Ex Parte Kobayashi et al

Patent Trials and Appeals Board

Jun 24, 2019

13972532 - (D) (P.T.A.B. Jun. 24, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/972,532 08/21/2013
36218 7590 06/26/2019
KLARQUIST SPARKMAN, LLP (OTT-NIH)
121 S.W. SALMON STREET
SUITE#l600
PORTLAND, OR 97204-2988
FIRST NAMED INVENTOR
Hisataka Kobayashi
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.
4239-85538-04 7030
EXAMINER
SANG,HONG
ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
06/26/2019 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
nicole. salazar@klarquist.com
AS CChair@klarquis t. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HISATAKA KOBAYASHI, PETER CHOYKE, and
MAKOTO MITSUNAGA
Appeal2018-004333
Application 13/972,532
Technology Center 1600
Before DEBORAH KATZ, TA WEN CHANG, and JOHN E. SCHNEIDER,
Administrative Patent Judges.
KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appeal2018-004333
Application 13/972,532
Appellants 1 seek our review, under 35 U.S.C. § I34(a), of the
Examiner's decision to reject claims 1-11. We have jurisdiction under 35
U.S.C. § 6(b). An oral argument was held on June 5, 2019. We REVERSE.
The Examiner entered four rejections, each under 35 U.S.C. § 103 that
Appellants' claims are obvious over the prior art, as provided in the table
below.
Claims Prior Art Citation in Answer
1-5, 8, 9, and 11 Ogawa2 and Peng3 Pages 3-5
1, 6-9, and 11 Gao4 and Peng Pages 5-7
1-5 and 8-11 Ogawa, Peng, and Pages 7-8
Frangioni5
1 and 6-11 Gao, Peng, and Frangioni Pages 8-9
Appellants' Specification is directed to methods and compositions for
killing tumor cells after antibody-IR700 conjugates that bind to the surface
of cells have been irradiated with near infrared (NIR) light. (See
Specification ("Spec.") 1:9-11.)
1 Appellants report that the real parties in interest are the United States of
America, as represented by the Secretary of Dept. of Health and Human
Services and licensee Aspyrian Therapeutics, Inc. (App. Br. 3.)
2 Ogawa et al., "In vivo Molecular Imaging of Cancer with a Quenching
Near-Infrared Fluorescent Probe Using Conjugates of Monoclonal
Antibodies and Indocyanine Green," 69 Cancer Res. 1268-72 (2009).
3 Peng et al., "Phthalocyanine dye as an extremely photostable and highly
fluorescent near-infrared labeling reagent," 6097 Proc. of SPIE 60970E-1-
60970E-I2 (2006).
4 Gao et al., "In vivo cancer targeting and imaging with semiconductor
quantum dots," 22 NATURE BIOTECHNOLOGY 969-76 (2004).
5 Frangioni et al., US 2008/0073566 Al, published March 27, 2008.
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Application 13/972,532
Appellants' claim 1 is directed to a composition of such conjugate and
recites:
A phototoxic pharmaceutical composition for the
treatment of a cancer expressing HERi, HER2 or PMSA,
compnsmg:
a phototoxic conjugate comprising an IR 700 molecule
conjugated to an antibody that binds to a cell surface protein,
wherein the antibody is selected from the group consisting of
Panitumumab, Trastuzumab, and J59I or an antigen binding
fragment thereof; and
a pharmaceutical carrier, wherein the phototoxic
conjugate exhibits phototoxicity to kill cells expressing the cell
surface protein bound by the antibody or antigen binding
fragment of the conjugate.
(Appeal Brief filed November 10, 2017 ("App. Br.") 31.)
Findings of Fact
1. Ogawa teaches compositions of the antibody trastuzumab
("Tra") or panitumumab ("Pan") conjugated to the near-infrared ionophore
indocyanine green ("ICG") to form Tra-ICG or Pan-ICG. (See Ogawa
Abstract; see Ans. 3.)
2. Ogawa teaches that the near-infrared ionophore/antibody
conjugates can be used to image and characterize in vivo tumors that
overexpress HERi and HER 2. (See Ogawa Abstract; see Ans. 3.)
