
5-methyl-(6S)-tetrahydrofolic acid or a pharmaceutically compatible salt, or
to consisting of a pharmaceutically compatible salt of 5-methyl-(6S)-tetra-
hydrofolic acid, particularly the calcium salt.
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THE REJECTIONS
Rejection 1 - The Examiner maintains the 35 U.S.C. § 102(b)
rejection of claims 158 and 167 as anticipated by Serfontein (EP 0 595 005
A1, published May 4, 1994), as evidenced by the Miller Declaration.5
Rejection 2 - The Examiner maintains the 35 U.S.C. § 102(e) rejection
of claims 158, 164, and 167 as anticipated by Smith (US 6,008,221, issued
December 28, 1999), as evidenced by Müller (US 5,324,836, issued June 28,
1994).
The Examiner maintains the rejection of claims 16 and 158‒177 under
35 U.S.C. § 103(a) as follows:
Rejection 3 - claims 158‒160, 167‒170, 173, 174, and 177 over
Serfontein in view of Marazza et al. (US 5,194,611, issued
March 16, 1993), Ambrosini et al. (EP 0 627 435 A1, published
December 7, 1994), and Ubbink et al. (Vitamin B-12, vitamin
B-6, and folate nutritional status in men with hyperhomo-
cysteinemia, Am. J. Clin. Nutr., 57: 47‒53 (1993));
Rejection 4 - claims 16, 161‒163, 171, and 175 over Serfontein in
view of Marazza, Ambrosini, Ubbink, Mills et al.
(Homocysteine and Neural Tube Defects, J. Nutr. 126: 756S‒
760S (1996) (Am Institute Supplement for June 14, 1995,
meeting)), Minns (Folic acid and neural tube defects, Spinal
Cord, 34: 460‒65 (1996)), Scott et al. (Folic acid to prevent
neural tube defects, The Lancet 338: 505 (August 24, 1991)),

5 Declaration of Joshua W. Miller, Ph.D., dated January 28, 2015, filed with
Request for Reexamination in REX ’445 on February 17, 2015.
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Lucock et al. (The Lancet 338: 894–95 (October 5, 1991)),
Leeming et al. (The Lancet 338: 895 (October 5, 1991)), and
Barford et al. (British Med. J. 282: 1793 (May 30, 1981));
Rejection 5 - claims 158‒160, 164‒170, 172‒174, 176, and 177 over
Smith in view of Marazza and Ambrosini;
Rejection 6 - claims 158‒163, 167‒171, 173‒175, and 177 over
Bailey et al. (WO 1997 027764 A1, published August 7, 1997)
in view of Serfontein and Mills; and
Rejection 7 - claims 164‒169, 172, 173, 176, and 177 over Regland et
al. (Homocysteinemia and schizophrenia as a case of
methylation deficiency, J Neural Transm [GenSect] 98: 143‒
152 (1994)) (“Regland 1”), Regland et al. (Homocysteinemia is
a common feature of schizophrenia, J Neural Transm [Gen
Sect] 100: 165‒169 (1995)) (“Regland 2”), Godfrey et al.
(Enhancement of recovery from psychiatric illness by
methylfolate, The Lancet 336: 392‒395 (August 18, 1990)), Le
Grazie (EP 0 388 827 A1, published September 26, 1990),
Marazza, and Ambrosini, and optionally Serfontein.6

6 We address, and affirm as discussed below, the rejection as set forth in the
combination including Serfontein.
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DISCUSSION
Anticipation
Rejection 1
Claims 158 and 167 require, inter alia, administration of a capsule or
tablet containing, inter alia, 1 to 15 mg of a tetrahydrofolate “consist[ing]
essentially of 5-methyl-(6S)-tetrahydrofolic acid or a pharmaceutically
compatible salt thereof.”
The Examiner finds “Serfontein discloses ‘a pharmaceutical
preparation . . . [that] includes ‘folate or a suitable active metabolite of folate
or a substance which releases folate in vivo,’ vitamin B6, and vitamin B12.”
Final Act. 14 (citing Serfontein 4, ll. 37‒42). In particular, the Examiner
finds Serfontein to teach three alternatives for administration, i.e., folate, a
suitable active metabolite of folate, or a substance which releases folate in
vivo. Ans. 22.
The Examiner relies on the disclosure of “a suitable active metabolite
of folate” as a disclosure of 5-methyl-(6S)-tetrahydrofolic acid as evidenced
by the Miller Declaration. Final Act. 15; Ans. 22; Miller Decl. ¶ 8.
The Examiner further finds Serfontein discloses in a table a preferred
dosage of folate of 1.0 or 5.0 mg, and relies on this disclosure for the recited
limitation as to the amount of tetrahydrofolate. Final Act. 14 (citing
Serfontein 8, ll. 19‒50).
Appellants argue, inter alia, that the relied on disclosure of the
amount of folate is limited to being a disclosure of folic acid or folate and,
thus, there is no anticipation. Appeal Br. 11.
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We agree with Appellants and find the relied on disclosure of amounts
of folate fails to anticipate the claims reciting 1 to 15 mg of tetrahydrofolate,
a different compound than folate (or folic acid). The error is further
manifest in that the Examiner finds Serfontein discloses folate and suitable
active metabolites of folate as distinct alternatives, and then relies on the
disclosure as to the amount of folate as supplying the necessary disclosure as
to the amount of the relied on suitable active metabolite (5-methyl-(6S)-
tetrahydrofolate). Accordingly, we do not sustain the rejection of claims 158
and 167 as anticipated by Serfontein.
Rejection 2
Claims 158, 164 and 167 require administration of a capsule or tablet
containing, inter alia, 1 to 15 mg of a tetrahydrofolate “consist[ing]
essentially of 5-methyl-(6S)-tetrahydrofolic acid or a pharmaceutically
compatible salt thereof.” Claims 158 and 167 also require “one or more
vitamin B group vitamins selected from (a) vitamin B12 or (b) vitamin B12
and vitamin B6,” while claim 164 requires the formulation to “not contain a
B group vitamin.”
As found by the Examiner, Smith teaches treatment of occlusive
vascular disease and Alzheimer’s disease, a cardiovascular disease and a
neurological disease, respectively, wherein the patient has elevated blood
levels of homocysteine. Final Act. 23 (citing Smith Abstract, col. 1, ll. 8‒
29, col. 2, ll. 29‒42). Smith discloses administration of a formulation
including a therapeutically effective amount of a drug from a list of nine
identified as suitable, which includes 5-methyltetrahydrofolate, for lowering
blood levels of homocysteine. Final Act. 23‒24 (citing Smith col. 4, ll. 11‒
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23, claims 6, 15). The Examiner further finds that the disclosure of 5-
methyltetrahydrofolate constitutes a disclosure of a racemic 1:1 mixture of
the R and S diastereomers as evidenced by Müller, and that Smith’s oral
dosages constitute disclosure of dosages of 5-methyl-(6S)-tetrahydrofolate
within the claimed range. Final Act. 24‒25 (citing Smith col. 6, ll. 22‒44).
With respect to claim 164, as to treating Alzheimer’s disease, Smith’s
particular disclosure that the B vitamins are optional constitutes disclosure
of a formulation that does not include a B vitamin. Final Act. 25 (citing
Smith, col. 2, ll. 43‒52). With respect to claims 158 and 167, Smith’s
disclosure of B vitamins includes vitamins B6 and B12. Final Act. 25
(citing Smith col. 2, ll. 43‒52, col. 6, ll. 41–47, col. 9, ll. 44‒46).
Appellants contend that the disclosure of “a racemate does not
anticipate the optical isomers thereof” because it is “a different chemical
entity, namely the 5-methyltetrahydrofolate racemic mixture.” Appeal Br.
42‒43. Appellants contend that the broadest reasonable interpretation of the
claims does not encompass 5-methyl-(6S)-tetrahydro-folate present in the 5-
methyltetrahydrofolate racemate disclosed in Smith. In support of this
position, Appellants point to the phrase “tetrahydrofolate in natural
stereoisomeric form” and the transition phrase “consisting essentially of.”
