Ex Parte Chapman et al

Patent Trial and Appeal Board

Mar 8, 2017

10539229 (P.T.A.B. Mar. 8, 2017)

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.
10/539,229 04/27/2006 John William Chapman 056159-5261 6003
9629 7590 03/10/2017
MORGAN LEWIS & BOCKIUS LLP (WA)
1111 PENNSYLVANIA AVENUE NW
WASHINGTON, DC 20004
EXAMINER
STEADMAN, DAVID J
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
03/10/2017 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):
patents @ morganlewis.com
karen.catalano @ morganlewis.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOHN WILLAIM CHAPMAN, TEUN van der LAAR, NIGEL
MALCOLM LINDNER, and CHRISTIANN VISSER
Appeal 2014-008089
Application 10/539,229
Technology Center 1600
Before DONALD E. ADAMS, DEMETRA J. MILLS, and TAWEN
CHANG, Administrative Patent Judges.
MILLS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for obviousness and obviousness-type double patenting. We have
jurisdiction under 35 U.S.C. § 6(b).
Appeal 2014-008089
Application 10/539,229
STATEMENT OF CASE
According to the Specification,
[a]ntifreeze proteins (AFPs) are polypeptides produced by a wide
range of species, particularly those indigenous to colder climes,
which have the ability to inhibit freezing of water and aqueous
materials at temperatures below 0°C. In general, it is thought
that these proteins function by means of interacting with and
inhibiting the growth of ice crystals, but it is now clear that
there are different classes of antifreeze protein which may have
different mechanisms of action and different effects.
Spec. 1.
The Specification further discloses that the present inventors have found that,
when the antifreeze protein type III HPLC-12 is prepared by
expression in a normal yeast strain of a nucleic acid sequence encoding the
protein, a substantial proportion of the secreted protein product has been
glycosylated. Such glycosylation is not present in the native protein, and
recrystallisation inhibition assays on the separated glycosylated and
unglycosylated fractions showed, surprisingly, that the glycosylation
effectively abolished the AFP activity of the protein.
Spec. 7. Finally, the Specification discloses that, “Among the most potentially
useful AFPs which have been identified is a type III AFP from the Ocean Pout,
which has been designated HPFC-12. This protein was found to excel in its ability
to aid in controlling the shape and size of ice crystals.” Spec. 2.
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Application 10/539,229
The following claim is representative.
1. A method for producing a type III antifreeze protein (AFP) which method
comprises expressing a nucleic acid sequence encoding the type III AFP in a
fungal host cell,
wherein the fungal host cell is Saccharomyces cerevisiae and is a mutant
strain made deficient in protein mannosyl transferase 1 (pmtl) and/or protein
mannosyl transferase 2 (pmt2);
and wherein the type III AFP has at least 80% amino acid sequence identity
with SEQ ID NO: 1 and has increased ice recrystallization inhibitory activity as
compared to glycosylated type III AFP.
Grounds of Rejection
Rejections previously applied to claim 19 in the August 23, 2013 Non-Final
Action have been withdrawn in view of the cancellation of claim 19. (Ans. 14—
15.) The remaining rejections, as articulated in the Answer, are set forth below.
1. Claims 1, 6—7, 12, and 14—16 are rejected under 35 U.S.C. § 103(a) as being
unpatentable over Chapman in view of Ng and Gentzsch.
2. Claims 1, 6—7, 12, and 14—16 are rejected under 35 U.S.C. § 103(a) as being
unpatentable over Chapman in view of Tanner and Gentzsch.
3. Claims 1, 6—7, 12, and 14—16 are rejected under the judicially created
doctrine of obviousness-type double patenting as being unpatentable over
claims 1—9 of US Patent 7,297,516 (hereinafter “’516 patent”) in view of Ng
and Gentzsch.
4. Claims 1, 6—7, 12, and 14—16 are rejected under the judicially created
doctrine of obviousness-type double patenting as being unpatentable over
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Appeal 2014-008089
Application 10/539,229
claim 11 of US Patent 7,560,249 (hereinafter “’249 patent”) in view of Ng
and Gentzsch.
5. Claims 1, 6—7, 12, and 14—16 are rejected under the judicially created
doctrine of obviousness-type double patenting as being unpatentable over
claims 1—9 of US Patent 7,297,516 (“’516 patent”) in view of Tanner and
Gentzsch.
6. Claims 1, 6—7, 12, and 14—16 are rejected under the judicially created
doctrine of obviousness-type double patenting as being unpatentable over
claim 11 of US Patent 7,560,249 (hereafter “’249 patent”) in view of Tanner
and Gentzsch.
Cited References
Chapman
Tanner
Ng
Chapman ’516
WO 97/02343
US 5,714,377
US 2002/0068325 A1
US 7,297,516 B2
(hereinafter “’516 patent”)
Van de Laar ’249 US 7,560,249 B2
(hereinafter “’249 patent”)
Jan. 23, 1997
Feb. 3, 1998
Jun. 6, 2002
Nov. 20, 2007
Jul. 14, 2009
Gentzsch, Protein O-glycosylation in Saccharomyce cerevisiae: the protein
O-mannosyltransferases Pmtlp and Pmt2p function as heterodimer, Fed. of
European Biochemical Societies, 128-130 (1995).
FINDINGS OF FACT
The Examiner’s findings of fact are set forth in the Answer at pages 2—14.
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Application 10/539,229
PRINCIPLES OF LAW
In making our determination, we apply the preponderance of the evidence
standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427 (Fed. Cir. 1988)
(explaining the general evidentiary standard for proceedings before the Office).
“The combination of familiar elements according to known methods is
likely to be obvious when it does no more than yield predictable results. “KSR
Inti Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Rejection 1 — Obviousness — Chapman, Ng, Gentzsch
The Examiner finds that “[t]he type III AFP polypeptide of Chapman is
100% identical to SEQ ID NO:l herein” and that “[t]he difference between the
method of Chapman and the claimed invention is that Chapman's Saccharomyces
cerevisiae is not deficient in pmtl and/or pmt2.” Ans. 2. The Examiner relies on
Ng and Gentzsch to provide the motivation for using a S. cerevisiae modified to
delete pmtl and pmt2 genes from proteins to prevent protein misfolding. Ans. 2-3;
Ng 172. In particular, Ng teaches it is possible that most heterologous proteins can
become O-glycosylated when produced in yeast and that O-glycosylation can
result in misfolding and compromised activity and stability. Ans. 3.
Ng teaches a solution for overcoming the problem of O-glycosylation, which
is the deletion of pmt genes in a S. cerevisiae expression host, noting the
deletion may be any of the six pmt genes or combination thereof, which
deletion promotes proper folding (p. 6, paragraph 71; p. 7, paragraph 72).
Ng teaches that using a pmt-deleted yeast as an expression host improves
yields and activity of a heterologously expressed protein where yeast
expression has shown success (p. 1, paragraph 12). Ng discloses a
comparison of heterologous protein expression in S. cerevisiae strains
individually deleted in each of pmtl-pmt6 (p. 4, paragraph 57; p. 12,
paragraph 152), where O-glycosylation of the heterologous protein was
shown to be dependent on pmtl and pmt2, but not on pmt3-pmt6 (p. 12,
paragraph 152, middle to bottom).
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Application 10/539,229
Gentzsch teaches a pmtl deletion, a pmt2 deletion, and a pmtl-pmt2
deletion of S. cerevisiae (p. 28, column 2, paragraph 2.1); teaches the
polypeptides encoded by pmtl and pmt2 function as a heterodimer having
O-mannosyl-transferase activity in the O-glycosylation of polypeptides (p.
128, abstract); and teaches that disruption of each of these genes leads to “a
dramatic decrease of mannosyltransferase activity in vitro.”
Ans. 3. The Examiner concludes that,
At the time of the invention, it would have been obvious to one of
ordinary skill in the art to combine the teachings of Chapman, Ng, and
Gentzsch to express type III AFP using a pmtl -pmt2-deleted S. cerevisiae.
One would have been motivated to do this in order to determine if the type
III AFP expressed using pmtl-pmt2-deleted S. cerevisiae has increased
activity and/or stability, particularly as Ng teaches “it is possible that most
heterologous proteins can become O-linked glycosylated” when produced in
yeast and that using a pmt-deleted yeast as an expression host improves
yields and activity of a heterologously expressed protein where yeast
expression has already shown success.
One would have had a reasonable expectation of success to express
type 111 AFP using pmtl-pmt2-deleted S. cerevisiae because of the results of
Chapman, Ng, and Gentzsch. Therefore, the method of claims 1, 6-7, 12, and
14-16 would have been obvious to one of ordinary skill in the art at the time
of the invention.
Ans. 4.
Appellants contend that
the cited references fail to suggest any correlation between
glycosylation specificity and the recited type III AFP. Specifically,
Chapman discloses only glycosylated type III AFP and is silent regarding
any underglycosylated type III AFP. Further, Ng and Gentzsch are silent
regarding any type III AFP. Accordingly, from reading the cited references,
one of ordinary skill in the art would not know whether any protein
mannosyl transferase mutant could be used to underglycosylate type III
AFP, and/or which protein mannosyl transferases would be specific to
glycosylation of type III AFP.
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Application 10/539,229
Br. 5. Appellants argue that they have unexpectedly found that,
as shown in Examples 5-6 and Tables 3-4 of the present specification, the
recited pmt 1-deficient mutant strain results in underglycosylation of type III
AFP compared to non-mutant parent strain. Thus, in view of the data
disclosed in the present specification, the underglycosylation of type III AFP
resulted from the deletion of pmt 1 was unexpected in view of the cited
references and the status of art at the time of the invention.
Br. 5. In response to this argument, the Examiner notes that “claims 1, 6, 7, 12,
and 14-16 are not limited to a S. cerevisiae that is deficient only in pmtl and/or
pmt2. Rather, claim 1 is broadly and reasonably interpreted to encompass a S.
cerevisiae that is deficient in at least pmtl and/or pmt2 (and any additional pmt3-
pmt6).” Ans. 18. The Examiner further finds that
Contrary to appellant's position, in view of the state of the art, one would
have expected type III AFP to be O-glycosylated by a pmt. As noted above,
Ng teaches “it is possible that most heterologous proteins can become O-
linked glycosylated” when produced in yeast[]. Indeed, all of the
recombinant proteins analyzed in Ng and Tanner and appellant’s cited
references of Gentzsch et al. (Glycobiology 7:481-486, 1997) and Strahl-
Bolsinger (Biochemica et Biophysica Acta 1426:297-307, 1999) were O-
glycosylated by pmtl, pmt2, a combination of pmtl -pmt2, or by pmt4 when
expressed in S. cerevisiae, which supports Ng’s noted teaching that most
heterologous proteins can become O-linked glycosylated when expressed in
yeast. Also, although it is acknowledged that Chapman’s expression system
successfully expresses type III AFP with ice recrystallization inhibitory
activity, as noted above, Ng recognizes that using a pmt-deleted yeast as an
expression host improves yields and activity of a heterologously expressed
protein even when yeast expression has already shown success. As such, in
view of the teachings of the prior art, one would have expected type III AFP
to be O-glycosylated by a pmt when recombinantly produced by S.
cerevisiae.
Ans. 16—17.
ANAFYSIS
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Application 10/539,229
Appellants provide separate arguments for claims 6, 7, and 12 in the Brief.
Br. 5 and 6. Because the rejection of these claims turn on the same issues as
rejection 1 and is addressed fully in the response to rejection 1, we address these
claims as part of rejection 1. We agree with the Examiner’s fact finding, statement
of the rejection and responses to Appellants’ arguments as set forth in the Answer.
We find that the Examiner has provided evidence to support a prima facie case of
obviousness and find no error in the Examiner’s indicated rationale in support of
the present obviousness rejection. We provide the following additional comment
to the Examiner’s argument set forth in the Final Rejection and Answer.
Appellants contend that
one of ordinary skill in the art would not have expected that
underglycosylated type III AFP would have increased ice recrystallization
inhibitory activity as compared to glycosylated type III AFP. As discussed
in page 4 of the original specification, for example, removing pendant
disaccharides of AFP found in northern cods and Antarctic notothenioids
resulted in loss of AFP activity, but when a naturally glycosylated AFP from
carrots was produced without its surface glycans, its activity was not
affected. See De Vries (Science, 172, 1152, 1971), and Worrall (Science,
282, 115-17, 1998). Moreover, the present inventors found that the activity
of a heterologously expressed AFP from rye grass did not depend on its
glycosylation. See Page 4 of the original specification. Further, the cited
references fail to suggest any correlation between glycosylation and AFP's
ice recrystallization inhibitory activity because the cited references are silent
regarding any underglycosylated AFP.
App. Br. 6. We are not persuaded. We agree with the Examiner, that
one would have looked to the relevant prior art of Ng ... to determine
the effect of decreasing O-glycosylation on the ice recrystallization
inhibitory activity of type III AFP. In view of these references, one would
have expected increased ice recrystallization inhibitory activity of type III
AFP produced in a pmt-deficient strain of S. cerevisiae. The references of
Ng and Tanner each correlate aberrant O-glycosylation with reduced activity
of a heterologous protein. For example, as noted above, Ng teaches O-
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Application 10/539,229
glycosylation can result in misfolding and compromised activity and Tanner
teaches a drawback of undesirable O-glycosylation on fungal-derived
recombinant products is that biological activity can be affected. Also, Ng
correlates using a pmt deletion strain with higher activity of a heterologous
recombinant protein. For example, as noted above, Ng teaches that using a
pmt-deleted yeast as an expression host improves activity of a
heterologously expressed protein even where yeast expression has shown
success. Therefore, in view of the prior art of record, one would have
expected that type III AFP has reduced O-glycosylation in a pmt-deficient S.
cerevisiae mutant and would have expected that reducing O-glycosylation of
type III AFP would increase its ice recrystallization inhibitory activity.
Ans. 20-21; See also, Ans. 4. In particular, Chapman discloses that the type III
AFP polypeptide (HPLC-12) is 100% identical to SEQ ID NO: 1, as claimed.
Chapman further discloses that when the SEQ ID NO: 1 peptide is used as an
additive it provides,
improved properties of modification of ice crystal growth processes
influencing size and shape characteristics of ice in particular in regrowth
thereby e.g. minimising potential freezing damage e.g. by preventing or
inhibiting ice recrystallisation of the product upon freezing, said use
occurring in a manner known per se for antifreeze peptides to obtain higher
specific modification activity in particular antifreeze activity.
Chapman Abstract, emphasis added. Chapman discloses that, “HPLC 12 appeared
to be the only fraction of the 12 AFP-type III fractions active in recrystallisation
inhibition at the concentrations tested.” Chapman, p. 4,11. 13-15. Thus, Chapman
discloses the type III AFP has increased ice recrystallization inhibitory activity.
Ng discloses that
heterologous proteins expressed in yeast are inappropriately modified by O-
linked glycosylation. In turn, the modification can have negative
consequences on the maturation and activity of the protein. The inventors
have established that coupling expression using an endogenous signal
sequence with specific mutant strains deficient in O-linked glycosylation,
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Application 10/539,229
the activity of heterologous proteins expressed in yeast can be drastically
improved.
Ng 171. Ng discloses that, “[i]n yeast, O-linked glycosylation begins in the
ER through the action of a family of genes called protein mannosyltransferases
(PMT).” Ng 168. “Since there are 6 PMT genes in yeast that are non-redundant
and exhibit differences in substrate specificity, deletion strains of any of the six
genes may provide the needed inhibition of aberrant O-glycosylation. In addition,
mutations can be combined to further promote proper folding.” Ng 171. Thus, Ng
discloses inhibition of aberrant O-glycosylation in yeast using pmt deletion, and
therefore deletion of pmt genes is a result effective variable which can be
optimized by those of ordinary skill in the art to achieve proper protein folding and
increase protein yields. “[Discovery of an optimum value of a result effective
variable in a known process is ordinarily within the skill of the art.” In re
Peterson, 315 F.3d 1325, 1329-1330 (Fed. Cir. 2003).
Ng further discloses that pmt 1 and /or pmt 2 deletions, in particular,
stabilize, “improve yields and activity of proteins,” and prevent misfolding of
proteins, i.e., increase the number of properly folded proteins. Ng, abstract, || 12,
71, 72, 152; Ng claim 8; Ans. 3. It would have been obvious to one of ordinary
skill in the art at the time of the invention that prevention of type III AFP protein
misfolding in yeast with specific pmt mutant strains deficient in O-linked
glycosylation (including pmt 1 and pmt 2) over glycosylated type III AFP, would
result in a higher active protein yield and thus increased recrystallization inhibitory
activity. Compare, Spec. Table 3, p. 28, showing increases in non-glycosylated
AFP protein yield, consistent with the teachings of Ng and Gentzsch.
Therefore, one of ordinary skill in the art would have expected increases in
properly folded proteins (including type III AFP), protein yield and protein activity
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Application 10/539,229
in view of the disclosure of Chapman, Ng, and Gentzsch. Expected beneficial
results are not evidence of nonobviousness. See, In re Skoner, 517 F.2d 947, 9502
(CCPA 1975). Appellants have not shown the unexpected results of increasing ice
recrystallization inhibitory activity of type III AFP in view of the closest prior art.
“[W]hen unexpected results are used as evidence of nonobviousness, the results
must be shown to be unexpected compared with the closest prior art.” In re
Baxter-TravenolLabs., 952 F.2d 388, 392 (Fed. Cir. 1991); Bristol-Myers Squibb
Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). Additional
arguments not made are waived.1
Rejection 1 is affirmed for the reasons of record.
Rejection 2- Obviousness - Chapman, Tanner and Genzsch
Appellants’ Brief does not respond to Rejection 2 and no Reply Brief has
been presented by Appellants. Tanner is relied on in rejection 2 in place of Ng.
Tanner similarly teaches that
A drawback of undesirable O-glycosylation on fungal-derived
recombinant products is that biological activity can be affected by
glycosylation (column 2, lines 40-44). To avoid undesirable O-
glycosylation, Tanner teaches using genetically modified fungal cells,
including Saccharomyces cerevisiae, with genetic modification to reduce O-
glycosylation (column 2, lines 47-56; column 3, lines 18-19), e.g., by
deletion of pmtl gene (column 3, lines 20-22; column 4, lines 31- 33).
1 We note that Appellants previously argued that Chapman was not prior art to the
present application because it had been antedated by a Declaration under 37 C.F.R.
1.131. Non-Final Action dated Aug, 23, 2013, p. 8. These arguments have not
been presented again in the Brief, and are, therefore, waived.
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Ans. 5. For the reasons similar to those discussed above with respect to rejection
1, we find that the Examiner has presented a prima facie case of obviousness and
rejection 2 is affirmed for the reasons of record.
Double Patenting Rejections 3 6
Appellants present similar arguments for all four double patenting rejections,
as presented for Rejections 1 and 2 above. In particular, Appellants argue that they
have presented data of unexpected, superior results not found in the cited
references. App. Br. 8—9.
For the reasons discussed above with respect to rejections 1 and 2, we are
unpersuaded by Appellants’ evidence of unexpected results as there is no
comparative evidence with respect to the closest prior art.
Rejections 3—6 are affirmed for the reasons of record.
CONCLUSION OF LAW
The cited references support the Examiner’s obviousness rejections 1 and 2,
which are affirmed for the reasons of record. The Examiner’s obviousness-type
double patenting rejections 3—6 are also affirmed for the reasons of record. All
pending, rejected claims fall.
No time period for taking any subsequent action in connection with this
appeal may be extend under 37 C.F.R. § 1.136(a)(i)(iv).
AFFIRMED
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