Ex Parte Lahn et al

Board of Patent Appeals and Interferences

Oct 13, 2011

09826319 (B.P.A.I. Oct. 13, 2011)

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.
09/826,319 04/03/2001 Michael F. Lahn 2879-80 4155
22442 7590 10/13/2011
SHERIDAN ROSS PC
1560 BROADWAY
SUITE 1200
DENVER, CO 80202
EXAMINER
SCHWADRON, RONALD B
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
10/13/2011 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MICHAEL F. LAHN, WILLI K. BORN, ARIHIKO KANEHIRO,
and ERWIN GELFAND
__________

Appeal 2011-001769
Application 09/826,319
Technology Center 1600
__________

Before ERIC GRIMES, JEFFREY N. FREDMAN, and STEPHEN
WALSH, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of reducing airway hyperresponsiveness. The Examiner has rejected the
claims for obviousness and lack of adequate written description. We have
jurisdiction under 35 U.S.C. § 6(b). We reverse the written description
rejection and affirm-in-part the obviousness rejection.
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STATEMENT OF THE CASE
“[A]llergens and other agents in allergic or sensitized mammals . . .
cause the release of inflammatory mediators that recruit cells involved in
inflammation” (Spec. 1: 19-21). “A common consequence of inflammation
is airway hyperresponsiveness (AHR)” (id. at 1: 23). “[I]nflammatory
diseases involving AHR [include] moderate to severe asthma and chronic
obstructive pulmonary disease” (id. at 2: 3-4).
Claims 1, 2, 9-32, and 34-36 are on appeal. Claim 1 is representative
and reads as follows:
1. A method to reduce airway hyperresponsiveness in a mammal that
has, or is at risk of developing, airway hyperresponsiveness, comprising
administering to the lungs of said mammal an aerosolized antibody
formulation comprising antibodies that selectively bind to a receptor on a T
cell selected from the group consisting of: a T cell antigen receptor (TCR)
selected from the group consisting of an αβ TCR and a γδ TCR, CD3, CD4
and CD8, wherein the binding of the antibodies to the receptor causes the
depletion or inactivation of the T cell, wherein administration of the
antibody formulation reduces airway hyperresponsiveness in said mammal;
and
wherein the administration of the aerosolized antibody formulation
affects pulmonary T cell responses in the mammal, while peripheral T cell
responses in the mammal are neither substantially stimulated nor
substantially inhibited.
I.
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 112, first paragraph, on the basis that the claims lack adequate descriptive
support because they encompass use of antibodies that bind to one of several
specified proteins “from any mammal” (Answer 4). The Examiner finds that
while “the aforementioned molecules derived from mouse or humans were
known in the art, there are thousands of mammalian species wherein said
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molecules have not been isolated or characterized at the amino acid
sequence level and wherein the identity of said molecules is unpredictable”
(id. at 4-5). The Examiner concludes that the claims are not adequately
supported because the “skilled artisan cannot envision the detailed structure
of the encompassed antibodies and therefore conception is not achieved until
reduction to practice has occurred” (id. at 5).
Appellants argue that they “are not claiming the discovery of any of
an αβ T cell receptor (TCR), a γδ TCR, CD3, CD4 and CD8, nor antibodies
that bind to such proteins, but rather, a novel method of using such
antibodies” (Appeal Br. 14). Appellants argue that the Specification
“teaches that each of the proteins recited in the claims were known in the art
at the time of the invention,” as were antibodies against the murine and
human forms of each of the recited proteins (id. at 15). Appellants conclude
that the “rejection implies that in order to meet the written description
requirement, the specification must describe each and every permutation of
an antibody that binds to such proteins, including all proteins from every
mammalian species,” contrary to Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir.
2005) (id. at 16).
We agree with Appellants that the rejection is based on an
overzealous application of the written description requirement. In this case,
as in Capon, the “invention does not concern the discovery of gene function
or structure, as in Lilly.” Capon, 418 F.3d at 1358. In Capon, the claims
were directed to chimeric genes, id. at 1352-1354, that “are produced by
selecting and combining known heavy- and light-chain immune-related
DNA segments.” Id. at 1355. Notably, the chimeric genes at issue in Capon
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could comprise a “gene segment encod[ing] the α, β, γ, or δ chain of [an]
antigen specific T cell receptor,” id. at 1353, a “gene segment encod[ing] a
polypeptide of the TCR/CD3 complex,” id., or “DNA encoding a
transmembrane domain which is obtained from a protein selected from the
group consisting of CD4 [or] CD8.” Id.
The Capon court held that “[i]t is not necessary that every permutation
within a generally operable invention be effective in order for an inventor to
obtain a generic claim, provided that the effect is sufficiently demonstrated to
characterize a generic invention.” Capon, 418 F.3d at 1359. In the
application on appeal, the Specification describes the claimed invention as a
method to reduce airway hyperresponsiveness by administering antibodies
that bind to one of proteins recited in the claims (see Specification 6: 5-12).
The Examiner has acknowledged that the mouse and human forms of these
proteins were known in the art (Answer 4), and has not disputed the
Specification’s statement that antibodies to those proteins were also known
(see Specification 3: 3-18).
While we appreciate the Examiner’s point that the claims encompass a
method of using antibodies that bind to an αβ TCR, a γδ TCR, CD3, CD4, or
CD8 from “thousands of mammalian species” (see Answer 4), the Examiner
has not adequately explained why a structural description of those proteins
would have been required in order for a person of ordinary skill in the art to
recognize possession of the generic method that is defined by Appellants’
claims. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351
(Fed. Cir. 2010) (en banc) (“[T]he test for sufficiency is whether the
disclosure of the application relied upon reasonably conveys to those skilled
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in the art that the inventor had possession of the claimed subject matter as of
the filing date.”). We therefore reverse the rejection based on lack of
adequate written description.
II.
Issue
The Examiner has rejected claims 1, 2, 9-32, and 34-36 under 35
U.S.C. § 103(a) as obvious based on Lobb,1 Arrhenius,2 Schramm,3
Wigzell,4 and Krause5 (Answer 7). The Examiner finds that Lobb discloses
a method of treating asthma by aerosol administration of an antibody
(Answer 7) but does not teach “use of antiTCR αβ antibodies” (id. at 8).
The Examiner finds that Schramm discloses “use of IV antiTCR αβ
antibodies to treat asthma” (id.), and that Krause and Wigzell also teach
pulmonary administration of antibodies (id.). The Examiner concludes that
it would have been obvious “to have created the claimed invention because
Lobb et al. teach aerosol administration of an antibody which binds T cells
to treat asthma and Schramm et al. teach that a different antibody which
binds T cells (antiTCR αβ) can be used to treat asthma” (id.).

