N OTE : This disposition is nonprecedential.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 LABORATO RIES, 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 No s . 1:13

- cv

- 01506

- GMS, 1:13

- cv

01508

- GMS, Judge Gregory M. Sleet.

______________________ Decided: December 18, 2017

______________________
P AUL H ENRY B ERGHOFF , McDonnell, Boehnen, Hu lbert & Berghoff, LLP, Chicago, IL, argued for plaintiffs

appellees. Also represented by A LISON J AMEEN B ALDWIN , P AULA F RITSCH , J AMES L EE L OVSIN , J EREMY E. N OE , K URT W ILLIAM R HODE ; J EFFREY B. B OVE , Ratner Prestia, Wi lmington, DE.GENZYME CORPORATION v. DR

. REDDY ’ S LABORATORIES , LTD

. 2

M ARTIN B. P AVANE , Cozen O’Connor, New York, NY, argued for all defendants

- appellants . Defendants

appellants Dr. Reddy’s Laboratories, Ltd., Dr. Reddy’s Laboratories, Inc. a lso represented by M ARILYN N EIMAN

.
E LAINE B LAIS , Goodwin Procter LLP, Boston, MA, for defendant

- appellant Teva Pharmaceuticals USA Inc. Also represented by E MILY L. R APALINO ; M ICHAEL B. C OTTLER , N ATASHA E LISE D AUGHTREY , A LEXANDRA D. V ALENTI , New York, NY ; W ILLIAM M. J AY , Washington, DC.

______________________ Before M OORE , P LAGER , and C HEN , Circuit Judges.
C HEN , Circuit Judge

. This cons olidated set of appeal s 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. (collect ively, 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 Pa tent) is invalid for obviousness

. We affirm

. B ACKGROUND Stem cells are immature blood cells that resid e 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 perip heral blood under certain conditions.
I. The ’590 Patent Genzyme developed a method for mobilizing and ha rvesting stem cells by sequentially administering two drug products. Specificall y, t he ’590 Patent makes use of aGENZYME CORPORATION v. DR

. REDDY ' S LABORATORIES , LTD

. 3

regimen co mprising a combi nation of granulocyte -colony st imulating 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 be tween

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 disruptin g that bond

. Claim 1 9 of the ’590 Patent is the only claim at issue in this set of appeal s

. It recites a “ method to obtain progenitor and/or stem cells ” by (1) administering G

- CSF to a sub ject; (2) administering plerixafor or a phar mace utically acceptable salt thereof to the subject, in an amou nt effective to mobilize the progen itor 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, t he 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 inv alidity of claim 19 of the ’590 Patent. J.A. 64.
The district c ourt concluded that claim 19 was not i nvalid for obviousness and entered a final judgment enjoi ning DRL from commercially manufacturing, using, offering for sale, selling, or importing its generic products before expiration of the ’590 Patent. J.A. 1–3 0.

1 Plerixafor (also known as JM

- 3100 and AMD

3100) is the active chemical ingredient in Mozobil® and Ge n zyme’s ANDA products. See J.A. 6

- 9.GENZYME CORPORATION v. DR

. REDDY ’ S LABORATORIES , LTD

. 4

DRL timely appealed. J.A. 2334

– 37. We have juri sdiction under 28 U.S.C. § 1295(a)(1).
D ISCUSSION 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. 2 013). After a bench tria l, 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 “t he diffe rences 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 obviou sness 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 relevan t 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 cl ear 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 A NTIMICRO

. A GTS

. AND C HEMO

. 1667

– 73 (Jun. 2000) (Hendrix); (2) International Patent Applic ation 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. He ndrix 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 p eripheral blood of all subjects after an administr ation of plerixafor. J.A. 12286. To explain this phenom enon, 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 traffic king and chemoattraction of lymphocytes; (2) the CXCR

- 4 cell receptor is widely expressed; 2 and (3) in experiments, plerixaf or has been shown to “completely inhibit” binding of SDF

- 1 to CXCR

- 4. J.A. 12288. From these observ ations, Hendrix hypothesized that “binding of [plerixafor] to CXCR4 may inhibit the chemotactic effects of SDF

