Ex Parte Koide

Board of Patent Appeals and Interferences

Jun 8, 2009

09903412 (B.P.A.I. Jun. 8, 2009)

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.
09/903,412 07/11/2001 Shohei Koide 17027.003US1 8219
53137 7590 06/09/2009
VIKSNINS HARRIS & PADYS PLLP
P.O. BOX 111098
ST. PAUL, MN 55111-1098
EXAMINER
WESSENDORF, TERESA D
ART UNIT PAPER NUMBER
1639
MAIL DATE DELIVERY MODE
06/09/2009 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte SHOHEI KOIDE
__________

Appeal 2009-1912
Application 09/903,412
Technology Center 1600
__________

Decided1: June 9, 2009
__________

Before ERIC GRIMES, RICHARD M. LEBOVITZ, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
modified Fibronectin type III molecule. We have jurisdiction under 35
U.S.C. § 6(b). We reverse and enter a new ground of rejection.

1 The two-month time period for filing an appeal or commencing a
civil action, as recited in 37 C.F.R. § 1.304, begins to run from the
decided date shown on this page of the decision. The time period
does not run from the Mail Date (paper delivery) or Notification
Date (electronic delivery).

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Application 09/903,412

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Statement of the Case
The Claims
Claims 1, 4, 7, 8, and 54-63 are on appeal. We will focus on claim 1,
which is representative and reads as follows:
1. A modified fibronectin type III (Fn3) molecule
comprising a stabilizing mutation of at least one residue
involved in an unfavorable electrostatic interaction as
compared to a wild-type Fn3, wherein the stabilizing
mutation is a substitution of at least one of Asp 7, Asp 23 or
Glu 9 with another amino acid residue.

The prior art
The Examiner relies on the following prior art references to show
unpatentability:
Lipovsek et al. US 6,818,418 B1 Nov. 16, 2004

Koide WO 98/56915 A2 Dec. 17, 1998

Spector et al., Rational Modification of Protein Stability by the
Mutation of Charged Surface Residues, 39 BIOCHEMISTRY 872-879 (2000).

The issue
The Examiner rejected claims 1, 4, 7, 8, and 54-63 under 35 U.S.C.
§ 103(a) as being obvious over Koide, Lipovsek, and Spector (Ans. 4-6).
The Examiner finds that “[e]ach of Koide or Lipovsek teaches stable
modified Fn3. However each of these references does not teach that the
regions containing e.g., amino acids 7, 9 or 23 are involved in an
unfavorable electrostatic interaction, as claimed” (Ans. 5). The Examiner
finds that “it would have been obvious to one having ordinary skill in the art
at the time the invention was made to determine whether amino acid
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residues at e.g., 1-9 or 21-31 of the Fn region of Lipovsek or Koide is
involved in an unfavorable electrostatic interactions as taught by Spector”
(Ans. 6).
Appellant contends “[t]he Examiner acknowledges that neither Koide
nor Lipovsek teaches that the regions of Fn3 containing amino acids 7, 9 and
23 are involved in an unfavorable electrostatic interaction. Applicant
respectfully submits that Spector does not remedy the deficiencies of Koide
and Lipovsek” (Reply Br. 11).
In view of these conflicting positions, we frame the obviousness issue
before us as follows:
Did the Examiner err in finding it obvious to modify Asp7, Asp23 or
Glu9 on the Fibronectin type III scaffolds of Koide and Lipovsek based
upon the teachings of Spector?
Findings of Fact (FF)
1. Koide teaches “a fibronectin type III (Fn3) polypeptide
monobody comprising a plurality of Fn3 B-strand domain sequences that are
linked to a plurality of loop region sequences” (Koide 6, ll. 12-14).
2. Koide teaches that “[o]ne or more of the monobody loop region
sequences of the Fn3 polypeptide vary by deletion, insertion or replacement
of at least two amino acids from the corresponding loop region sequences in
wild-type Fn3” (Koide 6, ll. 14-17).
3. Koide teaches that “the loop regions of the monobody comprise
amino acid residues . . . from 22 to 30 inclusive in a BC loop” (Koide 6, ll.
20-22).
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4. Koide teaches that a “nucleic acid phage display library having
seven variegated [randomly mutated] residues (residues number 78-84) in
the FG loop and five variegated residues (residue number 26-30) in the BC
loop was prepared” (Koide 35, ll. 25-27).
5. Lipovsek teaches “a protein that includes a fibronectin type III
domain having at least one randomized loop” (Lipovsek, col. 2, ll. 32-34).
6. Lipovsek teaches that the “three loops of 10Fn3 corresponding
to the antigen-binding loops of the IgG heavy chain run between amino acid
residues 21-31, 51-56, and 76-88” (Lipovsek, col. 8, ll. 18-20).
7. Lipovsek teaches that for the “human 10Fn3 sequence, this
analysis indicates that, at a minimum, amino acids 1-9, 44-50, 61-54 [sic],
82-94 (edges of beta sheets); 19, 21, 30-46 (even), 79-65 (odd) (solvent-
accessible faces of both beta sheets); 21-31, 51-56, 76-88 (CDR-like
solvent-accessible loops); . . . may be randomized to evolve new or
improved compound- binding proteins” (Lipovsek, col. 9, ll. 24-32).
8. Spector “focuses on the peripheral subunit-binding domain,
derived from the dihydrolipoamide acetyltransferase component . . . of the
pyruvate dehydrogenase multienzyme complex from Bacillus
stearothermophilus” (Spector 873, col. 1).
9. Spector teaches that “[t]his study provides a clear
demonstration that alleviating unfavorable surface interactions can increase
the stability of proteins” (Spector 879, col. 1).
10. Spector teaches that “[a]lthough the substitutions described in
this paper would not serve this protein well in vivo,” apparently because the
substitutions were in biologically active domains, “the methodology could
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nevertheless be applied to other proteins if care is taken to avoid residues
involved in catalysis or intermolecular interactions” (Spector 879, col. 1).
Principles of Law
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
The Supreme Court has recently emphasized that “the [obviousness] analysis
need not seek out precise teachings directed to the specific subject matter of
the challenged claim, for a court can take account of the inferences and
creative steps that a person of ordinary skill in the art would employ.” KSR
Int'l v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007).
“To differentiate between proper and improper applications of
‘obvious to try,’ this court outlined two classes of situations where ‘obvious
to try’ is erroneously equated with obviousness under § 103. In the first
class of cases, what would have been ‘obvious to try’ would have been to
vary all parameters or try each of numerous possible choices until one
possibly arrived at a successful result, where the prior art gave either no
indication of which parameters were critical or no direction as to which of
many possible choices is likely to be successful.” In re Kubin, 561 F.3d
1351, 1359 (Fed. Cir. 2009) (citing In re O'Farrell, 853 F.2d 894, 903 (Fed.
Cir. 1988)).
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“In such circumstances, where a defendant merely throws
metaphorical darts at a board filled with combinatorial prior art possibilities,
courts should not succumb to hindsight claims of obviousness.” Id.
Analysis
Lipovsek and Koide teach randomly screening Fibronectin type III
polypeptides at a variety of positions within the peptide sequence (FF 1-7).
Spector, in analyzing an unrelated protein, teaches that stabilization of
proteins by modifying their sequence is desirable, but provides no specific
guidance on selecting residues to be modified in Fibronectin type III (FF 8-
9). Spector also suggests that the residue selection may be difficult, noting
“the substitutions described in this paper would not serve this protein well in
vivo, [but] the methodology could nevertheless be applied to other proteins
if care is taken to avoid residues involved in catalysis or intermolecular
interactions” (Spector 879, col. 1; FF 10).
In Kubin, the court made clear that “where a defendant merely throws
metaphorical darts at a board filled with combinatorial prior art possibilities,
courts should not succumb to hindsight claims of obviousness.” Kubin, 561
F.3d at 1359. This rejection is such a situation, where the prior art gives an
immense number of possible mutations in the Fibronectin type III molecule
including more than 70 different amino acids which may be mutated,
potentially to any of the other 19 amino acids2 (see FF 7). Lipovsek, Koide,
or Spector do not provide any guidance on which parameters were critical
and no direction on which of these mutations is likely to be successful (FF 1-
10).