Appeal Br. 42‒43; see also Appeal Br. 5‒9 (citing Dr. Gregory’s declaration
dated September 24, 2013; IPR 2013-00117 Exhibit 2001 (“Gregory’s IPR
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Declaration”), ¶¶ 56‒60).7 Appellants further contend that the racemate
does not anticipate a stereoisomer. Id.
We begin our analysis by determining the scope and meaning of the
claims, giving claim terms the broadest reasonable interpretation consistent
with the Specification as they would be interpreted by one of ordinary skill
in the art. In re NTP, Inc., 654 F.3d 1279, 1288 (Fed. Cir. 2011) (citing In
re Suitco Surface, Inc., 603 F.3d 1255, 1259 (Fed. Cir. 2010)). In doing so,
we turn first to the claims themselves. See, e.g., Rappaport v. Dement, 254
F.3d 1053, 1059 (Fed. Cir. 2001). Regarding the phrase “consisting
essentially of,” it has long been understood to permit more than what is
recited in the claim provided any additional materials or steps do not
“materially affect the basic and novel properties of the invention.” AK Steel
Corp. v. Sollac, 344 F.3d 1234, 1239 (Fed. Cir. 2003).
Nothing in the claims or the Specification, indicates that the phrase
“5-methyl-(6S)-tetrahydrofolic acid” itself excludes the natural isomer when
it is present in a racemic mixture with the non-natural isomer, i.e., 5-methyl-
(6R)-tetrahydrofolic acid. There is no clear definition to this effect in the
Specification, and absent such, we will not import such into the claims.
Innova/Pure Water, Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111,
1117 (Fed. Cir. 2004) (“[E]ven where a patent describes only a single
embodiment, claims will not be ‘read restrictively unless the patentee has
demonstrated a clear intention to limit the claim scope using ‘words or

7 Gregory’s IPR Declaration was submitted in the merged reexamination
proceeding on September 14, 2015, in an information disclosure statement,
prior to subsequent merger with the reissue proceeding.
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expressions of manifest exclusion or restriction.’” (quoting Liebel-Flarsheim
Co. v. Medrad, Inc., 358 F.3d 898, 906 (Fed. Cir. 2004)); In re Van Geuns,
988 F.2d 1181, 1184 (Fed. Cir. 1993) (“[L]imitations are not to be read into
the claims from the specification.”).
As to Appellants’ relied on opinion evidence that a person of ordinary
skill in the art would interpret “the phrase ‘5-methyl-(6S)-tetrahydrofolic
acid’ as affirmatively denoting the single S-isomer which is . . . essentially
free of the unnatural isomer” (Gregory’s IPR Declaration ¶ 57), we find it
lacks sufficient factual corroboration for it to bear the weight required of it
in Appellants’ arguments. In re Am. Acad. of Sci. Tech Ctr., 367 F.3d 1359,
1368 (Fed. Cir. 2004) (“[T]he Board is entitled to weigh the declarations and
conclude that the lack of factual corroborations warrants discounting the
opinions expressed in the declarations.”); Yorkey v. Diab, 601 F.3d 1279,
1284 (Fed. Cir. 2010) (The Board has discretion to give more weight to one
item of evidence over another “unless no reasonable trier of fact could have
done so.”); Velander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir. 2003) (“In
giving more weight to prior publications than to subsequent conclusory
statements by experts, the Board acted well within [its] discretion.”). In
particular, the cited portions of Dr. Miller’s September 4, 2013, deposition
(“Miller’s IPR Deposition”)8 fail to sufficiently corroborate Dr. Gregory’s
opinion that one of ordinary skill in the art would not understand the phrase
“5-methyl-(6S)-tetrahydrofolic acid” to refer to the isomer in a mixture with

8 Miller’s IPR Deposition was submitted in the merged reexamination
proceeding on September 14, 2015, in an information disclosure statement,
prior to subsequent merger with the reissue proceeding.
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its enantiomer, including in a racemic mixture. Gregory’s IPR Declaration
¶¶ 56‒60.
We are, likewise, directed to neither persuasive argument nor
evidence that the presence of the 5-methyl-(6R)-tetrahydrofolic acid in the
racemic mixture “materially affects the basic and novel properties of the
invention.” AK Steel Corp. v. Sollac, 344 F.3d at 1239; see also In re De
Lajarte, 337 F.2d 870, 874 (CCPA 1964) (Applicants have the burden of
showing that a component in a reference would materially affect the basic
and novel characteristics of a claimed composition.). Appellants contend
that “one of ordinary skill in the art would recognize that the racemate would
affect the basic and novel characteristics of the natural stereoisomeric form
which consists essentially of the natural isomer.” Appeal Br. 7. Appellants
further rely on Bills,9 Marazza, and Lucock in contending that the skilled
artisan would recognize the racemate to be different than the recited 5-
methyl-(6S)-tetrahydrofolic acid (or salts thereof). Appeal Br. 8‒9.
Appellants contend the Examiner erred in relying on Bills because the
comparison was between twice a quantity of racemic 5-methyl-THF as the
amount of folate, rather than any comparison of racemic 5-methyl-THF and
its 6S stereoisomer. Appeal Br. 9. Appellants direct us to no evidence,
however, establishing that the 6R isomer present in the racemic 5-methyl-
THF has any effect on the activity and/or uptake of the 5-methyl-(6S)-THF.
Further, Bills finds “biologic activity of racemic . . . 5-methyltetra-
hydrofolate was half that of folic acid, and the R isomer did not affect

9 Bills et al., Biological Activity of Racemic Folate Mixtures Fed to Folate-
Depleted Rats, J. Nutr. 121: 1643‒48 (1991).
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growth at the levels fed” and that the result “suggests that the unnatural 6R
isomer [of 5-CH3-THF] did not adversely affect the utilization and
metabolism of the natural 6S isomer.” Bills, pp. 1643 (abstract), 1647.
Appellants cite to Gnosis I and to Marazza, column 2, lines 15‒32, for
Marazza’s disclosure “of studies that suggest ‘that the D-5-MTHF may
interfere with the transport of folate through the cell membrane in
mammals.’” Appeal Br. 9. The cited disclosure, however, is not evidence
that the unnatural 6R isomer has any effect, but rather only that it has been
“postulated, that the unnatural (6R)-diastereoisomer could interfere to the
folate transport system through the cell membranes of mammals, including
humans” (emphasis added). Marazza col. 2, ll. 15‒20. Similarly, Gnosis I
characterizes Marazza as “discuss[ing] previous studies suggesting that the
unnatural enantiomer D–5–MTHF may interfere with the transport of folate
through the cell membranes in humans” before “address[ing] this issue” by
separating the stereoisomers (emphasis added). Gnosis I, 808 F.3d at 832.
Appellants also cite to the Examiner’s reliance on Lucock as
“warn[ing] of the unknown and possible negative consequences of the
unnatural isomer of 5-MTHF” (emphasis added). Appeal Br. 9 (citing Final
Act. 22). While evidencing concern as to the possibility of negative
consequences, there is no evidence that there were any consequences.
In sum, Appellants have failed to establish that the presence of the 5-
methyl-(6R)-tetrahydrofolic acid in the racemic mixture materially affects
the basic and novel properties of the invention.

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In the absence of such a showing, Appellants’ reliance on case law
that distinguishes single optical isomers from racemate by requiring levels of
substantial purity from the unwanted isomer is unavailing because, as
explained above, the claims with the “consisting essentially of” transition
phrase do not require the single optical isomer, or exclude in any manner the
non-natural isomer. See, e.g., Appeal Br. 7‒8 (citing Sanofi-Synthelabo, 550
F.3d 1075, 1081). As to Appellants’ reliance on In re May, 574 F.2d 1082,
1090 (CCPA 1978) (see, e.g., Appeal Br. 7‒9; Reply Br. 3‒4), we likewise
find it fails to support patentability because while the claims at issue in May
did not include any customary words of exclusion, the claims were directed
to a composition, or its use, that required the composition to have properties
that were not met by the racemate due to the presence of the non-recited
isomer, May, 574 F.2d at 1084, 1091‒92, 1093‒94. Such a difference in the
recited properties of the claimed composition has not been shown in this
case, and absent such, the recited composition according to the claims is met
by Smith’s composition comprising 5-methyltetrahydrofolate racemate.
