Ex Parte TAKAMURA et al

Patent Trial and Appeal Board

Dec 12, 2018

14046386 (P.T.A.B. Dec. 12, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/046,386 10/04/2013
24280 7590 12/14/2018
CHOATE, HALL & STEWARTLLP
TWO INTERNATIONAL PLACE
BOSTON, MA 02110
FIRST NAMED INVENTOR
Kentaro TAKAMURA
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.
2004837-0058 3930
EXAMINER
ORWIG, KEVIN S
ART UNIT PAPER NUMBER
1611
NOTIFICATION DATE DELIVERY MODE
12/14/2018 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):
patentdocket@choate.com
jnease@choate.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte KENT ARO T AKAMURA,
SATOSHI GOJO, and SATORU KOBAYASHI
Appeal2017-004899
Application 14/046,386
Technology Center 1600
Before JEFFREYN. FREDMAN, MICHAEL J. FITZPATRICK, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1,2,3 under 35 U.S.C. § 134 involving claims to a
method for occluding a site of tissue damage using a peptide for hemostasis.
The Examiner rejected the claims as indefinite and as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We reverse.
1 Appellants identify the Real Party in Interest as 3-D MATRIX, LTD (see
App. Br. 3).
2 We have considered and herein refer to the Specification of Oct. 4, 2013
("Spec."); Final Office Action of Mar. 1, 2016 ("Final Action"); Appeal
Brief of Nov. 1, 2016 ("App. Br."); Examiner's Answer of Nov. 30, 2016
("Ans."); and Reply Brief of Jan. 30, 2017 ("Reply Br.").
3 An oral hearing was held on December 6, 2018.
Appeal2017-004899
Application 14/046,386
Statement of the Case
Background
"Tissue occlusion to prevent leakage of body fluids (blood, tissue
fluids and the like) caused by tissue damage have major significance in
clinical situations, including surgery" (Spec. ,r 2). "Hemostasis is
considered clinically important for the following reasons. 1. Blood loss is a
major cause of death ... 2. Hemorrhage during surgery is a major concern .
. . 3. Hemorrhage is also a problem with minimally invasive surgery" (Spec.
,r 3).
"Self-assembling peptides have a property whereby the peptide
molecules form regularly arranged self-assemblies according to their amino
acid sequence" (Spec. ,r 13). The self-assembly results in aggregates of
nanofibers that exhibit a gel-like form. (Spec. ,r,r 16-17). "Since the peptide
hydrogel is biodegradable and its decomposition product does not adversely
affect tissue, while it is also highly bioabsorbable, it is suitable for cellular
engraftment and growth" (Spec. ,r 19). The use of "self-assembling peptides
for hemostasis is indicated in Patent document 1 [, International Patent
Publication No. W02006-116524], but the video showing hemostasis at a
hepatic incision site, provided in an article cited in the examples thereof,
shows persistent blood leakage from the end of the incision site, and the
reported complete hemostasis was not achieved" (Spec. ,r 21 ).
The objective of the present invention is to provide a
self-assembling peptide tissue occluding agent that can
effectively occlude sites of tissue damage in large mammals
including humans and that does not carry the risk of infection
by viruses and the like, as well as a method for use of the same.
(Spec. ,r 22).
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The Claims
Claims 16, 17, 20-22, 30, and 33-36 are on appeal. Claim 33 is
representative as the sole independent claim and reads as follows:
33. A method for occluding a site of tissue damage in a
mammal, the method comprising steps of;
(a) removing excess body fluid from a site of tissue
damage from which body fluid is leaking ("a body fluid leakage
site");
(b) applying to the body fluid leakage site a composition
comprising a solution of a peptide whose amino acid sequence
consists of SEQ ID N0:8.
