Ex Parte Muir

Board of Patent Appeals and Interferences

Jun 13, 2008

10218315 (B.P.A.I. Jun. 13, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DAVID F. MUIR
__________

Appeal 2008-3327
Application 10/218,315
Technology Center 1600
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Decided: June 13, 2008
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Before TONI R. SCHEINER, DONALD E. ADAMS, 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 method
for preparing a nerve graft for implantation. We have jurisdiction under 35
U.S.C. § 6(b). We affirm.

Appeal 2008-3327
Application 10/218,315

Background
“Peripheral nerve injuries are a major source of chronic disability.
Poor management of nerve injuries is associated with muscle atrophy and
can lead to painful neuroma when severed axons are unable to reestablish
continuity with the distal nerve” (Spec. 1). The Specification notes that
“[n]erve grafting is warranted with nerve ablation but presents several
practical challenges. Over the years, various nerve graft alternatives have
been explored.” (Spec. 2). The Specification comments that “the nerve
sheath structure contains the essential scaffolding and adhesive cues to
promote axonal regeneration and significant regeneration has been achieved
in acellular (e.g., freeze-killed) nerve grafts” (Spec. 2).
Statement of the Case
The Claims
Claims 1-7, 10-19, 23-35, 39, and 41-45 are on appeal. We will focus
on claim 1, which is representative and reads as follows:

1. A method for preparing a nerve graft for
implantation, the method comprising the steps of:
a) providing a nerve graft capable of supporting
axonal ingress after implantation and comprising an intact
basal lamina tube;
b) rendering the nerve graft acellular by killing cells
in the nerve graft; and
c) degrading chondroitin sulfate proteoglycan of the
nerve graft by applying, in vitro, at least one chondroitin
sulfate proteoglycan-degrading enzyme to the nerve graft so
as to condition the nerve graft for enhanced post-
implantation axonal ingress from a damaged nerve into the
nerve graft at a site of coaptation relative to an untreated
nerve graft.
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The prior art
The Examiner relies on the following prior art references to show
unpatentability:
Toby A. Ferguson et al., MMP-2 and MMP-9 Increase the Neurite
Promoting Potential of Schwann Cell Basal Laminae and Are Upregulated
in Degenerated Nerve, 16 Molecular and Cellular Neuroscience 157-167
(2000).
Jian Zuo et al., Neuronal Matrix Metalloproteinase-2 Degrades and
Inactivates a Neurite-Inhibiting Chondroitin Sulfate Proteoglycan, 18 J.
Neuroscience 5203-5211 (1998).
Leung-Wah Yick et al., Chondroitinase ABC promotes axonal
regeneration of Clarke’s neurons after spinal cord injury, 11 Neuroreport
1063-1067 (2000).
Peter J. Evans et al., Regeneration Across Cold Preserved Peripheral
Nerve Allografts, 19 Microsurgery 115-127 (1999).
Leonard L. Jones et al., Neurotrophic factors, cellular bridges and
gene therapy for spinal cord injury, 533 J. Physiology 83-89, (2001).
Adarshi K. Gulati, Evaluation of acellular and cellular nerve grafts in
repair of rat peripheral nerve, 68 J. Neurosurgery 117-123 (1988).

The issues
The rejections as presented by the Examiner are as follows:
A. Claims 1-7, 10-14, 17-19, 23-34, 39, and 41-45 stand rejected under
35 U.S.C. § 102(b) as being anticipated by either Ferguson or Zuo (Ans. 3)..
B. Claims 1-7, 10-14, 17-19, 23-34, 39, and 41-45 stand rejected under
35 U.S.C. § 103(a) as being obvious over Ferguson and Zuo (Ans. 6).
C. Claims 1-7, 10-19, 23-35, 39, and 41-45 stand rejected under 35
U.S.C. § 103(a), as being obvious over Ferguson, Zuo, Yick, Evans, Jones,
and Gulati (Ans. 8).

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A. 35 U.S.C. § 102(b) rejection over either Ferguson or Zuo
Appellant argues that
Ferguson slices through the basal lamina tubes of the nerve
tissue longitudinally, destroying their integrity, to generate
20 µm thick sections. (Ferguson, page 158, figure 1 and
page 164, right column.) Thus, the substrate for Ferguson's
assay is a tissue slice that neither includes an intact basal
lamina tube nor has the capacity to allow axons to grow into
it because it has no interior space suitable for such growth.
Accordingly, Ferguson's nerve slice is utterly distinct, both
structurally and functionally, from a nerve graft capable of
supporting axonal ingress after implantation and including a
basal lamina tube, as recited in claim 1.

