Ex Parte Ballance et al

Patent Trial and Appeal Board

May 12, 2017

13855454 (P.T.A.B. May. 12, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/855,454 04/02/2013 David J. Ballance 06478.1576-01000 8356
22852 7590 05/16/2017
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON, DC 20001-4413
EXAMINER
ROBINSON, HOPE A
ART UNIT PAPER NUMBER
1652
NOTIFICATION DATE DELIVERY MODE
05/16/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DAVID J. BALLANCE and DARRELL SLEEP1
Appeal 2016-003295
Application 13/855,454
Technology Center 1600
Before JEFFREY N. FREDMAN, TIMOTHY G. MAJORS, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to methods
of treating a patient by administering an albumin fusion protein comprising a
Factor VII polypeptide. The claims have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
STATEMENT OF THE CASE
Appellants’ “invention relates generally to Therapeutic proteins
(including, but not limited to, a polypeptide, antibody, or peptide, or
1 Appellants identify the Real Party in Interest as NOVOZYMES
BIOPHARMA DK A/S. (App. Br. 3.)
Appeal 2016-003295
Application 13/855,454
fragments and variants thereof) fused to albumin or fragments or variants of
albumin.” (Spec. 1:12—13.)2 According to the Specification, such fusion
proteins “exhibit extended shelf-life and/or extended or therapeutic activity
in solution.” (Id. at 1:16—17.)
Claims 61, 63—74, and 16—783 are on appeal. Claim 61 is the only
independent claim and reads as follows:
61. A method of treating a patient in need of a Factor VII
polypeptide, comprising the step of administering an effective
amount of an albumin fusion protein comprising a Factor VII
polypeptide fused to an albumin polypeptide, wherein said
albumin polypeptide has the ability to prolong the serum half-life
of the fused Factor VII polypeptide compared to the unfused
Factor VII polypeptide, wherein the fused Factor VII polypeptide
has Factor VII coagulant activity, wherein the Factor VII
polypeptide is fused at the N-terminus of the albumin
polypeptide, and wherein the albumin polypeptide is selected
from:
a) a full-length albumin;
b) a mature albumin;
c) a fragment of albumin; and
d) a polypeptide consisting of an amino acid sequence
at least 95% identical to SEQ ID NO: 18;
e) amino acids 1 to 387 of SEQ ID NO: 18;
and wherein the Factor VII polypeptide is selected from:
i) a full-length Factor VII;
ii) an activated Factor VII (Factor Vila);
iii) a fragment of Factor VII having a deletion that
consists of 1—50 amino acid residues as compared
to mature Factor VII;
2 References to the Specification (“Spec.”) herein refer to Appellants’
substitute Specification dated Sept. 16, 2013.
3 The Examiner asserts that claims 61—78 stand rejected. (Ans. 3.) Claims
62 and 75 are, however, canceled. (See Adv. Act. (mailed Dec. 17, 2014) 2).
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iv) a polypeptide consisting of an amino acid sequence
at least 90% identical to the sequence of amino acids
39 (Ala) to 444 (Pro) of SEQ ID NO: 47; and
v) a mature Factor VII.
(App. Br. (Claims App’x 1).)
The claims stand rejected under 35 U.S.C. § 103(a) over Morrissey,4
Weimer,5 Ballance,6 Fleer,7 and Berkner.8 (Ans. 3.)
Appellants identify the following pending appeals as related:
1) U.S. Application No. 11/927,600 (Appeal No. 2016-003160);
2) U.S. Application No. 13/855,434 (Appeal No. 2016-003294); and
3) U.S. Application No. 11/927,602 (Appeal No. 2016-005026).
(See App. Br. 3.)
DISCUSSION
Issue
The Examiner rejected claims 61, 63—74, and 76—78 as obvious over
Morrissey (as evidenced by Weimer), Ballance, Fleer, and Berkner. (Ans.
3.) The Examiner finds that “Morrissey et al. teach a FVIIa for treatment of
bleeding disorders such as those resulting from hemophilia and cirrhosis of
the liver.” (Id.) According to the Examiner, “Weimer et al. disclose that
based on the short half-life of FVIIa of 2.5 hours multiple injections have to
4 Morrissey et al., US 5,504,067, issued April 2, 1996.
5 Weimer et al., Prolonged in-vivo half-life offactor Vila by fusion to
albumin, 99 Thromb. Haemost. 659-67 (2008).
6 Ballance, WO 97/24445, published July 10, 1997.
7 Fleer et al., US 5,876,969, issued Mar. 2, 1999.
8 Berkner et al., US 5,833,982, issued Nov. 10, 1998.
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be given, thus there is a need to fuse FVII with albumin to extend the half-
life.” (Id.) The Examiner finds “Ballance et al. teach fusion proteins
comprising human serum albumin (protein of 585 amino acids) and human
growth hormone . . . [and] that the albumin fusion protein extends the half-
life in the circulation of the fusion partner protein compared to an unfused
state.” (Id. at 3 4.) According to the Examiner, Ballance also teaches “the
fusion protein comprises a fragment that may be the N-terminal portion or
C-terminal portion.” (Id. at 4.)
The Examiner finds that Ballance “does not expressly teach the
stabilization of Factor VII (i.e. prolonging the half-life),” and thus turns to
Fleer. (Id. at 4.) According to the Examiner, “Fleer teach[es] albumin
fusion proteins with a number of therapeutic proteins and state [s] that
albumin can be fused to coagulation factors ... for the purposes of
prolonging the half-life.” (Id. at 4—5.) The Examiner finds “Berkner et al.,
teach modified FVII structures that encompass deletions, substitutions, etc.
and teach a structure that is homologous with SEQ ID NO: 47.” (Id. at 5.)
The Examiner concludes the claimed method of administering a FVII-
albumin fusion protein would have been obvious. (Id.) According to the
Examiner, “Morrissey et al. teach FVIIa administered to treat bleeding
disorders and as evidenced by Weimer et al. a fusion protein comprising
albumin and FVII is desirable to extend the short half-life of FVII of 2.5
hours to improve therapies.” (Id.) The Examiner reasons the skilled artisan
“would be motivated to modify the conjugate taught by Ballance et al. by
replacing the growth hormone with Factor VII. . . based on the disclosure of
Ballance et al. of the function of albumin as prolonging the half-life of other
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proteins in circulation.” (Id.) Further, the Examiner reasons, the skilled
person “would [] have a reasonable expectation of success . . . because Fleer
et al. teach that albumin can be fused to coagulation factors and Factor VII is
one such factor.” (Id.)
Appellants argue the Examiner’s combination of prior art fails to
render the claims obvious. Appellants contend Fleer’s disclosure of “a
genus of albumin fusion proteins containing a coagulation factor does not
render obvious the claimed species of a Factor VH-albumin fusion protein.”
(App. Br. 6—9.) Appellants further contend that, at the time of the invention,
the skilled artisan “would not have predicted that albumin fusion would
‘prolong the serum half-life of the fused Factor VII polypeptide’ as
claimed.” (Id. at 6, 10—19.) Appellants argue the skilled person “would not
have predicted the orientation-dependent coagulant activity of the claimed
Factor VH-albumin fusion proteins” and more specifically “Appellant’s
unexpected discovery that Factor VII retains biological activity only when
fused to the amino-terminal [N-terminal] end of albumin.” (Id. at 6, 20—29.)
Appellants further argue “there had been a long-felt need in the art for a
therapeutic Factor VII having an extended half-life” that “the claimed
invention satisfies,” and that “others . . . had tried and failed to develop an
extended half-life Factor VII protein.” (Id. at 31—33.)
In support of its arguments concerning the patentability of the claims
on appeal, Appellants cite to, among other things, several declarations from
skilled persons and publications in the scientific literature. We discuss
Appellants’ evidence further below. (App. Br .passim.)
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The issue on appeal is whether the preponderance of the evidence of
record supports the Examiner’s conclusion of obviousness.
Findings of Fact (FF)
The Examiner’s findings of fact and statement of the rejection are
provided at pages 3—6 of the Examiner’s Answer and pages 5—9 of the July
31, 2014 Non-Final Rejection. (See also Ans. 11—34 (Response to
Argument); Non-Final Act. 10—18 (Response to Arguments); Adv. Act. 2—
11.)
