Ex Parte Seifried et al

Patent Trial and Appeal Board

Apr 11, 2018

13001187 (P.T.A.B. Apr. 11, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/001, 187 05/19/2011
23557 7590 04/13/2018
SALIW ANCHIK, LLOYD & EISENSCHENK
A PROFESSIONAL ASSOCIATION
PO Box 142950
GAINESVILLE, FL 32614
FIRST NAMED INVENTOR
Erhard Seifried
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
BB.280 9537
EXAMINER
TSAY,MARSHAM
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
04/13/2018 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):
euspto@slepatents.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ERHARD SEIFRIED and JORG SCHUTTRUMPF
Appeal2016-006409
Application 13/001, 187
Technology Center 1600
Before ERIC B. GRIMES, DEBORAH KATZ, and JOHN G. NEW,
Administrative Patent Judges.
KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appellants 1 seeks our review, under 35 U.S.C. § 134(a), of the
Examiner's decision to reject claims 22, 24, 28-33, 35, 36, and 38--44.
(App. Br. 1.) We have jurisdiction under 35 U.S.C. § 6(b ). We REVERSE.
1 DRK-Blutspendedienst Baden-Wiirttemberghessen GGmbH is reported to
be the real party in interest. (See App. Br. 1.)
Appeal2016-006409
Application 13/001,187
Appellants' invention is related to protein factors of the coagulation
cascade that allow for blood clotting and, when mutated, contribute to
hemophilias. (See Spec. 1.) Appellants focus on factor IX ("F.IX"), which
forms a complex with factor VIII ("F.VIII") to activate their natural
substrate factor X ("F.X"), leading to blood coagulation. (See id. at 1-2.)
Individuals with hemophilia B have a mutation in the F .IX gene that disrupts
this activity. (See id. at 2.) Appellants report that they have invented
variants of F.IX that allow for activation of F.X in the absence of F.VIII.
(See id. at 7 .)
Variants in Appellants' claims are described by the original and new
amino acid present at a particular position in the protein chain. For example,
"K265A" indicates a change from lysine (K) to alanine (A) at position 265.
Appellants' claim 22 below recites: 2
A variant of factor IX (F .IX) or activated factor IX
(F.IXa) which is characterized in that it has clotting activity in
the absence of its cofactor,
wherein the cofactor is factor VIII (F.VIII) or activated
factor VIII (F.VIIIa),
said variant of factor IX or activated factor IX
comprising an amino acid substitution in position 265 in
combination with amino acid substitution VI 8 II,
wherein the amino acid substitution in position 265 is
selected from K265T, K265A, K265D, K265E, K265F, K265G,
K265H, K265I, K265N, K265S and K265V,
wherein the variant factor IX or activated factor IX does
not encompass variant Y259F/K265T/Y345F/I383V/E388G or
variant Y259F/A261K/K265T/Y345F/I383V/E388G, and
2 Claim 22 has been modified by adding indentations to separate the
elements. See 37 C.F.R. § 1.75(i).
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Application 13/001,187
wherein said amino acid substitutions are made at
positions in reference to amino acids 4 7 to 461 of the amino
acid sequence of SEQ ID NO. 2, and
wherein the blood clotting activity of said variant is at
least 1 % as measured in an aPTT assay in the absence of F. VIII
compared to wildtype having 0 % clotting activity in the
absence off.VIII and 100 % activity in the presence off.VIII.
(App. Br. 12, Claims App.) Claim 22 is drawn to a variant of F.IX that has
the recited level of blood clotting activity in the absence of F.VIII and that
also includes an amino acid substitution at position 265 (for example
K265A) and an amino acid substitution V181I. The claimed variant ofF.IX
cannot include one of the variants expressly recited in the claim (variant
Y259F/K265T/Y345F/I383V/E388G or variant Y259F/A261K/K265T/
Y345F/I383V/E388G).
