Christopher Bieniarz et al.

Patent Trials and Appeals Board

Dec 21, 2020

2019004264 (P.T.A.B. Dec. 21, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
15/064,792 03/09/2016 Christopher Bieniarz Ventana-061CON /
25023US4
8304
129826 7590 12/21/2020
Charney IP Law / Roche
233 Mount Airy Road - Suite 100
Basking Ridge, NJ 07920
EXAMINER
HAQ, SHAFIQUL
ART UNIT PAPER NUMBER
1641
NOTIFICATION DATE DELIVERY MODE
12/21/2020 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):
docket@charneyiplaw.com
pair_roche@firsttofile.com
uspto@dockettrak.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte CHRISTOPHER BIENIARZ, JEROME W. KOSMEDER,
MARK LEFEVER, CASEY A. KERNAG, JULIA ASHWORTH-SHARPE,
and JENNIFER WONG
Appeal 2019-004264
Application 15/064,792
Technology Center 1600
Before RICHARD M. LEBOVITZ, FRANCISCO C. PRATS, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
SCHNEIDER, Administrative Patent Judge.
DECISION ON APPEAL
STATEMENT OF THE CASE
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 18–29, and 31. See Non-Final Act. 1.
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the term “Appellant” to refer to “applicant” as defined in 37 C.F.R.
§ 1.42. Appellant identifies the real party in interest as Ventana Medical
Systems, Inc.. Appeal Br. 2.
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Application 15/064,792
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CLAIMED SUBJECT MATTER
The claims are directed to antibody conjugates having signal-
generating moieties. Claim 18, reproduced below, is illustrative of the
claimed subject matter:
18. A conjugate having the structure

wherein Ab is an antibody, SM is a signal-generating moiety, n
ranges from 1 to 50, and s ranges from 1 to 10.
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REFERENCE
The prior art relied upon by the Examiner is:
Name Reference Date
Hainfeld US 6,670,113 B2 Dec. 30, 2003
Husain Husain et al., Fc Site-Specific
Labeling of Immunoglobulins with
Calf Intestinal Alkaline Phosphatase,
5 Bioconjugate Chem. 482 (1994)
1994
Quanta Quanta Biodesign Catalogue, Nov. 5,
2004
Nov. 5, 2004
Anderson Anderson et al., Improved
fluoroimmunoassays using the dye
Alexa Fluor 647 with the RAPTOR, a
fiber optic biosensor, 271 J. Immun.
Meth. 17 (2002)
2002
O’Sullivan O’Sullivan et al., Enzyme
immunoassay: a review, 16 Ann. Clin.
Biochem. 221 (1979)
1979
Bieniarz Bieniarz et al., Thermally Stabilized
Immunoconjugates: Conjugation of
Antibodies to Alkaline Phosphates
Stabilized with Polymeric Cross-
Linkers, 9 Bioconjugate Chem. 399
(1998)
1988
Dhawan Dhawan, Design and construction of
novel molecular conjugates for signal
amplification (I): conjugation of
multiple horseradish peroxidase
molecules to immunoglobulin via
primary amines on lysine peptide
chains, 23 Peptides 2019 (2002)
2002