- 1α, causing release of WBCs from the endothe lium 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 admini stering 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.GENZYME CORPORATION v. DR

. REDDY ’ S LABORATORIES , LTD

. 6

DRL argues that the only d ifference 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 plerix a for could function as a blocking agent for releasi ng stem cells from the marrow.
The district c ourt , however, found that Hendrix was not analo gous art. J.A. 19

– 20. Whereas Hendrix focused on HIV treatment, the ’590 Patent focused on mobilizing stem cells for subsequent ha rvest and transplan t ation. Alt hough 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, the y 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 pu rsued CXCR

- 4 over the field of cytokines and other possible stem cell mobilizer s. J.A. 19. Without a specific focus on CXCR

- 4, the district court concluded that Hendrix would not have bee n reasonably pertinent to an ordinarily

skilled artisan focused on harvesting stem cells. Id

. But even if Hendrix were deemed analogous art, th e district court found that Hendrix would not have ren dered claim 19 obvious. J.A. 20. The district court expressly rejected DRL’s position that it was “reasonably predict able in October 2000 that plerixafor would mobilize stem cells in sufficient number s for harvesting and tranplant ation.” 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 par ties’ arguments, we discuss principally the p arties’ dispute over whether a person of skill in the art would have had a “reasonable expec tation of success” in achieving the claimed invention by combining the priorGENZYME CORPORATION v. DR

. REDDY ' S LABORATORIES , LTD

. 7

art

. See Insite Vision Inc. v. Sandoz Inc. , 783 F.3d 853, 859 (Fed. Cir. 2015). “Whet her 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 plerix afor 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 mobiliz ation of stem cells. J.A. 12834. To render the ’590 Patent obvious , DRL combine s 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 S DF -1.
The record , however, shows that CXCR

- 4 is in a co mpletely different f amily 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 th e 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 obv ious 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 m arrow like the CXCR

- 4/SDF

- 1 bond , and no expectation that CXCR

- 4 and VLA

- 4 would behave sim ilarly concerning mobiliza tion. Although Hendrix hypothesiz ed in an isolated se ntence , without explanation, that plerixafor may cause st em cell mobilization, the rest of the seven- page article focused on the elevation of WBC counts. Hendrix me n-GENZYME CORPORATION v. DR

. REDDY ’ S LABORATORIES , LTD

. 8

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 rathe r than stem cells. Id

. A skilled artisan would have recognized that Hendrix never tested for the pre sence of stem cells. J.A. 2877

– 78. T he primary speculation in Hendrix for the phenomenon associated with elevated WBC counts was “demargination
, ” which refers to the release of WBCs fro m 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 mobilizat ion

was highly unpre dictable at the time of the invention also runs counter to an expectation of success . J.A. 23

. In particular, t here 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 t here was a history of failure resulting from the investigation of more than a dozen candidates in the search for a better stem cell mobiliz ation 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 subj ect of research for a skilled artisan looking for a better stem cell mobilizer. The district court

3 DRL ’s r eliance 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 wi tnesses. 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 P atent 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 r elationship 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 in creased WB C 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 comb ination of WO ’814 and the ’304 Patent

. As noted, sufficient 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 antago nism of CXCR

- 4 to the stem cell

- mobilizing effect of the ’304 Patent’s anti

- VLA

- 4 antibody. But the district court considered and reason ably rej ected this analogy. J.A. 22 (“[T] he court is not persuaded

. . . that the ’304 Patent would teach a POSA to

us e plerixafor as a CXCR

- 4 blocking agent, simply b ecause plerixafor is an agent like an anti

- VLA

- 4 blocking agent.”).GENZYME CORPORATION v. DR

. REDDY ’ S LABORATORIES , LTD

. 10

C ONCLUSION After reviewing the record surrounding the prior art and analyzing the arguments of the parties , w e conclude that the dis trict court’s factual conclusion s regarding an insufficient reasonable expectation of success were not clearly erroneous. Th at evidence is suffi cient 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 arg ument for obviousness

. We have considered DRL’s remaining arguments but find them unpersuasive. For the foregoing reason s, we affirm the district court’s holding that the ’590 Patent is not invalid

. AFFIRMED