Ex Parte Ge et al

Patent Trial and Appeal Board

Jul 27, 2017

12868399 (P.T.A.B. Jul. 27, 2017)

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.
12/868,399 08/25/2010 XinGe CLFR.P0297US 5805
52034 7590 07/31/2017
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
AUSTIN, TX 78746
EXAMINER
DINES, KARLA A
ART UNIT PAPER NUMBER
1639
NOTIFICATION DATE DELIVERY MODE
07/31/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte XIN GE, YARIV MAZOR, and GEORGE GEORGIOU1
Appeal 2015-006671
Application 12/868,399
Technology Center 1600
Before ERIC B. GRIMES, RICHARD J. SMITH, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
SMITH, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134 involving claims to a method
of preparing a library of vectors encoding different antibody sequences. We
have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 According to Appellants, the real party in interest is The Research
Development Foundation. (Appeal Br. 3.)
Appeal 2015-006671
Application 12/868,399
STATEMENT OF THE CASE
Claims on Appeal
Claims 1—3, 9—12, and 14—25 are on appeal. (Claims Appendix,
Appeal Br. 15—17.) Claim 1 is illustrative and reads as follows:
1. A method of preparing a library of vectors encoding different
antibody sequences, comprising the steps of:
a) preparing a first population of chemically synthesized
polynucleotides and at least a second population of chemically synthesized
polynucleotides, said first population of polynucleotides comprising
nucleotide sequences encoding a population of immunoglobulin
complementarity determining regions (CDRs), wherein said population of
CDRs reflects diversity at one or more amino acid positions, said at least
second population of polynucleotides comprising nucleotide sequences
complementary to nucleotide sequences comprised in said first population of
polynucleotides;
b) mixing said first and said second population of polynucleotides
under conditions supporting the annealing of said first and second
populations of polynucleotides to produce annealed polynucleotides;
c) adding a polymerase directly to the mixture of step b), thereby
preparing double-stranded polynucleotides comprising nucleotide sequences
encoding an immunoglobulin variable domain that incorporates the
diversified CDRs by extending strands of the annealed polynucleotides of
step b); and
d) inserting the double-stranded polynucleotides of step c) into a
vector to provide a library of vectors, with two or more members of said
library comprising different CDR coding sequences,
steps a), b), c) and d) being performed without the use of PCR amplification.
Examiner’s Rejections
1. Claims 1—3, 9, 10, and 14—24 stand rejected under 35 U.S.C. § 103(a)
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Application 12/868,399
as unpatentable over Yamamoto,2 Queen,3 and Jirholt.4 (Ans. 5—8.)
2. Claims 11 and 12 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over Yamamoto, Queen, Jirholt, and GeneLink Custom
Oligonucleotide Synthesis Information Sheet.5 {Id. at 9-10.)
3. Claim 25 stands rejected under 35 U.S.C. § 103(a) as unpatentable
over Yamamoto, Queen, Jirholt, and Mazor.6 {Id. at 10-12.)
FINDINGS OF FACT
We adopt the Examiner’s findings as our own, including with regard
to the scope and content of, and motivation to combine, the prior art. The
following findings are included for emphasis and reference purposes.
FF 1. The Examiner finds that Yamamoto teaches
[a method of] synthesizing a first oligonucleotide and a second
oligonucleotide having base sequence portions complementary
to each other at a part of the terminal end region, binding the pair
of oligonucleotides at the complementary base sequence portions
and polymerization [of] the nucleotide bases by adding a
polymerase, thereby extending strands of the annealed
polynucleotides.
(Ans. 5, citing Yamamoto Abstract, claim 15, and Figure 1.)
2 Yamamoto et al., EP 0385410, pub. Sept. 5, 1990 (“Yamamoto”).
3 Queen et al., US 5,530,101, issued June 25, 1996 (“Queen”).
4 P. Jirholt et al., Exploiting sequence space: shuffling in vivo formed
complementarity determining regions into a master framework, Gene 215,
471-76 (1998) (“Jirholt”).