FF 1. Ballance teaches “fusion of a molecule of albumin, or variants
or fragments thereof, to a molecule of growth hormone or variants or
fragments thereof, the fusion proteins having an increased circulatory half-
life over unfused growth hormone.” (Ballance 3:27—30.)
FF 2. Ballance teaches:
Preferably, the fusion protein comprises HA [human albumin],
or a variant or fragment thereof, as the N-terminal portion, with
hGH [human growth hormone] or a variant or fragment thereof
as the C-terminal portion [i.e., hGH is fused to the C-terminal
end of the albumin], so as to minimise any possible negative
effects on receptor binding. Alternatively, a fusion protein
comprising HA, or a variant or fragment thereof, as the C-
terminal portion, with hGH or a variant or fragment thereof as
the N-terminal portion, may also be capable of signal
transduction. Generally, the polypeptide has only one HA-
derived region and one GH-derived region.
(Mat 4:3-11.)
FF 3. Fleer teaches “[biologically active polypeptides comprising a
therapeutically active polypeptide fused to human serum albumin or a
natural variant thereof.” (Fleer Abstract.) Fleer further teaches “albumin
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variants designate any protein with a high plasma half-life which is obtained
by modification.” {Id. at 1:23—25.)
FF 4. Fleer teaches
the polypeptide having a therapeutic activity is a polypeptide of
human origin or a molecular variant. For example, this may be
all or part of an enzyme, an enzyme inhibitor, an antigen, an
antibody, a hormone, a factor involved in the control of
coagulation, an interferon, a cytokine ... of a growth factor
and/or of differentiation [and for example the transformant
growth factors (TGFs), the blood cell differentiation factors
(erythropoietin, M-CSF, G-CSF, GM-CSF and the like), insulin
and the growth factors resembling it (IGFs), or alternatively cell
permeability factors (VPF/VEGF), and the like] ... of a
cytostatic factor (and for example the proteins which bind to
galactosides), of a plasma (and for example von Willebrand
factor, fibrinogen and the like)....
{Id. at 2:22-49 (brackets in original) (emphases added).)
FF 5. Fleer teaches
The active part of the molecules of the invention can be
coupled either directly or via an artificial peptide to albumin.
Furthermore, it may constitute the N-terminal end as well as the
C-terminal end of the molecule. Preferably, in molecules of the
invention, the active part constitutes the C-terminal part of the
chimera [i.e., polypeptide fused to C-terminal of albumin],
{Id. at 3:28-33.)
FF 6. Morrissey teaches administering “truncated tissue factor ... in
combination with factor Vila (FVIIa) to treat bleeding disorders such as
those resulting from hemophilia.” (Morrissey Abstract.) Morrissey teaches
“Factor Vila circulates with a relatively long half-life of about two hours . . .
[,] an unusual property among activated coagulation enzymes, which
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typically are inactivated very rapidly by various protease inhibitors in
plasma.” {Id. at 1:58—62.)
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSRIntI Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Prima facie obviousness may be rebutted with evidence of secondary
considerations and when such evidence is submitted, all of the evidence is
considered anew. In re Piasecki, 745 F.2d 1468, 1472—73 (Fed. Cir. 1984).
Secondary considerations include, inter alia, long-felt but unsolved needs,
failure of others, and unexpected results. In re Rouffet, 149 F.3d 1350, 1355
(Fed. Cir. 1998).
Analysis
Claim 61
Looking to the Examiner’s findings and reasoning concerning the
combination of Morrissey, Ballance, Fleer, and Berkner alone, we agree that
claim 61 would have been prima facie obvious.9 But considering the totality
9 The Examiner finds “there is a need in the art to improve bleeding episode
therapies, the advantage of cost savings and increased in vivo circulating life
of Factor VII” and “FVII was being used as a medicament and was known to
have a short half-life.” (Ans. 5 and 28.) The Examiner’s support for these
findings appears to come from Weimer, which was published roughly 8
years after the putative priority date of the present application. (Non-Final
Act. 12.) The Examiner asserted Weimer still shows the half-life of FVII
was minimal {id.), but Morrissey, which is prior art, discloses that FVII
variants have a “relatively long half-life.” (FF 6.) Although the Examiner
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of the evidence of record, we reach a different conclusion. Although Fleer
teaches albumin fusions and suggests use with factors involved in
coagulation, coagulation factors encompass dozens of potential
polypeptides. (App. Br. 7.) Also, the functionally closest peptide tested in
Fleer, von Willebrand factor, which can reasonably be characterized as a
coagulation factor, did not exhibit coagulant activity as required by the
claims. {Id. at 8—9.) As we discuss in greater detail below, Appellants have
provided persuasive and countervailing objective evidence of
nonobviousness. When this evidence is considered along with the teachings
of the applied prior art, the decision tilts in Appellants’ favor.
