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Parties Involved:
Gnosis Bioresearch S.A.
Appellee
Gnosis S.P.A.
Appellee
Gnosis U.S.A., Inc.
Appellee
South Alabama Medical Science Foundation
Appellant

Document Text:

United States Court of Appeals 

for the Federal Circuit ______________________ 

SOUTH ALABAMA MEDICAL SCIENCE 

FOUNDATION,

Appellant

v.

GNOSIS S.P.A., GNOSIS BIORESEARCH S.A., 

GNOSIS U.S.A., INC.,

Appellees

______________________ 

2014-1778, 2014-1780, 2014-1781

______________________ 

Appeals from the United States Patent and Trademark Office, Patent Trial and Appeal Board in No. 

IPR2013-00116.

______________________ 

Decided: December 17, 2015

______________________ 

 THOMAS J. PARKER, Alston & Bird LLP, New York, 

NY argued for appellant. Also represented by JITENDRA 

MALIK, Durham, NC; KIRK T. BRADLEY, Charlotte, NC; 

PETER ROGALSKYJ, Law Office of Peter Rogalskyj, Livonia, NY. 

JOSEPH CWIK, Amin Talati & Upadhye, LLC, 

Chicago, IL argued for appellees. Also represented by 

JONATHAN JACOB KRIT, Amin Talati, LLC, Chicago, IL. 

______________________ 

Case: 14-1781 Document: 17-2 Page: 1 Filed: 12/17/2015
2 SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S.P.A. 

Before NEWMAN, PLAGER, and HUGHES, Circuit Judges.

Opinion for the court filed by Circuit Judge HUGHES. 

Dissenting opinion filed by Circuit Judge NEWMAN. 

HUGHES, Circuit Judge.

This is a companion case to Merck & Cie v. Gnosis

S.p.A., No. 14-1777 (Fed. Cir. Dec. 17, 2015) (Gnosis I), 

also decided today. As Merck argued in that case, South 

Alabama Medical Science Foundation argues here that 

the prior art taught away from its claimed use of a reduced folate to treat folate deficiency, and that objective 

indicia of non-obviousness further demonstrate the validity of its patents. Although the Patent Trial and Appeal 

Board erred in its assessment of the evidence of licensing, 

the Board’s other factual findings are supported by substantial evidence. Because we agree with the Board’s 

ultimate conclusion of obviousness in light of those findings, we affirm.

I 

South Alabama Medical Science Foundation (SAMSF) 

owns U.S. Patent Nos. 5,997,915 (’915 patent), 6,673,381

(’381 patent), and 7,172,778 (’778 patent). At the request 

of Gnosis S.p.A., Gnosis Bioresearch S.A., and Gnosis 

U.S.A. (collectively, Gnosis) and after granting SAMSF’s 

motion to cancel certain claims, the Board instituted 

review of claims 37, 94–97, 99–100, and 110–111 of the 

’915 patent; claim 32 of the ’381 patent; and claim 15 of 

the ’778 patent. 

All three patents relate to administering the “natural” 

stereoisomer of 5-methyl-tetrahydrofolic acid (L-5-MTHF)

and other vitamins to treat symptoms associated with 

folate deficiency. We explained the background for this 

technology in Gnosis I, slip op. at 2–3. In brief, 5-MTHF 

is a reduced folate that is a critical component of certain 

metabolic cycles. A deficiency of folate causes a variety of 

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SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S.P.A. 3

health issues, including cardiovascular disease, neurological disorders, birth defects, and skeletal disorders. 

Claim 37 of the ’915 patent recites “a method of increasing a human subject’s dietary intake of folate comprising administering . . . one or more natural isomers of 

reduced folate selected from [a group including L-5-

MTHF]” and “an essential nutrient preparation . . . comprising a vitamin other than ascorbic acid . . . in an 

amount equal to or greater than 25% of the daily requirement for the vitamin.” ’915 patent, col. 23 ll. 16–31. 

Claims 94–97, 99–100, and 110–111 ultimately depend 

from claim 37, and specifically require that “the one or 

more natural isomers of reduced folate is substantially 

chirally pure [5-MTHF] or a polyglutamyl derivative 

thereof.” ’915 patent, reexamination certificate, col. 4 ll.

