Ex Parte Brocchini et al

Patent Trial and Appeal Board

Feb 4, 2019

12682057 (P.T.A.B. Feb. 4, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/682,057 04/08/2010
23117 7590 02/06/2019
NIXON & V ANDERHYE, PC
901 NORTH GLEBE ROAD, 11 TH FLOOR
ARLINGTON, VA 22203
FIRST NAMED INVENTOR
Stephen Brocchini
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.
GRT/37-91 1261
EXAMINER
PIPIC,ALMA
ART UNIT PAPER NUMBER
1617
NOTIFICATION DATE DELIVERY MODE
02/06/2019 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):
PTOMAIL@nixonvan.com
pair_nixon@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STEPHEN BROCCHINI, PENNY BRYANT, YUEHUA CONG,
JI-WON CHOI, ANTONY GODWIN, and KEITH POWELL 1
Appeal2018-001530
Application 12/682,057
Technology Center 1600
Before RICHARD M. LEBOVITZ, GEORGIANNA W. BRADEN, and
DAVID COTTA, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to a process for the preparation
of a compound comprising a water-soluble synthetic polymer conjugated to
a protein or peptide, where the conjugation is via a polyhistidine tag. The
Examiner rejected the claims as obvious under 35 U.S.C. § 103. Pursuant to
35 U.S.C. § 134, Appellants appeal the Examiner's determination that the
claims are unpatentable. We have jurisdiction under 35 U.S.C. § 6(b). The
Examiner's decision is affirmed.
1 The Appeal Brief ("Br."; entered June 23, 2017) lists POLYTHERICS
LIMITED as the real party in interest.
Appeal2018-001530
Application 12/682,057
STATEMENT OF THE CASE
The Examiner finally rejected claims 22-25, 29-31, 34, and 36-43
under pre-AIA 35 U.S.C. § 103(a) as obvious in view of Godwin et al. (WO
2005/007197 A2, published January 27, 2005) ("Godwin") and
Bosman et al. (WO 99/00670, published January 7, 1999) ("Bosman").
Claims 22, the only independent claim on appeal, is reproduced in the
Appeal Brief (Br. 21-22).
REJECTION
Claim 22 is directed to a process for preparing a compound
conjugated to a protein or peptide "via a polyhistidine tag." The compound
is shown in claim 22 as a structure having the general formula "(Ia)".
Formula (Ia) is reproduced below:
(Ia)
In formula (Ia) (reproduced above), "Z" represents the protein or peptide
linked to "A and B" "via a polyhistidine tag." A is "a C1-s alkylene or
alkenylene chain" and Bis "a bond or a Ci-4 alkylene or alkenylene chain."
X, X', Q, and Ware defined in claim 22 which is reproduced in its entirety
in the claim appendix of the Appeal Brief.
The Examiner found that Godwin describes the general structure of
formula (Ia), but not A and B conjugated to a protein or peptide via a
polyhistidine tag as required by claim 22. Final Act. 3-6. To make up for
this deficiency, Examiner further cited Bosman as teaching methods of
immobilizing biomolecules to carriers and membranes utilizing a
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polyhistidine tag as recited in claim 22. Id. at 6-7. The Examiner concluded
that it would have been obvious to one of ordinary skill in the art to utilize
the polyhistidine tag ("His-tag") of Bosman to conjugate Godwin's structure
to a protein or peptide because "Bosman teaches that His-tags do not
interfere with the conformation of the protein upon immobilization and
function as spacers, and suggests reaction conditions that would increase the
probability of having the reaction occur via the His-tag." Id. at 8.
Are Bosman and Godwin analogous art to the claimed subject matter?
Appellants contend a person of ordinary skill "would not have
considered combining the Godwin and Bosman disclosures because they are
not in the same field of endeavor, nor is Bosman pertinent to any problem
solved by Appellants' present invention." Br. 10. Appellants contend
"Bosman's field is the immobilization of biomolecules to carriers and
membranes," while in contrast "Godwin's field ( which is also the field of
Appellants' present invention) is the use of water-soluble synthetic polymers
to produce discrete therapeutic molecules." Id. at 11. Appellants also state
that Bosman and Goodwin address different problems: "Bosman is trying to
make a biomolecule insoluble by immobilizing it on a carrier while Godwin
is trying to keep a biomolecule soluble." Id.
