       NOTE: This disposition is nonprecedential.


  United States Court of Appeals
      for the Federal Circuit
                ______________________

GENZYME CORPORATION, SANOFI-AVENTIS U.S.,
                   LLC,
            Plaintiffs-Appellees

                           v.

     DR. REDDY'S LABORATORIES, LTD., DR.
      REDDY'S LABORATORIES, INC., TEVA
          PHARMACEUTICALS USA INC,
              Defendants-Appellants
             ______________________

                 2016-2206, 2016-2207
                ______________________

    Appeals from the United States District Court for the
District of Delaware in Nos. 1:13-cv-01506-GMS, 1:13-cv-
01508-GMS, Judge Gregory M. Sleet.
                 ______________________

              Decided: December 18, 2017
                ______________________

    PAUL HENRY BERGHOFF, McDonnell, Boehnen, Hul-
bert & Berghoff, LLP, Chicago, IL, argued for plaintiffs-
appellees. Also represented by ALISON JAMEEN BALDWIN,
PAULA FRITSCH, JAMES LEE LOVSIN, JEREMY E. NOE, KURT
WILLIAM RHODE; JEFFREY B. BOVE, Ratner Prestia, Wil-
mington, DE.
2   GENZYME CORPORATION    v. DR. REDDY’S LABORATORIES, LTD.



   MARTIN B. PAVANE, Cozen O’Connor, New York, NY,
argued for all defendants-appellants.        Defendants-
appellants Dr. Reddy’s Laboratories, Ltd., Dr. Reddy’s
Laboratories, Inc. also represented by MARILYN NEIMAN.

    ELAINE BLAIS, Goodwin Procter LLP, Boston, MA, for
defendant-appellant Teva Pharmaceuticals USA Inc. Also
represented by EMILY L. RAPALINO; MICHAEL B. COTTLER,
NATASHA ELISE DAUGHTREY, ALEXANDRA D. VALENTI, New
York, NY; WILLIAM M. JAY, Washington, DC.
                ______________________

      Before MOORE, PLAGER, and CHEN, Circuit Judges.
CHEN, Circuit Judge.
    This consolidated set of appeals arises from a Hatch-
Waxman action brought by Genzyme Corporation and
Sanofi-Aventis U.S. LLC (collectively, Genzyme) against
Dr. Reddy’s Laboratories, Ltd., Dr. Reddy’s Laboratories,
Inc., and Teva Pharmaceuticals USA, Inc. (collectively,
DRL). After a bench trial, the district court held, inter
alia, that DRL failed to prove that claim 19 of U.S. Patent
No. 7,897,590 (the ’590 Patent) is invalid for obviousness.
    We affirm.
                        BACKGROUND
    Stem cells are immature blood cells that reside in the
bone marrow, where they can develop into mature blood
cells, including white blood cells. Although stem cells are
normally present in the blood in very small numbers, they
can be “mobilized” from the bone marrow into the periph-
eral blood under certain conditions.
                   I.    The ’590 Patent
    Genzyme developed a method for mobilizing and har-
vesting stem cells by sequentially administering two drug
products. Specifically, the ’590 Patent makes use of a
GENZYME CORPORATION     v. DR. REDDY'S LABORATORIES, LTD.   3



regimen comprising a combination of granulocyte-colony
stimulating factor (G-CSF) and plerixafor 1 to increase the
number of stem cells in the blood for collection. See ’590
Patent, col. 3 l. 34–col. 4 l. 27.
    Under normal conditions, stem cells are anchored to
the bone marrow at least in part through a bond between
a particular receptor (CXCR-4) located on the stem cell
and a protein (SDF-1) produced in the bone marrow. See
id. at col. 2 ll. 31–63. Plerixafor releases the stem cells
into the bloodstream by disrupting that bond.
    Claim 19 of the ’590 Patent is the only claim at issue
in this set of appeals. It recites a “method to obtain
progenitor and/or stem cells” by (1) administering G-CSF
to a subject; (2) administering plerixafor or a pharmaceu-
tically acceptable salt thereof to the subject, in an amount
effective to mobilize the progenitor and/or stem cells; and
(3) harvesting the progenitor and/or stem cells. See ’590
Patent, claim 19.
                  II.   Procedural History
     Following a four-day bench trial before the district
court, the parties submitted proposed findings of facts and
conclusions of law. J.A. 63. DRL filed a motion under
Fed. R. Civ. P. 52(c) for a judgment on partial findings on
its affirmative defense and counterclaim asserting inva-
lidity of claim 19 of the ’590 Patent. J.A. 64.
    The district court concluded that claim 19 was not in-
valid for obviousness and entered a final judgment enjoin-
ing DRL from commercially manufacturing, using,
offering for sale, selling, or importing its generic products
before expiration of the ’590 Patent. J.A. 1–30.