34–50, 55–62; col. 6 ll. 26–31.

Claim 32 of the ’381 patent similarly recites a method 

of treating vascular disease using a composition including 

one or more substantially chirally pure natural isomers of 

reduced folate (e.g. L-5-MTHF) and an essential nutrient 

preparation comprising a vitamin other than ascorbic 

acid. ’381 patent, col. 18 ll. 33–35. 

Claim 15 of the ’778 patent covers a composition containing substantially chirally pure natural isomers of 

reduced folate (e.g. L-5-MTHF), in an amount effective for 

the treatment of vascular disease and certain pregnancyrelated conditions, and an essential nutrient preparation 

containing a vitamin other than ascorbic acid. ’778 patent, col. 18 ll. 18–20.

The Board found that all of the contested claims were 

obvious in light of two prior art references: European

Patent App. No. 0 595 005 (Serfontein) and U.S. Patent 

No. 5,194,611 (Marazza). Serfontein discloses a pharmaceutical preparation for treating elevated levels of homocysteine, which is often associated with folate deficiency. 

The preparation includes “folate or a suitable active 

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4 SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S.P.A. 

metabolite of folate,” along with vitamins B6 and B12. 

Serfontein, at 4 ll. 37–42. Marazza identifies L-5-MTHF 

as a “natural metabolite” of folate in which there is an 

“increasing interest” for the treatment of folate deficiencies. Marazza, col. 1 ll. 26–29.1 As in Gnosis I, the Board 

found that based on the close similarity of purpose and 

disclosure of these references a person of ordinary skill 

would have been motivated to combine them to arrive at 

the claimed use of L-5-MTHF and a vitamin supplement 

to treat symptoms of folate deficiency. 

The Board also considered SAMSF’s evidence of objective indicia of non-obviousness. The Board found that 

SAMSF failed to demonstrate an adequate nexus between 

that evidence and the novel features of the contested 

claims. Accordingly, the Board concluded that the contested claims of the ’915, ’381, and ’778 patents are invalid for obviousness under 35 U.S.C. § 103. 

SAMSF appeals. We have jurisdiction under 28 U.S.C. 

§ 1295(a)(4)(A). 

II

Obviousness is a question of law based on underlying 

findings of fact, which include the motivation to combine 

multiple prior art references and any objective indicia of 

non-obviousness. Medichem, S.A. v. Rolabo, S.L., 437 

F.3d 1157, 1164 (Fed. Cir. 2006); see also Graham v. John 

Deere Co., 383 U.S. 1, 17–18 (1966). We review the 

Board’s factual findings for substantial evidence and the 

ultimate conclusion of obviousness de novo. In re Mouttet, 

686 F.3d 1322, 1330–31 (Fed. Cir. 2012). 

SAMSF makes essentially the same arguments for reversing the Board’s obviousness analysis that Merck 

1 For more detail on these references, see Gnosis I, 

slip op. at 4–5.

 

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SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S.P.A. 5

made in Gnosis I. SAMSF argues that the Board’s obviousness analysis was insufficiently thorough, and that the 

prior art teaches away from combining Serfontein and 

Marazza, because it suggests that L-5-MTHF may increase homocysteine levels, is too unstable for therapeutic 

use, and is a poor substrate for polyglutamation. SAMSF 

also argues that the Board imposed an overly strict nexus 

requirement to find that its evidence of objective indicia of 

non-obviousness is not sufficiently tied to the novel features of the contested claims. 

For the same reasons discussed in Gnosis I, slip op. 7–

13, the Board’s finding of a motivation to combine Serfontein and Marazza was adequately explained and supported by substantial evidence. Serfontein calls for a 

“suitable active metabolite of folate,” and Marazza discloses that an increasingly popular option for treating 

folate deficiency is L-5-MTHF. Although SAMSF points 

to isolated disclosures suggesting L-5-MTHF may not be 

“suitable,” substantial evidence supports the Board’s 

finding that the prior art as a whole teaches otherwise. 

We find no error in the Board’s conclusion that the prior 

art and expert testimony here provide strong evidence 

that the contested claims were obvious. 