3. Ogawa does not teach the infrared ionophore IR700 conjugated
to either trastuzumab or panitumumab. (See Ans. 4.)
4. Peng teaches compositions of the near-infrared ionophore
IRDyeâ„¢ 700DX ("IR700") that can be conjugated with biomolecules,
including antibodies. (Peng Abstract; see Ans. 4.)
5. Peng teaches that IR700 was found to be 45 to 128 times more
photostable than "current near-IR fluorophores ... " and about 27 times more
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Application 13/972,532
photostable than tetramethylrhodamine, "one of the most photostable
organic dyes." (Peng Abstract; see Ans. 4.)
6. Peng teaches that IR 700 has excellent water solubility, does not
aggregate in high ionic strength buffer, has a large extinction coefficient and
high fluorescent quantum yield. (See Peng Abstract.)
7. Peng teaches formulating IR700 in PBS, a pharmaceutical
carrier. (Peng 60970E-6.)
8. Peng teaches that antibodies conjugated with IR 700 "generate
sensitive, highly specific detection with very low background in W estem
blot and cytoblot assays." (Peng Abstract; see Ans. 4.)
9. Gao teaches QD-PSMA antibodies, which are antibodies
specific to the PSMA ligand on prostate cancer cells that are conjugated to
semiconductor quantum dots ("QD") and that bind specifically to cells
expressing prostate-specific membrane antigen ("PSMA") 6 and can be used
to image cancer cells. (See Gao Abstract and Figure 2.)
10. Frangioni teaches a composition comprising a near infrared
fluorophore and a targeting ligand, such as an antibody, that binds to a
specific component on a cell. (See Frangioni ,r 9.)
11. Frangioni teaches that the fluorophore can be IR700. (See
Frangioni ,r 28.)
12. Frangioni teaches conjugating a near infrared fluorophore to the
specific antibody 7El 1-C5.3, which binds to PSMA. (See Frangioni ,r 43.)
6 We understand "PSMA" to be the same as "PMSA" claimed by
Appellants. (See Spec. 34:23-24 ("Other exemplary tumor-specific proteins
further include, but are not limited to, PMSA (prostate membrane specific
. ") antigen.... .
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13. Frangioni does not teach a composition of Panitumumab,
Trastuzumab, or 1591 antibodies conjugated to IR700.
Analysis
We agree with the Examiner that it was known before the time
Appellants filed their application that Panitumumab and Trastuzumab could
be conjugated to a near-infrared ionophore, for example to ICG. (See
Examiner's Answer issued January 18, 2018 ("Ans.") 3--4, citing Ogawa
Abstract; FFs 1 and 2.) We also agree with the Examiner that it was known
before the time Appellants filed their application that the near infrared
fluorescence labeling reagent IR 700 could be conjugated to antibodies. (See
Ans. 4 and 7-8, citing Peng Abstract and Frangioni ,r 28; FFs 4--8 and 10-
11.) We agree with the Examiner further that IR700 was characterized in
the prior art as having several advantages, including being about 45 to 128
times more photostable than current near infrared fluorophores known at the
time. (See Ans. 4, citing Peng Abstract; FF 5.) As the Examiner finds,
IR700 was known to have excellent water solubility, a large extinction
coefficient, high fluorescent quantum yield, and to not aggregate in high
ionic strength buffer. (See Ans. 4, citing Peng Abstract; FF 6.)
Furthermore, we agree with the Examiner's finding that Peng teaches IR700
antibodies generate sensitive, highly specific detection with very low
background in Western blot and cytoblot assays. (See Ans. 4, citing Peng
Abstract; FF 8.)
The Examiner determines that Pan-IR700 and Tra-IR700 molecules
would have been obvious to those of ordinary skill in the art because both
near infrared dyes, such as ICG and IR700 dye, were known to be useful in
labeling antibodies. (See Ans. 5.) The Examiner reasons that the
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Application 13/972,532
substitution of IR700 for another ICG is merely the substitution of one
known element for another known element. (See id.)