5 GeneLink Custom Oligonucleotide Synthesis Information Sheet, accessed
at http://www.genelink.com/newsite/products/unmodoligosINTRO.asp, on
Feb. 18, 2015.
6 Yariv Mazor et al., Isolation of engineered, full-length antibodies from
libraries expressed in Escherichia coli, Nature Biotechnology 25 (5), 563—
65 (2007).
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Application 12/868,399
FF 2. The Examiner finds that Yamamoto’s method “can simply form a
double-stranded oligonucleotide with good precision and high synthesis
yield.” (Ans. 13—14, citing Yamamoto 5,11. 22—23.)
FF 3. Queen teaches
methods for producing . . . humanized immunoglobulins having
one or more complementarity determining regions (CDR’s) . . .
Each humanized immunoglobulin chain will usually comprise,
in addition to the CDR’s, amino acids from the donor
immunoglobulin framework that are, e.g., capable of interacting
with the CDR’s to effect binding affinity. . . The heavy and light
chains may each be designed by using any one or all of various
position criteria. When combined into an intact antibody, the
humanized immunoglobulins . . . will be substantially non-
immunogenic in humans and retain substantially the same
affinity as the donor immunoglobulin to the antigen, such as a
protein or other compound containing an epitope.
(Queen Abstract.)
FF 4. Queen teaches:
Once designed, the immunoglobulins . . . may be produced
readily by a variety of recombinant DNA or other techniques.
Preferably, polynucleotides encoding the desired amino acid
sequences are produced synthetically and by joining appropriate
nucleic acid sequences . . . the methods . . . maximize the
likelihood of producing humanized immunoglobulins with
optimum binding characteristics without the need for producing
intermediate forms that may display stepwise improvements in
binding affinity. The humanized immunoglobulins will be
particularly useful in treating human disorders susceptible to
monoclonal antibody therapy, but find a variety of other uses as
well.
{Id. at col. 3,11. 43-57.)
FF 5. Queen teaches that “vectors containing the DNA segments of interest
(e.g., the heavy and light chain encoding sequences and expression control
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Application 12/868,399
sequences) can be transferred into the host cell by well-known methods.”
{Id. at col. 18,11. 47-50.)
FF 6. The Examiner finds that Jirholt teaches “a synthetic gene library that
contains random combinations of CDRs.” (Ans. 7, citing Jirholt 471, right
col., par. 2.)
FF 7. The Examiner finds that Jirholt teaches “that the probability of finding
antibodies with a certain specificity is higher in an antibody library which
contain[s] a larger number of clones because generation of diversity is the
key element.” (Ans. 8, citing Jirholt 471, left col.)
FF 8. The Examiner finds that:
One of ordinary skill in the art would have been motivated to
include the teachings of Queen [] with the method taught by
Yamamoto [], a method for preparing double-stranded
polynucleotides, without the use of PCR amplification, because
Queen [] teach[es] that the immunoglobulins will be
substantially non-immunogenic in humans and retain
substantially the same affinity to the antigen; [] and because
Queen [] teaches that methods of the invention maximize the
likelihood of producing immunoglobulins with optimized
binding characteristics without the need for producing
intermediate forms and that the immunoglobulins will be useful
in treating human disorders susceptible to monoclonal antibody
therapy but find a variety of other uses as well []. One further
would have been motivated to include the methods of Jirholt []
with the methods of Yamamoto [] and Queen [] because Jirholt
[] teach[es] that the probability of finding antibodies with a
certain specificity is higher in an antibody library which
contain[s] a larger number of clones because generation of
diversity is the key element.
(Ans. 17—18, citing Queen Abstract and col. 3,11. 50-57, and Jirholt 471, left
col.; see FF 1—7.)
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DISCUSSION
We adopt as our own the Examiner’s findings of fact and conclusions
of obviousness as set forth in the Answer. We discern no error in the
rejections of the claims as obvious.