1 Lobb et al., US 5,871,734, Feb. 16, 1999.
2 Arrhenius et al., US 5,869,448, Feb. 9, 1999. The Examiner cites
Arrhenius as evidence that Lobb’s antibody binds to a protein that is
expressed on T cells (Answer 7).
3 Craig M. Schramm et al., Proinflammatory Roles of T-Cell Receptor (TCR)
γδ and αβ Lymphocytes in a Murine Model of Asthma, 22 AM. J. RESPIR.
CELL MOL. BIOL. 218-225 (Feb. 2000).
4 Wigzell et al., US 5,958,410, Sept. 28, 1999.
5 Krause et al., US 2002/0037286 A1, Mar. 28, 2002.
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Appellants contend that “there is no teaching, suggestion or
motivation provided by any of the cited references to substitute the anti-
VLA-4 antibody of Lobb et al. with the anti-TCRαβ antibody of Schramm et
al.” (Appeal Br. 23). Appellants also contend they have provided evidence
that intravenous and aerosol administration of the same antibody do not
always have the same effect (id. at 29-30) and that Schramm did not analyze
airway hyperresponsiveness in mice that did not express TCR β (id. at 31-
34).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that it would have been obvious to
use Schramm’s αβ TCR-binding antibodies in Lobb’s method of treating
asthma, with a reasonable expectation of success?
Findings of Fact
1. Lobb discloses “the use of antibodies recognizing Very Late
Antigen-4 (VLA-4), a ligand on certain leukocytes for the endothelial cell
receptor Vascular Cell Adhesion Molecule-1 (VCAM-1), in the treatment of
asthma” (Lobb, col. 1, ll. 16-20).
2. Lobb discloses that the “inflammatory response in asthma is
typical for tissues covered by a mucosa and is characterized by . . .
recruitment of inflammatory cells such as neutrophils, monocytes,
macrophages, lymphocytes and eosinophils to the sites of inflammation” (id.
at col. 2, ll. 11-15).
3. Lobb discloses that “[i]nflammatory leukocytes are recruited to
sites of inflammation by cell adhesion molecules that are expressed on the
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surface of endothelial cells and which act as receptors for leukocyte surface
proteins” (id. at col. 2, ll. 49-52).
4. Lobb discloses that eosinophils bind to vascular endothelium via
binding of the eosinophil protein VLA-4 to the protein VCAM-1 expressed
on endothelial cells (id. at col. 2, ll. 52-61).
5. Lobb discloses that “administering anti-VLA-4 antibody inhibits
both the late phase response and airway hyperresponsiveness in allergic
sheep” (id. at col. 3, ll. 2-4).
6. Lobb discloses that its “pharmaceutical compositions . . . may be
administered by any suitable means such as orally, intraesophageally or
intranasally, intrabronchially . . . , as well as subcutaneously,
intramuscularly, intravenously, intra-arterially, or parenterally. Ordinarily
administration via inhalation is preferred.” (Id. at col. 9, ll. 7-14.)
7. Lobb discloses that “[d]osages will vary” depending on several
factors (id. at col. 6, ll. 41-50) but “it is preferred to use from about 0.05
mg/kg to 5.0 mg/kg of antibody . . . based on the weight of the patient” (id.
at col. 6, ll. 59-62).
8. Lobb provides a working example that describes aerosol delivery
of 8 mg per animal of HP1/2 (an anti-VLA-4 antibody; id. at col. 12, ll. 22-
23) to sheep, followed by antigen challenge (id. at col. 12, ll. 36-41).
9. Lobb discloses that treatment with anti-VLA-4 antibody caused
70% inhibition of airway responsiveness at 24 hours (id. at col. 12, ll. 45-
50).
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10. Lobb concludes that “treatment with HP1/2 aerosol at this dose
30 minutes before antigen challenge is also effective in blocking the late
response and airway hyperresponsiveness” (id. at col. 12, ll. 56-59).
11. Lobb discloses that “[a]lthough comparable protection was
achieved in both the intravenous and aerosol trials, the protection afforded
by HP1/2 in the aerosol trials was achieved without detectable blood levels
of the drug” (id. at col. 12, ll. 62-65).
12. Schramm discloses that “T cells are key regulators of the
inflammatory immune response underlying the pathogenesis of asthma”
(Schramm 218, left col.).
13. Schramm discloses that “[a]lthough most T lymphocytes express
T-cell receptors (TCRs) composed of α and β chains (TCRαβ cells), another
class of T lymphocytes is characterized by the expression of TCRs
containing γ and δ chains” (id. at 218, right col.).
14. Using a mouse model of asthma, Schramm “found diminished
injury in animals lacking TCRγδ cells and the complete absence of injury in
animals lacking TCRαβ cells” (id. at 219, left col.).
15. Schramm discloses that “[s]imilar results were observed in mice
treated with anti-TCRγδ or anti-TCRαβ monoclonal antibodies” (id. at 218,
abstract).
16. Schramm discloses that the antibodies were administered by
intraperitoneal injection (id. at 219, left col.).
17. Schramm discloses that “the decreased immune responses
observed in challenged TCRδ-/- mice were associated with diminished . . .
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degree of nonspecific airway hyperreactivity to methacholine” (id. at 222,
right col.).
18. Schramm discloses that “[m]ethacholine responses were not
studied in TCRβ-/- mice because every animal studied failed to mount an
inflammatory immune response” to antigen (id.).
19. Schramm concludes that “allergic airway inflammation and
hyperresponsiveness are dependent upon T-lymphocyte function. TCRαβ
cells are required if allergic airway sensitization is to occur.” (Id. at 224, left
col.)
Analysis
Lobb discloses treating asthma by administering an antibody that
binds VLA-4, a protein expressed on eosinophils; antibody-binding to VLA-
4 would thus block binding of VLA-4 to VCAM-1 and prevent eosinophils
from localizing at sites of inflammation (FFs 2-4). Lobb discloses that its
antibody-containing composition can be administered in a variety of ways
(FF 6) and that aerosol treatment is effective in blocking airway
hyperresponsiveness (FF 10). Lobb also discloses that aerosol
administration of anti-VLA-4 antibody provided protection “without
detectable blood levels of the drug” (FF 11).
Lobb’s antibody does not bind to any of the receptors recited in claim
1. However, Schramm discloses that mice lacking TCRαβ cells showed a
complete absence of injury in a mouse model of asthma (FFs 13, 14) and
that similar results were seen in mice treated by intraperitoneal injection of
anti-TCRαβ monoclonal antibodies (FFs 15, 16).
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We agree with the Examiner that it would have been obvious to
modify Lobb’s asthma treatment method by using Schramm’s anti-TCRαβ
monoclonal antibodies instead of Lobb’s anti-VLA-4 antibodies, because
Schramm discloses that airway hyperresponsiveness is dependent on T-
lymphocyte function and TCRαβ cells are required for allergic airway
sensitization (FF 19). A person of ordinary skill in the art would therefore
have reasonably expected that aerosol administration, as taught by Lobb, of
Schramm’s anti-TCRαβ monoclonal antibodies would reduce or prevent
airway hyperresponsiveness. A skilled worker also would have expected
that aerosol administration would affect pulmonary T cell responses but not
peripheral T cell responses, as recited in claims 1 and 36, because Lobb
discloses that aerosol administration of an anti-VLA-4 antibody was
effective in blocking airway hyperresponsiveness without resulting in
detectable levels of the antibody in the blood (FFs 10, 11).
Appellants argue that it would not have been obvious to substitute
Schramm’s anti-TCR αβ antibody for Schramm’s anti-VLA-4 antibody
(Appeal Br. 23-28) but, for the reasons discussed above, we disagree with
that position.
Appellants also argue that “Fahy et al. shows that provision of a
therapeutic effect by administration of antibodies systemically does not
necessarily mean that the same effect will be provided when the same
antibody is administered by aerosol” (Appeal Br. 296). Appellants assert

6 Citing Fahy et al., Effect of Aerosolized Anti-IgE (E25) on Airway
Responses to Inhaled Allergen in Asthmatic Subjects, 160 AM. J. RESPIR.
CRIT. CARE MED. 1023-1027 (1999). The copy in the Evidence Appendix of
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that, therefore, a skilled worker would not have reasonably expected Lobb’s
aerosol administration to achieve the results produced by Schramm’s
intraperitoneal injection (id. at 30).
This argument is also unpersuasive. Lobb discloses that anti-VLA-4
antibodies can be administered in a variety of ways (FF 6) and that aerosol
administration and intravenous injection provided comparable protection (FF
11). Based on Lobb’s teachings, a skilled worker would have reasonably
expected that Schramm’s antibodies – targeted, like Lobb’s, to immune
system cells involved in the inflammatory response in asthma – would also
be effective if administered by inhalation.
Fahy is inadequate to cast doubt on this expectation. Fahy discloses
that intravenous administration of an anti-IgE antibody attenuates response
to inhaled allergen in asthmatic subjects but aerosol administration does not
(Fahy, abstract). One reason Fahy gives for this result is that “it is possible
that the aerosol route of delivery did not result in high enough
concentrations of E25 to neutralize IgE in the lung tissue compartments
surrounding IgE effector cells. The vascular space, in particular, represents
a large ‘sink’ of IgE constantly available to move into the lung interstitium
to replace IgE complexed with E25.” (Fahy, page 7 of 9).
Thus, Fahy’s antibody was directed at IgE immunoglobulins, rather
than immune system cells as in Lobb and Schramm. Fahy discloses that the
IgE available in the vascular space could be responsible for the lack of
effectiveness of aerosol administration of its antibody. Appellants have