(App. Br. 8). Appellants also contend that “Zuo utilizes a cryoculture
neurite outgrowth assay . . . As with Ferguson, nerve segments are
cryosectioned and mounted on coverslips” (App. Br. 8). Appellants argue
that “the Examiner simply ignores the fact that Appellant's claims require a
nerve graft capable of supporting axonal ingress after implantation and an
intact basal lamina tube” (App. Br. 9).
The Examiner responds that
the nerve segments in the methods of both cited references clearly
contain Schwan cell basal laminae as substrate for neurite outgrowth
and because the "longitudinal sections" that are argued by applicant
(as shown on fig. 1 of the Ferguson' reference) were done in order to
visualize the neurite outgrowth along parallel array of basal lamina
exposed on longitudinal sections or in longitudinal images.

(Ans. 11.)
The Examiner argues that “Ferguson et al. clearly teaches that axon
regeneration occurs within the basal lamina . . . that neurite growth has been
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shown in association with the inner (luminal) surface of basal lamina
exposed in longitudinal section . . . and that the geometry observed on these
sections include basal lamina tube” (Ans. 11).
In view of these conflicting positions, we frame the anticipation issue
before us as follows:
Do either Ferguson or Zuo teach methods of preparing nerve grafts for
implantation as required by claim 1?
Findings of Fact
1. Ferguson teaches a method of preparing nerve sections in which
“Nerve segments (1 cm) were cryosectioned (20 µm), mounted on sterile
APTS-coated coverslips and stored at -20°C until use” (Ferguson 164, col.
2).
2. The Specification teaches that “the nerve tissue/graft is
rendered acellular by freeze-killing” (Spec. 9:18-19). The Ferguson method
freezes the nerve segments, which will necessarily render the segments
acellular by freeze killing as taught by the Specification (see Ferguson 164,
col. 2).
3. Ferguson teaches treatment of the chondroitin sulfate
proteoglycan with degrading enzymes (see Ferguson 164, col. 2).
4. Ferguson teaches that “neurite growth of both neonatal and
adult DRG neurons was significantly increased on nerve sections pretreated
with enzymes known to degrade inhibitory CSPG” (Ferguson 158, col. 2).
5. Zuo teaches “neurons cultured directly on unfixed nerve
sections” (Zuo 5204, col. 2).
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6. Zuo teaches that “Rat sciatic nerves were removed under
general anesthesia and rapidly frozen in dry ice. Nerve segments (1 cm)
were crysectioned (14 µm) and then mounted on sterile polyornithine-coated
glass coverslips” (Zuo 5204, col. 2).
7. Zuo teaches that “mounted sections were treated for 4 hr at
37°C with (1) activated MMP-2 . . . (2) chondroitinase ABC” (Zuo 5204,
col. 2).
8. Zuo teaches that “[n]euritic growth on sections was increased
by ~50% on sections deinhibited with either MMP-2 or chondroitinase”
(Zuo 5207, col. 1).
9. Zuo concludes that “axonal growth by regenerating embryonic
dorsal root ganglionic neurons (DRGn) cultured on sections of normal adult
nerve and on a synthetic substratum composed of laminin and inhibitory
CSPG was found to be dependent on metalloproteinase activity” (Zuo 5204,
col. 1).
Discussion of 35 U.S.C. § 102(b) over either Ferguson or Zuo
Both Ferguson and Zuo teach elements of the process steps of claim 1,
including providing a nerve section, rendering the nerve section acellular
and degrading the nerve section with a chondroitin sulfate proteoglycan
degrading enzyme (FF 1-3, 5-8). Additionally, Both Ferguson and Zuo
recognize that the enzymatic treatment improves neurite outgrowth and
axonal growth (FF 4, 9).
The Examiner acknowledges, however, that “the cited methods do not
provide a ready-to-use nerve graft as a final product” (Ans. 7). We think it
is clear that the claim requires a “nerve graft for implantation” which must
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be capable of being used in a nerve graft technique. The nerve sections of
either Ferguson or Zuo are either 20 µm or 14 µm in width, respectively (FF
1, 6). While the Specification does not provide a minimum size for a nerve
graft, the Specification notes that “the length of the nerve graft can be from
about 1 centimeter to about 10 centimeters, or over about 10 centimeters”
(Spec. 19:1-2). We find that the Examiner has not made a prima facie case
that a 20 µm nerve section, a section that is 500 times smaller than the
smallest length (1 cm) contemplated by the Specification, would be suitable
as a nerve graft. Therefore, the prior art of Ferguson or Zuo fails to disclose
every element of the claimed invention. See PPG Indus. Inc. v. Guardian
Indus. Corp, 75 F.3d 1558, 1566 (Fed. Cir. 1996). (“To anticipate a claim, a
reference must disclose every element of the challenged claim and enable
one skilled in the art to make the anticipating subject matter.”)
We therefore agree with Appellant that Ferguson and Zuo fail to
anticipate claim 1. We reverse the anticipation rejection of claims 1-7, 10-
14, 17-19, 23-34, 39, and 41-45 over either Ferguson or Zuo.

