Ex Parte Logtenberg et al

Patent Trial and Appeal Board

Jan 18, 2018

12589181 (P.T.A.B. Jan. 18, 2018)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/589,181 10/19/2009 Ton Logtenberg 737572000101 8201
25225 7590 01/22/2018
MORRTSON fr FOFRSTFR T T P
EXAMINER
12531 HIGH BLUFF DRIVE WEHBE, ANNE MARIE SABRINA
SUITE 100
SAN DIEGO, CA 92130-2040 ART UNIT PAPER NUMBER
1633
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01/22/2018 ELECTRONIC
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte TON LOGTENBERG, MARK THROSBY,
ROBERT A. KRAMER, RUI DANIEL PINTO, CORNELIS A. dE KRUIF,
and ERWIN HOUTZAGER1
Appeal 2016-004181
Application 12/589,181
Technology Center 1600
Before RICHARD J. SMITH, TAWEN CHANG, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
SMITH, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134 involving claims to a
transgenic mouse. A hearing was held on December 4, 2017. We have
jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 According to Appellants, the real party in interest is Merus B.V., a Dutch
corporation. (Appeal Br. 2.)
Appeal 2016-004181
Application 12/589,181
STATEMENT OF THE CASE
Claims on Appeal
Claims 82, 84—86, 91—93, 95—97, 99, 116—119, and 133 are on
appeal.2 (Claims Appendix, Appeal Br. 21—23.) Claim 82 is illustrative and
reads as follows (emphases added):
82. A transgenic mouse whose genome comprises a
transgene comprising a human immunoglobulin light chain
germline V gene segment joined to a human immunoglobulin
light chain germline J gene segment, wherein said joined
human V/J gene segments encode a rearranged human
immunoglobulin light chain variable region, and wherein said
transgenic mouse, in response to an antigen, produces
antibodies with immunoglobulin light chains comprising said
rearranged human light chain variable region and a murine light
chain constant region, paired with a diversity of
immunoglobulin heavy chains which bind said antigen.
Examiner’s Rejections
1. Claims 82, 8^86, 91-93, 95-97, 116, 117, 119, and 133 stand
rejected under pre-AIA 35 U.S.C. § 103(a) as unpatentable over Lonberg,3
Murphy,4 and de Wildt.5 (Ans. 2—6.)
2. Claim 99 stands rejected under pre-AIA 35 U.S.C. § 103(a) as
unpatentable over Lonberg, Murphy, de Wildt, and Schwenk.6 (Id. at 6—7.)
3. Claim 118 stands rejected under pre-AIA 35 U.S.C. § 103(a) as
2 Claims 120-130 and 134 are cancelled. (Adv. Act. dated June 22, 2015.)
3 Lonberg et al., US 2006/0015957 Al, pub. Jan. 19, 2006 (“Lonberg”).
4 Murphy et al., WO 02/066630 Al, pub. Aug. 29, 2002 (“Murphy”).
5 R.M.T. de Wildt, Analysis of Heavy and Light Chain Pairings Indicates
that Receptor Editing Shapes the Human Antibody Repertoire, J. Mol. Biol.
285, 895-901 (1999) (“de Wildt”).
6 Schwenk et al., EP 1439234 Al, pub. July 21, 2004 (“Schwenk”).
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unpatentable over Lonberg, Murphy, de Wildt, and Sharpe.7 {Id. at 7—9.)
FINDINGS OF FACT
The following findings are provided for emphasis and reference
purposes. Additional findings may be found throughout this Decision and in
the Examiner’s Answer.
FF 1. Lonberg teaches “transgenic non-human animals [] that contain
rearranged, unrearranged or a combination of rearranged and unrearranged
heterologous immunoglobulin heavy and light chain transgenes in the
germline of the transgenic animal.” (Lonberg 1197.)
FF 2. Lonberg teaches
transgenic animals containing germ line cells having a heavy and
light transgene wherein one of the said transgenes contains
rearranged gene segments with the other containing
unrearranged gene segments. In the preferred embodiments, the
rearranged transgene is a light chain immunoglobulin transgene
and the unrearranged transgene is a heavy chain immunoglobulin
transgene.
{Id. 1201.)
