SHEEHAN, JOHN P. et al.

Patent Trials and Appeals Board

Sep 16, 2019

14928689 - (D) (P.T.A.B. Sep. 16, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/928,689 10/30/2015 JOHN P. SHEEHAN WARF.P0050US 8987
108197 7590 09/16/2019
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
Austin, TX 78746
EXAMINER
TSAY, MARSHA M
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
09/16/2019 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):
docket@phiplaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOHN P. SHEEHAN and PANSAKORN TANRATANA
Appeal 2019-004134
Application 14/928,689
Technology Center 1600
BEFORE RYAN H. FLAX, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.
HARDMAN, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject certain claims directed to variants of Factor IX
as obvious over the prior art. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as “Wisconsin
Alumni Research Foundation.” Appeal Br. 3.
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STATEMENT OF THE CASE
According to the Specification, the invention concerns “variants of
Factor IX which can be used in improved methods of treating hemophilia.”
Spec. 2:16–17. Claim 1, reproduced below, is illustrative of the claimed
subject matter:
1. A Factor IX protein comprising a R→A substitution at
residue 150 of the native human Factor IX sequence and
either but not both (a) a K→A substitution at residue 126 of
the native human Factor IX sequence or (b) a K→A
substitution at residue 132 of the native human Factor IX
sequence, as defined by the human chymotrypsinogen
numbering system for the protease domain.
Appeal Br. 14 (Claims Appendix).
Claims 1–6, 8, 9, 26, and 28 are on appeal. Final Act. 2. The claims
stand rejected under 35 U.S.C. § 103 as being unpatentable over Westmark
II2 and Westmark I.3 Id. at 9–10.
ANALYSIS
The Examiner rejected the claims as being obvious over Westmark II
and Westmark I. Final Act. 9–10. According to the Examiner, Westmark II
discloses “human FIX proteins comprising alanine substitutions [] in the

2 Westmark et al., Selective mutagenesis of the heparin and antithrombin
exosites on human factor IX(a) enhances thrombin generation in human
plasma, Presentation, ISTH Meeting Amsterdam, Netherlands, July 2013
(“Westmark II”).
3 Westmark et al., Selective mutagenesis of the heparin and antithrombin
exosites on human factor IX(a) enhances thrombin generation in human
plasma, Abstract, ISTH Meeting, Amsterdam, Netherlands, July 2013
(“Westmark I”).
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heparin binding exosite (K126A, K132A, K126A/K132A)4, antithrombin-
binding exosite (R150A), or both (K126A/K132A/R150A).” Id. at 10. The
Examiner found that Westmark II further discloses “optimized combinations
of exosite mutations, such as K126A/R150A or K132A/R150A” (id.), which
are the two double mutations recited in the claims. The Examiner found that
one of ordinary skill in the art would have arrived at the claimed proteins
with the claimed mutations because Westmark II discloses that these double
mutations “may yield proteins with prolonged in vivo half-life and enhanced
activity.” Id.
With respect to reasonable expectation of success, the Examiner
stated:
Westmark I disclose that in contrast to their clotting
activities, both FIX R150A and K126A demonstrated markedly
enhanced TF-initiated TG [tissue factor-initiated thrombin
generation] relative to WT [wildtype] protein (≥ 2 fold)
(results) and Westmark II disclose K126A, K132A, and R150A
support substantial levels of TF-triggered thrombin generation
(slide 14). . . .
While the combined heparin exosite mutations FIX
K126A/K132A have reduced thrombin generation
proportionate to clotting activity (~20%), it is disclosed that
addition of R150A (triple mutant) increased TG activity of the
K126/K132A FIX zymogen and protease forms (Westmark I
results; Westmark II slides 11, 13). Mutation of the
antithrombin-binding site (R150A) tended to increase plasma
TG relative to clotting activity, either alone or in the context of
combined mutations in the heparin-binding exosite (double vs.
triple mutant) (Westmark I conclusion).