B. 35 U.S.C. § 103(a) rejection over Ferguson and Zuo
Appellant argues that
Ferguson and Zuo fail to teach or suggest degrading CSPG
of the nerve graft by applying, in vitro, at least one CSPG-
degrading enzyme to condition the nerve graft for enhanced
post-implantation axonal ingress from a damaged nerve into
the nerve graft at a site of coaptation. Quite the opposite, in
fact: Ferguson and Zuo suggest that application of CSPG-
degrading enzyme might be detrimental to this process.

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(App. Br. 10.) Appellant contends that “this art teaches that the in vivo
mechanism of nerve regeneration is one of CSPG-mediated inhibition of
axon growth into areas of the nerve where growth is undesirable and
facilitation of axon growth in those areas in which the CSPG-mediated
inhibitory mechanism is removed” (App. Br. 12).
The Examiner contends that
Ferguson and by Zuo disclose assays that clearly
demonstrate that the in vitro enzymatic treatment of nerve
segments provided for the enhanced neurite outgrowth of
the seeded nerve cells as compared to the non-
enzymatically treated segments and because the cited
references teach that the treatment of nerve segments with
the CSPG-degrading enzymes de- inhibit or unmasks the
growth-promoting properties of basal lamina.

(Ans. 12.)
In view of these conflicting positions, we frame the obviousness issue
before us as follows:
Would it have been obvious to an ordinary artisan to prepare nerve
grafts using the cryoculture methods of Ferguson or Zuo?
Findings of Fact
10. Ferguson teaches that “Our results imply that MMP expression
. . . may represent a degenerative mechanism which reveals the neurite-
promoting activity of laminin at the lumenal face of the endoneurial tubes
which, in effect, converts the distal nerve from a suppressive to a highly
[favorable] environment for axonal regeneration” (Ferguson 164, col. 1).
11. Zuo teaches that “axonal growth by regenerating embryonic
dorsal root ganglionic neurons (DRGn) cultured on sections of normal adult
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nerve and on a synthetic substratum composed of laminin and inhibitory
CSPG was found to be dependent on metalloproteinase activity” (Zuo 5204,
col. 1).
Discussion of 35 U.S.C. § 103(a) over Ferguson and Zuo
The case for Ferguson and Zuo under obviousness is significantly
better than that for anticipation since “the 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).
We disagree with Appellant’s arguments that Ferguson or Zuo oppose
the use of a CSPG degrading enzyme in preparing nerve tissue for neurite
regrowth (see App. Br. 10-12). In our opinion, Ferguson and Zuo recognize
and suggest the use of matrix metalloproteinases, such as MMP 9, for
treatment of nerve tissue to enhance axonal growth (FF 10-11).
The issue still remains as to whether, based solely on Ferguson and
Zuo, it would have been obvious to prepare nerve grafts following the
cryoculture methods of Ferguson and Zuo. This is a much more difficult
rejection to decide. The closest that either Ferguson or Zuo ever get to
discussing nerve grafts is when Ferguson notes that “MMPs contribute to the
success of nerve regeneration and that CSPG-degrading enzymes may
provide a means for therapeutic intervention to enhance nerve repair”
(Ferguson 164, col. 1). While this also rebuts Appellant’s argument that
Ferguson would not suggest the use of CSPG-degrading enzymes, it does
not provide a reason to apply the CSPG degrading enzymes to nerve grafts,
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only to nerve repair. The Examiner has not provided any evidence,
including from Ferguson and Zuo, regarding nerve grafts. In the absence of
such evidence in this rejection, we do not have any support for any
inferences which might be employed by the ordinary artisan.
We reverse the obviousness rejection of claims 1-7, 10-14, 17-19, 23-
34, 39, and 41-45 over Ferguson and Zuo.