The Re} ections
A. The Examiner rejected claims 16, 17, 20-22, 30, and 33-36 under
35 U.S.C. § 112, second paragraph as indefinite (Ans. 2-3).
B. The Examiner rejected claims 16, 17, 20-22, 30, and 33-36 under 35
U.S.C. § I03(a) as obvious over Horii4 and 3D Matrix5 (Ans. 3-10).
C. The Examiner rejected claims 16, 17, 20-22, 30, and 33-36 under 35
U.S.C. § I03(a) as obvious over Horii, 3D Matrix, and Obi-Tabot6 (Ans. 10-
11).
D. The Examiner rejected claims 16, 17, 20-22, 30, and 33-36 under 35
U.S.C. § 103(a) as obvious over Horii, 3D Matrix, Cochrum,7 Obi-Tabot,
and Gherli8 (Ans. 11-12).
4 Horii et al., US 2009/0162437 Al, published June 25, 2009.
5 3D Matrix, WO 2006/014570 A2, published Feb. 9, 2006.
6 Obi-Tabot, US 6,046,160, issued Apr. 4, 2000.
7 Cochrum, US 5,510,102, issued Apr. 23, 1996.
8 Gherli et al., Comparing Warfarin With Aspirin After Biological Aortic
Valve Replacement, 110 CIRCULATION 496-500 (2004).
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Application 14/046,386
A. 35 U.S.C. § 112, second paragraph
The Examiner finds that "SEQ ID N0:8 is intended to be independent
of terminal modification, indicating that N-terminal modification may be
allowed" (Ans. 2-3). The Examiner finds "in light of the newly added
'consisting of language in the claim, the scope of the claim is unclear" (id.
at 3). The Examiner finds the "'consists of language would appear to
exclude any modification of this peptide sequence because it has been
defined as lacking N-terminal modification in the sequence listing. Thus, it
is unclear how [ A ]ppellants believe that modification at the peptide termini
is allowed" (id).
Appellants respond "that the record is clear that the present claims do
not require N-terminal modification, because they recite a peptide 'whose
amino acid sequence consists of SEQ ID N0:8' and the term 'consists of
applies to the 'amino acid sequence' and not to the 'peptide"' (App. Br. 7).
We agree with Appellants. Our reviewing Court evaluated similar
claim language in In re Crish, 393 F.3d 1253 (Fed. Cir. 2004). The claims
in Crish were directed to an oligonucleotide "comprising at least a portion of
the nucleotide sequence of SEQ ID NO: 1, wherein said portions consists of
the nucleotide sequence from 521 to 2473 of SEQ ID N0:1. ... " Crish, 393
F.3d at 1254. The Court determined that the "reasonable interpretation of
the claims containing both of the terms 'comprising' and 'consists' is that
the term 'consists' limits the 'said portion' language to the subsequently
recited numbered nucleotides, but the earlier term 'comprising' means that
the claim can include that portion plus other nucleotides." Id. at 1257.
Applying Crish to instant claim 33, we interpret the "consists of SEQ ID
N0:8" limitation to require that the peptide have the amino acid sequence
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Application 14/046,386
specified by SEQ ID N0.8, but the earlier open transitional phrase
"comprising" means that the peptide of the solution can broadly include
other modifications, such as acylation or pegylation of the peptide, that do
not alter the amino acid sequence of the peptide. That claim 33, which
requires a peptide that has the amino acid sequence set forth in SEQ ID NO.
8, broadly allows modifications of the peptide, does not mean it is indefinite.
In re Johnson, 558 F.2d 1008, 1016 n.17 (CCPA 1977). Even "undue
breadth is not indefiniteness." Id.
B.-D. 35 U.S.C. § 103(a)
Because all of these rejections tum on the same issues and rely upon
Horii and 3D Matrix, we will consider them together.
The Examiner finds "Horii discloses self-assembling amphiphilic
peptides" that "self-assemble into macroscopic structures ( e.g. ~-sheets) in
solution in the presence of cations" (Ans. 3--4). The Examiner finds Horii
teaches "peptides having IEIK repeating sequences" and "expressly teaches
that the self-assembling peptides may be 12-16 amino acids in length" (id. at
4 ( emphasis omitted)).
The Examiner acknowledges that "[ w ]hile Horii teaches self-
assembling sequences encompassing that instantly claimed (i.e. SEQ ID NO:
8), most of the peptides described by Horii comprise two domains" (Ans. 6).
The Examiner finds 3D Matrix "teaches an overlapping set of self-
assembling, ~-sheet-forming peptides as Horii" (Ans. 9). The Examiner
finds 3D matrix teaches using these peptides "in hemostasis such as to stop
blood flow" (id. at 8). The Examiner concludes it would have been obvious
to combine Horii and 3D Matrix "to provide a means for occluding sites of
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body fluid leakage, e.g. to stop blood flow around blood vessels that have
been damaged during surgery" (id.).
The Examiner relies on Obi-Tabot to teach the use of glucose in
treatment of damaged tissue (Ans. 10), Cochrum to teach "polypeptide-
containing gel compositions as hemostatic gels in surgical applications" (id.
at 11) and Gherli to teach treatment of "patients having prosthetic heart
valves" (id. at 12).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner's conclusion
that Horii, 3D Matrix, Obi-Tabot, Cochrum, and Gherli render claim 33
prima facie obvious?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. Horii teaches "to modify self-assembling peptides by
incorporating an additional domain that does not self-assemble, while still
permitting assembly of the self-assembling portion. The additional domain
can confer a variety of properties on the resulting peptide" (Horii ,r 10).
2. Horii teaches "[ m ]aterials formed by self-assembly of the
peptides have a wide variety of uses, particularly in the areas of cell culture,
tissue engineering, and tissue repair" (Horii ,r 10).
3. Horii teaches "the peptide solution before gellation can be a
non-viscous fluid, viscous fluid or Sol form. Exemplary gellation agents
include, but are not limited to, electrolytes (e.g., NaOH, KCl, NaCl, saline
(NaCl-aqueous)" (Horii ,r 124).
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4. Horii teaches "[p ]referred peptides assume regular secondary
structures, such as ~-sheet structures, in solution ( e.g., aqueous solution)"
(Horii ,r 196).
5. Horii teaches "the self-assembling portion of a self-assembling
peptide is about 8-24, frequently about 12-20 ... amino acids" (Horii
,r 136).
6. Horii teaches exemplary self-assembling peptides in Table 21,
reproduced in part below:
TABLE 21
Functional Dei.:.-t.idea be:E:ed on Y ... '1.r ious self .... asaerc~b"': in~.-:1 s~gu.en~:e
SEQ ID :NG. 5-2 Ac- IE1KIE1KJ>CONH,
SEQ ID lJO. 13, A·:.:- I EI KI EI KIGGFRGSYRGDS- COU.-1:, Repetiti're ROD binding ,sequence
SEQ ID NO. 14 liC-IEIKIEIKIGGPPSSTKT-CO}J11:~·
"Functionalized peptides based on (IEIK)2I ... were synthesized as shown
in Table 21" (Horii ,r 464).
7. Horii teaches "(IEIK)2 is short sequence consists from 8
residues, but forms stiffer gels compared to (RADA)4 as it uses Isoleucine
(I) as hydrophilic amino acid components which are less flexible to Alanine
(A). Stiffer gels can be obtained by making the self-assembling repetitive
sequence longer, such as (IEIK)3, (IEIK)4" (Horii ,r 462).
8. 3D Matrix teaches "improved materials of biological origin that
have improved compatibility, present a reduced risk of contamination, and
provide the proper biomechanical characteristics for tissue repair are
desirable" (3D Matrix 2:3-5).
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9. 3D Matrix teaches "a composition including amphiphilic
peptide chains having alternating hydrophilic and hydrophobic amino acids
that are complementary and structurally compatible and self-assemble into a
beta-sheet macroscopic scaffold. The peptide chains contain at least 8
amino acids" (3D Matrix 5: 13-16).