FF 3. The Examiner finds that Lonberg teaches transgenic mice “whose
genome comprises human unrearranged or rearranged human
immunoglobulin heavy and light chain transcripts useful for producing
human or humanized antibodies.” (Ans. 2, citing Lonberg Figure 33 and
11 16, 17, 25, 196, 197, 201, 222, 232, 233, and 265.)
7 M.J. Sharpe et al., Somatic hypermutation of immunoglobulin x may
depend on sequences 3' of Cx and occurs on passenger transgenes, The
EMBO J. 10, 2139-45 (1991) (“Sharpe”).
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FF 4. The Examiner finds that “Lonberg as a whole does not discriminate
between the use of either germline or somatically mutated rearranged VJ
sequences to make a transgenic mouse and thus provides motivation to use
either germline or somatically mutated sequence[s].” (Ans. 11.)
FF 5. Lonberg teaches:
10. A transgenic mouse comprising an unrearranged
human light chain immunoglobulin variable region,
wherein the variable region comprises a plurality of
human VL gene segments and a plurality of human
Jl gene segments, and
wherein B lymphocytes of the transgenic mouse express
a chimeric antibody comprising a human
immunoglobulin light chain variable region and
mouse immunoglobulin light chain constant region.
(Longberg 195 (claim 10).)
FF 6. The Examiner finds that Lonberg “teaches transgenic mice
comprising unrearranged human light chain transgenes which express
chimeric immunoglobulin light chains comprising a human variable region
and a mouse constant regions.” (Ans. 2, citing Lonberg claims 10—20.)
FF 7. Lonberg teaches that:
Transgenic mice generated with [] rearranged light chain
constructs can be bred with heavy chain minilocus transgenics
to produce a strain of mice that express a spectrum of fully
human antibodies in which all of the diversity of the primary
repertoire is contributed by the heavy chain. . . . The advantage
of this scheme, as opposed to the use of unrearranged light
chain miniloci, is the increased light chain allelic and isotypic
exclusion that comes from having the light chain ready to pair
with a heavy chain as soon as heavy chain VDJ joining occurs.
(Longberg 1482.)
FF 8. The Examiner finds that Lonberg “provides specific motivation for
using a rearranged rather than an unrearranged light chain transgene by
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teaching that the advantage of using a rearranged light chain transgene, as
opposed to the use of unrearranged light chain miniloci, is the increased light
chain allelic and isotypic exclusion that comes from having the light chain
ready to pair with a heavy chain as soon as heavy chain VDJ joining
occurs.” (Ans. 4, citing Lonberg 1482.)
FF 9. Murphy teaches that “human antibodies produced by transgenic mice
with entirely human constructs have reduced affinity as compared to their
mouse counterparts,” and that “[rjeduced affinity could effect B-cell
maturation and survival.” (Murphy 42,11. 25—28.)
FF 10. The Examiner finds that Murphy teaches that the reduced affinity to
mouse receptors of fully human antibodies “can be avoided by producing
mice which express chimeric antibodies comprising human variable regions
and mouse constant regions.” (Ans. 4, citing Murphy 42-43.)
FF 11. de Wildt teaches that “[t]he sequencing of all the human V gene
segments has made it possible to dissect the contributions of germline
diversity and somatic mutation to the diversity of human antibody heavy or
light chains.” (de Wildt 895.)
DISCUSSION
We adopt the Examiner’s findings, analysis, and conclusions as our
own, including with regard to the scope and content of, and motivation to
combine, the prior art, as set forth in the Answer (Ans. 2—22). We discern
no error in the rejection of the claims as obvious.
Issue
Whether a preponderance of evidence of record supports the
Examiner’s rejections under pre-AIA 35 U.S.C. § 103(a).
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Principles of Law
A prior art reference “may be read for all that it teaches, including
uses beyond its primary purpose,” In re Mouttet, 686 F.3d 1322, 1331 (Fed.
Cir. 2012), and “is not limited to the disclosure of specific working
examples.” In re Mills, 470 F.2d 649, 651 (CCPA 1972).
‘“[A] reference must be considered not only for what it expressly
teaches, but also for what it fairly suggests.’” In re Baird, 16 F.3d 380, 383
(Fed. Cir. 1994) (quoting In reBurckel, 592 F.2d 1175, 1179 (CCPA 1979)).