REJECTIONS
Claims 18–28, and 31 are rejected under 35 U.S.C. § 103 as being
unpatentable over Husain in view of Quanta and Anderson. Non-Final Act.
2–5.
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Claim 29 is rejected under 35 U.S.C. § 103 as obvious over Husain in
view of Quanta and Anderson and further in view of O'Sullivan and
Hainfeld. Non-Final Act. 5–6.
Claims 18–29, and 31 are rejected under 35 U.S.C. § 103 as obvious
over either of Bieniarz or Dhawan in view of Quanta and Anderson. Non-
Final Act. 7.
OPINION
Obviousness Based on Husain combined with Quanta and Anderson
Issue
The issue with respect to this rejection is whether a preponderance of
evidence supports the Examiner’s conclusion that the subject matter of
claims 18–28, and 31 would have been obvious to one of ordinary skill in
the art at the time the invention was made over Husain combined with
Quanta and Anderson.
The Examiner finds that like claim 18, Husain teaches the use of an
alkaline phosphatase labeled antibody conjugate to detect the presence of a
molecule. Non-Final Act. 2. The Examiner finds that Husain teaches the
antibody conjugate comprises “an antibody covalently linked to the signal-
generating moiety (e.g. alkaline phosphatase) through a heterobifunctional
linker.” Id. at 3. The Examiner finds that Husain teaches that the linker
comprises “a maleimide functional group and a N-hydroxysuccinimide ester
(NHS) linked through a spacer (see the linker SMTCC in scheme 1) and also
teach that the linkers can be substituted with other heterobifunctional cross-
linkers thereby providing high degree of freedom in the design of labeled
Igs.” Id.
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The Examiner finds that while Husain does not disclose the use of a
polyethylene glycol (“PEG”) spacer as required by claim 18, Quanta teaches
the use of such spacers. Id. The Examiner finds that Anderson teaches
attachment of multiple labels to an antibody to increase net fluorescence per
antibody. Id. at 4.
The Examiner concludes
Therefore, given the above fact that the
heterobifunctional PEG linkers comprising maleimide and
NHS, linked through a PEG spacer is advantageous over other
conventional heterobifunctional linkers in being very
hydrophilic and water soluble and by being non-immunogenic,
one of ordinary skill in the art at the time the invention was
made, would have been motivated to substitute the
heterobifunctional linker of Husain et al with the commercially
available water soluble heterobifunctional cross-linkers of
Quanta Biodesign for conjugation of the antibody with the
alkaline phosphatase (i.e. signal generating molecules), with the
expectation of avoiding aggregation and to provide a
hydrophilic and a water soluble conjugate having less
immunogenicity, with a reasonable expectation of success
because Husain et al envision substituting the
heterobifunctional linkers with other heterobifunctional linkers
(page 488, lines 6-11 of right column) and Quanta Biodesign
catalogue discloses heterobifunctional linkers with PEG with
improved water solubility and immunogenicity. The linkers
MAL-dPEGs™ NHS ester and the MAL-dPEG4™ NHS of
Quanta Biodesign will form sulfide bond with the thiol groups
of the antibody and amine bond with Alkaline phosphatase (see
scheme 1 of Husain et al) as described in the reference by
Husain et al and the antibody having three to four incorporated
thiol group would be capable of conjugating up to 3-4 alkaline
phosphatase (see abstract).

Id. at 4–5.
Appellant contends that Husain in combination with Quanta and
Anderson does not teach the claimed conjugate. Appeal Br. 5. Appellant
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contends that Husain teaches that the linkers of Husain are indirectly
coupled to the antibody whereas the present claims call for the linker to be
directly linked to the antibody. Id. at 5–7. Appellant contends that while
Husain teaches that other linkers can be used in the practice of method
disclosed in Husain, Husain teaches that the linkers are indirectly coupled to
the antibody through a cystamine residue and not directly linked as required
by the claims. Appellant also contends that the linker compounds of Husain
are different in nature than the linker disclosed in Quanta.
Principles Law
“[N]ot unlike a determination of infringement, a determination of
anticipation, as well as obviousness, involves two steps. First is construing
the claim, followed by, in the case of anticipation or obviousness, a
comparison of the construed claim to the prior art.” Key Pharms. v. Hercon
Labs. Corp., 161 F.3d 709, 714 (Fed. Cir. 1998).
Although the PTO gives claims their broadest reasonable
interpretation during examination, claims must be interpreted as they would
be read by a person of ordinary skill in the art (POSITA). Prior art references
are indicative of how POSITA interprets terms. Therefore, claim terms
should not be interpreted so as to conflict with the interpretation of identical
terms in other patents from analogous art. In re Cortright, 165 F.3d 1353,
1358 (Fed. Cir. 1999) (“Although the PTO must give claims their broadest
reasonable interpretation, this interpretation must be consistent with the one
that those skilled in the art would reach.”).
“[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability. If
that burden is met, the burden of coming forward with evidence or argument
shifts to the applicant.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
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Analysis
We being our analysis by addressing the issue of whether the present
claims call for a direct or indirect coupling of the linker to the antigen.
Appellant contends that the claims require a direct coupling in that the
structure shown in claim 18 depicts a direct link between the sulfur group
and the antibody. Appeal Br. 9. Appellant contends that this is consistent
with how one skilled in the art would interpret the structure recited in claim
18. Id. at 9–10. To support this contention, Appellant cites to the Declaration
of Dr. Kosmeder2 as well as the references cited by the Examiner. Id.
The Examiner contends that the structurer in claim 1 does not show a
direct linkage between the sulfhydryl group and the antibody as the structure
does not show that the sulfhydride group arise from a disulfide bond in the
antibody. Ans. 11.
We have considered the arguments presented by both Appellant and
the Examiner and conclude that Appellant has the better positon. We agree
with Dr. Kosmeder that one skilled in the art would interpret the structure
Ab–S– as denoting that the sulfur atom serves as a point of conjugation to a
linker and that the PEG-based linker is directly attached to the antibody
through the sulfur atom. Kosmeder Decl. ¶ 10. This interpretation is
consistent with the prior art..
With respect to claim 24, the other independent claim, claim 24
recites that the antibody is directly linked to linker through a thiol –reactive
group. Appeal Br. 38 (Claims App.). Thus claim 24 recites a specific
requirement for a direct linkage.