10. 3D Matrix teaches "an aqueous solution comprising the peptide
chains. The solution may form a hydrogel that is stable with respect to
mechanical agitation" (3D Matrix 5: 19-21 ).
11. 3D Matrix teaches the
peptide solutions may be formed into a stable scaffold by
exposure to a monovalent salt solution. Sufficient electrolyte is
added to the solution to initiate self-assembly of the peptides
into a beta-sheet macroscopic structure. . . . Suitable
electrolytes include, but are not limited to, Li+, Na+, K+, and
cs+.
(3D Matrix 21:20-27).
12. Table 1 of 3D Matrix is reproduced in part below:
Table L"R~Prese»tlltiY.eJ3.~lf:. Assemhlin& Peptiw
Nan1e I J\.Iodufos
K. ··1·E~ ·1,-:t ~ .. -·- --~- L .. JiKIIIIK· -i·F1K.lE"' -tl . . . J .t •. ll ., C
"Exemplary peptide sequences for use with the invention include those listed
in Table 1" (3D Matrix 10:6-7, 11:26).
13. 3D Matrix teaches "gels may be injected into blood vessels
around a tumor or vessels that have been cut during surgery to stop blood
flow. The use of peptide gels as hemostatic agents is discussed" (3D Matrix
28:6-8).
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Application 14/046,386
14. The Specification teaches performance in Examples 9 and 10 of
comparisons that were performed between a peptide called IEIK9, identical
to SEQ ID NO: 52 of Horii, and a peptide called IEIK13, identical to the
claimed SEQ ID NO: 2 (see Spec. 27:26-30; 28:35 to 29:2).
15. The Specification teaches, in Example 9, that "[a]bsolutely no
gelling and no hemostatic effect was observed when the IEIK9 aqueous
peptide solution was used as the upper layer on the hemorrhage wound
surface, but the IEIK13 aqueous peptide solution and KLD aqueous peptide
solution gelled after applying, and no hemorrhage was observed" (Spec.
28:21-25).
16. The Specification teaches, in Example 10, that "[b ]ile-induced
self-assembly was confirmed in all of the aqueous peptide solutions except
for IEIK9" (Spec. 29:29-30).
17. Obi-Tabot teaches "providing a gradual release of glucose
which is particularly effective in nutrition of tissue, both damaged and
nascent, which have become relatively isolated from normal blood flow
nutrition" (Obi-Tabot 2:31-34).
18. Cochrum teaches "hemostatic and adhesive plasma and
polymer containing adhesives prepared from the platelet-rich plasma
concentrate and from a biocompatible polymer" (Cochrum 1:9-11).
19. Gherli teaches "although some researchers consider the use of
anticoagulation therapy appropriate in the prevention of thromboembolic
cerebral events[] during the first 3 months, others express concern over its
use because of the possibility of an increased risk of bleeding complications"
(Gherli 496, col. 1 ).
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Principles of Law
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007).
Prima facie obviousness can be rebutted by presenting evidence of
secondary considerations and when such evidence is submitted, all of the
evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472-73
(Fed. Cir. 1984).
Analysis
We adopt the Examiner's findings regarding the scope and content of
the prior art (Ans. 3-12) and agree with the conclusion that the method of
claim 33 would have beenprimafacie obvious in view of Horii, 3D Matrix,
Obi-Tabot, Cochrum, and Gherli (FF 1-13, 17-19). Appellants present
arguments disputing the prima facie case of obviousness, including
arguments regarding improper choice of lead compound in a Takeda type
analysis and no reason to select the particular sequence of SEQ ID N0:8,
which we find unpersuasive (App. Br. 8-12, 15-17).
However, we do not find it necessary to address these arguments
since, as discussed below, we conclude that the evidence of unexpected
results, when considered with the prima facie case of obviousness, has
successfully overcome the prima facie case of obviousness.