On this record, accordingly, we affirm the Examiner’s rejection of
claims 158, 164 and 167 as anticipated by Smith as evidenced by Müller.
Obviousness
We have reviewed the grounds of rejection for obviousness set forth
by the Examiner, Appellants’ arguments and proffered evidence, including
evidence of secondary considerations, and the Examiner’s response. On this
record, we are not persuaded that the Examiner erred reversibly in
determining that one of ordinary skill in the art, at the time of the invention,
armed with the knowledge of the cited prior art, would have been led to the
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subject matter of the claims within the meaning of 35 U.S.C. § 103(a) as
discussed below.
Rejection 3
The Examiner relies on Serfontein for its disclosure relating to, inter
alia, administration of a formulation including a suitable active metabolite of
folate for lowering levels of homocysteine or for prophylaxis or treatment of
elevated levels of homocysteine, including treatment of cardiovascular and
neurological disease due to elevated levels of homocysteine resulting from
hereditary enzyme defects. Final Act. 15‒16 (citing Serfontein p. 2, ll. 34‒
38, 45, 47‒48, p. 3, ll. 17, 20‒23, p. 4, ll. 25, 37‒42). Further, the Examiner
relies on Serfontein’s disclosure to teach including vitamin B6 and vitamin
B12 in the formulation, as well as details as to dosages and forms, and that
the use of the invention can be optimized by “monitoring homocysteine
levels in ‘human plasma.’” Final Act. 15‒16 (citing Serfontein p. 4, ll. 40‒
42, p. 6, l. 41‒p. 7, l. 3, p. 8, l. 19, table, p. 12, ll. 32‒33).
The Examiner relies on Marazza for its disclosure relating to chiral
resolution of racemic 5-methyl-tetrahydrofolate into its (6R) and (6S)
diastereoisomers, for identifying the natural diastereomer, and preparation of
the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid. Final Act. 17 (citing
Marazza col. 1, ll. 12‒16, 21‒28, 55‒67, col. 2, ll. 15‒32, col. 3, ll. 32‒40,
col. 7, ll. 8‒29, col. 11, ll. 9‒35 (Example 3)). The Examiner further relies
on Marazza for disclosing an interest in using 5-methyl-(6S)-tetrahydrofolic
acid as a therapeutic agent for folate deficient states. Final Act. 17 (citing
Marazza col. 1, ll. 21‒28, 55‒67).
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The Examiner relies on Ambrosini for its disclosure of 5-methyl-(6S)-
tetrahydrofolic acid and its identification as an “in vivo active form[] of folic
acid” that “find[s] an application in all of the forms of folate deficiencies.”
Final Act. 18 (citing Ambrosini p. 2, ll. 4‒8, 30‒33). The Examiner further
relies on Ambrosini for teaching that “the therapeutically acceptable
derivatives of [5-methyl-(6S)-tetrahydrofolic acid] . . . include [its] alkali
and alkaline earth metal salts” and the preparation of “ >97% pure calcium
salt of 5-methyl-(6S)-tetrahydrofolic acid.” Final Act. 18 (citing Ambrosini
p. 4, ll. 48‒59 (Example 4)).
The Examiner relies on Ubbink, “a study assessing vitamin B12,
vitamin B6, and ‘folate nutritional status’ in men with hyperhomo-
cysteinemia,” for its disclosure as to the association of elevated plasma
homocysteine concentrations with vascular disease and that the reasons for
hyperhomocysteinemia include enzyme defects, including possession of a
thermolabile variant of methylenetetrahydrofolate reductase. Final Act. 18
(citing Ubbink, p. 47, Title and Abstract, p. 50, 2nd col.).
The Examiner concludes, inter alia, that it would have been obvious
to one of ordinary skill in the art at the time of the invention to have used the
calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, as disclosed in Marazza
and Ambrosini as an active metabolite of folate, in Serfontein’s formulation
and method. Final Act. 19. The Examiner also concludes that one of
ordinary skill in the art would have had a reasonable expectation of success
in treating elevated levels of homocysteine, including that due to a
possession of a thermolabile variant of methylenehydrofolate reductase, and
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the diseases due to elevated levels of homocysteine, including
cardiovascular disease, as taught by Serfontein and Ubbink. Final Act. 19.
Appellants contend that the cited prior art does not teach or suggest
the use of a formulation consisting essentially of 5-methyl-(6S)-tetra-
hydrofolic acid or a pharmaceutically compatible salt thereof, particularly of
the calcium salt. Appeal Br. 25‒28. Appellants further contend that the
Examiner has failed to establish the requisite reasonable expectation of
success for the combination to establish a prima facie case of obviousness.
Appeal Br. 29‒36.
We do not find Appellants’ contentions well-grounded. We further
note that our reviewing court likewise found much these same arguments
directed to rejections over Serfontein in view of Marazza and Ubbink
unavailing. See Gnosis I, 808 F.3d 829. Appellants’ arguments that the
prior art does not teach or suggest the formulation as claimed are grounded
on the references individually and fail to take account of the teachings of the
references as a whole, and, thus, are not persuasive of reversible error.
Cf. In re Keller, 642 F.2d 413, 426 (CCPA 1981) (“[O]ne cannot show non-
obviousness by attacking references individually where, as here, the
rejections are based on combinations of references.”).
In particular, Appellants focus in turn on the failure of Serfontein to
identify 5-methyl-(6S)-tetrahydrofolate as an active metabolite of folate, the
absence of teachings in Marazza and Ambrosini to teach using 5-methyl-
(6S)-tetrahydrofolate to lower homocysteine levels so as to treat disease,
despite their teachings identifying it as the natural isomer and teaching its
use for treating all manner of folate deficiencies, and on Ubbink’s disclosure
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focusing on the use of folate. Appeal Br. 25‒28. Appellants argue that
Serfontein is in effect limited to teaching the use of folic acid or folates, as is
Ubbink, and that the disclosures of Marazza and Ambrosini would be
inadequate to overcome the prejudice against the use of reduced folates,
particularly where folate’s usefulness was recognized. Appeal Br. 25‒28
(citing Dr. Gregory’s declaration dated September 14, 2015 (“Gregory’s 2nd
Declaration”), ¶¶ 41, 48, 50‒56).10
We find the proffered evidence insufficient to establish error for the
reasons expressed by the Examiner, which we adopt expressly herein,
including those identified from the Federal Circuit’s decision affirming the
Board’s decision addressing the combination of Serfontein, Marazza, and
Ubbink, finding “[t]he record amply supports the Board’s finding of a
motivation to combine Serfontein and Marazza.” Ans. 41‒49; Gnosis I, 808
F.3d at 833‒34, 836. As to the argument that the Examiner’s Answer fails to
clearly identify which of Appellants’ arguments were addressed by reference
to the IPR 2013-00117 Decision, in the absence of identifying any particular
argument that was not addressed, we are apprised of no reversible error in
the absence of any particular identification of an argument. Reply Br. 2.
As to the requisite reasonable expectation of success for a prima facie
case, Appellants maintain both that no such finding was made by the Board
in the IPR 2013-00117 Decision, despite its affirmance by our reviewing

10 In addition to Gregory’s IPR Declaration (cited above), Appellants rely on
two further declarations by Dr. Gregory during the reexamination
proceedings, which we identify in like manner as Appellants for consistency
and ease of reference.
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court in Gnosis, 808 F.3d 829 (Appeal Br. 29‒30), and that there is, in fact,
no reasonable expectation of success (id. at 31‒36). Appellants’ reliance on
the argued absence of an explicit finding in the IPR 2013-00117 Decision is
without merit as to this proceeding because the Examiner has made such a
finding (Final Act. 19) supported with articulated reasoning (see, e.g., Ans.
