Ex Parte Wilson et al

Patent Trials and Appeals Board

Apr 12, 2019

14703253 - (D) (P.T.A.B. Apr. 12, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/703,253 05/04/2015
123410 7590 04/16/2019
Klarquist Sparkman, LLP (Triad)
121 SW Salmon Street, Suite 1600
Portland, OR 97204
FIRST NAMED INVENTOR
Justin Wilson
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.
8472-97211-01 2682
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
04/16/2019 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):
docketing@klarquist.com
AS CChair@klarquis t. com
docket@lanl.gov
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JUSTIN WILSON, EV A BIRNBAUM, KEVIN JOHN,
FRANCOIS NORTIER, MICHAEL FASSBENDER,
VALERY RADCHENKO, and JONATHAN WARD ENGLE
Appeal2018-007846
Application 14/703,253
Technology Center 1600
Before ULRIKE W. JENKS, TIMOTHY G. MAJORS, and
MICHAEL A. VALEK, Administrative Patent Judges.
VALEK, Administrative Patent Judge.
DECISION ON APPEAL
Appellants 1 submit this appeal under 35 U.S.C. § 134(a). Examiner
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM-IN-PART.
STATEMENT OF THE CASE
This appeal concerns both process and composition claims with
separate rejections as to each statutory class. Claims 1, 3, and 12-16 are
1 Appellants identify the real party in interest as Los Alamos National
Security, LLC. App. Br. 2. Herein we refer to the Non-Final Office Action
mailed April 21, 2017 ("Non-Final Act."), Final Office Action mailed
September 21, 2017 ("Final Act."), Appeal Brief filed February 13, 2018
("App. Br.") and Examiner's Answer mailed May 31, 2018 ("Ans.").
Appeal2018-007846
Application 14/703,253
claims to a process for separating bismuth radionuclide ions from actinium
radionuclide ions by forming a cationic complex of bismuth radionuclide
ions in the presence of actinium radionuclide ions. Claim 1 is representative
of the process claims and is copied from Appellants' Claims Appendix
below.
l. (Previously presented} A process, comprising:
fonning an aqueous mixt11re comprising a ligand, bismuth radionuclide ions, and actinium
radionuclide ions in form a cationic complex of the ligand and a bisrnuih radionuclide ion in the presence of
tht~ actinium radionuclide ions, the ligand having a s1nictural fomlllla
R-...,[ lr-R AlN N)
N N
R_./ L_J '---R
wherein A is selected from hydrogen and ~E); E is selected from -NOz, -Nib. -SCN. -N ,, -
alkyne, maldmide, iodoaccumide, -NH(-C""S}Nll-Z, 1:riazok-Z, and 1hioether-Z; Z is a pt.~ptidc, antibody,
antibody fragment, peptide nucleic ,tcid, nanopanicle, m· other targeting moiety: and R is selected from
H3C,
iOJ iO). -f{})_ i(j). tDJ. fN?J and f\)) and
separating the cat.ionic complex of the bismuth radirnrndide ion from the actinillln radionuclide
ions.
App. Br. 29. Appellants do not argue claims 3 and 12-16 separately from
claim 1 so those claims stand or fall with claim 1. 37 C.F.R. § 41.37
( C )(1 )(iv).
Claims 4--11 are composition claims. Independent claims 4 and 10
are directed to a ligand for complexing metal ions such as a radionuclide.
Independent claims 5 and 11 are directed to cationic complexes formed with
those ligands. Claims 4 and 5 are representative of the composition claims
on appeal and copied from Appellants' Claims Appendix below.
2
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Application 14/703,253
App. Br. 30-31.
Appellants seek review of the following grounds of rejection made by
Examiner:
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Application 14/703,253
I. Claims 1, 3, 12, 14, and 16 under 35 U.S.C. § 103 as obvious
over Morfin 2 and Morgenstern. 3
II. Claims 1, 3, and 12-16 under 35 U.S.C. § 103 as obvious over
Morfin, Morgenstern, and Deal. 4
III. Claims 4--8 under 35 U.S.C. § 103(a) as obvious over Morfin
and Zevaco. 5
IV. Claims 4--8, 10, and 11 under 35 U.S.C. § 103(a) as obvious
over Morfin, Zevaco, and Deal.
V. Claims 5, 7, and 9 under 35 U.S.C. § 103(a) as obvious over
Morfin, Zevaco, Halime, 6 and Yang. 7
2 Jean-Francois Morfin et al., Bismuth(III) Complexes With Tetra-
Pyridylmethyl-Cyclen, Inorganica Chimica Acta, Vol. 362, 1781-1786
(2009) ("Morfin").
3 Alfred Morgenstern et al., Bismuth-213 and Actinium-225 - Generator
Performance and Evolving Therapeutic Applications of Two Generator-
Derived Alpha-Emitting Radioisotopes, Current Radiopharmaceuticals,
Vol. 5, 221-227 (2012) ("Morgenstern").
4 Kim A. Deal et al., Improved In Vivo Stability of Actinium-225
Macrocyclic Complexes, J. Med. Chem., Vol. 42, 2988-2992 (1999)
("Deal").
5 Thomas Zevaco et al., Bismuth (111) Pyridine and Pyrazine-Carboxylates,
New J. Chem., Vol. 15, 927-930 (1991) ("Zevaco").
6 Zakaria Halime et al., Coordination of Bismuth and Lead in Porphyrins:
Towards an In-Situ Generator For a-Radiotherapy?, Biochimie, Vol. 91,
1318-1320 (2009) ("Halime").
7 Pan Yang et al., Hydrothermal Synthesis and Characterization of a Novel
Inorganic Organic Hybrid Complex of Pd(!!) With 5-Methyl-Pyrazine-2-
Carboxylic Acid, Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry, Vol. 43, 395-399 (2013) ("Yang").
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The issue for each of these rejections is: Does the preponderance of
evidence of record support Examiner's conclusion that the cited prior art
references render obvious the identified claims?
Findings of Fact
FF 1. Morfin teaches that bismuth radionuclides "show great promise in
radio-immunotherapy." Morfin 1781, col. 1. According to Morfin, "[t]he
half-life time of 213Bi is very attractive (46 min) for a cancer therapy, but
consequently a successful use of this isotope necessitates ... a chelating
agent able to associate rapidly the Bi(III) ion." Id. Morfin teaches that
"bismuth(III) exhibits a high affinity for nitrogen-donor ligands, so the
incorporation of this heteroatom into the host framework [ of the ligand used
to complex the Bi(III) ion] should enhance the complex stability." Id.
FF2. Morfin teaches the use of Tetra-pyridylmethyl-cyclen (TPC) as a
ligand for the formation of cationic Bi(III) complexes. Id. at 1782. An
excerpt from Figure 6 of Morfin is copied below.
Id. at 1785. In Figure 6, Morfin depicts the coordination scheme of TPC
(shown on the left) with Bi(NQ3)3 in ethanol, teaching that bismuth
coordinates to nitrogen atoms in both the cyclen moiety and the pyridyl
pendant arms of TPC. Id. at 1784--85.
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FF3. Morgenstern teaches the generation of bismuth radionuclides from
225 Ac. Morgenstern 223-24. Morgenstern explains that 213Bi is produced
from the decay of 225 Ac. Id. at 222, Fig. 1. Morgenstern teaches that "225 Ac /
213Bi radionuclide generators" use "cation and anion exchange or extraction
chromatography" to separate 213Bi radionuclides from 225 Ac radionuclides.
Id. at 223, col. 1.
FF4. Deal teaches macrocyclic complexes of 225 Ac. Deal 2988. An
excerpt from Chart 1 of Deal depicting the ligands in some of those actinium
complexes is shown below.