Appellants emphasize that, in mentioning “a factor involved in the
control of coagulation,” Fleer discloses a broad genus “that may comprise
many functionally and structurally distinct polypeptides.” (App. Br. 7
(citing Tanaka10).) Appellants also point out that, in the lone example in
which Fleer tested fusion proteins comprising a coagulation factor —
fragments of vWF —these fusion constructs “inhibit the physiological
function of vWF, [and do] not [] enhance its normal coagulant activity as
contemplated by the instant invention.” {Id. at 9.)
The fact that coagulation factors have diverse structures and functions
does not, in itself, persuade us that the Examiner’s reliance on Fleer is
flawed. To the contrary, as the Examiner noted, “Fleer provides a myriad of
did not provide evidence showing a recognized need in the art at the time of
invention to increase the circulating half-life of FVII therapeutics,
Appellants do not clearly challenge these findings in their appeal briefing.
10 Tanaka et al., Blood Coagulation: Hemostasis and Thrombin Regulation,
108:5 Anesthesia & Analgesia 1433^46 (2009).
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therapeutic proteins as potential fusion partners which demonstrates that
different protein structures with different functions can be fused to albumin.”
(Ans. 14.) Put differently, in expressly reciting polypeptides with quite
different structures and functions (e.g., EPO versus vWF), Fleer suggests the
design of active therapeutic fusion constructs despite the diversity. That
said, Appellants’ contention that the vWF-fusion constructs exemplified in
Fleer inhibit coagulant activity — opposite from vWF’s normal activity and
what is claimed — weakens somewhat the notion that an ordinarily skilled
person would have a reasonable expectation of success in designing a Factor
VII fusion protein with coagulant activity as claimed. (App. Br. 9.)
Appellants argue the prior art, and especially Ballance and Fleer, must
be viewed through the lens of “background knowledge in the art.” (App. Br.
12.) This knowledge, Appellants contend, is that “the circulatory half-life of
a polypeptide depended on its molecular size due to much faster renal
clearance of small polypeptides from the blood plasma.” {Id. at 10.)
According to Appellants’ declarant, Dr. Sleep,11 it was known in the art that
“plasma clearance of proteins decreased rapidly with increasing molecular
size from about 20 kD to about 60—70 kD . . . [and] a size of 60-70 kD or
above showed only very little or almost no renal clearance.” (Sleep Decl.
14.) It “was also known in the art that the serum half-life of a small protein,
such as human growth hormone (hGH), could be increased by expressing it
as a genetic fusion with human serum albumin (HSA), which is a large (67
11 Declaration of Dr. Darrell Sleep dated March 24, 2014 (“Sleep Deck”)
Dr. Sleep cites a number of publications in support of his opinions. We omit
citation to most of those references here for brevity.
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kD) protein.” (Id. at | 5.) Dr. Sleep declares that “at the priority date of [the
present application] it was thought in the art that FVII and FVIIa were too
large for clearance from circulation via the kidneys. . . . Thomsen [for
example] taught that ‘the 50 kDa glycoprotein FVIIa molecule is a low
clearance compound.’” (Id. at 17.)12 Thus, Dr. Sleep opines, “one skilled in
the art would have thought that Factor VII and Factor Vila are already large
enough to be excluded from renal secretion, and therefore would not have
expected that fusing Factor VII or Factor Vila to albumin would prolong the
circulatory half-lives of these factors to any useful extent.” (Id.)
When viewed in this historical context, Appellants contend, this
explains why the working examples in Ballance and Fleer fused albumin to
smaller polypeptides or fragments, with the largest having a molecular
weight of about 27 kD. (App. Br. 14.) According to Appellants, “nothing in
Ballance and Fleer provided any reasonable expectation that albumin fusion
would increase the half-life of substantially larger polypeptides, such as
Factor VII.” (Id. at 16.)
Here again, this evidence and argument alone from Appellants does
not persuade us the Examiner erred in concluding that claim 61 would have
been obvious. Fleer teaches that “albumin variants designate any protein
with a high plasma half-life which is obtained by modification” (FF 3) and,
in expressly teaching the fused polypeptide may be “all or part of an enzyme
[etc.],” Fleer suggests its constructs are not limited to fusions with fragments
12 See Thomsen et al., Pharmacokinetics of Recombinant Factor Vila in the
Rate A Comparison of Bio-, Immuno- and Isotope Assays, 70:3
Thrombosis and Haemostasis 458-64 (1993).
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or small molecules. (FF 4.) Also, as the Examiner notes, Fleer identifies a
number of polypeptides that have somewhat larger molecular weights (e.g.,
EPO). (Ans. 12—13.) Moreover, while FVII polypeptides may have been
recognized as a low clearance compound based on size (approx. 50 kD), the
size is still below the renal permeability threshold (60—70 kD) reported in
the art and Dr. Sleep’s declaration. (See, e.g., Sleep Deck 4, 7.)
Accordingly, by fusing to albumin, some increase in circulatory half-life —
even if minor — would have reasonably been expected. Nevertheless, the
Appellants’ evidence does at least suggest the skilled person at the time of
the invention would not have expected that fusing FVII to albumin would
have necessarily resulted in a substantial increase in half-life.
Appellants next cite to data concerning orientation dependency and
unexpected results when Factor VII is fused to the N-terminal end of
albumin. (App. Br. 20—29.) According to Appellants, testing provided by
Dr. Thomas Weimer13 shows the criticality of FVII fusions at the N-
terminus: “the activity-to-antigen ratio of the N-terminal fusion protein
(protein 937) is at least about 20-fold larger than that of the C-terminal
fusion protein (protein 2396.)” (Id. at 21 (citing Weimer 2012 Deck 6).)
In contrast, “the activity-to-antigen ratio approaches zero for the fusion
protein with Factor VII fused [only] at the C-terminal end of albumin.” (Id.)
Also citing Dr. Weimer’s testing, Appellants point out that double fusions
(fusing FVII to both the C- and N-terminal ends of albumin) provide a
13 Dr. Weimer submitted two declarations. (See Declaration of Dr. Thomas
Weimer dated April 25, 2012 (“Weimer 2012 Deck”); see also Declaration
of Dr. Thomas Weimer dated Sept. 3, 2013 (“Weimer 2013 Deck”).)
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protein with significant activity compared to fusion constructs at the C-
terminal end only, “which is virtually inactive.” (Id. at 22 (citing Weimer
2013 Decl. 17.) According to Appellants (and Dr. Weimer), “both Ballance
and Fleer teach that therapeutic polypeptides are preferably fused at the C-
terminal end of albumin, which is opposite to the orientation recited in the
claims on appeal.” (Id. at 24; see also Weimer 2013 Decl. 112.)
Appellants’ data concerning the claimed N-terminal fusions provides
persuasive objective evidence of nonobviousness. The Examiner’s response
relies heavily on the prima facie case, and the teachings in both Ballance and
Fleer that polypeptides may be fused to the N- or C- terminal end of
albumin. (Ans. 23—26.) The Examiner has not, however, provided
persuasive evidence or scientific reasoning explaining why the results
Appellants produced would have been expected.14 Indeed, as Appellants
contend, the prior art suggests the opposite — that optimal activity would
have been observed when a polypeptide is fused at the C-terminal end of
albumin. (Reply Br. 13—14; FF 2, 5.) Although we do not limit the prior art
to its preferred embodiments, here the evidence unexpectedly shows that,
had the skilled artisan modified the prior art to include FVII fused to the C-
terminus, the result would have been a virtually inactive protein.
We recognize, but are not persuaded by, the Examiner’s emphasis in
the Response to Argument, that Fleer claims a double-fusion construct.
14 The Examiner asserts that Drs. Weimer and Sleep appear to contradict
each other (Ans. 20), and that Appellants have provided “contradictory
statements” (id. at 25). For the reasons given by Appellants, we are
unpersuaded there is any discrepancy. (Reply Br. 11—12.)
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(Ans. 21—26.) On the record here, the mention of double fusions in Fleer’s
claims is not entitled to any talismanic importance without an accompanying
disclosure teaching or suggesting a particular advantage of such a construct.
Fleer, as does Ballance, clearly prefers fusions at the C-terminal end of the
albumin, and suggests those fusion proteins provide optimal therapeutic
activity. (FF 2, 5.) The Examiner, however, asserts that the skilled person
“could conclude that because Fleer claims a double fusion in claim 1 after
making single fusions at both terminus that they were aware that the double
fusion produced the highest activity.” (Ans. 22.) This is speculation. And,
in any event, when obviousness is at issue the question is not what the
skilled person could have concluded or done, but what they reasonably
would have done. See Belden Inc. v. Berk-TekLLC, 805 F.3d 1064, 1073
(Fed. Cir. 2015).
The Examiner also responds that “there is a high expectation of
success, because Ballance and Fleer made albumin fusion proteins
comprising therapeutic proteins that are C-terminally or N-terminally
oriented and Fleer also made a fusion that was N and C terminally oriented.”
(Ans. 23.) We are not persuaded. Fusions with Factor VII having any of
these orientations were not made. And, as noted by Appellants and Dr.
Weimer, neither Ballance nor Fleer disclose any in vivo therapeutic activity
when a polypeptide is fused to the N-terminal end of albumin, while such
activity is disclosed for C-terminal fusions. (See Weimer 2013 Decl. 13—
14.)15 Inasmuch as the Examiner invokes an inherency rationale (Ans. 23,
15 Ballance discloses that in vitro testing showed that fusions of hGH to the
N-terminal end of albumin were “significantly less potent” than fusions at
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27) to produce a FVII polypeptide with the claimed “coagulant activity”
when fused at the N-terminal, we are unpersuaded. See Par Pharma., Inc. v.
Twi Pharms., Inc., 773 F.3d 1186, 1195—96 (Fed. Cir. 2014) (holding that a
“high standard” must be met “to rely on inherency to establish the existence
of a claim limitation in the prior art in an obviousness analysis.”) This is
especially so when the “natural result” of the combination of Ballance and
Fleer would have been a fusion at the C-terminal end of albumin, yet
Appellants’ data shows the FVII polypeptide is unexpectedly inactive unless
there is a fusion at the N-terminus. Id. at 1196.
Appellants contend the claimed invention satisfies a long-felt need to
produce extended half-life FVII therapeutics, and that other “major players
in the field” have tried and failed to develop such therapeutics. (App. Br.
30—33.) In support, Appellants cite the declaration of Dr. Veldman.16 Dr.
Veldman declares “there are no extended half-life FVII constructs approved
for use in the United States.” (Veldman Decl. 13.) Dr. Veldman identifies
efforts by Novo Nordisk and Bayer Healthcare to develop an extended half-
life FVII, but states that these efforts were unsuccessful as evidenced by the
termination of phase II/III studies of Novo Nordisk’s and Bayer’s respective
constructs due to problems encountered during testing. {Id. at || 3 4.) In
contrast, Dr. Veldman states that “CSL Behring recently completed a phase I
the C-terminal end. {See Ballance 22:4—7; see also Weimer 2013 Decl.
114.)
16 See Declaration of Dr. Alex Veldman dated March 21, 2014 (“Veldman
Decl.”). The Veldman Decl. cites to various other documents, including
press releases, financial reports, and clinical trials. We do not cite each of
these documents here for brevity.
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clinical study . . . demonstrating the safety and prolonged half-life of a
Factor VH-albumin construct encompassed by the claims . . . [and] CSL
Behring has sought regulatory approval to move forward with a phase II/III
trial.” (Id. at 14.) Dr. Veldman thus opines “the claimed FVII-albumin
constructs may satisfy a long-felt medical need for FVII constructs
exhibiting extended half-life in an area where others in the field have not
met with success.” (Id. at | 5.)
In response, the Examiner again relies principally on the prima facie
case. (Ans. 28—29.) According to the Examiner, “[t]he need in the art was
addressed by the cited references .... The sole purpose of the fusions made
by Ballance and Fleer was to extend the half-life, Fleer made a fusion with a
coagulation factor (vWF) and suggest that other[s] can be made as well.”
(Id. at 28.)
Appellants’ evidence of an alleged long-felt need that is met by the
claimed fusion protein is not strong. Appellants did not persuasively show a
persistent need recognized by skilled persons. See In re Gershon, 372 F.2d
535, 538 (CCPA 1967). For example, Appellants and Dr. Veldman provide
no clear timetable showing when the need for extended half-life FVII
therapeutics was first recognized by skilled persons and its persistence over
the years. The evidence cited by Appellants and Dr. Veldman appears to
reflect work in much more recent times (e.g., 2011, 2013) well after the
putative priority date of the present invention. (Veldman Deck 3 4.)
Even assuming a long-felt need exists, Appellants also do not persuasively
show that the FVII-albumin construct that is being tested by CSL Behring
satisfies the need. See In re Cavanagh, 436 F.2d 491, 496 (CCPA 1971).
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Dr. Veldman’s opinion that this construct “may satisfy” the need is, at best,
equivocal. (Veldman Decl. 1 5.) And, while phase I testing of the construct
shows promise, there is no guarantee that problems will not arise in phase
II/III (as they did for Novo Nordisk and Bayer). (Id. at 13.)
We do, however, attribute weight to Appellants’ evidence showing an
apparent failure by others to develop extended half-life FVII therapeutics.
“The purpose of evidence of failure of others is to show indirectly the
presence of a significant defect in the prior art, while serving as a simulated
laboratory test of the obviousness of the solution to a skilled artisan.” In re
Cyclobenzaprine Hydrocholoride Extended-Release Capsule Patent Litig.,
676 F.3d 1063, 1082 (Fed. Cir. 2012) (citations and internal quotation marks
omitted). The record indicates that Novo Nordisk and Bayer were unable to
successfully develop effective extended half-life FVII constructs. (Veldman
Decl. 13.) The record also indicates that Novo Nordisk’s and Bayer’s
constructs did not comprise a FVII-albumin fusion protein. (Id. ) See In re
Cyclobenzaprine, 676 F.3d at 1082 (“Evidence that others were going in
different ways is strong evidence that the [inventor’s] way would not have
been obvious.”) (citation and internal quotation marks omitted).
When the Examiner’sprima facie case is considered anew, in light of
all the evidence of record, we are unpersuaded that claim 61 would have
been obvious over Morrissey (as evidenced by Weimer), Ballance, Fleer,
and Berkner. Appellants have provided persuasive argument and objective
evidence of nonobviousness that rebuts the Examiner’s evidence of
obviousness. Mintzv. Dietz & Watson, Inc., 679 F.3d 1372, 1379 (Fed. Cir.
2012) (“Obviousness requires . . . walking] a tightrope blindfolded (to avoid
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Appeal 2016-003295
Application 13/855,454
hindsight)—an enterprise best pursued with the safety net of objective
evidence.”) This is not a case where the prima facie case is so strong that it
controls the obviousness determination. See Pfizer, Inc. v. Apotex, Inc., 480
F.3d 1348, 1372 (Fed. Cir. 2007). We thus reverse the rejection of claim 61
and its dependent claims. We decline to address Appellants’ separate
argument and evidence concerning the patentability of claims 74 and 76—78,
as each of those claims depends from claim 61. In re Fritch, 972 F.2d 1260,
1266 (Fed. Cir. 1992) (“[Djependent claims are nonobvious if the
independent claims from which they depend are nonobvious.”)
Conclusion of Law
We conclude the preponderance of the evidence of record does not
support the Examiner’s conclusion that claims 61, 63—74, and 76—78 would
have been obvious.
SUMMARY
We reverse the rejection of claims 61, 63—74, and 76—78 under 35
U.S.C. § 103(a) over Morrissey, Weimer, Ballance, Fleer, and Berkner.
REVERSED
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