49‒56). The issue remaining, accordingly, is whether Appellants’ argument
and proffered evidence is persuasive of reversible error in the Examiner’s
finding that there was a reasonable expectation of success. On this record,
we are not persuaded that the Examiner erred as discussed further below.
Appellants rely on Dr. Gregory’s declaration dated April 13, 2015
(“Gregory’s 1st Declaration”), for the proposition that, prior to 1997,
reduced folates, such as 5-methyl-(6S)-tetrahydrofolic acid, were not
considered suitable for treating diseases associated with high levels of
homocysteine. Appeal Br. 31 (citing Gregory’s 1st Declaration ¶ 13).
Appellants discuss in turn references relied on in Gregory’s 1st Declaration
and proffered as support: Horne et al., J. Bio. Chem. 253: 3529‒35 (1978)
(“Horne”); Ueland et al., J. Lab. Clin. Med. 114: 473‒501 (1989)
(“Ueland”); Harpey et al., J. Pediatr. 98: 275‒78 (1981) (“Harpey I”); and
Harpey et al., J. Pediatr. 103: 1007 (1983), as well as deposition testimony
by Dr. Miller dated May 6, 2013) (“Miller’s ITC Deposition”).
We note that these references were relied on by Appellants in the
IPR 2013-00117 proceeding, as well as Gregory’s IPR Declaration, and that
the arguments that there was no reasonable expectation of success grounded
on them were found unpersuasive by our reviewing court in Gnosis I. Ans.
51. Further, we are directed to no particular basis to support the position
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that the expectation of success for the claims subject to this rejection would
differ from that as to the claims at issue in Gnosis I. Rather, Appellants
merely contend that the evidence and arguments are entitled to further
review because it includes further evidence and arguments without
identifying how they differ in substance. Appeal Br. 35–36; Reply Br. 2.
Appellants’ further argument as to Marazza fails, as explained above, to
address the rejection grounded on the combination including Serfontein,
where our reviewing court found “motivation to use the method disclosed in
Serfontein and Marazza to treat elevated homocysteine levels . . . supported
by substantial evidence.” Gnosis I, 808 F.3d at 836.
On this record, further, we do not find the evidence bears the weight
necessary to establish that there is no reasonable expectation of success in
treating diseases associated with elevated levels of homocysteine. As to the
reliance on Horne, we find Gregory’s 1st Declaration fails to provide
sufficient reasoning why the data from in vitro experiments with cultured
liver cells under the conditions in Horne’s study from 1991 would have
reasonably led the skilled artisan to understand that administration to
patients would not have led to sufficient retention and metabolism of 5-
methyl-(6S)-tetrahydrofolate by, if not liver cells, other cells within the body
to have an effect on homocysteine levels. Appeal Br. 31‒32 (citing Gregory
1st Declaration ¶¶ 26‒28). In particular, the opinion is grounded on
reasoning that “[a] compound that is not retained by cells or metabolized to
any significant degree cannot be used by the body effectively for its intended
purpose” (Gregory 1st Declaration ¶ 28), but this reasoning fails to account
for other studies of record in which 5-methyl-(6S)-tetrahydrofolate or its
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racemate is demonstrated to provide clinically useful effects (see, e.g., Le
Grazie, Godfrey, Harpey I, Harpey II).
Further, while Appellants contend that it was understood in the art that
5-methyl-(6S)-tetrahydrofolate was a poor substrate for the required
polyglutamylation that would allow for it to become metabolically active
within a cell, there is an insufficient evidence on this record to support the
contention that one skilled in the art would not reasonably still expect
sufficient uptake, retention, and activity for an effect. Appeal Br. 32‒33
(citing Gregory 1st Declaration ¶¶ 29‒32). This is borne out by the factual
findings relied on by our reviewing court in its analysis that despite “some
prior art references suggest[ing] that L-5MTHF is a poor substrate for
polyglutatamation,” other prior art discloses that “5-MTHF does, in fact,
accumulate in the cell” and that, as to activity, in discussing Harpey I and II,
our reviewing court found that “although, switching to 5-MTHF may have
correlated with a slight increase in homocysteine, the net effect is still a
reduction of homocysteine levels.” Ans. 52‒53 (quoting Gnosis I, 808 F.3d
at 834‒35). Appellants do not squarely address that other references do in
fact show that “5-MTHF does, in fact accumulate in the cell” (see generally
Appeal Br.; Reply Br.).
Likewise, we find the proffered evidence as to the import of Harpey I
and Harpey II (Gregory’s 1st Declaration ¶¶ 19‒22) insufficient to establish
error in the determination by the Examiner, as well as that by our reviewing
court, that “substantial evidence supports the Board’s finding that a person
of ordinary skill in the art would not understand the Harpey references to
teach that 5‒MTHF would increase previously untreated homocysteine
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levels” (Gnosis I, 808 F.3d at 334). Specifically, the proffered opinion fails
to sufficiently explain why the observed limited increase in homocysteine
does not reasonably support the position that the drug would be understood
by the skilled artisan as having a beneficial effect, particularly where the
homocysteine levels absent prior treatment with a different drug were much
higher and the treatment with 5-MTHF was admittedly discontinued due to
its instability rather than lack of efficacy. Gregory’s 1st Declaration ¶ 20. It
follows that we do not find “Harpey I and Harpey II demonstrated that in
their study 5-MTHF was completely ineffective in lowering homocysteine
levels” as contended by Appellants. Appeal Br. 34‒35. Further, as found by
our reviewing court, and relied on by the Examiner, “other prior art
references show that 5-MTHF would nonetheless be effective for lowering
homocysteine levels.” Ans. 54 (quoting Gnosis I, 808 F.3d at 835). We find
this is also borne out by the improvement of conditions understood to be
associated with, or due to, elevated homocysteine levels upon administration
of 5-MTHF, including Godfrey and Le Grazie, as explained below in our
discussion of Rejection 7.
As to Appellants’ further arguments grounded on the “uncertain
predictability of biological response . . . not provid[ing] a reasonable
likelihood of successful treatment with any selected stereoisomer” (Appeal
Br. 35), we find Appellants’ arguments unpersuasive of reversible error. A
finding of obviousness does not require certainty. See, e.g., In re O’Farrell,
853 F.2d 894, 903-904 (Fed. Cir. 1988) (“Obviousness does not require
absolute predictability of success. . . . [A]ll that is required is a reasonable
expectation of success.”). Further, “obviousness cannot be avoided simply
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by a showing of some degree of unpredictability in the art so long as there
was a reasonable probability of success.” Pfizer, Inc. v. Apotex, Inc., 480
F.3d 1348, 1364 (Fed. Cir. 2007).
As to Appellants’ reliance on Miller’s ITC Deposition (Appeal Br.
33‒34), Appellants rely on a portion of deposition testimony that was relied
on in IPR 2013-00117. In that proceeding, this same evidence was found
lacking because the “report” at issue was neither properly identified, nor a
copy provided, and the testimony does not indicate that Dr. Miller was told
to consider the testimony in the context of what the ordinary artisan would
have understood in 1997 or earlier. IPR 2013-00117 Decision, 2014 WL
2875385, *13 fn.7. On this record, likewise, we find the same deficiencies
and, accordingly, likewise find it lacking weight.
Rejection 4
Claims 16, 161‒163, 171, and 175 are directed to prevention of neural
tube deficiencies.
The Examiner relies on Serfontein, Marazza, Ambrosini, and Ubbink,
as in Rejection 3, further identifying teaching from Serfontein as to the
applicability of Serfontein’s invention to lower total homocysteine blood
levels if elevated by any known cause, including elevation due to pregnancy.
Final Act. 19 (citing Serfontein p. 4, ll. 43‒48).