Issue
Whether a preponderance of evidence of record supports the
Examiner’s rejections under 35 U.S.C. § 103(a).
Analysis
Rejection No. 1
The Examiner concludes that it would have been prima facie obvious
to one of ordinary skill in the art at the time of the invention to modify
Yamamoto’s method for producing a population of polynucleotides without
the use of PCR to encode immunoglobulins having one or more CDRs as
taught by Queen, and to modify Yamamoto and Queen with the use of a
vector library as taught by Jirholt. (Ans. 7—8; see FF 1—8.)
Appellants advance several arguments in response to Rejection No. 1.
We address Appellants’ arguments below, and limit our consideration to
claim 1 because the claims were not argued separately.
As an initial matter, Appellants are reminded that the test for
obviousness is what the combined teachings of Yamamoto, Queen, and
Jirholt would have suggested to those of ordinary skill in the art. See In re
Keller, 642 F.2d 413, 425 (CCPA 1981) (citing cases). Moreover, the test
for obviousness is not “that the claimed invention must be expressly
suggested in any one or all of the references.” Id.
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Picking and Choosing
Appellants argue that picking and choosing is not permitted. (Appeal
Br. 6—8; see also Reply Br. 5—6.) In particular, Appellants argue that
“Yamamoto mentions nothing about (a) antibodies or (b) creating diversity
within the molecules produced.” (Appeal Br. 7.) Appellants argue that
Queen “perform[s] a method nothing like that described by Yamamoto, and
again certainly do[es] not envision creating a library of molecules having
diversity.” (Id.) Appellants argue that “Jirholt clearly relies on PCR
amplification to create their variant nucleotide sequences.” (Id.) Thus,
according to Appellants, “none of these references truly ‘fits’ with the
others, and the examiner has clearly been forced to to ‘pick and choose’ only
certain elements from each reference, while discarding those elements that
don’t ‘fit’ with either the claimed subject matter or the other references.”
(Id. at 8.)
We are not persuaded. It is well settled that “picking and choosing
may be entirely proper in the making of a 103, obviousness rejection.” In re
Arkley, 455 F.2d 586, 587 (CCPA 1972). Moreover, Appellants’ claimed
invention need not be expressly suggested in any one or all of Yamamoto,
Queen, or Jirholt in order for those references to support a conclusion of
obviousness. See Keller, 642 F.2d at 425.
Here, Appellants acknowledge that Jirholt describes a method of
“preparing a library of vectors encoding different antibody sequences.”
(Appeal Br. 9.) Moreover, it was entirely proper for the Examiner to rely on
Queen’s teachings of synthetically producing immunoglobulins “by a variety
of recombinant DNA or other techniques” (FF 4), including Yamamoto’s
method (FF 1). See Keller, 642 F.2d at 425.
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Principle of Operation
Appellants argue that the cited references are not properly combinable
because their combination would change their principle of operation.
(Appeal Br. 8—9.) In particular, Appellants argue that the claimed method of
“preparing a library of vectors encoding different antibody sequences”
requires a “substantial modification of Yamamoto.” {Id. at 8.) Appellants
argue further that “only Jirholt describes such a method,” and that it is
improper to “selectively [use] Jirholt’s teachings of diverse antibody
sequences, while discarding its use of amplification.” {Id. at 9.)
We are not persuaded, including for the reasons already discussed
above. Moreover, “it is not necessary that the inventions of the references
be physically combinable to render obvious the invention under review.” In
re Sneed, 710 F.2d 1544, 1550 (Fed. Cir. 1983) (citing cases). Rather, the
test for obviousness is what the combined teachings of the references would
have suggested to those of ordinary skill in the art. See Keller, 642 F.2d at
425. Here, the teachings of the references would have suggested the method
of claim 1 to those of ordinary skill in the art, and the Examiner has
established the rationale or motivation to so combine those teachings. (FF
1-8.)
