Court Opinion

ID: 4262919
Source: CourtListenerOpinion
Date Created: 2018-04-11 15:00:40.616148+00
Date Added: 2024-06-11T14:30:09.059112
License: Public Domain

NOTE: This disposition is nonprecedential.

  United States Court of Appeals
      for the Federal Circuit
                 ______________________

                IN RE: MERCK & CIE,
                        Appellant
                 ______________________

                       2017-1960
                 ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. 12/688,034.
                  ______________________

                 Decided: April 11, 2018
                 ______________________

    CSABA HENTER, Millen, White, Zelano & Branigan PC,
Arlington, VA, argued for appellant. Also represented by
RYAN POOL.

    KAKOLI CAPRIHAN, Office of the Solicitor, United
States Patent and Trademark Office, Alexandria, VA,
argued for appellee Andrei Iancu. Also represented by
NATHAN K. KELLEY, THOMAS W. KRAUSE, LORE A. UNT.
                ______________________

       Before O’MALLEY, MAYER, and TARANTO, Circuit
                        Judges.
TARANTO, Circuit Judge.
   The Patent Trial and Appeal Board, affirming the ex-
aminer, rejected, as unpatentable for obviousness, certain
2                                        IN RE: MERCK & CIE

claims of U.S. Patent Application No. 12/688,034, titled
“Use of Folates for the Prevention and Treatment of
Vascular Diseases.” Merck & Cie is the real party in
interest in the prosecution of this patent. The application
describes and claims the use of folates to improve dilation
of blood vessels—specifically, nitric oxide (NO) mediated
endothelial dependent vasomotor responses.         As the
matter was presented to the Board and is presented to us,
claim 35 is representative. It reads:
    35. A method for improving NO-mediated endo-
    thelial-dependent vasomotor responses consisting
    of:
         administering to a subject with a cardiovascu-
    lar disease an effective amount of a pharmaceuti-
    cal composition consisting of a pharmaceutically
    active agent suitable for improving NO-mediated
    endothelial-dependent vasomotor responses and
    one or more pharmaceutically acceptable carriers,
         wherein the pharmaceutically active agent
    consists of one or more folates or a pharmaceuti-
    cally acceptable salt or ester thereof,
         and wherein said effective amount of the
    pharmaceutical composition achieves improve-
    ment of the NO-mediated endothelial-dependent
    vasomotor responses.
The Board concluded, and it is undisputed before us, that
the restrictive “consists of” language limits the claim to
administering one or more folates (or salt or ester)
alone—“folate alone,” as a shorthand—not in combination
with any other substance related to NO-mediated endo-
thelial-dependent vasomotor responses, though a combi-
nation with drugs unrelated to such responses is not
excluded. Ex parte Antoniades, Appeal 2016-003411, at
7–8 (P.T.A.B. Feb. 28, 2017) (Decision).
    The Board’s decision in this matter rested entirely on
the van Etten prior art: R.W. van Etten et al., “Impaired
IN RE: MERCK & CIE                                        3

NO-dependent vasodilation in patients with Type II (non-
insulin-dependent) diabetes mellitus is restored by acute
administration of folate,” 45 Diabetologia 1004–1010
(2002). The article first notes that the authors “recently
showed that folate reverses eNOS [endothelial nitric oxide
synthase] uncoupling in vitro” and on that basis the
authors hypothesized “that folate improves endothelial
function in Type II (non-insulin dependent) diabetes
mellitus in vivo.” Id. at 1004. The article then reports
the results of a study the authors conducted to test the
hypothesis.
    The study involved testing the effect of “5-
methyltetrahydrofolate (5-MTHF, the active form of folic
acid)” on forearm blood flow in twenty-three patients with
Type II diabetes (some given 5-MTHF, some not) and
twenty-one control (no diabetes, no 5-MTHF) subjects. Id.
at 1004, 1007. The ratio of blood flow in the infused
(measurement) arm to blood flow in the other (control)
arm—the M:C ratio—was recorded in two tests. Id. at
1006–07. In one, all subjects were infused with serotonin
(a stimulator of vasodilation dependent on nitric oxide); in
the other, all subjects were infused with sodium nitro-
prusside (a stimulator of “endothelium-independent
vasodilation”). Id.
    Figures 1 and 2 of the article show the test results for
the three subgroups (“control”; “diabetes”; “diabe-
tes+MTHF”—as the article labels them):
4   IN RE: MERCK & CIE
IN RE: MERCK & CIE                                       5

    The figures reveal the following. First: in both tests,
as the non-folate external stimulator (serotonin, nitro-
prusside) increased from zero to various higher levels, so
did the M:C ratio, for all three subgroups. Second: in both
tests, the M:C ratio for all three subgroups was essential-
ly the same when there was no external stimulator.
Third: in the serotonin test, the diabetes+MTHF sub-
group showed M:C ratios, as the level of serotonin admin-
istered rose, very close to the M:C ratios of the control
group, noticeably higher than those of the diabetes (no
MTHF) subgroup. Fourth: in the nitroprusside test, the
diabetes+MTHF subgroup showed M:C ratios, as the level
of nitroprusside administered rose, very close to the M:C
ratios of the diabetes (no MTHF) subgroup, noticeably
lower than those of the control group. Id.
     The article contains a number of observations of sig-
nificance to the present case. (All emphases in the follow-
ing quotes have been added.) “[A]melioration of eNOS
function also can be achieved by using folic acid. The
active form of folic acid, 5-methyltetrahydrofolate (5-
MTHF), restores the function of uncoupled eNOS.” Id. at
1005. “If folate is capable of restoring the endothelial
dysfunction, commonly encountered in diabetic patients,
this could have important clinical implications because
endothelial dysfunction is associated with increased
cardiovascular risk.” Id. “[I]n patients with Type II
diabetes, administration of 5-MTHF, the active form of
folic acid, restores endothelial dysfunction as measured by
serotonin-induced vasodilation. In addition to serotonin-
induced vasodilation, also nitroprusside-induced vasodila-
tion was impaired in patients with Type II diabetes.
Nitroprusside-induced vasodilation, however, was not
affected by 5-MTHF infusion. These data indicate an
important role of 5-MTHF on endogenous NO-availability
and could support previous studies suggesting a direct
beneficial effect of 5-MTHF on NO-synthase function.” Id.
at 1007. “[The study] showed that 5-MTHF administra-
6                                         IN RE: MERCK & CIE