The Examiner relies on Mills for teaching, inter alia, that sufficiently
large doses of folic acid, when taken periconceptionally, can prevent many
neural tube defects that appear to result from a metabolic defect
characterized in that women carrying affected fetuses have significantly
higher levels of homocysteine due to their relative inability to metabolize
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homocysteine, which could result from a cystathionine synthase defect, a
methionine synthase defect or a 5,10 methylene tetrahydrofolate reductase
defect. Final Act. 20 (Mills Abstract, 758S).
The Examiner relies on Minns for teaching, inter alia, that higher
elevated homocysteine levels were known for mothers of neural tube defect
patients, including in association with various enzyme defects, and for
teaching supplementation with folic acid or folate to prevent recurrences of
neural tube defects. Final Act. 20‒21 (Minns p. 461‒62).
The Examiner relies on Scott for disclosing the “use of 5-MTHF
instead of folic acid when administering folate for the prevention of neural
tube defects in order to avoid exposing the mother and fetus to
unmetabolized folic acid, considered to be a neurotoxin.” Final Act. 21
(citing Scott). The Examiner further relies on Scott for suggesting studies
with doses of 200 μg or 400 μg of 5-MTHF. Id.
The Examiner relies on Lucock, in commenting on Scott, for warning
of unknown and possible negative consequence of the unnatural isomer of 5-
MTHF, thereby recommending the natural isomer, and disclosing that it is
likely that 5-MTHF, rather than folic acid itself, prevents neural tube
defects. Final Act. 22 (citing Lucock pp. 894‒95).
The Examiner relies on Leeming for, inter alia, teaching there were
concerns as “to unmetabolized folic acid causing ‘damaging effect’” and for
contrasting folic acid to the major natural folate 5-methyltetrahydrofolic acid
and for “explain[ing] that ‘[h]igh-dose folic acid may therefore damage
neural tissue during early embryonic development.” Final Act. 22 (citing
Leeming).
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The Examiner relies on Barford for teaching that an inhibitory effect
of folate on dihydropteridine reductase could cause serious problems in
developing fetuses and that use of “a reduced folate such as calcium
leucovorin” “would be prudent to avoid any problems that may be caused by
folic acid.” Final Act. 22‒23 (citing Barford p. 1793).
The Examiner concludes that:
It would have been obvious to one of ordinary skill in the
art at the time the invention was made to have used the
pharmaceutical preparation of Serfontein in view of Marazza,
Ambrosini and Ubbink for treating a woman so as to lower
homocysteine levels that have been increased due to 5, 10-
methylenetetrahydrofolate reductase and/or cystathionine
synthesase abnormalities, as taught by Serfontein, Ubbink,
Mills and Minns, and thus, prevent neural tube defects, as
taught by Mills, Minns and Scott, and so as to avoid the
neurotoxicity dangers with respect to folic acid identified by
Scott, Lucock, Leeming and Barford.

Final Act. 23.
Appellants contend that Mills and Minns are both limited to disclosing
the use of folic acid, rather than 5-methyl-(6S)-tetrahydrofolate, to prevent
neural tube defects. Appeal Br. 37.
Appellants contend that Scott speculates as to which of folic acid or
the metabolite 5-methyltetrahydrofolate is effective and that Scott “clearly
does not suggest replacing the folic acid used in the method of Serfontein
with a tetrahydrofolate in natural stereoisomeric form . . . with a reasonable
expectation of success.” Appeal Br. 37‒38 (citing Gregory’s 2nd
Declaration ¶¶ 68‒69). Appellants further contend that it “is incorrect” that
“Scott discloses the use of 5-MTHF instead of folic acid for preventing
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neural tube defects” as stated in the Final Office Action. Appeal Br. 38
(citing Gregory’s 2nd Declaration ¶¶ 68‒69). In regards to the disclosure in
Scott as to further trials, including those using 5-MTHF, the Appellants note
that “Scott speculates about possible further trials involving a high dose folic
acid arm and a low dose folic acid arm, and further alludes to the possibility
of an arm using a relatively low dose of 5-MTHF.” Appeal Br. 38
Appellants further argue that the publication of Mills and Minns five
years after Scott and their use of folic acid without mention or suggestion of
the use of 5-MTHF “demonstrates that Scott’s mere proposal of a potential
study involving a low dose arm using 5-MTHF does not suggest replacing
the folic acid in the method of Serfontein . . . [and that] [a]s evidenced by the
art, Scott’s musing seem to have been rejected by those skilled in the art.”
Appeal Br. 38.
Appellants dismiss Lucock’s cited teachings, like Scott’s, as “simply
more speculation” and likewise discount such teachings on the basis that
later published Mills and Minns do not “mention or suggest the use of 5-
MTHF.” Appeal Br. 38‒39. Similarly, Appellants dismiss Barford’s
teaching to use a reduced form of reduced folate calcium leucovorin on the
basis that later published Mills and Minns do not mention or suggest the use
of a reduced folate. Appeal Br. 39‒40. Appellants contend that Leeming
merely “echoes Scott’s concerns about possible damaging effects due to the
use of high dosages of folic acid . . . [but] do[es] not suggest that low
dosages of folic acid will have such possible damaging effects.” Appeal Br.
39.
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Appellants further contend, citing again to the arguments as to Horne,
Harpey I, Harpey II, and Ueland, that there is no reasonable expectation of
success, and raise that “[o]ne of ordinary skill in the art is charged with
knowledge of . . . relevant art that teaches away from the claimed invention.”
Appeal Br. 40‒41.
Appellants further reiterate arguments as to Serfontein and Marazza,
discussed above, and contend that the combined disclosures of Serfontein,
Mills, and Minns do not teach or suggest the use of 5-methyl-(6S)-
tetrahydrofolic acid in Serfontein’s method to lower homocysteine levels,
but rather the use of folic acid. Appeal Br. 40‒41.
As explained above in our discussion of Rejection 3, Appellants’
reliance on Horne, Harpey I, Harpey II, and Ueland is unavailing, and we are
not persuaded that the Examiner erred in Rejection 3, grounded on
Serfontein in view of Marazza, Ambrosini, and Ubbink. Being unpersuaded
that these references do not teach or suggest, inter alia, the use of the
calcium salt of 5-methyl-(6S)-tetrahydrofolic acid to lower homocysteine
levels, we turn to Appellants’ arguments as to the further references relied
on in Rejection 4 and also find them unpersuasive of reversible error.
Appellants’ arguments focusing on Mills and Minns teaching the use
of folic acid and on Barford teaching the use of L-5-MTHF, a different
metabolite than the 5-methyl-(6S)-tetrahydrofolate recited in the claims, fail
to squarely address what is suggested by the references as combined, in
which reduced forms are taught as preferred in supplementation to prevent
neural tube defects in order to avoid toxicity to fetuses, see, e.g., Scott,
Leeming, and Barford. Further, contrary to Appellants’ characterization of
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Scott’s relevant disclosure as being mere speculation (Appeal Br. 38), and
the opinion that “Scott only recommends administering folic acid”
(Gregory’s 2nd Declaration), Scott explicitly discloses 5-MTHF as an
alternative to be used instead of folic acid, at least in a trial, because reduced
forms of folate were expected to be less toxic than folate (Scott). The
absence of certainty as to the effect, as discussed above, does not establish
that there is no reasonable expectation of success. O’Farrell, 853 F.2d at
903–904.
Appellants’ further argument grounded on the absence of mention or
suggestion in Mills and Minns to use a reduced folate, despite these
references coming later than Scott and Barford, is without persuasive merit.
In effect, Appellants’ argument is that Mills and Minns teach away from use
of the earlier taught reduced folates, including 5-MTHF, in failing to
disclose any form of reduced folate; however, we will not read such into
these references. See, e.g., DyStar Textilfarben GmbH & Co. Deutschland
KG v. C.H. Patrick Co., 464 F.3d 1356, 1364 (Fed. Cir. 2006) (“We will not
read into a reference a teaching away from a process where no such
language exists.”); Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371, 1380
(Fed. Cir. 2005) (“Under the proper legal standard, a reference will teach
away when it suggests that the developments flowing from its disclosures
are unlikely to produce the objective of the applicant’s invention.”).