2 We note that 1970 is equal to 3.25 x 1089 different possibilities.
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Unlike Kubin, where performing the detailed methodology of cloning
would necessarily result in obtaining a molecule within the genus of nucleic
acids being claimed, there is no predictable expectation that performing the
random screening methods of Lipovsek or Koide would predictably, or even
likely, result in polypeptides with mutations at positions 7, 9 or 23 of the
Fibronectin type III molecule. Further, even if such polypeptides were
obtained, there is no predictable or even minimally likely expectation that
the mutations would result in stabilization of the Fibronectin type III
molecule as recited in the claim.
We are not persuaded by the Examiner’s finding that “[i]t would be
within the ordinary skill in the art at the time the invention was made to
choose other residues at e.g., position 7 as taught by Lipovsek” (Ans. 10).
The Examiner has not explained why information regarding positions in the
peripheral subunit-binding domain of pyruvate dehydrogenase taught by
Spector has any relevance whatsoever to Fibronectin type III, which is an
entirely different protein.
Additionally, however, the Examiner has not established, and we do
not find, that the ordinary artisan would have predictably modified positions
7, 9, or 23 of the Fibronectin type III protein in order to obtain a stabilizing
mutation. The Examiner has provided no evidence that mutations at any of
these three positions would have predictably or reasonably have been
expected to have this property, nor has the Examiner presented any other
reason to select any of these three positions from the 70 positions disclosed
by Lipovsek as mutation targets (FF 7).
Conclusion of Law
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The Examiner erred in finding it obvious to modify Asp7, Asp23 or
Glu9 on the Fibronectin type III scaffolds of Koide and Lipovsek based
upon the teachings of Spector.

New Ground of Rejection
35 U.S.C. § 102(e)
Under the provisions of 37 CFR § 41.50(b), we enter the following
new ground of rejection: claims 1, 4, 7, 8, and 54-63 are rejected under 35
U.S.C. § 102(e) as anticipated by Lipovsek.
Findings of Fact (FF)
11. The Specification teaches that “[t]he invention specifically
relates to the generation of both nucleic acid and polypeptide libraries
encoding the molecular scaffolding of a modified Fibronectin Type III (Fn3)
molecule” (Spec. 1, ll. 13-15).
12. The Specification teaches that a “stabilizing mutation is defined
herein as a modification or change in the amino acid sequence of the Fn3
molecule, such as a substitution of one amino acid for another, that increases
the melting point of the molecule [Tm] by more than 0.1°C as compared to a
molecule that is identical except for the change” (Spec. 6, ll. 20-24).
13. The Specification teaches that a mutation of the Asp residue at
position 7 for Asparagine resulted in increased Tm (Spec. 37, l. 25 to Spec.
38, l. 1).
14. The Specification teaches that “mutations at Glu 9 and/or Asp
23 also enhance the stability of Fn3. Furthermore, mutations at one or more
of these three residues can be combined” (Spec. 38, ll. 11-13).
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15. The Specification teaches that “[o]ne or more of the monobody
loop region sequences of the Fn3 polypeptide vary by deletion, insertion or
replacement of at least two amino acids from the corresponding loop region
sequences in wild-type Fn3” (Spec. 7, ll. 6-8).
16. The Specification teaches the sequence of Fibronectin type III
in Figure 2, which is reproduced below:

“Figure 2. Amino acid sequence (SEQ ID NO:110) and restriction sites of
the synthetic Fn3 gene” (Spec. 12, ll. 17-18).
17. Lipovsek teaches an alignment of Fibronectin type III
sequences in Figure 4, reproduced below with annotations which identify the
locations of positions 7, 9 and 23 on the Fibronectin type III molecule:
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“FIG. 4 is a graph illustrating a sequence alignment between fibronectin type
III protein domain and related protein domains” (Lipovsek, col. 6, ll. 31-33).
18. Lipovsek teaches a Canis familiaris (Cf) sequence which is a
Fibronectin type III molecule with a substitution of Asp 7 by neutral
Asparagine, a substitution of Glu 9 by positively charged Arginine and a
substitution of Asp 23 by Glutamine relative to the wild type human
Fibronectin type III sequence (see Lipovsek, Figure 4, 8th line (“Cf”) in
alignment; FF 16).
19 Lipovsek teaches another sequence, RN, in which the
Fibronectin type III molecule has a substitution of Asp 23 for Glutamic acid
relative to the human fibronectin wild type sequence (see Lipovsek, Figure
4, 3rd line in alignment; FF 16).
20. Lipovsek teaches another sequence, HS CAP, in which the
Fibronectin type III molecule has a substitution of Glu 9 by asparagine
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relative to the human fibronectin wild type sequence (see Lipovsek, Figure
4, 13th line in alignment; FF 16).
Principles of Law
“[T]he PTO gives a disputed claim term its broadest reasonable
interpretation during patent prosecution”. In re Bigio, 381 F.3d 1320, 1324
(Fed. Cir. 2004). The court recognizes the fairness of reading claims
broadly “before a patent is granted [since] the claims are readily amended as
part of the examination process.” Burlington Indus. v. Quigg, 822 F.2d
1581, 1583 (Fed. Cir. 1987). “Thus, a patent applicant has the opportunity
and responsibility to remove any ambiguity in claim term meaning by
amending the application”. Bigio, 381 F.3d at 1324. Applying the broadest
reasonable interpretation to claims also “serves the public interest by
reducing the possibility that claims, finally allowed, will be given broader
scope than is justified.” In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359,
1364 (Fed. Cir. 2004).
“A rejection for anticipation under section 102 requires that each and
every limitation of the claimed invention be disclosed in a single prior art
reference.” In re Paulsen, 30 F.3d 1475, 1478-79 (Fed. Cir. 1994); see
Karsten Manufacturing Corp. v. Cleveland Golf Co., 242 F.3d 1376, 1383
(Fed. Cir. 2001) (“Invalidity on the ground of ‘anticipation’ requires lack of
novelty of the invention as claimed … that is, all of the elements and
limitations of the claim must be shown in a single prior reference, arranged
as in the claim.”).
“Whether the rejection is based on ‘inherency’ under 35 U.S.C. § 102,
on ‘prima facie obviousness' under 35 U.S.C. § 103, jointly or alternatively,
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the burden of proof is the same, and its fairness is evidenced by the PTO's
inability to manufacture products or to obtain and compare prior art
products”. In re Best, 562 F.2d 1252, 1255 (CCPA 1977). “Where, as here,
the claimed and prior art products are identical or substantially identical, or
are produced by identical or substantially identical processes, the PTO can
require an applicant to prove that the prior art products do not necessarily or
inherently possess the characteristics of his claimed product.” Id.
Analysis
Claim 1 requires a “modified” Fibronectin type III molecule. The
Specification does not directly define “modified” (FF 11), but discloses that
a “stabilizing mutation is defined herein as a modification or change in the
amino acid sequence of the Fn3 molecule, such as a substitution of one
amino acid for another” (Spec. 6, ll. 20-24; FF 12). Also, the Specification
states that “[o]ne or more of the monobody loop region sequences of the Fn3
polypeptide vary by deletion, insertion or replacement of at least two amino
acids from the corresponding loop region sequences in wild-type Fn3”
(Spec. 7, ll. 6-8; FF 15). Therefore, the word “modified” is reasonably
interpreted in light of the Specification as representing a Fibronectin type III
molecule in which there are one or more changes or substitutions in the
amino acid sequence relative to the human wild type sequence.
Claim 1 also requires that at least one of Asp 7, Asp 23, or Glu 9 be
substituted with another amino acid, which the claim indicates functions as a
“stabilizing mutation” (see claim 1; FF 13). Dependent claims 4 and 7
specifically identify replacement of Asp 7 or Asp 23 with asparagine as a
mutation within the scope of claim 1 (see claims 4 and 7).
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Lipovsek teaches a human Fibronectin type III sequence which is
identical to that disclosed in the Specification (FF 16-17).
Lipovsek also teaches Fibronectin type III sequences which are
“modified” relative to the human sequence (FF 18-19). Specifically,
Lipovsek teaches a Canis familiaris (Cf) sequence which is a Fibronectin
type III molecule with a substitution of Asp 7 by Asparagine, a mutation of
Glu 9 by Arginine and a substitution of Asp 23 by Glutamine relative to the
wild type human FND (Fibronectin type III domain) sequence among other
sequence differences (see Lipovsek, Figure 4, 8th line in alignment; FF 17-
18). Lipovsek also teaches another sequence, RN, in which the Fibronectin
type III molecule has a substitution of Asp 23 by Glutamic acid relative to
the human FND wild type sequence (see Lipovsek, figure 4, 3rd line in
alignment; FF 17, 19). Lipovsek also teaches another sequence, HS CAP, in
which the Fibronectin type III molecule has a substitution of Glu 9 by
asparagine relative to the human FND wild type sequence (see Lipovsek,
Figure 4, 13th line in alignment; FF 17, 20).
The Cf, RN, and HS CAP sequences are reasonably interpreted as
modified Fibronectin type III molecules with substitutions which would
reasonably be believed as inherently stabilizing based upon the teachings of
the Specification (FF 12-14).
With regard to claims 4, 55, 57-59, 61, and 63, Lipovsek teaches the
Cf Fibronectin type III sequence with a neutral asparagine at the position of
Asp 7 (FF 18).
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With regard to claims 7, 8 and 57, Lipovsek teaches both the Rn and
Cf Fibronectin type III sequences with substitutions of one other amino acid
residue at Asp 7, Asp 23, and Glu 9 (FF 18-19).
With regard to claims 54 and 56, Lipovsek teaches a Cf Fibronectin
type III sequence in which the Glu 9 is substituted with a positively charged
arginine residue (FF 18).
With regard to claims 55 and 58-60, Lipovsek teaches a Cf
Fibronectin type III sequence in which the Asp 23 is substituted with a
neutral glutamine residue (FF 18).
With regard to claim 62, Lipovsek teaches a Hs CAP Fibronectin type
III sequence in which the Glu 9 is substituted with asparagine (FF 20).
In particular regarding the functional requirement that the mutation is
a “stabilizing” mutation, we find that since the mutations disclosed by
Lipovsek are identical to those required by the claims, the mutations would
reasonably be expected to inherently function as “stabilizing” mutations in
the absence of evidence to the contrary (FF 16-19). See In re Spada, 911
F.2d 705, 708 (Fed. Cir. 1990) (“[W]hen the PTO shows sound basis for
believing that the products of the applicant and the prior art are the same, the
applicant has the burden of showing that they are not.”)
Conclusion of Law
Claims 1, 4, 7, 8, and 54-63 are anticipated under 35 U.S.C. § 102(e)
by Lipovsek.
SUMMARY
In summary, we reverse the rejections under 35 U.S.C. § 103(a) and
enter a new rejection under 35 U.S.C. § 102(e).
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This decision contains a new ground of rejection under 35 U.S.C.
§ 101 pursuant to 37 C.F.R. § 41.50(b) (effective September 13, 2004, 69
Fed. Reg. 49960 (August 12, 2004), 1286 Off. Gaz. Pat. Office 21
(September 7, 2004)). 37 C.F.R. § 41.50(b) provides “[a] new ground of
rejection pursuant to this paragraph shall not be considered final for judicial
review.”
37 C.F.R. § 41.50(b) also provides that the Appellant, WITHIN TWO
MONTHS FROM THE DATE OF THE DECISION, must exercise one of
the following two options with respect to the new ground of rejection to
avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate amendment
of the claims so rejected or new evidence relating to the
claims so rejected, or both, and have the matter reconsidered
by the Examiner, in which event the proceeding will be
remanded to the Examiner .…

(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same record
.…

REVERSED, 37 C.F.R. § 41.50(b)

lp

VIKSNINS HARRIS & PADYS PLLP
P.O. BOX 111098
ST. PAUL MN 55111-1098