the Appeal Brief does not include the original pagination, so our citations are
to the pages of the Evidence Appendix copy.
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provided no cogent explanation of why a similar problem would be expected
in administering Schramm’s T-lymphocyte-binding antibody even though it
was not observed in Lobb’s administration of an eosinophil-binding
antibody. We therefore conclude that Fahy would not provide an adequate
basis to doubt the reasonable expectation of success of combining Lobb and
Schramm.
Appellants also argue that Schramm only analyzed airway
hyperresponsiveness in wild-type mice and mice missing TCR δ, but not in
mice that were missing TCR β (Appeal Br. 31-34).
This argument is not persuasive. Schramm discloses that TCR δ
knock-out mice showed reduced immune responses that were associated
with reduced airway hyperresponsiveness to methacholine (FF 17).
Schramm also discloses that immune responses were “completely absent” in
TCR β knock-out mice (Schramm, abstract) and that their response to
methacholine was not studied because “every animal studied failed to mount
an inflammatory immune response” (FF 18). That is, the methacholine
response was not studied in the TCR β knock-out mice because they had no
immune response to start with, and therefore no airway hyperresponsiveness
to methacholine would have been expected.
Appellants also argue that Krause and Wigzell do not make up for the
deficiencies of Lobb and Schramm (Appeal Br. 35-37), but we conclude that
Lobb and Schramm provide sufficient evidence to support a prima facie case
of obviousness. We do not consider Krause or Wigzell necessary to support
the Examiner’s rejection, so we will not discuss them further.
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Appellants argue that “the claimed invention provides unexpected and
surprising advantages over the prior teachings in the art” (Appeal Br. 39) but
do not point to any evidence showing that the asserted results were
unexpected. This argument is therefore unpersuasive.
Appellants also argue that the cited references would not have made
obvious the dosages required by claims 16 and 19-23 (Appeal Br. 42). With
respect to claims 20-23, we agree with Appellants. Those claims require
dosages of less than 1 µg/kg of body weight. Lobb discloses a preferred
dosage range of “about 0.05 mg/kg to 5.0 mg/kg” of body weight (FF 7).
Although Lobb discloses that dosages will vary, the Examiner has not
adequately explained how a skilled worker would reach a dosage of less than
one-fiftieth of the lowest dosage preferred by Lobb through routine testing
(see Answer 9, 16). The Examiner points to a disclosure of lower dosages in
Wigzell (Answer 21) but does not explain why a skilled worker would have
expected Wigzell’s dosages to be applicable to Lobb’s method. We
therefore reverse the rejection of claims 20-23.
However, we affirm the rejection of claims 16 and 19. As the
Examiner pointed out (Answer 19), claim 16 does not recite a dosage, only a
concentration of antibody in the formulation that is administered. Claim 16
therefore does not, as Appellants argue, “recite the use of very low doses of
antibody” (Appeal Br. 42). Appellants have provided no reasoned basis for
concluding that it would not have been obvious to administer the dosages
taught by Lobb using a formulation with the concentration recited in claim
16.
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Claim 19 is directed to the method of claim 1, where the antibody
formulation is “administered at a dose of less than about 40 µg x kilogram-1
body weight of said mammal” (claim 19). Lobb discloses dosages as low as
“about 0.05 mg/kg,” or about 50 µg/kg, body weight (FF 7). Although 40 is
less than 50, both ranges are modified by “about,” so the claimed range
extends above 40 and Lobb’s range extends below 50. See Modine
Manufacturing Co. v. U.S. Intern. Trade Com’n, 75 F.3d 1545, 1554 (Fed.
Cir. 1996) (“Such broadening usages as ‘about’ must be given reasonable
scope.”).
We conclude that the upper end of the claimed range is close enough
to the lower end of Lobb’s range that a skilled worker would expect the
claimed and prior art dosages to have the same properties. See In re
Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“We have also held that a
prima facie case of obviousness exists when the claimed range and the prior
art range do not overlap but are close enough such that one skilled in the art
would have expected them to have the same properties.”). We therefore
affirm the rejection of claim 19.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that it
would have been obvious to use Schramm’s αβ TCR-binding antibodies in
Lobb’s method of treating asthma, with a reasonable expectation of success.
SUMMARY
We reverse the rejection of claims 1, 2, 9-32, and 34-36 under 35
U.S.C. § 112, first paragraph. We affirm the rejection under 35 U.S.C.
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§ 103(a) with respect to claims 1, 2, 9-19, 24-32, and 34-36, and reverse it
with respect to claims 20-23.
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-IN-PART

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