The test for obviousness is “what the combined teachings of the
references would have suggested to those of ordinary skill in the art” and not
“that the claimed invention must be expressly suggested in any one or all of
the references.” In re Keller, 642 F.2d 413, 425 (CCPA 1981) (citing cases).
An 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.” KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 418
(2007).
“‘Comprising’ is a term of art used in claim language which means
that the named elements are essential, but other elements may be added and
still form a construct within the scope of the claim.” Genentech, Inc. v.
Chiron Corp., 112 F.3d495, 501 (Fed. Cir. 1997).
Rejection No. 1
Analysis
We limit our consideration to claims 82 and 91 because the claims
subject to this rejection were not argued separately.
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Claim 82
We begin with claim construction. See In re Hiniker, 150 F.3d. 1362,
1369 (Fed. Cir. 1998) (“[T]he name of the game is the claim.”).
Claimed Structure
Claim 82 is directed to an article of manufacture; namely, a transgenic
mouse. (Appeal Br. 21.) As such, the patentability of claim 82 “depends on
the claimed structure, not on the use or purpose of that structure.” Catalina
Mktg. Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir.
2002). The claimed structure is a “transgenic mouse whose genome
comprises a transgene comprising a human immunoglobulin light chain
germline V gene segment joined to a human immunoglobulin light chain
germline J gene segment,” referred to as “said joined human V/J gene
segments.” (Appeal Br. 21.)
Claim 82 also includes two “wherein” clauses. (Id.) The first wherein
clause recites that the “joined human V/J gene segments encode a rearranged
human immunoglobulin light chain variable region”; that is, the wherein
clause indicates that the claimed structure is capable of encoding a
rearranged human immunoglobulin light chain variable region. (Id.) The
second wherein clause indicates that the claimed structure is capable of
producing certain recited antibodies in response to an antigen. (Id.)
Comprises/Comprising
Claim 82 uses the terms comprises or comprising three times. (Id.)
Those terms are “inclusive or open-ended, [and] the use of [those terms]
does not exclude unrecited elements.” Regeneron Pharms., Inc. v. Menus
N.V., 864 F.3d 1343, 1352 (Fed. Cir. 2017) (“A germline that ‘comprises’
human variable region gene segments may very well also include human
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constant gene segments.”); see also Genentech, 112 F.3d at 501. For
example, claim 82 does not exclude endogenous (murine) gene segments or
any particular heavy chain construct. Furthermore, claim 82 does not
exclude the production of antibodies having human variable regions and
murine constant regions. (See Ans. 16.)
Examiner’s Position
The Examiner concludes that claim 82 would have been prima facie
obvious
based on the motivation provided by Lonberg [] to make a
transgenic mouse whose genome comprises a human
immunoglobulin light chain transgene and which expresses a
chimeric immunoglobulin light chain comprising a human light
chain variable region and a mouse light chain constant region,
the motivation provided by Lonberg [] to use a rearranged
human immunoglobulin light chain transgene over an
unrearranged light chain transgene, the detailed guidance
provided by Lonberg [] for making immunoglobulin light chain
transgenes comprising a rearranged human light chain variable
region, and the motivation to use mouse constant region genes
over human constant region genes in transgenic mice taught by
Murphy.
(Ans. 5, 16; see FF 1—11.)
The Examiner further relies on de Wildt as a reason “to select a
germline rearranged human light chain variable region sequence.” (Ans. 5—
6.)
Appellants frame their arguments around the contention that claim 82
includes “three basic requirements.” (Appeal Br. 5—6; see also Reply Br. 4.)
The first requirement is that the transgenic mouse comprise a germline
rearranged transgene whereby “the mouse [can] be caused to generate a
repertoire of antibodies with a predictable and common light chain variable
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region.” (Appeal Br. 5.) The second requirement is that the antibodies
generated by the claimed mouse “have chimeric light chains as the variable
regions are human and the constant regions are murine.” (Id.) The third
requirement is “that a repertoire of diverse heavy chains is produced and
successfully pairs with the provided fixed light chain.” (Id.) We address
Appellants’ arguments with respect to each of these purported requirements
below.
Rearranged Germline Light Chain
Appellants argue that nothing in the cited art suggests the concept of
“obtaining a repertoire of immunoglobulins that are immunoreactive with a
desired antigen that share a common light chain, wherein the diversity of the
repertoire is a function essentially of variations in the heavy chain.” (Appeal
Br. 4—5.) Appellants contend that this objective is achieved by providing “a
transgene containing germline DNA encoding a rearranged human light
chain variable region.” (Id. at 5.)
Appellants argue that “a transgene with a rearranged light chain
variable region” is not suggested by the art. (Id.) We are not persuaded.
Lonberg expressly teaches rearranged light chain transgenes, including
transgenic mice with a rearranged transgene (V/J) variable region. (Lonberg
1482; FF 1-3,7, 8.)
Appellants further argue that Lonberg does not suggest that the
rearranged V/J region “be a germline rearranged sequence.” (Appeal Br. 5,
7—8.) We remain unpersuaded. As to the specific working example at
paragraphs 481 and 482, the Examiner explains that Lonberg “does not
identify [the actual sequences of the isolated rearranged VJ] as either
germline or somatically mutated. Thus, Lonberg as a whole does not
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discriminate between the use of either germline or somatically mutated
rearranged VJ sequences to make a transgenic mouse.” (Ans. 11; FF 4.)
Moreover, Lonberg clearly teaches and suggests germline transgenes. (See,
e.g., FF 1, 2.)
Appellants argue that paragraph 482 of Lonberg is directed to the
expression of fully human antibodies, and that “the advantage envisioned by
Lonberg is that the rearranged form can overcome the competing
endogenous light chains that the murine B cells would otherwise generate
from the unrearranged murine sequences.” (Appeal Br. 7—8.) However,
claim 82 does not exclude the generation of endogenous light chains.
Moreover, while the specific working example at paragraph 482 of Lonberg
references fully human antibodies, Lonberg also teaches and suggests
chimeric antibodies having a human immunoglobulin light chain variable
region and mouse immunoglobulin light chain constant region. (See, e.g.,
FF 5, 6; see also Mills, 470 F.2d at 651.) Furthermore, the rejection is based
on the combination of Lonberg and Murphy, and Murphy teaches and
suggests the desirability (over entirely human constructs) of transgenic mice
that produce antibodies containing human variable regions and mouse
constant regions. (FF 9, 10.)
Appellants also argue that “it would [not] be predictable based on
Lonberg, that a germline rearranged light chain can pair with a diversity of
heavy chains.” (Appeal Br. 8.) We are not persuaded. Lonberg teaches and
suggests the use of a rearranged light chain wherein “all of the diversity of
the primary repertoire is contributed by the heavy chain.” (FF 7, 8.)
Moreover, “obviousness cannot be avoided simply by a showing of some
degree of unpredictability in the art so long as there was a reasonable
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probability of success.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364
(Fed. Cir. 2007) (“[A] rule of law equating unpredictability to patentability,
applied in this case, would mean that any new salt. . . would be separately
patentable, simply because the formation and properties of each salt must be
verified through testing.”). Thus, contrary to Appellants’ argument, there is
no requirement for a conclusion of obviousness that Lonberg teach that the
pairing of “a germline rearranged light chain” with a diversity of heavy
chains be a “predictable” result.
Murphy and Lonberg
Appellants contest the Examiner’s reliance on Murphy by arguing that
Murphy “suggests to replace all mouse heavy chain V, D and J gene
segments with their human counterparts” and “all mouse light chain V and J
gene segments with their human counterparts, such that the mouse constant
regions, in particular the Fc regions, are retained.” (Appeal Br. 9.)
Appellants further contend that “[tjhere is no teaching in Murphy, that the
light chain considered by itself independent of the stipulated heavy chain
should have a murine constant region.” (Id.)
Appellants’ argument is unavailing. Claim 82 does not exclude the
production of antibodies having a chimeric light chain and a chimeric heavy
chain wherein the variable regions are human and the constant regions are
murine. (See Ans. 16 and Claim Construction discussion above.)