Hindsight
Appellants argue that the Examiner’s rejection “is a forced ‘hodge­
podge’ of references that could only be combined in hindsight impermissibly
using appellants’ claims as a roadmap.” (Appeal Br. 9.) We are not
persuaded. Rather than using hindsight, the Examiner points to specific
disclosures in the prior art that describe the limitations of Appellants’
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claimed method, (See, e.g., FF 1-8.) The Examiner also provides
reasoning, supported hv the references, why a person of ordinary skill in the
art would have combined their teachings. (Ans. 7..8.) We therefore find
that the Examiner’s obviousness conclusion is based on sufficiently
articulated reasoning that overcomes any concerns about hindsight bias. See
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).7
Reasonable Expectation of Success
Appellants argue that the “radical departures from the described
methodologies [of the prior art] void any reasonable expectation of success.”
(Appeal Br. 10.) We are not persuaded. As the Examiner explains, “[t]here
is a likelihood of success of combining [the cited art] because all use
methodologies of preparing oligonucleotides used to encode sequences of
interest.” (Ans. 8, 19.) Thus, we disagree with Appellants’ contention that
the Examiner’s finding of a likelihood of success is nothing other than
“unsupported opinion.” (Appeal Br. 10.)
DeLisa Declaration8
Appellants provide the DeLisa Declaration and argue that “this
underscores with evidence that the combination of these three references,
7 For the reasons stated in response to Appellants’ arguments, we are
similarly unpersuaded by Appellants’ contention that the Examiner’s
citations to the references for specific purposes fails to follow the rule of
considering the prior art as a whole. (Appeal Br. 9-10.)
8 Declaration of Matthew P. DeLisa under 37 C.F.R. § 1.132, dated Jan. 23,
2015 (“DeLisa Declaration” or “Deck”).
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however it might be attempted, simply does not lead one to the presently
claimed subject matter.” (Appeal Br. 12—13; see also Reply Br. 7—8.)
We are not persuaded. As an initial matter, the DeLisa Declaration is
not evidence of unexpected results, commercial success, or other secondary
considerations that might rebut a prima facie case of obviousness. Rather, it
consists primarily of a discussion of Yamamoto, Queen, and Jirholt that is
intended to support, and is substantially repeated by, Appellants’ arguments
that are addressed above. (See Decl. H 3—6.) For example, the DeLisa
Declaration states that:
Neither Yamamoto nor Queen seek to create such antibody
diversity. On the other hand, Jirholt does provide such a method,
but lacks any mention of synthetic methods that avoid
amplification. Thus, the very combination of these references
presents something of a conflict, with only certain elements from
each reference being consistent with the combination, while
others are clearly not.
(Decl. 15.)
Accordingly, we are unpersuaded by the DeLisa Declaration or
Appellants’ arguments related thereto. The rejection of claim 1 is affirmed.9
9 We also note Appellants’ contention regarding certain statements by the
Examiner in the Advisory Action dated Feb. 13, 2015, and Appellants’
contention that they have not attacked the references individually. (Appeal
Br. 6 and 10—12.) However, in asserting those contentions, Appellants have
not pointed to any persuasive evidence of error that overcomes the
preponderance of evidence supporting the Examiner’s obviousness
conclusion.
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Rejection Nos. 2 and 3
Appellants do not contest the rejections of claims 11, 12, or 25.
Accordingly, those rejections are summarily affirmed. See 37 C.F.R.
§ 41.37(c)(l)(iv); Hyatt v. Dudas, 551 F.3d 1307, 1314 (Fed. Cir. 2008).
Conclusions of Law
A preponderance of evidence of record supports the Examiner’s
rejection of claim 1 under 35 U.S.C. § 103(a). Claims 2, 3, 9, 10, and 14—24
were not argued separately and fall with claim 1.
A preponderance of evidence of record supports the Examiner’s
rejections of claims 11, 12, and 25 under 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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