tion restores impaired NO-mediated vasodilation in pa-
tients with Type II diabetes despite the presence of sever-
al diabetes-related risk factors such as hyperglycaemia,
dyslipidaemia and hypertension.” Id. at 1008. “The
ameliorative effect of 5-MTHF seems to be specific for
endothelium-derived NO, because an improvement could
not be observed for endothelium-independent NO-
mediated     vasodilation.”       Id.      The     “conclu-
sion/interpretation” of van Etten states:
    These data imply that folate can be used to im-
    prove nitric oxide status and to restore endothelial
    dysfunction in patients with Type II diabetes. Our
    results provide a strong rationale for the initiation
    of studies that investigate whether supplementa-
    tion with folic acid prevents future cardiovascular
    events in this patient group.
Id. at 1004; see also id. at 1008 (“Our results provide a
strong rationale for the initiation of studies that investi-
gate whether in this patient group supplementation with
folic acid, a safe, readily available, not expensive and
well-tolerated drug, prevents future cardiovascular
events.”).
     The Board concluded that the method of claim 35
would have been obvious to a person of ordinary skill in
the art in light of van Etten. Decision at 5–6. The Board,
affirming the examiner, found that van Etten supplied a
motivation to use folate alone, as claim 35 requires, with
a reasonable expectation of success. Id. at 5. It rejected
Merck’s contentions that van Etten did not supply to a
relevant skilled artisan a motivation to use folate alone or
a reasonable expectation of success but, to the contrary,
taught away from such use. Id. at 5–6. These elements of
the obviousness analysis, and what van Etten teaches, all
present issues of fact, with the Board’s findings on those
issues reviewed only for substantial evidence. See, e.g.,
PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186,
IN RE: MERCK & CIE                                        7

1196–97 (Fed. Cir. 2014); In re Gartside, 203 F.3d 1305,
1316 (Fed. Cir. 2000); Para-Ordnance Mfg., Inc. v. SGS
Importers Int’l, Inc., 73 F.3d 1085, 1088 (Fed. Cir. 1995).
    Merck’s challenge ultimately rests on its contention
that the Board’s reading of van Etten, on which the
Board’s findings of fact rest, is simply unreasonable and
therefore unsupported by substantial evidence.        See
TriVascular, Inc. v. Samuels, 812 F.3d 1056, 1061 (Fed.
Cir. 2016) (“Substantial evidence ‘means such relevant
evidence as a reasonable mind might accept as adequate
to support a conclusion.’”) (quoting Consol. Edison Co. v.
NLRB, 305 U.S. 197, 229 (1938)). This standard does not
require the Board’s reading of van Etten to be the only
reasonable one for us to uphold it. “[T]he possibility of
drawing two inconsistent conclusions from the evidence
does not prevent an administrative agency’s finding from
being supported by substantial evidence.” Consolo v. Fed.
Maritime Comm’n, 383 U.S. 607, 620 (1966); see In re
Jolley, 308 F.3d 1317, 1320 (Fed. Cir. 2002) (“If the evi-
dence in record will support several reasonable but con-
tradictory conclusions, we will not find the Board’s
decision unsupported by substantial evidence simply
because the Board chose one conclusion over another
plausible alternative.”); AK Steel Corp. v. United States,
192 F.3d 1367, 1371 (Fed. Cir. 1999).
    At its core, Merck’s challenge relies on the Second and
Fourth aspects of the van Etten study, described above:
that the only subgroup given MTHF had essentially the
same M:C ratio in both tests at the zero level of the non-
folate external stimulator; and that, in the nitroprusside
test, the M:C ratios were essentially the same for the
diabetes+MTHF subgroup and the diabetes (no MTHF)
subgroup. Merck contends that those facts would give
rise to only one possible understanding to a skilled arti-
san, namely, that folate alone would have no beneficial
effect of the type at issue, but requires a combination with
serotonin or another substance that improves dilation
8                                        IN RE: MERCK & CIE

response. As a result, Merck says, the Board was re-
quired to find no motivation to use folate alone and no
reasonable expectation of success in doing so and, even, to
find a teaching away from the claim 35 method.
     We need not and do not decide whether Merck’s view
of what van Etten teaches is the better view. We conclude
only that Merck’s view is not the only reasonable view.
Above we italicized excerpts from van Etten that support
the key findings of the Board. Those excerpts are reason-
ably capable of being read as conveying sufficiently posi-
tive implications about the use of folate alone—without
also administering other substances, like serotonin,
related to NO-mediated endothelial-dependent vasomotor
responses—that they would provide a relevant skilled
artisan a motivation to do what claim 35 requires with a
reasonable expectation of success and not leave the arti-
san discouraged from doing so by the article as a whole
within the meaning of the “teaching away” principle. See,
e.g., DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
567 F.3d 1314, 1327 (Fed. Cir. 2009).
   For that reason, and having considered all of Merck’s
arguments, we affirm the Board’s decision.
    No costs.
                      AFFIRMED