The Examiner rejected claims 22, 24, and 28 under 35 U.S.C. § 103(a)
over Kolkman3 and Hamaguchi. 4 (See Ans. 2-5.) In addition, the Examiner
rejected claims 22, 28-30, and 41--44 over Kolkman, Hamaguchi and
Hopfner, 5 (see Ans. 5-7) and claims 31-33, 35, 36, and 38--40 over
3 Kolkman and Mertens, "Insertion Loop 256-268 in Coagulation Factor IX
Restricts Enzymatic Activity in the Absence but Not in the Presence of
Factor VIII," 39 BIOCHEMISTRY 7398-7405 (2000).
4 Hamaguchi et al., "Mutations in the Catalytic Domain of Factor IX That
Are Related to the Subclass Hemophilia Bm," BIOCHEMISTRY 32:6324---6329
(1993).
5 Hopfner et al., "Converting blood coagulation factor IXa into factor Xa:
dramatic increase in amidolytic activity identifies important active site
determinants," 16 THE EMBO JOURNAL 6626-6635 (1997).
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Appeal2016-006409
Application 13/001,187
Kolkman, Hamaguchi, and DeFrees, 6 (Ans. 7-8), both under 35 U.S.C.
§ 103(a). 7
Findings of Fact
1. Kolkman teaches that the catalytic efficiency of F.IXa with a
K265A substitution is 20 times higher than normal F.IXa in the absence of
F.VIIIa, as measured by an in vitro activation assay. (See Kolkman abstract,
7401, and Figure 1.)
2. The in vitro activation assay of Kolkman involves incubating
F .IX or an F .IX variant and inactive F .X with phospholipid vesicles and
calcium ions and quantitating the amount of activated F.X formed. (See
Kolkman 7400 (FX Activation).)
3. The aPTT assay recited in claim 22 involves adding F .IX or an
F .IX variant to a F .IX or F. VIII deficient plasma and measuring clotting time
to evaluate the activity of the F.IX variant. (See Spec. 9-10.)
4. Kolkman does not teach F .IX with a VI 8 II substitution.
5. Hamaguchi teaches that the major structural change to activate
serine proteases is at the N-terminus in the catalytic domain. (Hamaguchi
6327.)
6. Hamaguchi teaches:
6 DeFrees et al., US 2006/0040856 Al; published February 23, 2006.
7 Claim 27 is also pending and the Examiner has indicated that it stands
rejected. (Office Action mailed March 3, 2015, page 1.) However, claim 27
is not included in any of the rejections set out in the Final Action or in the
Answer. In view of our reversal of the rejections on appeal, however, this
oversight appears to be harmless.
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Appeal2016-006409
Application I3/00I,I87
The clotting activities of factor IXs with mutations at the first
two amino acids of the heavy chains [positions I 8 I and I 82]
share similarities with Bode's previous study; however, there
are differences. First, although dipetides with isoleucine at the
first position bind tighter to the activation pocket than dipeptide
with amino-terminal valine, isoleucine at the amino terminus of
the catalytic domain of factor IX did not increase clotting
activity.
(Hamaguchi 6328.)
7. Hamaguchi provides Table II, which reports the aPTT activity
of F .IX variant VI 8 II to be I 00% of normal F .IX activity. (Hamaguchi
6326, Table II.)
Analysis
Rejection over Kolkman and Hamaguchi
The Examiner determined that it would have been obvious for one of
ordinary skill in the art to construct a variant F .IX comprising amino acid
substitutions K265A and VI 8 II based on the finding that Kolkman teaches
K265A has a catalytic efficiency 20-fold higher than wild type F.IX in the
absence off.VIII. (See Ans. 3, citing Kolkman 7389, 7400-DI, Fig. I, and
Table 2.) The Examiner finds further that one of ordinary skill in that art
would have combined the K265A variant with the VI 8 II variant because
Hamaguchi teaches that VI 8 II is a "preferable amino terminal primary
structure in the catalytic domain that retains clotting activity." (See Ans. 4,
citing Hamaguchi 6327-28.) According to the Examiner, "it would be
reasonable and obvious to combine the amino acid substitutions to arrive at a
variant F.IX that has increased catalytic efficiency and/or favorable
activity." (Ans. 4.)
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Appeal2016-006409
Application 13/001,187
The Examiner also finds that the clotting activity recited in claim 22
("wherein the blood clotting activity of said variant is at least 1 % as
measured in an aPTT assay in the absence of F.VIII compared to wildtype")
is a latent property, which does not render claim 22 non-obvious. (See Ans.
4--5.)
Appellants argue that the increase in catalytic efficiency reported in
Kolkman (20X) is "miniscule and irrelevant" compared to the 1,000 to
10,000-fold increase needed to achieve minimal clinically-relevant blood
clotting activity. (App. Br. 3.) Appellants base this argument on the
declaration of inventor Jorg Schiittrumpf. (See Second Declaration of Jorg
Schiittrumpfunder 37 C.F.R. § 1.132, filed January 27, 2015 ("Second
Schiittrumpf Deel.").)
Dr. Schiittrumpf testifies that the K265A F.IX variant has extremely
low activity in in vitro assays when compared to the activity of wild type
F.IX and so would not have been pursued as a significant variant. (See
Second Schiittrumpf Deel. 1-2.) Specifically, Dr. Schiittrumpf reasons that
the activity of wild type F .IX increases by a factor of 105 to 106 in the
presence of F. VIII compared to in the absence of F. VIII, when there is no
activity. (See id. at 2.) Dr. Schiittrumpf testifies, further, that to be
clinically significant, the activity of F .IX must reach at least 1 % of that
increase (that is, by a factor 103-104). (See id.) According to Dr.
Schiittrumpf, because Kolkman teaches that the K265A variant increased
F.IX activity only 20-fold (less than 100 or 102) in the in vitro assay, it
would not have been considered clinically relevant and may not have even
led to detectable clotting in vivo. (See id.) Dr. Schiittrumpf testifies that
"[t]here is no reason to expect that a mutation that results in only a 20-fold
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Appeal2016-006409
Application 13/001,187
increase of catalytic efficiency in the in vitro assay would cause a greater
increase in blood clotting." (Id.)
The Examiner considered Dr. Schiittrumpf s declaration to be
unpersuasive because, to the Examiner, Dr. Schiittrumpf was equating the
20-fold increase in activity of F.IX K265A variant in the absence of F.VIII
with the increased activity of wild-type F.IX in the presence versus the
absence of F.VIII. (See Ans. 9-10.) According to the Examiner, Appellants
have not provided evidence that a variant F.IX with a 20-fold increase in
activity over wild type F.IX would not also have increased activity in in vivo
conditions. (See id. at 10.)
Unlike the Examiner, we are persuaded by Dr. Schiittrumpf' s
declaration. Although Dr. Schiittrumpf refers to the very large increase in
activity of wild type F.IX caused by F.VIII (105-106 fold), his testimony is
that a variant of F .IX must have at least 1 % of that very large increase to be
significant. This testimony is consistent with the functional limitation in
Appellants' claims and the explanation in Appellants' Specification (see
Spec. 10). Dr. Schiittrumpf testifies that the 20-fold increase in activity
reported for K265A in Kolkman from the in vitro assay would be less than
1 % and not significant. (See Second Schiittrumpf Deel. 2.)
It is not clear from Dr. Schiittrumpf s testimony how the in vitro assay
used in Kolkman is related to the aPTT assay recited in Appellants' claims,
but the burden falls on the Office to show why one of ordinary skill in the art
would have pursued the K265A variant given the 20-fold increase in the in
vitro assay. The Examiner fails to do so. The Examiner merely reiterates
that the K265A variant demonstrates 20 fold higher activity than wild type
F.IX in the absence of F.VIII. (See Ans. 9-10.)