The Board also properly determined that SAMSF’s evidence of objective indicia of non-obviousness was insufficient to overcome the other evidence of obviousness. Like 

Merck in Gnosis I, SAMSF argued here that the commercial success of the Metanx®, Cerefolin®, CerefolinNAC®, 

Néevo®, and NéevoDHA® products manufactured by 

Pamlab demonstrate non-obviousness. But these products contain a specific combination of L-5-MTHF and 

several vitamins and other active ingredients that are not 

recited in the claims. See Gnosis I, slip op. at 14–15. 

Substantial evidence thus supports the Board’s finding 

that the commercial success of these products was inadequately linked to the claimed methods and composition—

which call for L-5-MTHF or another reduced folate and 

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6 SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S.P.A. 

any number of vitamins other than ascorbic acid—as 

opposed to the specific formulations in these products. 

Contrary to SAMSF’s argument, the Board’s analysis

does not effectively require SAMSF to produce evidence of 

commercial success for every potential embodiment of the 

claims. See Rambus Inc. v. Rea, 731 F.3d 1248, 1257 

(Fed. Cir. 2013) (holding such a strict requirement is 

improper). Rather, the Board applied the appropriate 

standard and found that the commercially successful 

products were not “reasonably commensurate in scope 

with the claims” and that SAMSF had not provided an 

“adequate basis to support the conclusion that other 

embodiments falling within the claim will behave in the 

same manner.” J.A. 39–40, 84–86, 131–32 (citing In re

Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011)). 

We therefore reject SAMSF’s contention that the Board 

applied an overly strict nexus requirement. 

The Board’s nexus analysis for the evidence of industry praise was also sound. This evidence consisted of 

praise for the Pamlab products, which the Board found 

were not reasonably commensurate with the scope of the 

claims. Moreover, substantial evidence supports the 

Board’s finding that the praise was particularly directed

to the use of L-5-MTHF, an element already known in the 

prior art. The industry award touted by SAMSF was for

Metafolin®, the L-5-MTHF ingredient in the Pamlab 

products. Likewise, although the industry praised the 

positive patient outcomes associated with the Pamlab 

products, SAMSF’s experts testified that those outcomes 

are attributable to the patient’s increased dietary intake 

of folate, referring to the L-5-MTHF ingredient. The 

Board’s finding that SAMSF failed to connect the evidence 

of industry praise to the novel elements of the claims was 

thus supported by substantial evidence. 

SAMSF further argues that its inventors were the 

first to recognize that a subset of the population had 

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SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S.P.A. 7

difficulty processing folic acid, and that L-5-MTHF would 

therefore be an effective alternative. But the claims are 

not limited to treating this subset of the population. And

administering L-5-MTHF generally was known in the 

prior art. Accordingly, substantial evidence supports the 

Board’s finding that this evidence was not adequately tied 

to the novel features of the claimed invention.2 

We agree with SAMSF, however, that the Board erred 

in assessing SAMSF’s licensing evidence. The Board 

discounted SAMSF’s licenses to Merck, and Merck’s 

sublicenses to Pamlab, because SAMSF failed to show a 

nexus between the claimed inventions and Pamlab’s

products. But the relevant inquiry is whether there is a 

nexus between the patent and the licensing activity itself, 

such that the factfinder can infer that the licensing “arose 

out of recognition and acceptance of the subject matter 

claimed” in the patent. In re GPAC Inc., 57 F.3d 1573, 

1580 (Fed. Cir. 1995). Although evidence that the licensee ultimately manufactured a product that embodies the 

claimed invention may be probative of a nexus between 

the claimed invention and the licensing activity, the 

patentee is not necessarily required to establish an inde2 An inventor’s discovery of a previously unrecognized problem is generally accounted for in the analysis of

the scope of the prior art and a motivation to combine 

prior art elements. See Leo Pharm. Prods., Ltd. v. Rea, 

726 F.3d 1346, 1353–54 (Fed. Cir. 2014) (finding that 

because the prior art does not disclose the problem discovered, there was no motivation to combine prior art 

elements to solve that problem). Any error in treating 

this point as a secondary consideration, however, was 

harmless. Under either heading, this evidence does not 

show patentability in this case, because the contested 

claims are not limited to solving the allegedly unrecognized problem. 

 

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8 SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S.P.A. 

pendent nexus between those products and the claimed 

invention for the licensing activity to be relevant. The 

Board erred in requiring SAMSF to make this showing 

here. 

Nonetheless, the Board’s error was harmless. The 

Board found persuasive the evidence that a person of 

ordinary skill would have been motivated to combine 

Serfontein and Marazza to arrive at the contested claims. 

And it applied the correct legal standards to the remainder of SAMSF’s evidence of secondary considerations, 

finding that it was not adequately tied to the merits of the 

claimed inventions. These findings were supported by 

substantial evidence. Even if the Board had correctly 

considered SAMSF’s evidence of licensing, that evidence 

is not enough to overcome the strong evidence of obviousness found in the prior art and the expert testimony, 

relied upon by the Board to reach its conclusion of obviousness. We therefore agree with the Board that the 

contested claims are invalid for obviousness. 

III

Because substantial evidence supports the Board’s 

factual findings, except on the evidence of licensing, and

because we agree with the ultimate conclusion of obviousness, we affirm the Board’s finding that claims 37, 94–97, 

99–100, and 110–111 of the ’915 patent; claim 32 of the 

’381 patent; and claim 15 of the ’778 patent are invalid 

under 35 U.S.C. § 103. 

AFFIRMED

Case: 14-1781 Document: 17-2 Page: 8 Filed: 12/17/2015
United States Court of Appeals 

for the Federal Circuit ______________________ 

SOUTH ALABAMA MEDICAL SCIENCE 

FOUNDATION,

Appellant

v.

GNOSIS S.P.A., GNOSIS BIORESEARCH S.A., 

GNOSIS U.S.A., INC.,

Appellees

______________________ 

2014-1778, 2014-1780, 2014-1781

______________________ 

Appeals from the United States Patent and Trademark Office, Patent Trial and Appeal Board in No. 

IPR2013-00116.

______________________ 

NEWMAN, Circuit Judge, dissenting.

This appeal is a companion to Merck & Cie v. Gnosis 

S.p.A., No. 14-1777 (Gnosis I), decided concurrently, and

consolidates the appeals of three related Inter Partes 

Review decisions of the Patent Trial and Appeal Board 

(PTAB). The claims of the three appeals are directed to 

compositions containing L-5-methyltetrahydrofolic acid 

(L-5-MTFA) and various uses thereof. In each IPR proceeding the PTAB held the claims invalid as obvious 

based on the combination of the Serfontein reference 

(European Patent No. 0595005 (“EP ’005”)) and the 

Marazza reference (United States Patent No. 5,194,611 

(the “’611 Patent”)). One IPR decision, IPR2013-00119, 

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2 SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S.P.A. 

included in the combination a third reference, Ueland and 

Redsum, Plasma homocysteine, a risk factor for vascular 

disease: Plasma levels in health, disease, and drug therapy, J. Lab. Clin. Med., Vol. 114, pp. 473–501 (1989). 

For the reasons I discussed in Gnosis I, these references do not fill the gap between the folate compounds 

described by Marazza and the uses described by Serfontein, such that a person of ordinary skill in this field 

would have been motivated to combine these references to 

treat elevated homocysteine with a reasonable expectation of success. Ueland provides a description of folate 

and homocysteine biochemistry, and shows the biochemical relationship between homocysteine and L-5-MTHF. 

Ueland adds to the scientific investigations that have 

been conducted, but Ueland does not suggest that L-5-

MTHF would successfully treat the specified diseases and 

overcome the known uncertainties of stability, metabolism, and bioavailability. Ueland does not suggest that 

there would be a likelihood of success in using L-5-MTHF

compositions for the specific purposes discovered and 

developed by the South Alabama scientists. The scientific

acclaim and licensing and copying that followed their 

work add to the evidence of unobviousness. The PTAB 

erred in evaluating and weighing this evidence.

For the reasons discussed in my dissenting opinion in 

Gnosis I, obviousness was not established by a preponderance of the evidence. From my colleagues’ contrary 

ruling, I respectfully dissent. 

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