PEPA HEHA
c-DOTA
Deal teaches that "DOT A [ as depicted in Chart 1 above] formed an Ac
complex of which considerable improvements both in whole body clearance
rates and decreased organ uptake were evident." Id. at 2989, col. 1. Deal
teaches that the use of REHA as a chelate for 225 Ac provided even better
results "[p ]resumably [because] the larger ring size and macrocyclic effect
has led to the formation of a kinetically and thermodynamically stable
species." Id. at 2990, col. 2 -2991, col. 1.
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FF5. Zevaco teaches bismuth (III) pyridine and pyrazine complexes.
Zevaco 927. Figure 3 of Zevaco is copied below.
.. ... .. .
){( .... w.l"~ ·§. ... · .... t~.t~: ....'..'.,.-~.s-=tB}·-~i~~~ -~J~:;:.:\t~r-;.r~;.~1t .. ~Y'::.~~-~~f·~~ i· ::'"" >·~: ... '~ .... ~ . .-
As shown in Figure 3 above, Zevaco teaches that bismuth forms complexes
by coordinating to nitrogen atoms in pyrazine containing ligands. Id. at 929.
FF6. Halime teaches the coordination of bismuth and lead radionuclide
ions to nitrogen atoms in porphyrin ring ligands. Halime 1318-19.
FF7. Yang teaches the coordination of lead ions to a nitrogen atom in a
pyrazine moiety. Yang 396.
Analysis
Process Claim Rejections8
Examiner finds that Morfin teaches the formation of cationic bismuth
complexes as recited in Appellants' process claims. Final Act. 5; Ans. 3.
According to Examiner, it would be obvious to use TPC as a ligand, as
taught in Morfin, to complex bismuth in a 225 Ac/ 213Bi generator and then
8 This refers to Examiner's first and second obviousness rejections: (RI)
Claims 1, 3, 12, 14, and 16 over Morfin and Morgenstern; and (R2) Claims
1, 3, and 12-16 over Morfin, Morgenstern, and Deal.
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separate the two radionuclides using an ion exchange column as taught in
Morgenstern. Final Act. 6.
Appellants contend that none of the cited references teach that TPC
selectively coordinates to form cationic complexes with bismuth in the
presence of actinium radionuclides. App. Br. 9. Thus, Appellants urge that
it would not be obvious to use TPC to coordinate bismuth radionuclides in
the presence of actinium radionuclide ions, nor to use the selective formation
of bismuth complexes as a means to separate bismuth from actinium
radionuclide ions, as claimed. Id.
On this record, we find that Appellants have the better position.
Examiner's rejection largely turns on a claim construction issue, i.e.,
whether the process claims require the selective coordination of bismuth
radionuclide ions over actinium radionuclide ions. Claim 1 requires
"forming an aqueous mixture" of bismuth and actinium radionuclide ions
and the recited ligand "to form a cationic complex of the ligand and a
bismuth radionuclide ion in the presence of the actinium radionuclide ions."
The next step of that process, according to both claim 1 and claim 12, is
"separating the cationic complex of the bismuth radionuclide ion from the
actinium radionuclide ions." Thus, the language in both independent
process claims indicates that the actinium radionuclides remain
uncomplexed after exposure to the ligand.
Our interpretation of the claim language, as set forth above, is
consistent with the Specification. See In re Am. Academy of Sci. Tech. Ctr.,
367 F.3d 1359, 1364 (Fed. Cir. 2004) ("During examination, claims ... are
to be given their broadest reasonable interpretation consistent with the
specification, and ... claim language should be read in light of the
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specification as it would be interpreted by one of ordinary skill in the art.")
(internal quotations omitted). The Specification explains that the claimed
process involves "separating the cationic complexes of the bismuth
radionuclide ions from uncomplexed actinium radionuclide ions." Spec. 2,
11. 18-20; see also id. at 18, 11. 1-10 ("Because this class of ligands is
selective for Bi over Ac, they can be applied as elution agents in a
225 Ac/2 13Bi generator .... ") ( emphases added). Accordingly, the broadest
reasonable interpretation of Appellants' process claims that is consistent
with the Specification is that the recited ligands are added to a solution
containing both bismuth and actinium radionuclide ions to selectively form
cationic complexes with the bismuth ion such that the resulting bismuth
cationic complexes are separated from the uncomplexed actinium
radionuclide ions.
Neither Morfin, nor Morgenstern, suggest that TPC will selectively
coordinate with bismuth ions over actinium ions. Examiner determines it
would be obvious to add TPC to Morgenstern' s solution of bismuth and
actinium radionuclide ions "because it would advantageously enable stable
complexation of bismuth" and the TPC's selectivity of bismuth ions over
actinium ions "is [a] property of the T[PC] that [is] inseparable from T[PC]."
Ans. 4--5. While it may be true that such selectivity is inherent to TPC,
Examiner has failed to articulate a rationale for why one of ordinary skill
would find it obvious to add TPC to a solution containing both bismuth and
actinium ions absent knowledge that the TPC would selectively complex
with the former. Indeed, Morgenstern teaches that bismuth ions may be
separated from actinium ions by selective complexation with other
compounds such as iodide. Morgenstern 223. Examiner has not articulated
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why one of ordinary skill would find it obvious to complex bismuth
radionuclide ions prior to separating them from the actinium generator
solution, particularly when doing so might interfere with the other separation
techniques taught in Morgenstern.
Deal does not provide the missing rationale. Examiner finds that
"selective complexation of 213Bi over 225 Ac with TPC would have been
obvious" because TPC has the same four nitrogen cyclen ring as DOT A and
Deal teaches that 225 Ac "requires a larger macrocyclic ring than the [ cyclen]
ring of DOTA for complexation." Final Act. 6. Deal, however, does not
support that finding. To the contrary, Deal teaches that actinium
radionuclide ions form complexes with DOTA. FF4. Thus, applying
Examiner's logic, one of ordinary skill in the art reading Deal would expect
actinium radionuclide ions to form complexes with TPC just as it does with
DOT A. Accordingly, if anything, Deal supports that it would not be obvious
to add TPC to a solution containing both bismuth and actinium radionuclide
ions to selectively form complexes with the bismuth ions, as claimed.
For the reasons discussed above, we conclude that Examiner did not
establish by a preponderance of the evidence that Appellants' process claims
would have been obvious over the cited prior art references. Accordingly,
we reverse Examiner's obviousness rejections as to claims 1, 3, and 12-16.
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Composition Claim Rejections 9
R3: Claims 4-8 over Morfin and Zevaco
Examiner finds that Morfin teaches all of the limitations of claims 4--8
other than the R group moiety. Non-Final Act. 9; Ans. 6. Instead, the TPC
ligand taught in Morfin has a pyridine group in the place of each of the
claimed R groups. Examiner finds that Zevaco teaches pyridine and
pyrazine carboxylate complexes with bismuth(III). Ans. at 6-7. Examiner
determines that it would have been obvious to "substitute the pyridines in
T[PC] for pyrazines in order to further enhance the stability of the complex
by increasing the number of nitrogen donor atoms into [sic] the host
framework." Id. at 12; Final Act. 6-7; see also Non-Final Act. 10 ("A
chemist of ordinary skill [ would] contemplate art recognized equivalents in
order to try to obtain compounds with improved properties.").
Appellants argue that they "deleted 'pyridinyl' from the list of R
substituents for claims 4--8 during prosecution to further distinguish" the
TPC ligand taught in Morfin. App. Br. 19. Appellants contend that there is
"insufficient suggestion to combine" Morfin and Zevaco because Zevaco
"does not teach or suggest forming macrocycle[]" complexes with bismuth.
Id. at 19-20. Even assuming the references were combined, Appellants urge
that Zevaco teaches that the ligand "must include one or more ---C02H acid
moieties," a feature not present in the claimed compositions. Id. at 20-21.
9 This refers to Examiner's third, fourth, and fifth obviousness rejections:
(R3) Claims 4--8 over Morfin and Zevaco; (R4) claims 4--8, 10, and 11 over
Morfin, Zevaco, and Deal; and (R5) claims 5, 7, and 9 over Morfin, Zevaco,
Halime, and Yang.
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Application 14/703,253
We are not persuaded by Appellants' arguments. As our reviewing
court has explained, "structural similarity between claimed and prior art
subject matter, proved by combining references or otherwise, where the
prior art give reason or motivation to make the claimed compositions,
creates a prima facie case of obviousness, and ... the burden ( and
opportunity) then falls on an applicant to rebut that prima facie case." In re
Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990) (en bane). As shown below, the
chemical structure of the pyridinyl groups in TPC is similar to that of
Appellants' claimed R groups.
pyridinyl group R groups in claims 4 and 5
iO) -f01 I~ i()) andt;O) +(_/) N N /
' ; '
For most of the claimed R groups, the only difference from the prior art is
the presence of an additional nitrogen atom in the aromatic ring. The TPC
ligand and Bi(III)TPC complexes taught in Morfin are otherwise identical to
the compositions in claims 4--8. This structural similarity combined with
Morfin' s teaching that TPC has the same utility as the claimed compositions,
i.e., as a ligand to chelate bismuth radionuclides, is sufficient to support a
prima facie case of obviousness. See Dillon, 919 F.2d at 692.
We likewise determine that Examiner has articulated a sufficient
rationale to combine Zevaco' s teachings with Morfin. Zevaco teaches that
bismuth coordinates to the nitrogen atoms in both pyridinyl and pyrazinyl
groups. FF5. While it is true, as Appellants urge, that Zevaco does not
show such coordination with pyrazine in a macrocyclic ligand, "[ n Jon-
obviousness cannot be established by attacking references individually
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where the rejection is based upon the teachings of a combination of
references." Soft Gel Techs., Inc. v. Jarrow Formulas, Inc., 864 F.3d 1334,
1341 (Fed. Cir. 2017) (quoting In re Merck & Co., 800 F.2d 1091, 1097
(Fed. Cir. 1986)). The rejection here is premised on the teaching on
Morfin's teaching of a macrocyclic ligand (TPC) in which the pyridinyl
nitrogens coordinate to bismuth(III). FF2. Zevaco evidences that pyrazine
is functionally equivalent to pyridine for this purpose. See In re Mayne, 104
F.3d 1339, 1343 (Fed. Cir. 1997) (affirming obviousness decision premised
on substitution of "obvious functional equivalent" to prior art compound).
We are likewise unpersuaded by Appellants' argument that Zevaco
teaches that the coordinating ligand must contain "---C02H acid moieties."
App. Br. 20-21. The TPC ligand taught in Morfin does not contain any
carboxylic acid moieties. Moreover, Morfin teaches that bismuth(III) has a
strong affinity for nitrogen-donor ligands, which further evidences that a
skilled artisan would not consider a carboxylic acid moiety to be necessary
to coordinate bismuth. See FFI. Thus, we agree with Examiner's
determination that a skilled artisan would find it obvious to substitute
pyrazine, as taught in Zevaco, for the pyridinyl groups in TPC to increase
the number of nitrogen donor atoms in the ligand.
Finally, there is no evidence in the record that compositions with the
claimed R groups exhibit any surprising or unexpected properties as
compared to the close structural analogs taught in Morfin. 10 Appellants
10 To the contrary, the Specification states that Appellants observed
"selective chelation of [TPC]1°to the bismuth-213 ions" and that "ligands
LPY