Ex Parte Low et al

Patent Trial and Appeal Board

Feb 8, 2018

13463447 (P.T.A.B. Feb. 8, 2018)

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.
13/463,447 05/03/2012 Philip S. Low 3220-221268 8906
23643 7590 02/12/2018
Barnes & Thornburg LLP (IN)
11 S. Meridian Street
Indianapolis, IN 46204
EXAMINER
BELYAVSKYI, MICHAIL A
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
02/12/2018 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 PHILIP S. LOW and MARY JO TURK1
Appeal 2016-004311
Application 13/463,447
Technology Center 1600
Before ERIC B. GRIMES, DEBORAH KATZ, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
SCHNEIDER, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method for treating arthritis which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
Rheumatoid arthritis (RA) is a systemic disease
characterized by chronic inflammatory synovitis, usually
involving peripheral joints. The synovial inflammation causes
cartilage deterioration and bone erosion with consequent
1 Appellants identify the Real Party in Interest as Purdue Research
Foundation. App. Br. 2.
Appeal 2016-004311
Application 13/463,447
destruction of joint integrity. Rheumatoid factors, which are
autoantibodies reactive with the Fc region of IgG, are found in
more than two-thirds of patients with RA indicating that RA has
an autoimmune component.
RA is seen throughout the world in as much as 2% of the
population, with 80% of RA patients developing the disease
between the ages of 35 and 50. The clinical manifestations of RA
include pain, swelling, and tenderness in the joints resulting in
limitation of motion, weakness, fatigue, and weight loss. RA is a
systemic disease and, consequently, has extra-articular
manifestations, especially in patients with high titers of
rheumatoid factors. These symptoms include rheumatoid nodules
with an inner zone of necrotic material, a mid-zone of
macrophages, and an outer zone of granulated tissue, muscle
atrophy, osteoporosis, pulmonary fibrosis, and rheumatoid
vasculitis which may result in cutaneous ulceration, digital
gangrene, or neurovascular disease.
Spec. 1-2.
The Specification discloses a method for treating RA moderated by
activated macrophages by killing the activated macrophages using ligands
that bind to the activated macrophages. Spec. 2. The ligands are conjugated
to a cytotoxin. Id.
Claims 20-37 are on appeal. Claim 20 is the sole independent claim
and reads as follows:
20. A method of treating arthritis, said method
comprising the step of administering to a patient suffering from
arthritis an effective amount of a composition comprising a
conjugate of the general formula
Ab-X
wherein the group Ab comprises folate, wherein folate binds to
the folate receptor and is capable of binding to the activated
macrophages, and wherein the group X comprises a cytotoxin
that is an antifolate or a corticoid, wherein folate is conjugated
2
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Application 13/463,447
to the cytotoxin through a y-carboxy moiety of a glutamic acid
of folate.
The claims stand rejected under 35 U.S.C. § 103(a) as unpatentable
over Nakashima2 in view of Leamon3, Kranz4, Sudimack5, Feldman6,
2 Nakashima-Matsushita et al., Selective Expression of Folate Receptor ft
and Its Possible Role in Methotrexate Transport in Synovial Macrophages
from Patients with Rheumatoid Arthritis, 42 Arthritis & Rheumatism 1609
(1999) (“Nakashima”).
3 Leamon and Low, Selective Targeting of Malignant Cells with Cytotoxin-
Folate Conjugates, 2 J. Drug Targeting 101 (1994) (“Leamon”).
4 Kranz et al., US 5,547,668, issued Aug. 20, 1996 (“Kranz”).
5 Sudimack and Lee, Targeted drug delivery via folate receptor, 41 Adv.
Drug Delivery Rev. 147 (2000) (“Sudimack”).
6 Feldman et al., US 6,270,766 Bl, issued Aug. 7, 2001 (“Feldman”).
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Application 13/463,447
Wedeking7, as evidenced by Barrera8, Weinberg9, Nagayoshi10, Guzaev* 11,
Mathias12, Linder13, and Ilgan.14
DISCUSSION
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that claims 20-37 would
have been obvious over Nakashima in combination with Leamon, Kranz,
Sudimack, Feldman, Wedeking, as evidenced by Barrera, Weinberg,
Nagayoshi, Guzaev, Mathias, Linder, and Ilgan.
The Examiner finds that Nakashima teaches that a folate antagonist
ligand capable of binding to a folate receptor on an activated macrophage
7 Wedeking et al., US 6,093,382, issued July 25, 2000 (“Wedeking”).
8 Barrera et al., Synovial Macrophage Depletion with Clodronate-
Containing Liposomes in Rheumatoid Arthritis, 43 Arthritis & Rheumatism
1951 (2000) (“Barrera”).
9 Weinberg et al., US 5,759,546, issued June 2, 1998 (Weinberg”).
10 Nagayoshi et al., Effectiveness of Anti-folate Receptor ft Antibody
Conjugated with Truncated Pseudomonas Exotoxin in the Targeting of
Rheumatoid Arthritis Synovial Macrophages, 52 Arthritis & Rheumatism
2666 (2005) (“Nagayoshi”).
11 Guzaev et al., US 6,335,434 Bl, issued Jan. 1, 2002 (“Guzaev”).
12 Mathias et al., Synthesis of j"m TcjDTPA-Folate and Its Evaluation as a
Folate-Receptor-Targeted Radiopharmaceutical, 11 Bioconjugate Chem.
253 (2000) (“Mathias”).
13 Linder et al., In Vitro Studies with a- and y-Isomers of99m Tc-OXA-Folate
Show Uptake of Both Isomers in Folate-Receptor (+) KB Cell Lines, Proc.
47th Ann. Mtg Soc. Nucl. 119P (2000) (“Linder”)
14 Ilgan et al., 99m TcEthylenedicysteine-Folate: A new Tumor Imaging Agent.
Synthesis, Labeling and Evaluation in Animals, 13 Cancer Biotherapy &
Radiopharm. 427 (1998) (“Ilgan”).
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Appeal 2016-004311
Application 13/463,447
can be used to treat rheumatoid arthritis. Non-Final Act.15 3. The Examiner
finds that Leamon discloses the use of folate-toxin conjugates as an effective
therapeutic to kill cells that overexpress a folate receptor. Id. The Examiner
finds that Feldman teaches treating arthritis using methotrexate. Id. The
Examiner finds that Wedeking teaches the use of folate conjugates of either
y-isomers or a-isomers for therapeutic applications. Id. The Examiner
concludes
it would have been obvious to one of the ordinary skill in the art
at the time the invention was made to use folate-cytotoxin
conjugate to treat RA with a reasonable expectation of success
because the prior art suggests that targeting and elimination of
activated macrophages [that overexpress] folate receptor was an
effective therapeutic for treatment of RA. Said targeting and
elimination can be performed using conjugate, comprising a
folate and cytotoxin successfully used in the in the prior art.
Non-Final Act. 4.
Appellants contend that Nakashima only suggests that folate receptor
P (FR-P) is expressed on macrophages but does not actually show that FR-P
is expressed. App. Br. 5-6. Appellants point to the Declaration of Dr.
Low16 to support this contention. App. Br. 7. Appellants also contend that
Nakashima does not establish the FR-P number on synovial cells. Id.
Appellants contend that Nakashima does not suggest any affinity for folate
of the FR-P on synovial cells. App. Br. 8. Appellants contend that at the
time the invention was made, the art taught that the affinity of FR-P for
15 Non-Final Action mailed Oct. 16, 2014.
16 Declaration Under 37 C.F.R. § 1.132 of Dr. Phil S. Low, filed Feb. 17,
2015 (“Low Decl.”).
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Application 13/463,447
folate was unpredictable. App. Br. 9. Appellants next argue that
Nakashima only shows in vitro data and does not teach the effectiveness of
the conjugate in vivo. Id. Appellants argue that Nakashima reaches away
from the invention in that Nakashima is directed to decreasing levels of
folate whereas the present invention would increase folate levels. App. Br.
10. Finally, Appellants argue that the additional references do not address
the deficiencies of Nakashima. App. Br. 11-18.
Findings of Fact
We adopt the Examiner’s findings as our own, including with regard
to the scope and content of, and motivation to modify or combine, the prior
art. The following findings are included for emphasis and reference
purposes.
FF1. Nagayoshi teaches that
Activated synovial macrophages are thought to play an
important role in the pathogenesis of rheumatoid arthritis (RA).
These macrophages release proinflammatory cytokines,
proteinases, and other chemical mediators that lead to the
development of synovitis and joint destruction. The removal of
macrophages decreases the severity of joint disease in animal
models of RA.
Nagayoshi 2666 (reference numbers omitted).
FF2. Barrera teaches
Rheumatoid arthritis (RA) is a common autoimmune
disorder that is characterized by chronic arthritis leading to
irreversible joint destruction. The pathogenesis of RA is not
fully understood, but current models are based on the
recognition of peptides bound to HLA class II molecules on
macrophages and other antigen-presenting cells by T cells.
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Application 13/463,447
Barrera 1951.
FF3. Barrera teaches that “the depletion of the lining macrophages
does decrease cartilage destruction in chronic experimental arthritis.” Id.
1957.
FF4. Nakashima teaches
FR-P expression is selectively elevated in RA synovial
macrophages and suggest that MTX is transported through FR-
P in RA synovial macrophages. The findings suggest that folate
antagonists with higher affinity for FR-P would be useful in the
treatment of RA.
Nakashima 1609.
FF5. Nakashima states
The observed significant inhibition supports the notion that a
large part of MTX transport in RA SMC may be through FR,
probably FR-P on RA synovial macrophages, and furthermore,
that the target cells of MTX in RA SMC are synovial
macrophages.
Nakashima 1615.
FF6. Nakashima also states “In conclusion, the present findings
strongly suggest a role for FR-P in the transport of folic acid and folate
derivatives in RA SMC and imply that folic acid antagonists with a high
affinity for FR-P may be useful in the treatment of RA.” Id.
FF7. Leamon discloses the use of cytotoxin-folate conjugates as
tumor specific therapeutic agents. Leamon Abstract.
FF8. Wedeking discloses therapeutic agents comprising derivatives
of folic acid coupled to a drug through the gamma carboxylate. Wedeking
col. 8,11. 61-64.
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Application 13/463,447
FF9. Methotrexate is a cytotoxin. Spec. 8.
Principles of Law
[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.
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
Analysis
Claim 20 is representative of the rejected claims and is reproduced
above.
We agree with the Examiner that the subject matter of claim 20 would
have been obvious to one of ordinary skill in the art at the time the invention
was made. Nakashima teaches the use of folic acid antagonists to treat RA
and that the target cells of methotrexate are synovial macrophages. FF4-6.
Barrera teaches that the reduction of lining macrophages decreases cartilage
damage in patients with RA. FF3. Leamon teaches the use of folate-
cytotoxin conjugates to destroy cells. FF7. Wedeking teaches that the
constructs can be formed by linking the active component through a y-
carboxy moiety of glutamic acid of a folate. FF8. One skilled in the art
would have found it obvious to use the folate conjugates known in the art to
treat RA as suggested by Nakashima. Further motivation would arise from
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Application 13/463,447
the teachings of Barrera that reduction of the macrophages would reduce
joint damage. FF3.
Appellants contend that Nakashima does not actually show that FR-P
is expressed on the macrophages, asserting that the data provided relies on
populations of cells that are not exclusively macrophages. App. Br. 5-6.
Appellants contend that one skilled in the art reading Nakashima, would not
have a reasonable expectation of success in using conjugates that bind the
FR-P to treat RA.
We have considered Appellants’ arguments and find them
unpersuasive. As shown above, Nakashima discusses the role of FR-P in the
transport of methotexrate and that methotexrate targets synovial
macrophages. FF4-6. Moreover, Nakashima specifically states that “folate
antagonists with high affinity for FR-P would be useful in the treatment of
RA.” FF4. Based on the statements in Nakashima, one skilled in the art
would have a reasonable expectation that administration of folate-conjugates
would be effective in treating RA.
Appellants present the declaration of inventor Low in support of the
attorney argument on pages 5 and 6 of the Appeal Brief regarding the data
shown in Nakashima. See Low Decl. ^ 2. Because we are not persuaded by
the reasoning of Appellants’ arguments in the brief regarding a reasonable
expectation of success for the claimed methods, Dr. Low’s mere agreement
with these arguments is no more persuasive.
Appellants next argue that Nakashima does not teach the FR-P
number on the synovial cells and that this would lead one skilled in the art to
conclude that the conjugates are not effective. App. Br. 7-8. We find this
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Application 13/463,447
argument unpersuasive. The present claims only call for the folate to bind to
a folate receptor and be capable of binding to macrophages. See claim 20
above. Nakashima teaches that folate receptors are present on the
macrophages and that folates are capable of binding to them. FF4-6.
Appellants also contend that Nakashima teaches away from the
present invention in that Nakashima is directed towards reducing folate
levels whereas the present invention would increase folate levels. App. Br.
10. Again, we are unpersuaded.
A prior art reference may be considered to teach away when “a person
of ordinary skill, upon reading the reference, would be discouraged from
following the path set out in the reference, or would be led in a direction
divergent from the path that was taken by the applicant.” In re Gurley, 27
F.3d 551, 553 (Fed. Cir. 1994). As the Examiner points out, Nakashima
specifically teaches “that methotrexate is transported through FR in synovial
macrophages from patients with rheumatoid arthritis.” Ans. 5. The
Examiner continues by noting that “Nakashima et al, further teach that folate
antagonist with higher affinity to FR would be useful in the treatment of
arthritis.” Ans. 5. We agree with the Examiner that this does not constitute
a teaching away from the invention because it does not discourage targeting
the folate receptor. Id.
With respect to the secondary references, Appellants’ argument that
they do not cure the deficiencies of Nakashima are unpersuasive. As
discussed above, the teachings of Nakashima are not deficient.
Finally, with respect to Wedeking, Appellants’ argument that one
skilled in the art would not have been motivated to use y-isomers of folates
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because of lower safety margins is unpersuasive. App. Br. 14-17. As the
Examiner points out, Wedeking teaches the use of both a and y-isomers.
Ans. 6. That Wedeking teaches that the a-isomer may be preferred does not
negate from Wedeking’s teaching regarding the y-isomer. “The prior art’s
mere disclosure of more than one alternative does not constitute a teaching
away from . . . alternatives because such disclosure does not criticize,
discredit, or otherwise discourage the solution claimed.” In re Fulton,
391 F.3d 1195, 1201 (Fed. Cir. 2004).
Conclusion
We conclude that a preponderance of the evidence supports the
Examiner’s conclusion that claim 20 would have been obvious over
Nakashima in combination with Feamon, Kranz, Sudimack, Feldman,
Wedeking, as evidenced by Barrera, Weinberg, Nagayoshi, Guzaev,
Mathias, Finder, and Ilgan.
Claims 21-37 have not been argued separately and therefore fall with
claim 20. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm the rejection under 35 U.S.C. § 103(a).
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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