    1   Plerixafor (also known as JM-3100 and AMD-
3100) is the active chemical ingredient in Mozobil® and
Genzyme’s ANDA products. See J.A. 6-9.
4   GENZYME CORPORATION    v. DR. REDDY’S LABORATORIES, LTD.



    DRL timely appealed. J.A. 2334–37. We have juris-
diction under 28 U.S.C. § 1295(a)(1).
                        DISCUSSION
     The determination of obviousness is a legal conclusion
based on underlying facts. Allergan, Inc. v. Sandoz Inc.,
726 F.3d 1286, 1290–91 (Fed. Cir. 2013). After a bench
trial, we review the district court’s factual findings for
clear error and its conclusions of law de novo. Honeywell
Int’l, Inc. v. United States, 609 F.3d 1292, 1297 (Fed. Cir.
2010).
    A patent claim is invalid for obviousness if “the differ-
ences between the claimed invention and the prior art are
such that the claimed invention as a whole would have
been obvious before the effective filing date of the claimed
invention to a person having ordinary skill in the art to
which the claimed invention pertains.” 35 U.S.C. § 103.
    The “underlying factual considerations in an obvious-
ness analysis include the scope and content of the prior
art, the differences between the prior art and the claimed
invention, the level of ordinary skill in the art, and any
relevant secondary considerations[,]” which include
“commercial success, long-felt but unsolved needs, failure
of others, and unexpected results.” Allergan, 726 F.3d at
1290–91 (citations omitted). Patent invalidity must be
established by clear and convincing evidence. Microsoft
Corp. v. i4i Ltd. P’ship, 564 U.S. 91, 95, 131 S.Ct., 180
L.Ed.2d 131 (2011).
    As part of its obviousness challenge, DRL presented,
inter alia, the following prior art: (1) Hendrix et al.,
Pharmacokinetics and Safety of AMD-3100, a Novel
Antagonist of the CXCR-4 Chemokine Receptor, in Human
Volunteers, 44:6 ANTIMICRO. AGTS. AND CHEMO. 1667–73
(Jun. 2000) (Hendrix); (2) International Patent Applica-
tion Publication No. WO 00/45814 (WO ’814); and (3) U.S.
Patent No. 5,824,304 (the ’304 Patent).
GENZYME CORPORATION      v. DR. REDDY'S LABORATORIES, LTD.   5



        I.   Hendrix in combination with the ’304 Patent
     DRL’s first § 103 challenge to the ’590 Patent is based
on a combination of Hendrix and the ’304 Patent. Hen-
drix focused on evaluating the safety and pharmacology of
plerixafor for treating HIV. J.A. 18. The authors of
Hendrix reported an increase in white blood cells (WBCs)
in the peripheral blood of all subjects after an administra-
tion of plerixafor. J.A. 12286. To explain this phenome-
non, Hendrix observed the following: (1) Chemokines such
as stromal cell-derived factor 1 (SDF-1) are produced
locally in tissue, and their primary purpose is the traffick-
ing and chemoattraction of lymphocytes; (2) the CXCR-4
cell receptor is widely expressed; 2 and (3) in experiments,
plerixafor has been shown to “completely inhibit” binding
of SDF-1 to CXCR-4. J.A. 12288. From these observa-
tions, Hendrix hypothesized that “binding of [plerixafor]
to CXCR4 may inhibit the chemotactic effects of SDF-1α,
causing release of WBCs from the endothelium and/or
stem cells from bone marrow.” Id.
    The ’304 Patent teaches a method for increasing the
number of stem cells in the peripheral blood by adminis-
tering a blocking agent of VLA-4 antigens. The VLA-4
block agent releases stem cells from the marrow to the
peripheral blood by inhibiting the VLA-4 receptor on stem
cells, thereby disrupting the tether between the receptor
and its natural ligand, VCAM-1, found in the marrow.
J.A. 2617–20; J.A. 12819; J.A. 12834. The ’304 Patent
also teaches that G-CSF mobilized stem cells from the
marrow to the peripheral blood by stimulating production
of such cells in the marrow. J.A. 12834; J.A. 12836.
Thus, by administering G-CSF and a VLA-4 blocking
agent, mobilization is achieved. Id.


    2   The CXCR-4 receptor is not unique to stem cells
and can be on found on blood cells that are more mature.
J.A. 2591.
6   GENZYME CORPORATION   v. DR. REDDY’S LABORATORIES, LTD.



    DRL argues that the only difference between the
claimed invention and the ’304 Patent is that the ’304
Patent does not teach that the blocking agent can be
plerixafor. But that would have been obvious, DRL
argues, because Hendrix expressly suggested that
plerixafor could function as a blocking agent for releasing
stem cells from the marrow.
    The district court, however, found that Hendrix was
not analogous art. J.A. 19–20. Whereas Hendrix focused
on HIV treatment, the ’590 Patent focused on mobilizing
stem cells for subsequent harvest and transplantation.
Although the parties agreed that a person of ordinary
skill in the art would have been aware of the need for a
better stem cell mobilizing regimen, they disputed the
likelihood that CXCR-4 (and using plerixafor as a CXCR-4
antagonist) would become the object of research as a stem
cell mobilizing agent. J.A. 18. The Court found that
Defendants failed to show that a POSA would have pur-
sued CXCR-4 over the field of cytokines and other possible
stem cell mobilizers. J.A. 19. Without a specific focus on
CXCR-4, the district court concluded that Hendrix would
not have been reasonably pertinent to an ordinarily-
skilled artisan focused on harvesting stem cells. Id.
    But even if Hendrix were deemed analogous art, the
district court found that Hendrix would not have rendered
claim 19 obvious. J.A. 20. The district court expressly
rejected DRL’s position that it was “reasonably predicta-
ble in October 2000 that plerixafor would mobilize stem
cells in sufficient numbers for harvesting and tranplanta-
tion.” J.A. 23. It also found that the evidence established
a “history of failure in the field[.]” Id.
    While we have carefully considered the findings below
and all of the parties’ arguments, we discuss principally
the parties’ dispute over whether a person of skill in the
art would have had a “reasonable expectation of success”
in achieving the claimed invention by combining the prior
GENZYME CORPORATION   v. DR. REDDY'S LABORATORIES, LTD.   7



art. See Insite Vision Inc. v. Sandoz Inc., 783 F.3d 853,
859 (Fed. Cir. 2015). “Whether a person of ordinary skill
in the art would narrow the research focus to lead to the
invention depends on the facts.” Id. at 860. Here, the
district court found that a skilled artisan would not have
had a reasonable expectation of success that plerixafor
would mobilize stem cells. DRL has not shown that this
determination was clearly erroneous.
     As noted, the ’304 Patent discloses that blocking the
receptor VLA-4 with an antibody can result in mobiliza-
tion of stem cells. J.A. 12834. To render the ’590 Patent
obvious, DRL combines this teaching with the use of
plerixafor in Hendrix to argue that plerixafor can mobilize
stem cells in the same way – i.e., by blocking CXCR-4, a
different receptor, and disrupting the connection between
CXCR-4 and SDF-1.
    The record, however, shows that CXCR-4 is in a com-
pletely different family of receptors than VLA-4. The ’304
Patent never mentions CXCR-4, SDF-1, or plerixafor. It
explains that the stem cell mobilization seen with VLA-4
antagonists is “due to the specific blocking of VLA-4.”
J.A. 12839. Further, DRL’s expert testified that a typical
stem cell has around one hundred different types of
receptors on its surface. J.A. 2679; 3261–62. The district
court, noting the parties’ arguments and evidence, agreed
with Genzyme that “the ’304 Patent’s discussion of VLA-4
antibody blocking agents would not have rendered obvi-
ous claim 19, which covers CXCR-1 and not VLA-4.” J.A.
21–22. There is no evidence that VLA-4 localizes stem
cells in the marrow like the CXCR-4/SDF-1 bond, and no
expectation that CXCR-4 and VLA-4 would behave simi-
larly concerning mobilization.
    Although Hendrix hypothesized in an isolated sen-
tence, without explanation, that plerixafor may cause
stem cell mobilization, the rest of the seven-page article
focused on the elevation of WBC counts. Hendrix men-
8   GENZYME CORPORATION    v. DR. REDDY’S LABORATORIES, LTD.



tioned SDF-1 and its function of attracting lymphocytes,
not stem cells. J.A. 12288. The discussion of CXCR-4
being widely expressed was also directed to different
types of WBCs rather than stem cells. Id. A skilled
artisan would have recognized that Hendrix never tested
for the presence of stem cells. J.A. 2877–78. The primary
speculation in Hendrix for the phenomenon associated
with elevated WBC counts was “demargination,” which
refers to the release of WBCs from the endothelium. J.A.
2882. This emphasis on demargination is consistent with
how an independent group of contemporary researchers
perceived Hendrix. J.A. 13245.
    The district court’s finding that stem cell mobilization
was highly unpredictable at the time of the invention also
runs counter to an expectation of success. J.A. 23. In
particular, there was great uncertainty about the role of
SDF-1 or CXCR-4, if any, in the process of stem cell
mobilization. J.A. 27. CXCR-4 antagonists were only
studied in the HIV field, and there was a history of failure
resulting from the investigation of more than a dozen
candidates in the search for a better stem cell mobiliza-
tion agent. J.A. 23. No one had ever mobilized stem cells
with any CXCR-4 antagonist, let alone plerixafor. 3 And
there were many different cytokines and growth factors
that were the subject of research for a skilled artisan
looking for a better stem cell mobilizer. The district court



    3   DRL’s reliance on various secondary references
(Aiuti, Mohle, Peled, and Ma) to establish the CXCR-
4/SDF-1 connection does not call for a different result in
this case. Some of the references focused on the migration
of stem cells to the marrow, the opposite of mobilization of
stem cells from the bone marrow into the peripheral
blood. None of the papers report any in vivo experiments
demonstrating that manipulation of either CXCR-4 or
SDF-1 mobilizes stem cells.
GENZYME CORPORATION   v. DR. REDDY'S LABORATORIES, LTD.   9



weighed all evidence and assessed the credibility of wit-
nesses. Its view that there was no reasonable expectation
of success, based on the evidence presented at trial on a
combination of Hendrix and the ’304 Patent, was not
clearly erroneous.
    II. WO ’814 in combination with the ’304 Patent
    DRL’s alternative basis for invalidating the ’590 Pa-
tent is the combination of the WO ’814 Patent and the
’304 Patent. Like Hendrix, “WO ’814 does not disclose
information about using plerixafor to mobilize stem cells,
but instead reveals the relationship between plerixafor
and white blood cell elevation.” J.A. 22. As the district
court explained, DRL’s argument that WO ’814 would
have led a skilled artisan to use plerixafor to mobilize
stem cells “depends upon the assumption that a [person of
ordinary skill in the art] would have known that white
blood cells are a proxy for stem cells.” J.A. 22. But the
record included ample evidence showing that an increased
WBC count did not necessarily correlate to stem cell
mobilization. J.A. 2906–9; J.A. 2870.
    Ultimately, the deficiency regarding the combination
of Hendrix and the ’304 Patent also undercuts the combi-
nation of WO ’814 and the ’304 Patent. As noted, suffi-
cient evidence supports the district court’s finding of a
lack of a reasonable expectation of success. It is also
significant that a gap exists between using plerixafor to
enhance WBC counts and for stem cell mobilization. DRL
attempted to bridge that gap with the ’304 Patent by
analogizing plerixafor’s antagonism of CXCR-4 to the
stem cell-mobilizing effect of the ’304 Patent’s anti-VLA-4
antibody. But the district court considered and reasona-
bly rejected this analogy. J.A. 22 (“[T]he court is not
persuaded . . . that the ’304 Patent would teach a POSA to
use plerixafor as a CXCR-4 blocking agent, simply be-
cause plerixafor is an agent like an anti-VLA-4 blocking
agent.”).
10   GENZYME CORPORATION   v. DR. REDDY’S LABORATORIES, LTD.



                       CONCLUSION
    After reviewing the record surrounding the prior art
and analyzing the arguments of the parties, we conclude
that the district court’s factual conclusions regarding an
insufficient reasonable expectation of success were not
clearly erroneous. That evidence is sufficient to uphold
the district court’s determination against the arguments
DRL has presented for reversal, and we need not review
the district court’s analysis of secondary considerations
that, if sound, could only further undermine DRL’s argu-
ment for obviousness.
     We have considered DRL’s remaining arguments but
find them unpersuasive. For the foregoing reasons, we
affirm the district court’s holding that the ’590 Patent is
not invalid.
                      AFFIRMED