2 Declaration of Jerry W. Kosmeder II, Ph.D., Pursuant to 37 C.F.R. § 1.132,
filed June 11, 2018 (“Kosmeder Decl.”).
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Applying this interpretation to the rejected claims we conclude that
the Examiner has not shown that the subject matter of the claims would have
been obvious over Husain combined with Quanta and Anderson.
As shown on the reaction scheme of Husain below, Husain teaches
that the antibody is first modified to add a cystamine linker which is then
reduced to present a sulfide group for coupling to the linker. Husain, 485;
Kosmeder Decl. ¶ 11.

Reaction Scheme of Husain showing preparation of a conjugated antibody.
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We agree with Dr. Kosmeder that the reaction scheme to Husain creates an
indirect coupling and not a direct coupling as required by the claims.
Conclusion
Based on the foregoing we conclude that a preponderance of the
evidence does not support the Examiner’s conclusion that the subject matter
of claims 18–28, and 31 would have been obvious to one of ordinary skill
in the art at the time the invention was made over Husain combined with
Quanta and Anderson. The rejection is reversed.

Obviousness Based on Husain Combined with Quanta, Anderson, O'Sullivan
and Hainfeld

Claim 29 which depends from claim 24 has been rejected as obvious
over Husain combined with Quanta, Anderson, O'Sullivan and Hainfeld.
Non-Final Act. 5–6. Claim 29 includes the limitation calling for a direct
coupling between the linker and the antibody. 35 U.S.C. § 112(d). For the
reasons discussed above, we reverse this rejection.

Obviousness Based on Bieniarz or Dhawan Combined with Quanta and
Anderson

While the Examiner has stated the rejection as a single rejection with
Bieniarz and Dhawan as alternative primary references, we will address each
combination of references separately.
Bieniarz
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
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claims 18–29, and 31 would have been obvious to one skilled in the art at
the time the invention was made over Bieniarz combined with Quanta and
Anderson.
The Examiner finds that Bieniarz teaches detection of analyte using an
enzyme label antibody conjugate. Non-Final Act. 7. The Examiner finds that
Bieniarz teaches that the conjugate comprises “an antibody covalently linked
to the signal-generating moiety (e.g. alkaline phosphatase, HRP) through a
heterobifunctional linker.” Id. (Citing Bieniarz Fig. 2(a)). The Examiner
finds that Bieniarz teaches that the heterobifunctional linker comprises “a
maleimide functional group comprising a spacer and antibody is linked to
the maleimide functional group through reduced thiol groups obtained by
reducing cystamine residues in the antibody with a reducing agents.” Id.
The Examiner finds that while Bieniarz does not teach or suggest
the use of a PEG heterobifunctional cross-linker, that element is taught by
Quanta. Id. at 8.
The Examiner concludes
Therefore, given the above fact that the
heterobifunctional PEG linkers comprising maleimide and
NHS, linked through a PEG spacer is advantageous over other
conventional heterobifunctional linkers with reduced problems
of aggregation and by being non-immunogenic, very
hydrophilic and water soluble, one of ordinary skill in the art at
the time the invention was made, would have been motivated to
substitute the heterobifunctional linker of Bieniarz . . . with the
commercially available water soluble heterobifunctional cross-
linkers of Quanta Biodesign for conjugation of the antibody
with the signal generating molecules (e.g. alkaline phosphatase
or HRP), with the expectation of avoiding aggregation and to
provide a hydrophilic and a water soluble conjugate having less
immunogenicity, with a reasonable expectation of success
because Quanta Biodesign catalogue discloses
Appeal 2019-004264
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heterobifunctional linkers with PEG has improved water
solubility and immunogenicity.

Id. at 8–9.
Appellant contends that while Bieniarz discloses the use of SMCC
linkers, Bieniarz does not teach or suggest the use of other linkers. Appeal
Br. 32. Appellant contends that the SMCC linker of Bieniarz have properties
significantly different from the claimed linker. Id. Appellant contends that
“the skilled artisan would not have substituted any of the PEG-based linkers
of the Quanta Biodesign Catalog for the SMTCC linker of Bieniarz given
the different properties of the two types of linkers.” Id. at 32–34.
Analysis
We have considered the arguments presented by the Examiner and
Appellant and conclude that a preponderance of the evidence does not
support the Examiner’s finding of obviousness.
As shown below, claim 18 calls for coupling the linker to the antibody
via a sulfur atom:

Claim 24 also calls for the coupling of the antibody to the linker using a
sulfur group. Appeal Br. 38 (Claims App.). However, in the conjugate taught
by Bieniarz, the coupling of the antibody to the linker is through a nitrogen
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atom with the signaling moiety couple through the sulfur atom the exact
opposite of the structure recited in the rejected claims.

Structure of the conjugate from Scheme I of Bieniarz. Bieniarz 400. We
discern nothing in the cited references nor has the Examiner pointed to any
teaching in the references to reverse the orientation of the cross-linker
disclosed in Bieniarz to mirror the structure in the present claims.
Conclusion
Based on the foregoing we conclude that a preponderance of the
evidence does not support the Examiner’s conclusion that the subject matter
of claims 18–29, and 31 would have been obvious to one skilled in the art at
the time the invention was made over Bieniarz combined with Quanta and
Anderson.
Dhawan
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
claims 18–29, and 31 would have been obvious to one skilled in the art at
the time the invention was made over Dhawan combined with Quanta and
Anderson.
The Examiner makes the same findings and conclusions with respect
Dhawan as with Bieniarz discussed above. Non-Final Act. 7–9.
Appellant contends that Dhawan discloses antibody conjugates having
multiple enzyme signaling moieties attached to a single cross-linker which is
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then coupled to the antibody. Appeal Br. 35. Appellant contends that
Dhawan does not teach the use of a PEG cross-linker nor does it teach a
plurality of linker conjugated to an antibody with each linker having a single
signaling moiety. Id. at 35–36. Appellant contends that that PEG linkers of
Quanta are not suitable for use in Dhawan as the PEG linkers only has one
primary amino group to link to the signaling moiety whereas Dhawan
teaches the use of linkers with multiple primary amines. Id. at 36. Appellant
contends that Anderson does not cure the deficiencies of Dhawan and
Quanta.
Analysis
We adopt the Examiner’s findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer regarding this rejection. We find the Examiner has established a
prima facie showing that the subject matter of the claims would have been
obvious over Dhawan combined with Quanta and Anderson to a person of
ordinary skill in the art at the time the invention was made. Appellants have
not produced evidence showing, or persuasively argued, that the Examiner’s
determinations on obviousness are incorrect. Only those arguments made by
Appellants in the Briefs have been considered in this Decision. Arguments
not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv)
(2018). We have identified claim 18 as representative; therefore, all claims
fall with claim 18. We address Appellants’ arguments below.
Appellant contends that Dhawan discloses the use of large peptide
linkers that are dissimilar to the linkers disclosed in Quanta. Appeal Br. 35.
Appellant contends that the Examiner engaged in impermissible hindsight in
combining the references as there is no teaching in Dhawan which would
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have led one skilled in the art to substitute the PEG linkers of Quanta for the
linker of Dhawan. Id. at 35–36. We are not persuaded by this argument.
Dhawan discloses a “conventional” horseradish peroxidase (“HRP”)
antibody conjugate having the following structure:

Dhawan, 2093, Fig. 1. This conjugate is similar in structure to the conjugate
recited in claim 18 with the exception of the absence of a PEG linker.
Quanta teaches the use of PEG linkers for antibody conjugates.
Quanta 20. Quanta teaches that the PEG linkers have the benefits of being
hydrophilic. Id. Quanta also teaches that the PEG linkers reduce or eliminate
problems with aggregations and immunogenicity which are issues with
hydrophobic linkers. Id.
We agree with the Examiner that it would have been obvious to one
skilled in the art to substitute the conventional linker of Dhawan with the
PEG linker of Quanta to link the HRP signaling moiety to the S- group of
the antibody to produce the claimed invention. The motivation to combine
the teachings of Dhawan with Quanta arises from Quanta where it teaches
the advantages of the PEG linkers.
Appellant’s contention with respect to hindsight is also unpersuasive.
“Any judgment on obviousness is in a sense necessarily a reconstruction
based upon hindsight reasoning, but so long as it takes into account only
knowledge which was within the level of ordinary skill at the time the
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claimed invention was made and does not include knowledge gleaned only
from applicant’s disclosure, such a reconstruction is proper.” In re
McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). As discussed above the
motivation to combine the references arises from the references themselves.
Appellant has not pointed to nor have we discerned any knowledge gleaned
solely from the present disclosure.
Appellant contends that the PEG linkers of Quanta are unsuitable for
use in the conjugates of Dhawan as the PEG linker have only one amine
group for coupling to the signal moiety whereas the purpose of Dhawan is
to introduce a linker with multiple amine groups to attach multiple signal
moieties. Appeal Br. 36. Again, we are unpersauded by this argument.
While we agree with Appellant that Dhawan teaches the use of linker
with multiple amines, Dhawan also teaches a “conventional” conjugate
having a linker with only one amine. Dhawan, 2093–2095, Figures 1B and
2B. It is the teaching of this conventional conjugate that serves as the basis
for the Examiner’s rejection. Final Act. 7. Prior art is relevant for all it
contains. In re Lemelson, 397 F.2d 1006, 1009 (CCPA 1968).
Conclusion
Based on the foregoing we conclude that a preponderance of the
evidence supports the Examiner’s conclusion that the subject matter of
claims 18 would have been obvious to one skilled in the art at the time the
invention was made over Dhawan combined with Quanta and Anderson.
Claims 19–29, and 31 have not been argued separately and therefore fall
with claim 18. 47 C.F.R. § 41.37(c)(iv).
CONCLUSION
The Examiner’s decision to reject claims 18–29, and 31 is affirmed.
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More specifically,
The rejection of claims 18–28, and 31 under 35 U.S.C. § 103 as being
unpatentable over Husain in view of Quanta and Anderson is reversed.
The rejection of claim 29 under 35 U.S.C. § 103(a) as being
unpatentable over Husain in view of Quanta and Anderson and further in
view of O'Sullivan and Hainfeld is reversed.
The rejection of claims 18–29, and 31under 35 U.S.C. § 103(a) as
being unpatentable over Bieniarz in view of Quanta and Anderson is
reversed.
The rejection of claims 18–29 and 31 under 35 U.S.C. § 103 as
unpatentable over Dhawan in view of Quanta and Anderson is affirmed.
DECISION SUMMARY
Claim(s)
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
18–28, 31 103 Husain, Quanta,
Anderson,
18–28, 31
29 103 Husain, Quanta,
Anderson,
O’Sullivan,
Hainfeld
29
18–29, 31 103 Bieniarz, Quanta,
Anderson,
18–29, 31
18–29, 31 103 Dhawan, Quanta,
Anderson
18–29, 31
Overall
Outcome
18–29, 31

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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). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED