# United States **Court of Appeals**  **for the Federal Circuit**

______________________
SOUTH ALABAMA MEDICAL SCIENCE FOUNDATION, Appellant

v.

GNOSIS S.P.A., GNOSI S BIORESEARCH S.A., GNOSIS U.S.A., INC., Appellees

______________________

2014

- 1778, 2014

- 1780, 2014

- 1781

______________________ Appeals from the United States Patent and Trad emark Office, Patent Trial and Appeal Board in No. IPR2013

- 00116.

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Decided: Decemb er 17, 2015

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T HOMAS J. P ARKER , Alston & Bird LLP, New York, NY argued for appellant. Also represented by J ITENDRA M ALIK , Durham, NC; K IRK T. B RADLEY , Charlotte, NC; P ETER R OGALSKYJ , Law Office of Peter Rogalskyj, Liv onia, NY

.

J OSEPH C WIK , Amin Talati & Upadhye, LLC, Chicago, IL argued for appellees. Also represented by J ONATHAN J ACOB K RIT , Amin Talati, LLC, Chicago, IL.

______________________SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S

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Before N EWMAN , P LAGER , and H UGHES , Circuit Judges. Opinion for the court filed by Circuit Judge H UGHES

.

Dissenting opinion filed by Circuit Judge N EWMAN

. H UGHES , 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 i ts claimed use of a r educed folate to treat folate deficiency, and that objective indicia of non

- obviousness further demonstrate the valid ity of its patent s . Althoug h the Patent Trial and Appeal Board erred in its assessment of the evidence of licensing, the Board’s other factual findings are supported by su bstantial evidenc e. Because we agree with the Board’s ultimate conclusion of obviousness in light of those fin dings, we affirm.

I

South Alabama Medical Science Foundat ion (SAMSF) owns U.S. Patent No s . 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. (collectiv ely, Gnosis) and after granting SAMSF’s motion to cancel certain claims, the Boar d instituted review of c laims 37, 94

– 97, 99

– 100, and 110

– 111 of the ’915 pa tent; c laim 32 o f the ’381 patent; and c laim 15 of the ’778 patent.

A ll th ree 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 cause s a variety ofSOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S

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

Claim 37 of the ’915 p atent recite s “ a method of i ncreasing a human subject’s dietary intake of folate co mprising administering

. . . one or more natural isomers of reduced folate selected from [a group including L -5- MTHF]” and “an essential nutrient preparation .

. . co mprisin g a vitamin other than ascorbic acid .

. . in an amount equal to or greater than 25% of the daily r equirement for the vitamin.” ’915 patent, col. 23 ll. 16

– 31. Claims 94

– 97, 99

– 100, and 110 –11 1 ultimately depend from c laim 37, and specifically require th at “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 natura l 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 1 5 of the ’778 patent covers a composition co ntaining substantially chirally pure natur al isomers of reduced folate ( e. g. L-5- MTHF), in an amount effective for the treatment of vascular disease and certain pregnancy

related conditions, and an essential nutrient preparation containing a vitamin other than ascorbic acid . ’778 p atent, 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 pharm aceutical preparation for treating elevated l evels of hom ocysteine, which is often associated with folate deficiency

. The preparation includes “f olate or a suitable activeSOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S

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metabolite of folate,” along with vitamins B 6 and B 12

. 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 deficie nc ie s. Marazza, col. 1 ll. 26

– 29. 1 As in Gnosis I

, t he 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- MTH F and a vitamin supplement to treat symptoms of folate deficien cy. The Board also considered SAMSF’s evidence of obje ctive indicia of non

- obviousness

. The Board found that SAMSF failed to demonstrate an adequate nexus between that evidence and the novel fea tures of the contested claims. Accordingly, the Board concluded that the co ntested claims of the ’915, ’381, and ’778 patents are inv alid for obviousness under 35 U.S.C. § 103.

SAMSF appeals. We have jurisdiction under 28 U.S.C. § 1295(a)(4)(A).

II

O bviousness 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 r eversing the Board’s obviousness analysis that Merck

1 For more detail on these references, see Gnosis I

, slip op. at 4

– 5.SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S

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made in Gnosis I . SAMSF argues that the Board’s obv iousness analysis was insufficiently thorough, and that the prior art teaches away from combining Serfontein and Marazza, because it suggests that L -5- MTHF may i ncrease homocysteine levels, is too unstable for therapeutic

use , and is a poor substrate for polyglutamation. SAMSF also argues that the Board impos ed an overly strict nexus requirement to find that its evidence of objective indicia of

non

- obviousness is not sufficiently tied to the novel fe atures 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 Serfo ntein and Marazza was adequately explained and suppor ted by su bstantial evidence. Serfontein calls for a “suitable active metabolite of folate,” and Marazza di scloses 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. W e find no error in the Board’s conclusi on that the prior art and expert testimony here provide strong evidence that the contest ed claims were obvious.
The Board also properly determined that SAMSF’s e vidence 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 comme rcial success of the Metanx®, Cerefolin®, CerefolinNAC®, Néevo® , and N é evoDHA® products manufactured by Pamlab demonstrate non

- obviousness. But these pro ducts contain a specific combination of L-5- MTH F and several vitamins and other active ingredients that are not recited in the claims

. See Gnosis I , slip op. at 14

– 15. S ubstantial evidence thus supports the Board’s finding that the commercial success of the se products was inad equately linked to the c laimed methods and composition

— which call for L -5- MTHF or another reduced folate andSOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S

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any number of vitamins other than ascorbic acid

— as opposed to the specific formulations in these products

. Contrary to SAMSF’s argument, t he Board ’s analysis does not effectively require SAMSF to produce evidence of commercial success for every potential embodiment of the claim s

. 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 requi rement.

The Board’s nexus analysis for the evidence of indu stry praise was also sound. T his 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 in gredient in the Pamlab products. Lik ewise, although the industry praised the positive patient outcomes associat ed 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 hadSOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S

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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 administer ing 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 th e Board erred in assessing SAMSF’s li censing 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, 1 580 (Fed. Cir. 1995). Although evidence that the lice nsee 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 ind e2 An inventor’s discovery of a previously unreco gnized problem is generally accounted for in the analysis of the scope of the prior art and a motivation to combine prior art elements. Se e 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 di scovered, there was no motivation to combine prior art elements to solve that problem). Any error in treating thi s point as a secondary considera tion, however, was harmless. U nder either heading, this evidence does not show patentability in this case , because the contested claims are not limited to solving the allegedly unreco gnized problem.SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S

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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 remai nder of SAMSF’s evidence of secondary considerat ions, 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 overcom e the strong evidence of obviou sness found in the prior art and the expert testimony

, relied upon by the Board to reach its conclusion of obv iousness . We there fore agree with the Board that the contested claims are invalid for obviousness.

III

Because s ubstantial evidence supports the Board’s factual findings

, except on the evidence of licensing, and because we agree with the ultimate conclusion of obviou sness, we affirm the Board’s finding that c laims 37, 94

– 97, 99

– 100, a nd 110

– 111 of the ’915 patent; c l aim 32 of the ’381 patent; and claim 15 of the ’778 patent are invalid under 35 U.S.C. § 103.

AFFIRMED

# United States **Court of Appeals**  **for the Federal Circuit**

______________________
SOUTH ALABAMA MEDICAL SCIENCE FOUNDATION, Appellant

v.

GNOSIS S.P.A., GNOSI S BIORESEARCH S.A., GNOSIS U.S.A., INC., Appellees

______________________

2014

- 1778, 2014

- 1780, 2014

- 1781

______________________ Appeals from the United States Patent and Trad emark Office, Patent Trial and Appeal Board in No. IPR2013

- 00116.

______________________ N EWMAN , C ircuit J udge, 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- MT F A) and various uses thereof. I n each IPR pr oceeding t he P TAB held the claims invalid as obvious based on the combination of the Serfontein referenc e ( European P atent N o. 0595005 ( “ EP ’ 005 ”) ) and the Marazza reference ( United States Paten t No. 5,19 4,611 (the “’ 611 Patent ” ))

. One IPR decision, IPR2013

- 00119,SOUTH ALABAMA MEDICAL SCIENCE v. GNOSIS S

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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 ther apy , J. Lab. Clin. Med., Vol. 114, pp. 473

– 501 (1989)

. For the reasons I discussed in Gnosis I

, these refe rences do not fill the gap between the folate compound s described by Maraz za and the uses described by Serfo ntein, such that a person of ordinary skill in this field would have been motivated to combine the se references to
treat elevated homocysteine with a reasonable expect ation of success. Ueland provides a description of folate and homocysteine biochemistry , and shows the biochem ical 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, metab olism, and bioavailability . Ueland does not suggest that there would be a likelihood of success in using L -5- MTHF composition s for the specific purposes discovered and developed by the South Alabama scientists. The scientific acclai m 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 prepo nderance of the evidence. From my colleagues ’ contrary ruling , I respectfully dissent

.