Appellants contend:
The Present Application demonstrates (in Examples 9 and 10)
that a peptide that consists of IEIKIEIKIEIKI shows
unexpectedly good properties. A 9-mer having the amino acid
sequence IEIKIEIKI, which is exactly the sequence identified in
the Horii Application and cited in the Office Action was
confirmed by the Present Application not to effectively self
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Application 14/046,386
assemble. However, the Present Application surprisingly
establishes that a peptide whose amino acid sequence consists
of IEIKIEIKIEIKI effectively self-assembled in a rabbit
hemorrhage model, and in the presence of the rabbit bile,
providing results comparable to those of known self-assembling
peptides RADARADARADARADA and KLDLKLDLKLDL.
(App. Br. 13-14).
The Examiner identifies two concerns with the unexpected results.
First, the Examiner contends the asserted results "are not commensurate with
the broad instant claim, which is unlimited by any concentration of the
peptide and/or other conditions (e.g. such as pH, temperature, and ion
concentration)" (Ans. 29). Second, the Examiner contends:
However, the alleged unexpected results are not unexpected.
Appellants base the assertion of unexpected results on the fact
that an IEIK 9-mer did not effectively self-assemble under the
conditions of Examples 9-10 while IEIKl 3 (SEQ ID NO: 2,
NOT SEO ID NO: 8) did effectively self-assemble under these
conditions. However, neither of these results is unexpected.
There is evidence in this case that longer peptides are more
effective than shorter peptides.
(Id. at 28).
We agree with Appellants that the composition of claim 33
demonstrates unexpected results when compared to the closest prior art of
SEQ 52 of Horii (FF 6, 14--16). In this case, the comparison performed in
the Specification was between the closest prior art peptide actually disclosed
by the Horii prior art reference cited by the Examiner and the claimed
peptide, under conditions consistent with the functional requirement in claim
33 of "occluding a site of tissue damage" (FF 14--15).
To the extent that the Examiner contends the results were not
commensurate in scope with claim 3 3 because Appellants did not
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Application 14/046,386
demonstrate results for every possible condition of use of the peptide
product, we hold that such is not necessary to provide adequate rebuttal of
the primafacie case. See, e.g., In re Chupp, 816 F.2d 643, 646 (Fed. Cir.
1987) ("[t]o be patentable, a compound need not excel over prior art
compounds in all common properties. . . . Evidence that a compound is
unexpectedly superior in one of a spectrum of common properties, as here,
can be enough to rebut a primafacie case of obviousness."). Appellants
have provided data showing that the peptide recited in claim 33 has the
unexpected property of forming a gel in a hemorrhage wound surface
environment, a site of tissue damage, while the closest prior art peptide in
Horii ( the IEIK 9-mer) does not form a gel in that same environment (FF
14). Appellants similarly show the claim 33 peptide gelled even in the
presence of bile, while the prior art peptide of Horii did not (FF 15).
We note that claim 33 is drawn to a method for occluding a tissue
damage site using a "peptide whose amino acid sequence consists of SEQ ID
N0:8". The requirement for using this specific sequence in a particular
environment renders the method relatively narrow in scope. And,
Appellants have provided comparative testing in at least one experiment
representative of that claimed environment. We, therefore, conclude that the
evidence of unexpected results in the Specification are reasonably
commensurate in scope with the narrow ambit of claim 33.