C. 35 U.S.C. § 103(a) rejection over Ferguson, Zuo, Yick, Evans, Jones,
and Gulati.
Appellant argues that “[o]ne of skill in the art would not find the
teaching of these secondary references relevant to understanding how to
prepare nerve grafts by applying CSPG-degrading enzyme to nerve grafts in
vitro in order to enhance axonal ingress” (App. Br. 17). Appellant also
argues that “these references suggest that viable cells are required during
axonal regeneration as well as in allografting, and therefore teach away from
methods involving acellular nerve grafts” (App. Br. 19).
The Examiner contends that “Ferguson et al and/or Zuo et al.
demonstrate(s) that in vitro treatment of nerve tissues with CSPG-degrading
enzymes promote neurite growth on/across the enzymatically treated nerve
tissues ant, thus the prior art provides motivation to make nerve graft tissues
intended for implantation by in vitro treatment with CSPG-degrading
enzymes” (Ans. 14). The Examiner also argues that the “term ‘acellular’
nerve graft means lack of viable cells in the nerve graft and the lack of
viable cells reduces or eliminates concerns of host-graft immunorejection as
encompassed by the instant specification” (Ans. 15).
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In view of these conflicting positions, we frame the obviousness issue
before us as follows:
Would it have been obvious to an ordinary artisan to prepare nerve
grafts using the cryoculture methods of Ferguson and Zuo as well as the
teachings of Yick, Evans, Jones, and Gulati?
Findings of Fact
12. Yick teaches that “chondroitinase ABC promoted the axonal
regeneration of neurons in CN after spinal cord injury” (Yick 1066, col. 2 to
1067, col. 1).
13. Evans teaches that the “availability of nerve allografts for the
repair of large peripheral nerve gaps would be of great benefit to patients
and reconstructive surgeons” (Evans 119, col. 2).
14. Gulati teaches that “[a]cellular basal lamina grafts derived from
skeletal muscle are also effective in supporting axonal growth and
maturation” (Gulati 117, col. 1).
15. Gulati teaches that “[r]egenerated axons were seen only in the
proximal 2 cm of the acellular grafts” (Gulati 119, col. 1).
Discussion of 35 U.S.C. § 103(a) over Ferguson, Zuo, Yick, Evans, Jones,
and Gulati.
The obviousness case rests on whether a person of ordinary skill in the
art would have considered it obvious to apply the chondroitin degrading
enzymes of Ferguson or Zuo on nerve sections (FF 3, 7) to entire nerve
grafts such as those taught by Evans and Gulati (FF 13-15). Yick supports
the concept that chondroitin degrading enzymes assist in axonal regeneration
(FF 12).
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We conclude that the Examiner has set forth a prima facie case that
claim 1 would have been obvious to the ordinary artisan in view of
Ferguson, Zuo, Yick, Evans, Jones, and Gulati. In KSR, the Supreme Court
indicated that “[w]hen a work is available in one field of endeavor, design
incentives and other market forces can prompt variations of it, either in the
same field or a different one. If a person of ordinary skill can implement a
predictable variation, §103 likely bars its patentability.” KSR Int’l v.
Teleflex Inc., 127 S. Ct. 1727, 1740 (2007). Unlike the previous rejection
over Ferguson and Zuo alone, where there was no reason to use nerve grafts,
the current rejection supplies such evidence (see FF 13-15). Applying the
chondroitin degrading enzymes of Ferguson and Zuo to the grafts of Evans
and Gulati would have been a known and predictable way to improve axonal
regeneration (see FF 4, 8, 9, 12). Evans and Gulati provide strong
motivation for the use of nerve grafts (see FF 13). An ordinary practioner
would have predictably expected that “neurite growth of both neonatal and
adult DRG neurons was significantly increased on nerve sections pretreated
with enzymes known to degrade inhibitory CSPG” (Ferguson 158, col. 2).
This predictable expectation would have led to treatment of Gulati’s
acellular nerve grafts with these enzymes in order to increase neurite
outgrowth (FF 14-15).
We are not persuaded by Appellant’s argument that “Ferguson and
Zuo suggest that application of CSPG-degrading enzyme might be