Appellants' arguments do not persuade us that the Examiner erred in
rejecting the claims. It is well-established that there are two criteria to be
applied when determining whether a reference is analogous prior art: ( 1)
whether the reference is from the "same field of endeavor" as the claimed
invention, and (2) if the reference is not within the same field of endeavor,
"whether the reference still is reasonably pertinent to the particular problem
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with which the inventor is involved." In re Clay, 966 F.2d 656, 658-59
(Fed. Cir. 1992). A reference is "reasonably pertinent" to the inventor's
particular problem when the reference "is one which, because of the matter
with which it deals, logically would have commended itself to an inventor's
attention in considering his problem." In re Klein, 647 F.3d 1343, 1348
(Fed. Cir. 2011) (citation omitted).
Appellants have defined the fields of endeavor in each publication too
narrowly. Godwin is not restricted to therapeutic molecules as asserted in
the Appeal Brief, because it also states that its compounds are useful in
"non-clinical applications," such as "enzymes [that] are able to catalyse
reactions in organic solvents" and that can be used "as diagnostic tools."
Godwin 18: 17-23. Bosman discloses that the His-tags can be used for
therapeutic and diagnostic purposes. Bosman 6:24--25. The fields of
endeavor in each of Godwin and Bosman overlap and, thus, the Examiner's
finding that the publications are in the same field of endeavor as the rejected
claims is supported by the evidence of record.
In addition, as found by the Examiner, the Godwin and Bosman are in
the same field of endeavor as the claims because "both references are
concerned with covalently attaching peptides to polymers via engineered
amine groups that are not a part of the native protein structure." Final Act.
10-11. Appellants do not identify a defect in this reasoning which is fact-
based and reasonable.
Furthermore, Bosman does not restrict its carrier to insoluble
supports, but explicitly states that the carrier can be beads or microparticles
that remain in solution:
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The beads or microparticles can be that small that they will no
longer result in a suspension that is precipitable, but will result
in a colloidal solution or a solution. Such microparticles thus
can be comprised of any molecule or molecules that allow for a
covalent crosslinking with biomolecules by means of amino
acid residues of the His-tag of said biomolecules, and that are
small enough that they will not precipitate. However, through a
process of crosslinking between such particles a process such as
precipitation can still be engaged, providing a tool for e.g.
diagnostic purposes.
Bosman 13:18-25.
Appellants respond that neither Godwin nor "the present invention"
utilize beads or microparticles. Br. 11. However, the Examiner cited the
disclosure above to establish that Bosman was not limited to insoluble
materials, but rather also disclosed that its His-tag could be used to make
soluble materials, and thus pertinent to the soluble materials in Godwin.
Final Act. 7. Therefore, Bosman's method of using polyhistidine tags is not
restricted to only insoluble materials as asserted by Appellants.
While Appellants did not establish that Godwin and Bosman are in
different fields of endeavor, Bosman would also "have commended itself to
an inventor's attention in considering his problem" because, as found by the
Examiner, Bosman' s teaches "His-tags do not interfere with the
conformation of the protein upon immobilization and function as spacers"
and this would be advantageous for linking proteins and peptides to a
polymer or other molecule. Final Act. 8. Bosman's method is being used
for its known and expected advantages. As held in KSR Int 'l Co. v. Teleflex
Inc., 550 U.S. 398, 417 (2007):
[I]f a technique has been used to improve one device, and a
person of ordinary skill in the art would recognize that it would
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improve similar devices in the same way, using the technique is
obvious unless its actual application is beyond his or her skill.
Was there a lack of a reasonable expectation of success?
Appellants contend that there was a lack of a reasonable expectation
of success that Bosman's method could be applied to Godwin. Br. 8.
Appellants provide a declaration under 37 CF.R. § 1.132 by co-
inventor Antony Godwin, Ph.D. (executed Sept. 10, 2015; "Godwin 2015
Deel." or the "Second Godwin Deel.") in which Dr. Goodwin found that
"Bosman's method does NOT lead to selective conjugation at a
polyhistidine attached to a protein." Br. 12.
Dr. Godwin described experiments examining the reaction of the Rose
Bengal reagent with the interferon alpha and p24 proteins. Godwin 2015
Deel. ,r,r 3--4. Dr. Godwin found that histidine tagged and non-histidine
tagged proteins "showed a similar pattern and extent of multimerisation,
indicating that the reagent reacts non-specifically with the non-tagged
protein." Godwin 2015 Deel. ,r 5. Dr. Goodwin stated in his 2015
declaration that "the Rose Bengal mediated cross linking does not appear to
be specific for histidine tags" and that the results of his experiments showed
that "there was no indication of a peptide peak corresponding to two
peptides cross-linked by their Histidine tags. Several peptide peaks were
detected as oxidation products, indicating modification occurring at
methionine or tryptophan, in addition to histidine." Godwin 2015 Deel.
,r,r 6, 8. Dr. Godwin concluded, based on his experimental evidence, that
"the reaction at histidine tags using the method of Bosman is random and
statistical and cannot be considered a site-specific approach to his-tag
conjugation." Godwin 2015 Deel. ,r 10.
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The Examiner found Dr. Godwin's declaration unpersuasive because
the method utilized in the declaration followed Example 1 of Bosman in
which the Rose Bengal reagent was used to cross-link His-tagged proteins
by forming covalent bonds between the His-tags, while the claims "do not
require conjugation between a His-tagged synthetic polymer and a His-
tagged protein to occur by covalent bonding of the two His-tags." Final Act.
12; Bosman 11:5-7, 16:1-15 (Example 1). The Examiner found that the
claims require conjugation of a protein or peptide (Z of claim 22) to a
polymer (A and B connecting to the remaining structure of Formula (Ia)) via
a polyhistidine tag, with no requirement that the covalent linking is between
histidine residues. Final Act. 12. The Examiner found that Example 2 of
Bosman is more relevant to the claims because it disclosed immobilizing the
His-tagged peptides to a polymer and not to another His-tagged peptide as in
Example 1. Ans. 17. The Examiner also found that Bosman teaches
optimizing histidine binding to a polymer, i.e., "that one or more physico-
chemical parameters of the reaction conditions may be manipulated to
increase the selectivity of the reaction towards the histidine residues that
comprise the His-tag." Final Act. 11.
The Examiner's determination is persuasive and supported by a
preponderance of the evidence in this appeal. The experiments performed in
Dr. Godwin's 2015 second declaration utilized only one reagent, the Rose
Bengal reagent, to cross-link histidine tagged proteins to each other via the
histidine residue. The claims, however, require conjugation of Z via a
polyhistidine tag to A and B, which are chemical groups, not other histidine
residues. Thus, as found by the Examiner, Example 2 of Bosman's
publication is more pertinent to the claims than Example 1 because it
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involves attachment of a polyhistidine to a polymer, the latter fact not
dispute by Appellants.
In addition, the rejected claims are not limited to the use of the Rose
Bengal reagent which is described in Bosman as being used for mediating
reactions between histidine residues (Bosman 11 :5-7, 15-17). Thus, even if
the experiments performed by Dr. Godwin are pertinent to the claims, they
are not commensurate with the scope of the claim because only one reagent
was utilized, while the claims are unrestricted as to the reagent used to
perform the conjugation step.
In sum, Dr. Godwin's 2015 declaration is insufficient to establish a
lack of a reasonable expectation of success that Bosman could be used to
conjugate a protein or peptide to a polymer via a polyhistidine tag.
Bosman, as found by the Examiner, provides adequate guidance to
one of ordinary skill in the art to have utilized a polyhistidine tag, as
required by claim 22, to attach peptide or protein ("Z") to chemical
structures A and B.
Bosman discloses that "any kind of reagent that can react with
histidine residues without having a particular selectivity for histidine" can be
used for immobilization, and lists a number of different reagents. Bosman
7:8-20. As found by the Examiner (Final Act. 6-7), Bosman teaches that
conditions can be manipulated to achieve greater specificity for histidine
residues:
According to a further embodiment the present invention relates
to the manipulation of one or more physico-chemical
parameters of the reaction conditions, thereby increasing the
selectivity of the reaction towards the histidine residues that
comprise the His-tag. The reaction pattern of the above-listed
reagents with protein can be markedly affected by the reaction
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conditions ( e.g. pH, temperature, solvent and/ or buffer used,
degree of illumination, excess of reagent, and other physico-
chemical parameters): i.e. the specificity of these reagents can
be significantly increased to a reactive group by adaptation of
the conditions.
Bosman 7:24--8:1.
Based on teachings from Bosman like the one reproduced above, the
Examiner had a persuasive, fact-based reason to conclude that there "would
have been a reasonable expectation of success in applying Bosman's method
of conjugation via a His-tag to Godwin's method of conjugation" because
the ordinary skilled artisan would have been "capable of," utilizing the
guidance described in Bosman, to "optimiz[ e] reaction conditions of
Bosman in order to obtain conjugation via the His-tag through routine
experimentation." Final Act. 11. Appellants did not provide adequate
evidence to the contrary.
Appellants argue that the working examples in Bosman are not
relevant because they involve covalent immobilization to a solid support and
making a protein insoluble, which is opposite of what Godwin and the
claims are trying to accomplish. Br. 13. We do not agree. Bosman is not
limited to its working examples. Bosman has broader disclosure as
discussed above. The Examiner generally relies upon Godwin for teaching
attaching a protein to a polymer and Bosman for describing a method of
doing so utilizing a polyhistidine tag as required by the rejected claims.
Final Act. 4. Bosman is not limited to insoluble proteins, but discloses
soluble ones as well. Bosman 13: 18-25. Appellants have not identified a
reason as to why there would be a lack of an expectation of success that a
protein could not be linked to a polymer utilizing the reagents described in
Bosman. The evidence provided by Appellants is of experiments involving
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the Rose Bengal reagent, and these experiments did not show the failure of
the histidine residues of the tag to covalently bond to other proteins, just the
lack of histidine-histidine linkages between the proteins which, as explained
by the Examiner, are not required by the claims. Indeed, Dr. Godwin stated
that "there was no indication of a peptide peak corresponding to two
peptides cross-linked by their Histidine tags," but did not state that histidine
did not covalently bond to other amino acid residues in the protein. Godwin
2105 Deel. ,r 8. Thus, Appellants' statement that "Appellants' declaration
evidence proves conclusively that Bosman's process does not lead to a
product selectively bonded via its His-tag" is not supported by adequate
evidence because the declaration only showed the lack of histidine to
histidine bonds. Br. 14.
Appellants also argue that the second Godwin 2015 declaration
establishes that one of ordinary skill in the art would not have expected
selectivity to be obtained by Bosman's method. Br. 15. This argument is
not persuasive.
First, the claims do not require selectivity as long as some protein
linkages are via the histidine. Dr. Godwin's 2015 declaration did not
establish a lack of protein linkages between histidine and other amino acid
residues. In fact, Appellants admitted that Bosman' s Rose Bengal reagent
"not only attacks histidine residues, but other amino acids as well, and would
have been reasonably expected to do so by a person of ordinary skill." Br.
15. Thus, Appellants do not deny that linkages could occur via histidine
residues to other amino acid residues, and thus generally to other chemical
groups. Claim 22 covers such linkages ("a water-soluble synthetic polymer
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conjugated to a protein or peptide, said conjugation being via a polyhistidine
tag").
Second, Bosman discloses that non-specific reagents - i.e., reagents
that are not selective for histidine residues - can be utilized, identifies
examples of such reagents, and explains how the probability of a reaction
with a histidine residue can be enhanced. Bosman 7:8-10:6. Thus, as
discussed above, Bosman provides guidance to one of ordinary skill in the
art regarding how to achieve greater selectivity between histidine and other
chemical groups, and also identifies various reagents to do so.
Appellants also contend that there is nothing in Godwin that would
have taught or suggested "that it would have been reasonable to expect
selective conjugation at a His-tag attached to a protein when using Godwin's
conjugation reagent." Br. 19. However, the Examiner did not rely on
Godwin for this teaching, but rather Bosman.
Histidine "selectivity"
Claim 22 is directed to a "process for the preparation of a compound
comprising a water-soluble synthetic polymer conjugated to a protein or
peptide, said conjugation being via a polyhistidine tag." The claim recites
that the conjugation is via a polyhistidine tag, but does not exclude
conjugation via other residues and chemical groups, as long as some of them
are with the polyhistidine tag.
Appellants' contention that the Rose Bengal reagent utilized by
Bosman "not only attacks histidine residues, but other amino acids as well,
and would have been reasonably expected to do so by a person of ordinary
skill" (Br. 15) does not distinguish Bosman from the claims because the
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claims do not exclude other linkages between "Z" and "A" and "B".
Moreover, as discussed above, it would have been reasonably expected that
at least some histidine linkages to the polymer (and A and B chemical
group) would occur, a fact not disputed by Dr. Godwin's second declaration
and admitted by Appellants (see Br. 15 ("It was demonstrated therein that
the reagent used by Bosman not only attacks histidine residues, but other
amino acids as well, and would have been reasonably expected to do so by a
person of ordinary skill.")).
Appellants further contend:
[Bosman] failed to teach how to perform the highly selective
conjugation reaction that would have been required to obtain
the desired conjugated compound with a reasonable expectation
of success because Bosman's nonspecific reaction conditions
( e.g., Rose Bengal reagent) would have led to conjugation with
many cysteine, lysine, and histidine residues in the amino acid
sequence, and would have resulted in the formation of highly
heterogeneous conjugation products.
Br. 18-19.
This argument is not persuasive. Appellants have not identified
language in the claim which would exclude conjugation via residues other
than the polyhistidine tag. In addition, as already addressed above, Bosman
teaches numerous coupling reagents in addition to the Rose Bengal reagent,
and discloses how to "increase[ e] the selectivity of the reaction towards the
histidine residues that comprise the His-tag." Bosman 7:8-10:6. Thus,
based on this disclosure, one of ordinary skill in the art would have
reasonably expected that histidine conjugation between the histidine tag and
chemical groups of A and B could be enhanced by following the guidance in
Bosman. Dr. Godwin's 2015 declaration did not rebut this reasonable
expectation since it showed only one set of conditions and did not show that
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histidine conjugation was absent, only the lack of histidine to histidine
linkages.
Appellants contend that "specific conjugation" between "(a) a water-
soluble synthetic polymer to (b) a protein via a His-tag" would not have
been reasonably expected (Br. 18), but fail to address the disclosure in
Bosman's describing how histidine selectivity would be achieved (see
Bosman 7:24--8:1).
First Godwin Declaration
Dr. Godwin provided a declaration describing conjugating TrkAd-5 to
PEG via a histidine tag on TrkAd5 (executed Sept. 19, 2014; "Godwin 2014
Deel." or "First Godwin Deel."). "As a negative control, the same
experiment was carried out using TrkAd-5 without any histidine tag." Id.
,r 2. Dr. Godwin reported that the "results obtained show that binding of the
PEG reagent to the TrkAd5 with a histidine tag is increased four-fold
compared with binding to the negative control, TrkAd5 with no histidine tag.
This indicates the selectivity of the process for the histidine tag." Godwin
2014 Deel. ,r 3.
The declaration does not persuade us that the Examiner erred in
rejecting the claims as obvious. The Examiner thoroughly explained that
Bosman teaches methods of covalently linking histidine residues to
polymers as required by claim 22. Ans. 13. The Examiner also explained
how Bosman teaches how to enhance the specificity of binding of the
histidine to the polymer. Id. at 14. Thus, the Examiner reasonably
concluded that it was not unexpected that the probability of histidine binding
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to the polymer would be increased utilizing Bosman's methods. Id. at 14--
15.
To the extent that the results are asserted to be "unexpected," it is well
established that unexpected results must be "commensurate in scope with the
degree of protection sought by the claimed subject matter." In re Harris,
409 F.3d 1339, 1344 (Fed. Cir. 2005). In this case, the declaration described
experiments which utilized only one chemical reagent (Bis-sulfone PEG)
(see Appendix of Godwin 2014 Deel.), but claim 22 is not limited to the
chemical reagent utilized in the experiments. Appellants have not
demonstrated that the alleged "unexpected" result described in the 2014
declaration would be achieved using other chemical reagents to accomplish
conjugation between the polyhistidine tag and A and B.
SUMMARY
For the foregoing reasons, the obviousness rejection of claim 22 is
affirmed. Claims 23-25, 29-31, 34, and 36-43 were not argued separately
and fall with claim 22. 37 C.F.R. § 4I.37(c)(l)(iv).
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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