Appellants also argue that there is no motivation to combine the
teachings of Murphy and Lonberg. (Appeal Br. 6, 9—10.) Appellants
specifically argue that the only instance in Lonberg where a rearranged
variable encoding region is suggested is in the context of providing fully
human antibodies, “and [because] the substitution of a murine constant
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region in the rearranged light chain presumably also would require a murine
constant region in the heavy chain to insure pairing, this would defeat the
purpose of Lonberg to use of the rearranged light chain encoding nucleic
acid to obtain fully human antibodies.” (Appeal Br. 9—10.)
We are not persuaded. The “purpose of Lonberg” is not limited to
fully human antibodies. (See FF 5; see also Mills, 470 F.2d at 651 .)8
Rather, as the title of Lonberg indicates, Lonberg relates to “Transgenic
Non-Human Animals For Producing Chimeric Antibodies.” (Lonberg
Title.) Moreover, at least because Lonberg is not limited to “the principles
set forth in paragraph 482” (Appeal Br. 11), combining the teachings of
Lonberg and Murphy would not change the overall principle of operation of
Lonberg. See Mouttet, 686 F.3d at 1332 (Fed. Cir. 2012) (affirming the
Board’s determination that “the difference in the circuitry—electrical versus
optical—does not affect the overall principle of operation of a programmable
arithmetic processor.”). Appellants’ arguments are thus unavailing.
tie Wildt
While Lonberg provides motivation to use either germline or
somatically mutated sequences (FF 4), the Examiner points to de Wildt as
teaching the added diversity resulting from a germline sequence, as well as
its demonstration “that a single rearranged germline light chain sequence can
associate with multiple rearranged heavy chains.” (Ans. 5—6, 13.)
Appellants contest the Examiner’s reliance on de Wildt by arguing that “de
Wildt does not predict that a nucleic acid encoding a germline rearranged
8 We also note that Lonberg teaches “chimeric heavy chains comprising a
human sequence heavy chain variable region and a murine sequence heavy
chain constant region.” (Lonberg 139.)
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human light chain variable region would result in expression of a common
light chain that would successfully associate with a multiplicity of different
heavy chains.” (Appeal Br. 11—12 (emphasis added); see also Reply Br. 12—
17.) Appellants argue further that:
DeWildt . . . fails to provide any prediction that a rearranged
germline variable region nucleic acid provided as the only option
to a developing B cell for formation of light chains would in fact
generate a consistent light chain in the B cell repertoire and
would be successful in pairing with a vast repertoire of heavy
chain regions.... DeWildt does not take account of the situation
required by the claims where the B cells of the mouse are forced
to use the light chain generated by the rearranged germline form
with a multiplicity of heavy chains.
(Appeal Br. 15 (italicized emphasis added).)
Appellants further contend that de Wildt’s “added diversity” teaching
is “inconsistent with appellants’ goal of providing a repertoire with
essentially no diversity in the light chains.” (Reply Br. 13.)
We are not persuaded. As an initial matter, Appellants’ “goal of
providing a repertoire with essentially no diversity in the light chains” is not
determinative of patentability. See KSR, 550 U.S. at 419 (“In determining
whether the subject matter of a patent claim is obvious, neither the particular
motivation nor the avowed purpose of the patentee controls.”). Moreover,
there is no requirement that de Wildt “predict” a certain outcome, see Pfizer,
480 F.3d at 1364, nor is there a requirement in claim 82 that the B cells of
the claimed mouse are “forced to use” the light chain generated by the
rearranged germline form (see Claim Construction discussion above).
Appellants also refer to “unexpected” or “surprising” results, which
Appellants contend are “that the unaltered germline—encoded light chain can
pair with a diversity of heavy chains in antibodies that bind to antigen.”
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(Reply Br. 22—23; see also Appeal Br. 15—18.) According to Appellants, the
pie chart at page 16 of the Appeal Brief demonstrates this result, but that
“nothing in de Wildt [] showed that this would be the case.” (Reply Br. 22;
see also Appeal Br. 15—17.) However, neither the alleged failure of de
Wildt “to show the essential element of the invention — that the actual
encoded rearranged light chain without further modification is able to pair
with the heavy chain repertoire” (Reply Br. 22), nor Appellants’ pie chart
based on a specific transgenic mouse, is evidence of unexpected results
sufficient to rebut a prima facie case of obviousness. (See Ans. 20.) See
also In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005).
Claim 91
Claim 91 is likewise directed to a transgenic mouse, includes
limitations similar to claim 82 as well as similar “comprises” and
“comprising” terms, and is thus construed in a manner similar to claim 82.
(Appeal Br. 21—22.) In addition, as argued by Appellants, claim 91
“specifically requires particular promoters and the inclusion of a murine or
human leader sequence,” which Appellants contend the Examiner does not
address. (Appeal Br. 18—19; Reply Br. 20.)
We are not persuaded. As the Examiner explains, Lonberg teaches a
human leader sequence because “the oligos used to amplify the rearranged
VJ sequence include amplification of the human leader sequence.” (Ans. 20,
citing Lonberg 1482.) Regarding the claimed promoter (e.g., kLC or kLC),
the Examiner points to Lonberg’s teaching of using either human or murine
promoters specific to the light chain transgene, Lonberg’s disclosure of both
lambda and kappa light chains, and Lonberg’s suggestion of the use of either
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a kappa light chain (LC) promoter or a lambda light chain (LC) promoter.
(Ans. 21.)
Summary
Appellants’ focus on the use or purpose of the claimed transgenic
mouse is not persuasive of patentability, which depends on the claimed
structure and not its use or purpose. See Catalina Mktg., 289 F.3d at 809.
Thus, Appellants contentions regarding the “concept of the invention,”
“eschewing diversity and relying on essentially [a] fixed light chain,” and
the prior art “[teaching] away from [Appellants’] approach” are unavailing.
{See, e.g., Reply Br. 1—12.)
The rejections are based on the combined teachings of the references,
as viewed from the perspective of one having ordinary skill in the art. See
Keller, 642 F.2d at 425; see also KSR, 550 U.S. at 418. Here, for example,
Appellants point to the Examiner’s statement that Lonberg “does not
specifically teach a transgenic mouse comprising a rearranged human light
chain transgene which expresses chimeric immunoglobulin light chains
comprising a human variable region and a mouse constant region” (Ans. 4
(emphasis added)), in an effort to overcome the prima facie case of
obviousness. (Appeal Br. 8; Reply Br. 5.) In doing so, however, Appellants
do not persuasively address the full scope of Lonberg’s teachings or the
combined teachings and suggestions of the cited references.
Accordingly, for the reasons of record and as set forth above, we
affirm the rejections of claims 82 and 91 for obviousness. Claims 84—86,
92, 93, 95—97, 116, 117, 119, and 133 fall with claims 82 and 91 because
they were not argued separately.
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Rejection No. 2
Claim 99 depends from claim 979 and recites “wherein said trans gene
is located at a Rosa-locus.” (Appeal Br. 22.) Appellants state that “inclusion
of the Rosa locus is not necessary for patentability,” and that “[cjlaim 99 is
patentable for the same reasons discussed above with respect to claim 82.”
(Appeal Br. 19-20; Reply Br. 20.) Appellants’ also advance brief comments
regarding Schwenk {id.), but those comments do not persuade us of any
error in the Examiner’s rejection of claim 99. (Ans. 6—7.)
Accordingly, for the reasons of record and as set forth above in
connection with claim 82, we affirm the rejection of claim 99 for
obviousness.
Rejection No. 3
Appellants state that the rejection of claim 118 “is in error for the
same reasons as set forth above with regard to the broader claims.” (Appeal
Br. 20.) Accordingly, for the reasons of record and as set forth above in
connection with claim 82, we affirm the rejection of claim 118 for
obviousness.10
Conclusions of Law
A preponderance of evidence of record supports the Examiner’s
rejections of claims 82, 84—86, 91—93, 95—97, 99, 116—119, and 133 under
9 Claim 97 depends from claim 82 and recites “wherein said trans gene is
located at a locus outside of the endogenous mouse immunoglobulin loci,
wherein said locus is resistant to gene silencing.” (Appeal Br. 22.)
10 Appellants’ arguments regarding claim 118 in the Reply Brief (See Reply
Br. 20—22) are waived for failure to raise them in the Appeal Brief. See 37
C.F.R. § 41.37(c)(l)(iv); see also MPEP § 1205.02.
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pre-AIA 35 U.S.C. § 103(a).
SUMMARY
We affirm the rejections of all claims on appeal.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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