detrimental to the process of axon growth” (App. Br. 16). In our opinion,
the evidence does not support this statement (FF 3, 4, 7-9). Specifically,
Zuo concludes that “axonal growth by regenerating embryonic dorsal root
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ganglionic neurons (DRGn) cultured on sections of normal adult nerve and
on a synthetic substratum composed of laminin and inhibitory CSPG was
found to be dependent on metalloproteinase activity” (Zuo 5204, col. 1). In
concord, Ferguson states “degradation of inhibitor CSPG by the MMPs
contributes to the growth-promoting properties of degenerated nerve”
(Ferguson, abstract). We find that Ferguson and Zuo suggest that the use of
chondroitin degrading enzymes would be expected to improve, not inhibit,
axonal growth. This is also supported by Yick, who teaches that
“chondroitinase ABC promoted the axonal regeneration of neurons in CN
after spinal cord injury” (Yick 1066, col. 2 to 1067, col. 1).
We also reject Appellant’s argument that “the references have nothing
to do with each other or with the problem at hand” (App Br. 18). Ferguson,
Zuo, Evans and Gulati are all involved in the issue of how to enhance nerve
growth on basal lamina, and Evans and Gulati indicate that one reasonable
goal of such enhanced nerve growth is to enhance nerve grafting (FF 13-15).
This is a situation of the “predictable use of prior art elements according to
their established functions.” KSR, 127 S. Ct. at 1740.
We disagree with Appellants conclusion that rendering the nerve graft
acellular distinguishes the invention (see App. Br. 18). Ferguson and Zuo
were solely focused on acellular situations (FF 2, 6). While Appellants
correctly note that Evans states that autografts with Schwann cells were
superior, Evans also notes that “only FT allografts appeared similar to
autografts on gross inspection” (Evans, abstract), where FT stands for freeze
thawed, which renders Evans’ FT allografts acellular. Gulati expressly
teaches that acellular nerve grafts function over short distances (FF 15).
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We do not find Appellant’s argument that Evans and Gulati teach
away from method involving freeze thawing persuasive (App. Br. 19). At
best, Gulati teaches that freeze thawing is undesirable in long grafts, but
claim 1 includes no length limitation and encompasses grafts of 1-2 cm,
which Gulati demonstrates are permissive of axonal growth (FF 14-15).
Additionally, while Evans teaches that autografts are superior to freeze
thawed allografts, Evans recognizes that freeze thawed grafts are superior to
fresh allografts and notes “these storage techniques can provide a means of
transporting nerve allografts between medical centres and for converting
urgent into elective procedures” (Evans, abstract). The Federal Circuit notes
“We will not read into a reference a teaching away from a process where no
such language exists.” DyStar Textilfarben GmbH & Co. Deutschland KG v.
C.H. Patrick Co., 464 F.3d 1356, 1364 (Fed. Cir. 2006). There is no
language in any of the references which directly teaches away from the
preparation of a nerve graft by use of chondroitin degrading enzymes after
freeze thawing. There is specific teaching that freeze thawed nerve grafts
permit axonal regrowth (FF 14-15) and that the use of chondroitin degrading
enzymes enhances axonal and neurite growth (FF 4, 8, 9, 12).
We affirm the rejection of claim 1 under 35 U.S.C. § 103(a). Pursuant
to 37 C.F.R. § 41.37(c)(1)(vii)(2006), we also affirm the rejections of claims
2-7, 10-19, 23-35, 39, and 41-45 as these claims were not argued separately.
CONCLUSION
In summary, we reverse the rejections over Ferguson and Zuo under
35 U.S.C. § 102(b). We reverse the rejection over Ferguson and Zuo under
35 U.S.C. § 103(a). We affirm the rejection of claim 1 under 35 U.S.C.
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§ 103(a) over Ferguson, Zuo, Yick, Evans, Jones, and Gulati. Pursuant to 37
C.F.R. § 41.37(c)(1)(vii)(2006), we also affirm the rejections of claims 2-7,
10-19, 23-35, 39, and 41-45 as these claims were not argued separately.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).
AFFIRMED

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