We are unpersuaded by Appellants’ further arguments addressing
Leeming and Scott. Appeal Br. 39. The high doses of folic acid raising
concern in Scott and Leeming are doses of 4 or 5 mg of folic acid per day,
respectively. The amounts administered in the relied on combination also
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include corresponding high doses and as such, Appellants’ arguments fail to
address the Examiner’s well founded determination that concerns that high
levels of folate were toxic would have led one of ordinary skill in the art to
the use of reduced forms of folate in the method of Serfontein as modified in
the combination. See also Ans. 62.
Rejection 5
The Examiner relies on Smith, as in Rejection 2, further applying the
teachings to the dependent claims subject to this rejection. Final Act. 25‒26.
The Examiner further relies on Smith for disclosing that “not only does the
patient have elevated levels of homocysteine, but also has at least
moderately reduced blood levels of folate.” Final Act. 26 (citing Smith
col. 1, ll. 9‒15).
The Examiner relies on Marazza and Ambrosini as relied on in
Rejection 3, including for identifying the active isomer of 5-methyltetra-
hydrofolate and for teaching the use of the calcium salt of 5-methyl-(6S)-
tetrahydrofolic acid as a therapeutically acceptable form of 5-methyl-
tetrahydrofolate, and concludes that it would have been obvious to one of
ordinary skill in the art at the time of the invention to have used the calcium
salt of 5-methyl-(6S)-tetrahydrofolate in Smith’s method with a reasonable
expectation of success. Final Act. 26‒27.
Appellants contend that Smith does not disclose or suggest the use of
tetrahydrofolate in natural stereoisomeric form. Appeal Br. 44. Appellants
contend that Marazza fails to overcome the prejudice against the use of
reduced folates such that one of ordinary skill in the art would use them
instead of folic acid. Appeal Br. 44‒45. Appellants contend that Ambrosini
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fails to suggest using a tetrahydrofolate in natural stereoisomeric form to
lower homocysteine levels, and that “disclosure by Ambrosini of the calcium
salt of 5-methyl-(6S)-tetrahydrofolic acid (Example 4) does not provide one
of ordinary skill in the art motivation to overcome the prejudice against the
use of reduced folates.” Appeal Br. 45. Appellants further, by citing earlier
discussion, rely on the Gregory’s 2nd Declaration and the arguments
grounded on Horne, Harpey I, Harpey II, and Ueland. Appeal Br. 44‒45.
Appellants’ arguments are unpersuasive of reversible error because
they fail to squarely address the rejection grounded on Smith identifying a
reduced folate, specifically, 5-methyltetrahydrofolate, as suitable for
lowering blood levels of homocysteine, and for disclosing its use to treat
cardiovascular, or neurological disease, and on Marazza and Ambrosini for
their teachings, inter alia, as to which optical isomer is the active form and
that the calcium salt of the active form, i.e., 5-methyl-(6S)-tetrahydrofolate
is a therapeutically acceptable form of 5-methyl-tetrahydrofolate. Ans. 66‒
67, 69; see also Final Act. 25‒26. As to Appellants’ contentions grounded
on prejudice against reduced folates, and to contended deficiencies in
Marazza and Ambrosini, these are unpersuasive for the reasons discussed
above and as set forth by the Examiner. See, e.g., Ans. 67‒69. Likewise, for
reasons discussed above, we find the arguments grounded on the lack of a
reasonable expectation of success unpersuasive.
Rejection 6
The Examiner relies on Bailey for disclosing a composition including
natural isomers of reduced folate, such as 5-methyl-(6S)-tetrahydrofolic
acid, to supply folate, for disclosing the composition in tablet form in an
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amount rounding to 1 mg, for disclosing the inclusion of vitamin B6, and for
teaching that the calcium salt can be used. Final Act. 28 (citing Bailey
Abstract, p. 6. ll. 17‒31, p. 17, ll. 29‒32, p. 21, ll. 21‒25). Further, the
Examiner relies on Bailey’s teaching that the “natural isomer of reduced
folate, e.g., said 5-methyl-(6S)-tetrahydrofolic acid (III) disodium salt or
said calcium salt is an improved source compared to folic acid.” Final Act.
28 (citing Bailey p. 5, l. 9‒p. 6, l. 31).
The Examiner further relies on Bailey for disclosing that “a significant
correlation has been discovered between vitamin deficiency, especially of
folate, and peripheral vascular disease, a major cause of death. A high
percentage of individuals have abnormal blood levels of homocysteine.”
Final Act. 27 (citing Bailey pp. 1‒2).
The Examiner relies on Serfontein for disclosing, inter alia, “‘a
pharmaceutical preparation for lowering levels of homocysteine or for the
prophylaxis or treatment of elevated levels of homocysteine in a patient . . . ,
[t]his preparation includ[ing] ‘folate or a suitable active metabolite of folate
or a substance which release folate in vivo,’ vitamin B6, and vitamin B12.”
Final Act. 28‒29 (citing Serfontein p. 4, ll. 37‒42).
The Examiner relies on Mills for teaching, inter alia, that a
sufficiently large dose of folic acid, when taken periconceptionally, can
prevent many neural tube defects that appear to result from a metabolic
defect characterized in that women carrying affected fetuses have
significantly higher levels of homocysteine due to their relative inability to
metabolize homocysteine, which could result from a cystathionine synthase
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defect, a methionine synthase defect, or a 5,10 methylene tetrahydrofolate
reductase defect. Final Act. 29‒30 (Mills Abstract, 758S).
The Examiner concludes, inter alia, that:
It would have been obvious to one of ordinary skill in the
art at the time the invention was made to have administered
Bailey's composition for preventing/treating vascular disease or
neural tube defects, wherein such vascular disease or neural
tube defects are associated with elevated levels of
homocysteine, because Bailey refers to an association with
“abnormal blood levels of homocysteine”, and there are
cardiovascular disease and neural tube defects associated with
elevated levels of homocysteine, as taught by Serfontein and
Mills. In fact, as noted above, Serfontein teaches administering
“folate or a suitable active metabolite of folate or a substance
which releases folate in vivo” for lowering homocysteine levels
associated with cardiovascular disease and pregnancy.
Likewise, as noted above, Mills teaches administering folic acid
to prevent neural tube defects associated with elevated levels of
homocysteine. Further rationale is based on the fact that, as
noted above, Bailey’s natural isomer of reduced folate, e.g. said
5-methyl-(6S)-tetrahydrofolic acid (Ill) disodium salt or said
calcium salt, is an improved source compared to folic acid,
whose oral bioavailability has been shown to be widely
variable.
Final Act. 30.
Appellants contend that Bailey does not disclose a correlation
between peripheral vascular disease or neural tube defects and increased
levels of homocysteine levels and, thus, “does not disclose treating neural
tube defects or vascular disease associated with increased levels of
homocysteine.” Appeal Br. 46.
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As to Serfontein, Appellants contend Serfontein suggests neither “the
racemic compound 5-methyltetrahydrofolic acid . . . [nor] 5-methyl-(6S)-
tetrahydrofolic acid or a pharmaceutically compatible salt thereof” despite
disclosing the use of a “composition contain[ing] a compound which is
selected from the genus comprising folic acid (folate), suitable metabolites
of folate, and substances which release folate in vivo.” Appeal Br. 46. The
argument is grounded, in the main, on the contention that “[t]he only
specific compound disclosed by Serfontein for use in lowering levels of
homocysteine is folic acid.” Appeal Br. 47.
As to Mills, Appellants contend that it is consistent with Serfontein
wherein folic acid is used because it “do[es] not mention or suggest the use
of tetrahydrofolate in natural stereoisomeric form in the treatment or
prevention of neural tube defects.” Appeal Br. 47.
Appellants further contend that “the combined disclosures . . . would
at best suggest using folic acid to treat cardiovascular disease associated
with increased levels of homocysteine or to prevent prenatal neural tube
deficiencies associated with increased maternal homocysteine levels.”
Appeal Br. 48.