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Appeal2016-006409
Application I3/00I,I87
The Examiner also finds that Kolkman teaches F.IX K265A has
similar catalytic efficiency compared to normal F .IX when both are in the
presence of F.VIII in the in vitro assay. (See Ans. 8 and I0-11, citing
Kolkman 7400-01.) This finding is similarly unpersuasive because it does
not indicate that the K265A variant would contribute to an increase in
activity of at least I 03-I 04 fold (1 % ) in the aPTT assay in the absence of
F.VIII.
The Examiner cites Hamaguchi as teaching variants of F .IX. (See
Ans. 3--4.) Although Hamaguchi teaches the VI 8 II variant recited in claim
22, it also teaches that this amino acid substitution produces no increase in
clotting activity. (See Hamaguchi 6328, left col and Table II (reporting
IOO% the level of wild type activity for VI81I).) As Appellants note,
Hamaguchi is silent about the activity ofF.IX VI81I in the absence of
F.VIII. (See App. Br. 6.)
The Examiner concludes that it would have been obvious to one of
ordinary skill in the art to construct a variant F.IX with substitutions K265A
and VI 8 II because they are equivalents known for the same purpose. (See
Ans. 4.)
We agree with Appellants that, because Kolkman does not report
significantly increased activity for K265A and Hamaguchi does not
demonstrate increased activity for VI81I in the absence ofF.VIII, the
Examiner has not shown there would have been a reason for one of ordinary
skill in the art to have combined these two substitutions in an F .IX variant.
(See App. Br. 6.) Furthermore, we agree with Appellants that there would
not have been a reasonable expectation of success in creating a variant with
at least I% blood clotting activity as measured in the aPTT assay by
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Appeal2016-006409
Application 13/001,187
combining these two amino acid substitutions (see App. Br. 7) despite the
Examiner's conclusion to the contrary (see Ans. 13).
Accordingly, we agree with Appellants that the Examiner erred in
rejecting claim 22, as well as claims 24 and 28, as being obvious over the
teachings of Kolkman and Hamaguchi.
Rejection over Kolkman, Hamaguchi, and Hopfner
The Examiner also rejected Appellants' claim 22, 28-30, and 41--44
as being obvious over Kolkman, Hamaguchi, and Hopfner. (See Ans. 5-7.)
According to the Examiner, Hopfner teaches F .IX variants comprising
combinations of the substitutions K265T and I383V, which result in an
increase in catalytic efficiency of at least 130-fold over wild-type F.IX. (See
Ans. 5, citing Hopfner 6629-30.) The Examiner concluded that it would
have been obvious to incorporate the I383V substitution with the K265A and
V181I substations of Kolkman and Hamaguchi. (See Ans. 6.)
The Examiner does not dispute Appellants' argument that Hopfner
reports activity of F.IX variants only the presence of F.VIII. (See App. Br.
8; see also Ans. 14.) Accordingly, we are not persuaded that the teachings
of Hopfner regarding F .IX variants with substitutions at amino acid positions
265 and 3 83 cure the deficiency of Kolkman discussed above. We agree
with Appellants that the Examiner erred in this rejection.
Rejection over Kolkman. Hamaguchi, and DeFrees
The Examiner rejected claims 31-33, 35, 36, and 38--40 over
Kolkman, Hamaguchi, and DeFrees. (See Ans. 7-8.) DeFrees is cited only
for the addition of water-soluble polymers as attachments to F .IX proteins,
not for variants of the amino acid sequence of F.IX. Accordingly, for the
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Appeal2016-006409
Application 13/001,187
reasons discussed above, we agree with Appellants that the Examiner erred
in this rejection.
Conclusion
Upon consideration of the record and for the reasons given, the
rejection of claims 22, 24, 28-33, 35, 36, and 38--44 under 35 U.S.C.
§ 103(a) are not sustained.
Therefore, we reverse the decision of the Examiner.
REVERSED
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