Similarly, the Examiner determines that it would have been obvious to
substitute Panitumumab and Trastuzumab for the antibodies and fragments
conjugated to IR 700 as taught in Frangioni because Frangioni teaches that
they are useful for immunofluorescence detection. (See Ans. 8-9.) The
Examiner determines, further, that one of ordinary skill in the art would have
had a reasonable expectation of success making any of these substitutions
because Peng teaches how to conjugate IR 700 molecules to an antibody.
(See Ans. 5 and 8, see Peng 60970E-2.) According to the Examiner, one of
ordinary skill would have had a reason to and would have been motivated to
make this substitution because of the advantages of IR 700 over other near
infrared fluorophores taught in Peng. (See Ans. 5, citing Peng Abstract.)
Each of the Examiner's findings is supported by the record and we
agree with the Examiner's reasoning. We disagree with Appellants'
argument that the Examiner fails to identify all the elements of the claimed
compositions in the prior art, specifically a phototoxic composition,
comprising an IR 700 molecule conjugated to Panitumumab, Trastuzumab,
and J59I or an antigen binding fragment thereof. (See App. Br. 6-8.)
Appellants argue that the phototoxic nature of the claimed composition was
not recognized in the prior art at the time, citing the declaration of inventors
Hisataka Kobayashi, M.D., Ph.D. and Peter Choyke, M.D. ("Kobayashi and
Choyke Deel.") in support. (See id. at 7.)
Although the Examiner acknowledges that the phototoxic nature of
the claimed composition was not recognized, we agree that the phototoxic
property of the claimed composition does not further limit the scope of the
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claimed antibody-IR700 conjugate. (See Ans. 10-11.) Drs. Kobayashi's
and Choyke' s testimony that they are not aware of any prior publication
teaching use of an antibody-IR700 molecule to treat a tumor is not in
dispute. (See Kobayashi and Choyke Deel., ,r 4.) Nevertheless, as the
Examiner explains, the antibody-IR700 conjugates suggested by the
combinations of the teachings of the cited prior art have the same structure
as the claimed antibody-IR700 conjugates. (See Ans. 11.) Appellants'
current claims recite a composition with this structure, not the use of the
composition.
The structural limitations recited in Appellants' claims are the IR 700
molecule, the antibodies Panitumumab, Trastuzumab, and 1591 or an antigen
binding fragment thereof, and a pharmaceutical carrier. "[T]he patentability
of apparatus claims must be shown in the structure claimed and not merely
upon a use, function, or result thereof." In re Gardiner, 171 F.2d 313, 315-
16 (Fed. Cir. 1948). Regardless of Appellants' arguments that the Examiner
improperly relied on inherency, the claim term "phototoxicity" does not
change the nature of these structural elements. (See App. Br. 8-9.) For
example, Appellants do not argue or cite to any evidence that for the claimed
composition to be phototoxic the antibody and IR700 must be linked in a
specific way or that only a subset of conjugates is phototoxic. Thus, the
Examiner need not have provided prior art that teaches the claimed
antibody-IR700 conjugate composition would be phototoxic for it to have
been obvious.
We are also not persuaded by Appellants' arguments that those of
ordinary skill in the art would not have been motivated to combine the cited
references. (See App. Br. 12-18.) Appellants argue that the unappreciated
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feature of phototoxicity "destroys the motivation to combine the cited
references relied upon by the Examiner." (Id. at 13.) The Supreme Court
teaches that "[ u ]nder the correct analysis, any need or problem known in the
field of endeavor at the time of invention and addressed by the patent can
provide a reason for combining the elements in the manner claimed." KSR
Int'! Co. v. Teleflex Inc., 550 U.S. 398,420 (2007). Because the
determination of a reason to combine the references is "at the time of [the]
invention," we are not persuaded that an unrecognized property can negate
what was known. The record supports the Examiner's determination that it
was known that antibodies could be conjugated to fluorophores and that
IR700 was known to offer advantages over other fluorophores. Thus, the
record supports the Examiner's determination that those of ordinary skill
would have had a reason to make antibody-IR700 fluorophores. KSR
instructs that even though this reason is different from the reason Appellants
had for conjugating IR700 to antibodies, the claimed composition could still
have been obvious.
Despite the Examiner's citation of prior art teaching the structural
components of the claimed composition and a reason to combine these
teachings, we are persuaded that the Examiner erred in evaluating
Appellants' evidence of secondary considerations, specifically unexpected
results. (See App. Br. 18-23.) See In re Sullivan, 498 F.3d 1345, 1352 (Fed.
Cir. 2007) ("Whether the composition would have been obvious cannot be
determined without considering evidence attempting to rebut the prima facie
case.").
Appellants present persuasive evidence that the claimed composition
is unexpectedly phototoxic against cancer cells displaying the antigen of the
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cognate antibody. Appellants present the testimony of Drs. Kobayashi and
Choyke, that it was surprising that antibody-IR700 molecules effectively
treat tumor cells, given that IR700 without an attached antibody is
ineffective. (See Kobayashi and Choyke Deel., ,r,r 5 and 12.) Drs. Kobayahi
and Choyke support their testimony with data, for example, Figure 6E of
Appellants' Specification, which is reproduced below.
~· P::-i1 )(:\: :.:1) :'·/. r,,::, :~n-
""*'" P~::), :R?-C:: :K"}~ ::::.: :".-· ::o Pn-
FIG, 6E
Figure 6E is a graph of tumor volume as a function of time after injection
under different treatments. As Drs. Kobayashi and Choyke explain,
irradiated IR700 alone ("IR700 dye iv. PIT 30 J/cm2" in Fig. 6E) did not
have any detectable effect on tumor growth over no treatment, but irradiated
Pan-IR700 conjugate ("Pan-IR700 300 µg iv, PIT 30 J/cm2" in Fig. 6E)
resulted in significant tumor growth inhibition at 3, 7, 10, 14, and 17 days
after treatment. (See id. ,r 9.) Drs. Kobayashi and Choyke testify further
that the Pan-IR700 conjugate without irradiation also failed to reduce tumor
volume. (See id.)
Drs. Kobayashi and Choyke also testified about Figure 6F of
Appellants' Specification, which is reproduced below.
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Application 13/972,532
0·'···
p W 20 30 40 50
Time after MAb injection (day)
FIG. 6F
Figure 6F is a graph of survival of mice as a function of time after injection
under different treatments. As Drs. Kobayashi and Choyke explain,
irradiated IR700 alone ("IR700 dye iv PIT 30 J/cm2" in Fig. 6F) did not
increase the survival of mice, but irradiated Pan-IR 700 conjugate ("Pan-
IR 700 300 µg iv, PIT 30 J/cm2" in Fig. 6F) resulted in a significant increase
in survival time. (See Kobayashi and Choyke Deel. ,r 10.) Drs. Kobayashi
and Choyke testify further that other treatments (Pan-IR700 conjugate
without irradiation, antibody alone, irradiation alone) failed to increase
survival for comparison. (See id.)
In addition to the testimony of Drs. Kobayashi and Choyke regarding
Pan-IR700 compositions, Appellants present the testimony of Gary L.
Griffiths, Ph.D., who is not a named inventor. (See App. Br. 20, citing
Declaration Under 37 C.F.R. § 1.132 of Gary L. Griffiths, Ph.D. ("Griffiths
Deel.").) Dr. Griffiths testifies to the unexpected therapeutic value of the
claimed compositions:
Finally, the IR 700-MAb conjugates of the current invention do
not require cellular internalization for their therapeutic
effectiveness. This importance of this unexpected finding cannot
be overemphasized due to the following general observations:
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MAbs are [in some quarters] considered ineffective due to their
limited abilities to be internalized after binding. As such they
may be considered by some as poor delivery vehicles for
therapeutic drugs generally [ not just PDT agents] since drugs
need to exert their therapeutic effects inside cells. Thus, despite
their promise over 30 years, only limited numbers of approved
agents have been approved clinically, and these use
exceptionally toxic drugs (Teicher and Doroshow, New. Engl. J.
Med. (2012), 367:1847-1848, Exhibit F). Since the PIT of the
current invention exerts its potent effects without need for
cellular internalization of the long circulating IR700-MAbs and
is toxic only when cell-bound and exposed to near-infra red
light, it represents a paradigm-shifting approach to MAb-
directed cancer therapies not heretofore envisaged in the general
or scientific literatures.
(Griffiths Deel. ,r 19 (bracketed text in original).) We understand from Dr.
Griffith's testimony that the other antibody-IR700 conjugates recited in
Appellants' claims (IR700 conjugated to Trastuzumab and 1591) would have
similarly unexpected results as Pan-IR700 because they would also be
phototoxic without the need for cellular internalization.
In light of the testimony of Drs. Kobayashi, Choyke, and Griffiths, we
are persuaded that even if one of ordinary skill in the art would have had
reason to combine the teachings of the prior art to make Pan-IR700 and Tra-
IR 700, the phototoxic properties of the conjugate would have been
unexpected.
The Examiner's reasoning does not persuade us that the claimed
composites are obvious regardless of these unexpected results. According to
the Examiner, because antibody-IR700 conjugates are taught in Peng and
Frangioni, and there is no evidence that only Pan-IR 700, Tra-IR700, and
J591-IR700 conjugates are phototoxic, Appellants have not shown that the
claimed conjugates demonstrate specifically unexpected results. (See Ans.
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24--26.) In the Examiner's view, phototoxicity is an unrecognized property
of any anti-tumor antibody-IR700 conjugate, and Appellants have not
presented evidence that the phototoxicity of Appellants' specifically claimed
conjugates (Pan-IR700, Tra-IR700, and J591-IR700) is unexpected
compared to the conjugates taught in Peng and Frangioni. (See Ans. 24--25.)
Thus, the Examiner does not consider Appellants' evidence of unexpected
results to overcome the rejections for obviousness. (See id. at 25.)
We disagree with the Examiner. Appellants claim compositions of
IR700 conjugated to Panitumumab, Trastuzumab, and 1591 or an antigen
binding fragment thereof, only. Therefore, we evaluate only whether these
conjugates produce unexpected results over the closest prior art. Neither
Peng nor Frangioni, nor any other art cited by the Examiner, teaches these
specific conjugates. The prior art teaches IR 700, but not that it is
phototoxic. Indeed, none of the cited prior art teaches that any antibody-
IR 700 conjugate is phototoxic. Whether or not other antibody-IR700
conjugates would also be phototoxic does not negate that at the time of
Appellants' filing, given the cited knowledge in the art, the phototoxic
nature of the claimed composition would have been unexpected.
When we consider Appellants' evidence of unexpected results along
with the evidence of obviousness the Examiner finds in the prior art, we are
persuaded that the claimed compositions would not have been obvious to
those of ordinary skill in the art. Although the prior art cited teaches
conjugating near infrared fluorophores, including IR700, to antibodies in
general, none of the prior art teaches the specific conjugates claimed.
Furthermore, although the prior art cited suggests that the claimed
conjugates would be expected to be useful as tumor imaging agents, there is
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no suggestion from the cited prior art that the claimed compounds would be
useful as phototoxic agents. Considered as a whole, the unexpected and
different property of phototoxicity outweighs the suggestion in the art to
combine the recited elements. See Honeywell Int 'l Inc. v. Mexichem
Amanco Holding S.A. DEC. V., 865 F.3d 1348, 1355 (Fed. Cir. 2017)
("What is important regarding properties that may be inherent, but unknown,
is whether they are unexpected. All properties of a composition are inherent
in that composition, but unexpected properties may cause what may appear
to be an obvious composition to be nonobvious. ").
Conclusion
Upon consideration of the record and for the reasons given, the
rejections of claims 1-11 as being obvious over the prior art are not
sustained.
Therefore, we reverse the decision of the Examiner.
REVERSED
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