Appellants’ arguments are unpersuasive because they fail to squarely
address that the combination includes, inter alia, Bailey’s teaching that the
calcium salt of 5-methyl-(6S)-tetrahydrofolate is an improved source of
folate relative to folic acid (or folate) and Serfontein’s teaching that the
included source of folate can be selected from “folic acid (folate), suitable
metabolites of folate, and substances which release folate in vivo” (Appeal
Br. 46). Cf. Keller, 642 F.2d at 426 (“[O]ne cannot show non-obviousness
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by attacking references individually where, as here, the rejections are based
on combinations of references.”). As set forth by the Examiner, Appellants’
arguments as to the lack of sufficient association in Bailey between
homocysteine levels and “neural tube defects or vascular disease” fail to
account for the further teachings from Serfontein and Mills. Ans. 70‒72.
Appellants’ arguments as to Serfontein are likewise unpersuasive because,
contrary to being limited to teaching the administration of folic acid,
Serfontein also includes express teaching to administer “suitable
metabolites” and “substances which release folate in vivo” and the
combination includes, inter alia, Bailey’s teaching that the calcium salt of 5-
methyl-(6S)-tetrahydro-folate is an improved source of folate. Ans. 70‒72.
Rejection 7
The Examiner relies on Regland 1 for, inter alia, stating “that
‘[t]heoretically, MTHF [i.e., methyltetrahydrofolate] should be the optimal
treatment’ for the patient” in its disclosure relating to a patient with
schizophrenia with a significantly increased serum level of homocysteine
and for its teaching that a defect in methylenetetrahydrofolate reductase
activity indicates a deficiency in methyltetrahydrofolate. Final Act. 34
(Regland 1 Abstract). The Examiner further relies on Regland 1 for its
disclosure relating to “the combination of homocysteinemia and a psychotic
disorder.” Final Act. 35 (citing Regland 1 p. 150).
The Examiner relies on Regland 2, which cites Regland 1 for, inter
alia, “report[ing] that ‘a significant proportion of patients with schizophrenia
have increased homocysteine levels.” Final Act. 35 (citing Regland 2
p. 165); see also Ans. 72 (citing Regland 2 pp. 165, 168).
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The Examiner relies on Godfrey for, inter alia, teaching the use of the
“methyl derivative of folate for treatment [of acute psychiatric disorders,
e.g., major depression or schizophrenia] as it is this form [i.e., the methyl
derivative] which is actively transported across the blood brain barrier and
which is detectable in the cerebrospinal fluid in concentrations three times
greater than in serum.” Final Act. 35‒36 (citing Godfrey Abstract, p. 392).
The Examiner identifies the methyl derivative in Godfrey as
“methyltetrahydrofolate.” Final Act. 36.
The Examiner relies on Le Grazie for, inter alia, “teach[ing] the use
of 5-MTHF ‘in the therapy of organic mental disturbances . . . with
depression of mood,” the use of MTHF calcium salt, “pharmaceutical
composition, e.g., a tablet, containing preferably 10 to 50 mg of the 5-
MTHF.” Final Act. 36 (citing Le Grazie pp. 2‒3, 7). The Examiner further
finds Le Grazie to disclose both the racemic mixture of R and S isomers of
5-methyl tetrahydrofolic acid, in reciting (±)-L-5-methyl-5,6,7,8-
tetrahydrofolic acid, and 5-methyl-(6S)-tetrahydrofolic acid, i.e., the
compound recited in the claims, in reciting (-)-L-5-methyl-5,6,7,8-
tetrahydrofolic acid. Ans. 74 (citing Le Grazie p. 2, ll. 8‒10). The
Examiner determines that Le Grazie discloses a pharmaceutical composition
to treat organic mental disturbances that includes 5-methyl-(6S)-
tetrahydrofolic acid or its salt. Ans. 74. The Examiner’s determination is
not contested.11 See generally Reply Br.

11 We, accordingly, find Appellants’ argument and proffered opinion
evidence fails to bear the required weight as to any contended failure of Le
Grazie to disclose 5-methyl-(6S)-tetrahydrofolic acid and its salts.
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The Examiner relies on Marazza and Ambrosini as in Rejection 3.
Final Act. 36.
The Examiner further relies on Serfontein for its teachings relating,
inter alia, to a pharmaceutical preparation, e.g., tablet, containing of a
pharmaceutical preparation including “a suitable active metabolite of folate
or substance which releases folate in vivo, for lowering homocysteine levels
and treating the conditions associated therewith, such as homocysteine-
associated psychiatric problems.” Final Act. 37 (citing Serfontein p. 3,
ll. 20‒23, p. 4, ll. 37‒48, p. 6, l. 41‒p. 7, l. 3).
The Examiner concludes that one of ordinary skill in the art at the
time of the rejection, armed with the cited prior art, including Serfontein,
would have found it obvious to have treated depression and/or schizophrenia
associated with increased levels of homocysteine using the active form of
methyl tetrahydrofolate, e.g., the calcium salt of 5-methyl-(6S)-
tetrahydrofolic acid, based on the teachings of correlations between
increased homocysteine levels and certain mental disorders, including
depression and/or schizophrenia, the teachings as to treating organic mental
disturbance using methyltetrahydrofolate, and the teachings as to the active
stereoisomeric form and active salts, including the calcium salt of 5-methyl-
(6S)-tetrahydrofolic acid. Final Act. 36‒37.
As to the Examiner’s reliance on Regland 1, Appellants again contend
that one of ordinary skill in the art would not have had a reasonable
expectation of success because of the “problems associated with MTHF as a
substrate for glutamation and the uptake thereof by the cells.” Appeal Br.
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51‒52 (citing the discussion regarding Horne, Harpey I, Harpey II, and
Ueland).
Appellants’ repeated argument is again unpersuasive for the same
reasons as discussed above.
Appellants’ argue that “Regland 2 does not repeat the theory of
Regland 1 regarding supplementing such patients [with schizophrenia
having increased levels of homocysteine] with MTHF” and that neither
Godfrey nor Le Grazie tested or monitored patients with respect to
homocysteine levels. Appeal Br. 52‒53; Reply Br. 11. Appellants argue the
references do not, therefore, disclose the treatment of diseases associated
with increased levels of homocysteine. Reply Br. 11.
Appellants’ arguments are not persuasive of reversible error because,
as well-expressed by the Examiner, the absence of these teachings in these
particular references is of no import as the rejection is grounded on their
provision from other references in the combination, including Serfontein.
Ans. 72‒74 (finding Regland 1, which cites Godfrey, Regland 2, and
Serfontein teach elevated levels of homocysteine in patients with mental
disorders). Further, regardless of whether Godfrey or Le Grazie reasonably
teach that their treatments lowered homocysteine levels, it is not disputed
that they disclose the administration of methyltetrahydrofolate or 5-MTHF
to treat the cited neurological disturbances. Cf. Alcon Research, LTD v.
Apotex Inc., 687 F.3d 1362, 1368 (Fed. Cir. 2012) (“[T]he motivation to
modify a prior art reference to arrive at the claimed invention need not be
the same motivation that the patentee had.”).
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As to Appellants’ further argument “that Le Grazie do[es] not disclose
how to separate (-)-5-MTHF from the racemic mixture” (Appeal Br. 53), the
Examiner finds that such separation was known in the art at the time of the
instant invention (Ans. 75), which is not contested by Appellants (see
generally Reply Br.). Further, the disclosures of a prior art reference are
presumed to be enabled. Amgen Inc. v. Hoechst Marion Roussel, Inc., 314
F.3d 1313, 1354‒55 (Fed. Cir. 2003). Appellants bear the burden of
showing Le Grazie is not enabled (id. at 1355), but have not done so on this
record.
As to Appellants’ further contention that Marazza, Ambrosini, and
Serfontein “do not suggest the use of L-MTHF (or salts thereof) [i.e., 5-
methyl-(6S)-tetrahydrofolic acid (or salts thereof)] for the treatment of
disease associated with increased levels of homocysteine” (Appeal Br. 53
(citing earlier arguments as to these references and to Horne, Harpey I,
Harpey II, and Ueland), the contention, and referenced arguments, is
unpersuasive for the reasons discussed above.
Secondary Considerations
Notwithstanding what the teachings of the prior art would have
suggested to one of ordinary skill in the art at the time of the invention, the
totality of the evidence submitted, including objective evidence of
nonobviousness may lead to the conclusion that the claimed invention would
not have been obvious to one of ordinary skill in the art. In re Piasecki,
745 F.2d 1468, 1471‒72 (Fed. Cir. 1984). Objective evidence of non-
obviousness may include solving a long-felt but unsolved need, failure of
others, unexpected results, commercial success, copying, licensing, industry
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praise, and industry skepticism. Graham v. Deere, 383 U.S. 1, 17 (1966);
Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling USA, Inc.,
699 F.3d 1340, 1347, 1349‒55 (Fed. Cir. 2012).
Appellants must establish a nexus between the proffered objective
evidence and the merits of the claimed invention for the objective evidence
to be accorded substantial weight. In re Kao, 639 F.3d 1057, 1068 (Fed. Cir.
2011). “A prima facie case of nexus is made when the patentee shows both
that there is commercial success, and that the product that is commercially
successful is the invention disclosed and claimed in the patent.” Crocs, Inc.
v. Int’l Trade Comm’n, 598 F.3d 1294, 1310‒11 (Fed. Cir. 2010) (citing In
re GPAC Inc., 57 F.3d 157, 1580 (Fed. Cir. 1995)). “Where the offered
secondary consideration actually results from something other than what is
both claimed and novel in the claim, there is no nexus to the merits of the
claimed invention.” Kao, 639 F.3d at 1068.
Addressing the Examiner’s “assert[ion] that ‘Applicants [sic]
arguments remain unpersuasive and there remains a lack of nexus with the
claims,’” Appellants contend that they have established a prima facie case of
nexus because there is evidence of commercial success for products related
to the claimed methods, i.e., products corresponding to the compositions or
formulations administered in the claims. Appeal Br. 54‒55 (citing Final
Act. 107). Appellants further maintain that the “Examiner’s arguments do
not dispute nexus” and fail to rebut the prima facie case of a nexus because
“[t]he Examiner merely asserts that the commercial products contain further
ingredients” and that “[t]here is no suggestion that, for example, the
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commercial success of the commercial products is associated with these
further ingredients.” Reply Br. 11‒12.
In their arguments, Appellants further contend that “‘[w]hile objective
evidence of non-obviousness lacks a nexus if it exclusively relates to a
feature that was ‘known in the prior art,’ Ormco Corp. v. Align Tech., Inc.,
463 F.3d 1299, 1312 . . . (Fed. Cir. 2006), the obviousness inquiry centers on
whether ‘the claimed invention as a whole’ would have been obvious.’”
Appeal Br. 57 (quoting Rambus Inc. v. Rao, 731 F.3d 1248, 1257 (Fed. Cir.
2013)).
Appellants contend that the evidence of record with respect to
secondary considerations is sufficient to support that the claims are
nonobvious. Appeal Br. 57‒82.
On this record, we are neither persuaded that that the Examiner failed
to dispute the nexus, nor that the Examiner has failed to properly consider
the proffered evidence of secondary considerations. As set forth in detail by
the Examiner, the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, and its
use in amounts according to the claims for the treatment of neurological
disease, was known in the prior art, particularly as disclosed in Le Grazie.
Ans. 94‒95 (citing Godfrey, Le Grazie, and Smith). Thus, we agree with the
Examiner that there is no nexus between any evidence grounded on
Appellants’ Deplin® product which contains the calcium salt of 5-methyl-
(6S)-tetrahydrofolic acid, which was identified in the prior art as being used
to treat organic mental disorders and as a preferred folate source for
remedying folate deficiencies, including for the treatment of associated
diseases. Ans. 94‒96; see Kao, 639 F.3d at 1068. As to Appellants’
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Metafolin® product, there is likewise no nexus where it is simply
“substantially chirally-pure 5-methyl-(6S)-tetrahydrofolic acid (L-5-MTHF),
as a calcium salt.” Ans. 92.
As to Appellants’ further products relied on for evidence of secondary
considerations, i.e., the mixed products Metanx®, Cerefolin®,
CerefolinNAC®, Neevo®, and NeevoDHA®, the Examiner explains that
these include the same calcium salt of 5-methyl-(6S)-tetrahydrofolic acid
and, variously, a vitamin B12 or vitamins B12 and B6. Ans. 94. We agree
with the Examiner. The lack of novelty as to a tablet, as well as its use
relating to neural tube defects and vascular disease, including the
combination of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid and a
vitamin B12 or vitamins B12 and B6, is evidenced by Bailey’s disclosure.
Ans. 99‒100 (citing Bailey p. 21, ll. 21‒25; example bridging pp. 19‒20);
see also Ans. 96 (citing Bailey p. 17, ll. 29‒32, p. 21, ll. 21‒25; example
bridging pp. 19‒20.
Appellants further argue that commercial success need not be shown
for the entire scope of the claimed invention, namely for multiple
embodiments within a claim. Appeal Br. 55‒56 (citing, inter alia, In re
Glatt Air Techniques Inc., 630 F.3d 1026, 1030 (Fed. Cir. 2011) (“The fact
that Glatt’s commercial products only contain one type of shielding does not
make its commercial success evidence irrelevant.”); Kao, 639 F.3d at 1069
(“[A]n applicant ‘need not sell every conceivable embodiment . . . so long as
what was sold was within the scope of the claims.” (quoting In re DBC, 545
F.3d 1373, 1384 (Fed. Cir. 2008))). Appellants proffer arguments relating to
the commercial products including further ingredients and to the content and
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weight of the declaration of Mr. Ladner dated October 15, 2013 (“Ladner
Declaration) and the declaration of Dr. Jacobs dated October 15, 2013
(“Jacobs Declaration”). Appeal Br. 55‒56; Reply Br. 12‒14. Appellants’
position, most fully developed in the Reply Brief, is grounded on contended
synergistic effects due to the combination of the 5-methyl-(6S)-tetrahydro-
folic acid with pyridoxal 5′-phosphate, the active form of vitamin B6, and
methylcobalamin, a particular form of vitamin B12. Reply Br. 12‒14 (citing
Ladner Declaration ¶¶ 38, 48; Jacobs Declaration ¶ 44). Appellants contend
in effect that there is a nexus because the recitation of vitamin B6 and B12
encompasses these particular forms of vitamins B6 and B12. Appeal Br.
55‒56; Reply Br. 12‒14.
Appellants’ argument fails, however, because the issue is not that the
combination is merely an embodiment of what is claimed, but rather that
what is recited in the claim is not novel. See Kao, 639 F.3d at 1068 (“Where
the offered secondary consideration actually results from something other
than what is both claimed and novel in the claim, there is no nexus to the
merits of the claimed invention.”). In particular, the claims reciting the
combination of 5-methyl-(6S)-tetrahydrofolic acid with vitamin B12, or with
vitamins B12 and B6, are not directed to novel aspects and, thus, there is
insufficient nexus.
For these reasons, we are not persuaded of error in the Examiner’s
findings with respect to the secondary considerations, and the weight
accorded them by the Examiner.
On balance, as to each of Rejections 3‒7, in view of the strength of
the evidence in favor of obviousness and the noted deficiencies in the
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evidence of nonobviousness, the evidence of record weighs most heavily in
favor of the Examiner’s conclusion of obviousness. Thus, we sustain the
obviousness rejections of claims 16 and 158‒177.

DECISION
The Examiner’s decision rejecting claims 158 and 167 under 35
U.S.C. § 102(b) is REVERSED.
The Examiner’s decision rejecting claims 158, 164, and 167 under 35
U.S.C. § 102(e) is AFFIRMED.
The Examiner’s decision rejecting claims 16 and 158‒177 under 35
U.S.C. § 103(a) is AFFIRMED.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).
AFFIRMED

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