We agree with Appellants that the Examiner has not persuasively
demonstrated that the artisan would have expected improved gelling from
IEIK13, the compound of claim 33, relative to IEIK9, the prior art
compound of Horii shown as SEQ ID NO: 52 (FF 6) in the environment
claimed. Horri describes a functional IEIK 9-mer of a self-assembling
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sequence (FF 6). Horri does not provide any expectation regarding the
ability of the IEIK 9-mer to form a gel in a hemorrhaging wound. At best,
one of ordinary skill in the art would presume that a gel can form in an in
vitro environment and might hope that this would be true in other
environments. But as Appellants demonstrated, that is not the case with a
hemorrhaging wound. Thus, Appellants' testing of the 9-mer establishes an
unexpected result in the claimed environment. We agree that Horii clearly
teaches that increasing the number of IEIK repeats from two as in SEQ ID
NO: 52 to three or four repeats would have been expected to result in stiffer
gels (FF 7). However, Horii does not address whether any gelling, much
less improved gelling, would have been expected in the context of a
hemorrhaging wound surface or bile mixture (FF 14--15).
As with the hemorraghing wound testing, Horri does not provide any
expectation of whether the 9-mer or longer repetitive sequences will gel in
the presence of a body fluid such as bile. Here again one of ordinary skill
might have hoped this would be the case with a 9-mer, but Appellants
demonstrated such was not true. Given the unexpected results with the 9-
mer in a hemorrhaging wound even though Horii teaches that the 9-mer
forms a gel, we determine that just because Horii indicates that "Stiffer gels
can be obtained by making the self-assembling repetitive sequence longer,
such as (IEIK)3, (IEIK)4" (FF7), there would be no basis to expect these
longer sequences would maintain a gel in a hemorrhaging wound.
We note that the Examiner also contends
[ t ]hat the 9mer was the least effective peptide of this group is
consistent with the '483 Patent,[ 9] where peptides having self-
9 Zhang et al., US 5,670,483, issued Sept. 23, 1997.
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assembly sequences were only effective in lengths of 12 amino
acids or more, and it shows an art-recognized preference for
longer peptides over shorter peptides of the same sequence.
(Ans. 29). We find this argument unpersuasive. While the '483 patent may
suggest that, consistent with Horii, longer repeat units may form stiffer gels,
and may even suggest some degree of stability in serum, the '483 patent
does not provide an expectation of gel formation in the hemorrhaging wound
environment.
Moreover, Horii demonstrates that, unlike the 8 amino acid sequences
in the '483 Patent that "did not form macroscopic membranes" (' 483 Patent
4: 12), "(IEIK)2 is [a] short sequence [that] consists [ofJ ... 8 residues, but
forms stiffer gels compared to (RADA)4" (FF 7). Thus, Horii, which was
filed much later in time than the '483 Patent, demonstrates that the
Examiner's conclusion that the 9-mer as compared to a 12-mer would be
expected to be the least effective rests on a faulty premise. Horri
demonstrates that stiffer gelling is achievable using IEIK with fewer than 12
amino acids and compared to what was shown in the '483 patent, the gel was
stiffer.
But, even with that teaching, as discussed above, the results
Appellants observed with the IEIK 9-mer of SEQ ID N0.52 in a
hemorraghing wound were unexpected. The Specification demonstrates
that the 9 amino acid sequence of SEQ ID NO: 52 does not form a gel under
conditions consistent with those required by claim 33. Therefore, we are not
persuaded that the evidence of record persuasively supports the Examiner's
position that the use of longer IEIK sequences would necessarily be
expected to be gel forming under the conditions required by claim 33.
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Conclusion of Law
(i) The evidence of record supports the Examiner's conclusion that
Horii, 3D Matrix, Obi-Tabot, Cochrum, and Gherli render claim 33 prima
facie obvious.
(ii) However, Appellants have presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
SUMMARY
In summary, we reverse the rejection of claims 16, 17, 20-22, 30, and
33-36 under 35 U.S.C. § 112, second paragraph as indefinite.
We also reverse all of the obviousness rejections, specifically we
reverse the rejections of claims 16, 17, 20-22, 30, and 33-36 under 35
U.S.C. § 103(a) as obvious over Horii and 3D Matrix alone, or in
combination with Cochrum, Obi-Tabot, and Gherli.
REVERSED
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