4 We understand this nomenclature to mean that, e.g., at position 126 of the
protein’s amino acid sequence the K is substituted with A, and at position
132 the K is substituted with A.
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Therefore, given that it was recognized that the
antithrombin-binding site mutation (R150A) markedly
enhanced TG relative to WT protein (≥ 2 fold) and tended to
increase plasma TG relative to clotting activity, one of ordinary
skill would have a reasonable expectation of success that the
combination of an antithrombin and heparin exosite mutation
(i.e. R150A/K126A and R150A/K132A) would yield FIX
variants having significantly enhanced TG activity since FIX
K126A, like R150A, was also demonstrated to have markedly
enhanced TG relative to WT protein (≥ 2 fold) and FIX K132A
had TG activity similar to WT FIX.
Ans. 6–7.
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (id. at 9–13; Ans. 3–11), and agree that
claims 1–6, 8, 9, 26, and 28 would have been obvious over Westmark II and
Westmark I for the reasons the Examiner articulated. Indeed, Westmark II
expressly suggests two specific, “optimized” combinations of exosite
mutations, K126A/R150A and K132A/R150A, which are the very same
double mutations recited in Appellant’s claims. We note, both Westmark I
and Westmark II are prior art publications (it is not disputed), co-authored
by one of the named inventors, on the subject matter of the appealed claims.
Appellant argues a lack of reasonable expectation of success, asserting
that “the general expectation is that making mutations in molecules like
those claimed here would lead to decreased activity.” Appeal Br. 9. As
support for this assertion, Appellant points to Tables 1 and 2 in the
Specification, arguing that the “single substitution mutants K126A, K132A
and R150A lost varying degrees of thrombin generation activity” as
compared to wildtype, while double and triple substitution mutants
(K126A/R150A, K132A/R150A, K126A/K132A/R150A) lost varying
degrees of coagulant activity as compared to wildtype. Id. at 9–11.
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Appellant argues that the “take away” from these data and from Westmark II
is that “most mutations tend to reduce activity, not improve it,” and that
“any given double mutant would be expected to lose activity of all types.”
Id. at 10; see also id. at 11 (arguing that “Westmark II shows that a double
mutant lost activity, which would discourage, not encourage the skilled
artisan, and also would eliminate any reasonable expectation of success”).
We are not persuaded by Appellant’s argument that a person of
ordinary skill in the art would have held a “general expectation” that all
mutations in Factor IX proteins would lead to decreased activity. First,
Appellant’s reliance on data in the Specification is irrelevant. Obviousness
and reasonable expectation of success are “measured from the perspective of
a person of ordinary skill in the art at the time the invention was made.”
Velander v. Garner, 348 F.3d 1359, 1379 (Fed. Cir. 2003) (emphasis added).
Accordingly, our focus must be on the information available in the prior art.
Appellant has not established that the data in Table 2 of the Specification
were known in the prior art, and in fact, Appellant has argued that the data in
the Specification are more “complete” and “mature” than the data in
Westmark I and II. See Reply Br. 4, 5 n.1.
Second, Appellant’s argument overstates the purported “take away”
from Westmark II. According to Westmark II, the double mutation
K126A/K132A in the heparin binding exosite markedly reduced coagulant
and thrombin generation activity. See Westmark II at slide 14. But, there is
no basis to extrapolate this to a broader teaching that all double mutants
would be expected to lose activity of all types. To the contrary, Westmark II
teaches that “optimized combinations of exosite mutations,” such as a
double mutation comprised of one mutation in the heparin binding exosite
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(either K126A or K132A) and one mutation in the antithrombin binding
exosite (R150A), “may yield proteins with prolonged in vivo half-life and
enhanced activity.” See id.
In the Reply Brief, Appellant argues that we should discount the data
in Westmark I and II because they are “preliminary,” and because
“discrepancy in the data sets of Westmark I and II was clearly evident.”
Reply Br. 4–7. Appellant argues that the “discrepancy” was found to be
caused by protease contamination, which purportedly caused “substantial[]
overestimat[ion]” of the amount of thrombin generation in the zymogen
samples. Appellant thus asserts that “reliance on this clearly inconsistent
and facially unreliable data is completely misplaced.” Id. at 7.
We are not persuaded by Appellant’s arguments. In the Appeal Brief,
Appellant cites a “subsequent analysis” of protease contamination in the
zymogen samples (see Appeal Brief 11, citing Westmark 20155), but did not
attempt to establish that the purported contamination would have been
known to a person of ordinary skill in the art at the time of Appellant’s
invention. In the Reply Brief, Appellant argues for the first time that “the
presence of contaminating FIXa in zymogen preparations has been
previously recognized.” Reply Br. 6. This argument was not timely
presented, and is therefore waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015);
see also Ex Parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010)
(informative) (“Any bases for asserting error, whether factual or legal, that

5 Westmark et al., Selective disruption of heparin and antithrombin-
mediated regulation of human factor IX, 13 J. Thromb. Haemost. 1053–63
(2015) (“Westmark 2015”).
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are not raised in the principal brief [but could have been to rebut the
Examiner’s rejection] are waived.”).
However, even if we were to assume that a person of ordinary skill in
the art would have known at the time of Appellant’s invention that protease
contamination could affect zymogen samples in the thrombin-generation
assay, the record nevertheless lacks evidence that a person of ordinary skill
in the art would have wholly ignored the zymogen results presented in
Westmark I and II because of potential contamination. In fact, Westmark
2015 states that only two zymogen samples, K132A and R150A, were
contaminated, such that thrombin generation was “likely mildly or
moderately overestimated” for samples K132A and R150A, respectively.
Westmark 2015 at 1061. Westmark 2015 further states that three other
zymogen samples were not contaminated, and that “the higher TG activity
demonstrated by rFIX K126A, K126A/R150A, and K132A/R150A cannot
be explained by protease contamination.” Id. The Specification additionally
states that contamination does not explain the higher TG activity
demonstrated by the triple mutant (K126A/K132A/R150A) relative to
coagulant activity. Spec. 68:7–9.
Accordingly, we are not persuaded by Appellant’s argument that a
person of ordinary skill in the art would have discounted data in Westmark I
or II based on the purported “preliminary” nature of the data, purported
inconsistencies, or purported contamination.
Appellant next asserts that statements on Westmark II slide 14
“should not be permitted to argue in favor of obviousness.” Reply Br. 7.
Specifically, Appellant argues that the reference to “substantial” levels of
thrombin generation for K126A, K132A, and R150A on slide 14 “does not
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infer that these levels are greater than” wildtype activity, because each of
these mutants had “somewhat reduced” activity compared to wildtype. Id. at
6–8. These arguments are not persuasive, because they ignore the zymogen
data in Westmark I, which indicated that the K126A and R150A zymogens
“demonstrated markedly enhanced TF-initiated TG relative to WT protein
(≥ 2-fold),” and that K132A had thrombin generation similar to that of
wildtype. See Westmark I (Results). For the reasons discussed above, we
decline to ignore this zymogen data. When read in the context of the
zymogen data, the statement on Westmark II slide 14 is consistent with an
inference that these mutants had at least the same or more thrombin
generation than the wildtype protein.
Appellant also argues that the final point on Westmark II slide 14 is
“forward-looking” and “speculative,” because “no experimental data
existed to support it.” Reply Br. 7, 8. This is not persuasive, because for the
reasons discussed above and by the Examiner, Westmark I and II contain
sufficient data to support Westmark II’s suggestion that the claimed double
mutations “may yield proteins with prolonged in vivo half-life and enhanced
activity.” Final Act. 9–13; Ans. 3–11.
Appellant also argues that the claimed double mutants demonstrate
surprising and unexpected properties. Appeal Br. 12. Relying on the data in
Table 2 of the Specification, Appellant argues that “the fact that each of the
three individual substitutions lost thrombin generation activity, as did
K126A/K132A and the triple substitution, the increase in thrombin
generation activity that appears only with K126A/R150A and K132A/R150A
must be considered as highly unexpected.” Id.
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We are not persuaded by this argument, because it improperly
discounts the zymogen data reported in Table 2 (and in the prior art).
Focusing only on the right-hand columns of Table 2, Appellant is correct
that only the claimed mutants showed an increase in thrombin generation
activity compared to wildtype. Spec. 63 (Table 2). However, the zymogen
data in the left-hand columns show that each of the K126A, K132A, and
R150A single mutants showed increased thrombin generation activity
compared to wildtype. Id. Even if we ignore the results for K132A and
R150A due to contamination, K126A showed increased thrombin generation
activity. Westmark 2015 at 1061; Spec. 68:5–7. The double mutant
K126A/K132A showed reduced thrombin generation activity compared to
wildtype, but this was explained in Westmark II, where the authors stated
that these combined mutations, both of which are in the heparin binding
exosite, “may synergistically reduce cofactor affinity.” Westmark II (slide
14). Consistent with the teachings in Westmark I, Table 2 in the
Specification indicates that addition of the R150A mutation to the
K126A/K132A double mutant increased thrombin generation. Spec. 63
(Table 2). Thus, when viewing the entire collection of data (including the
zymogen data in the left-hand columns of Table 2), we disagree with
Appellant that the claimed double mutations (K126A/R150A and
K132A/R150A) are the only mutations that resulted in increased thrombin
generation.
CONCLUSION
We affirm the obviousness rejection of claims 1–6, 8, 9, 26, and 28 as
being obvious over Westmark II and Westmark I.
In summary:
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Claims Rejected Basis Affirmed Reversed
1–6, 8, 9, 26, and
28
§ 103 Westmark
II, Westmark I
1–6, 8, 9, 26, and
28

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED