Ex Parte Flynn et al

Patent Trial and Appeal Board

Jun 14, 2013

11750866 (P.T.A.B. Jun. 14, 2013)

MOD PTOL-90A (Rev.06/08)

APPLICATION NO./
CONTROL NO.
FILING DATE FIRST NAMED INVENTOR /
PATENT IN REEXAMINATION
ATTORNEY DOCKET NO.
11/750,866 05/18/2007 Gary A. Flynn et al.

EXAMINER
BANNER & WITCOFF, LTD.
1100 13TH STREET, N.W.
SUITE 1200
WASHINGTON, DC 20005-4051
GITOMER, RALPH
ART UNIT PAPER NUMBER
1657
MAIL DATE DELIVERY MODE

06/14/2013 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.

UNITED STATES DEPARTMENT OF COMMERCE
U.S. Patent and Trademark Office
Address : COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
UNITED STATES PATENT AND TRADEMARK OFFICE
_____________________________________________________________________________________

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte GARY A. FLYNN, SANDRA AEYOUNG LEE, MARY FARIS,
DAVID WILLIAM BRANDT, and SUBRATA CHAKRAVARTY
____________

Appeal 2011-010594
Application 11/750,866
Technology Center 1600
____________

Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and JOHN G. NEW,
Administrative Patent Judges.

JENKS, Administrative Patent Judge

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims directed to
a composition and methods of using a composition comprising protein
kinase inhibitors. The Patent Examiner has rejected the claims for lacking
written descriptive support in the Specification. We have jurisdiction under
35 U.S.C. § 6(b). We affirm-in-part.

1 Appellants state that the Real Party in Interest is MannKind Corporation
(App. Br. 4).
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Application 11/750,866

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STATEMENT OF THE CASE
The Specification provides that “[i]ntracellular kinases play important
functions in cells of the immune system. . . . [The] inhibitors of intracellular
kinases are useful for treating blood cell malignancies, solid tumors and for
suppressing the immune system, for example in patients with autoimmune
disorders or organ transplants.” (Spec. ¶ 03.) The compounds “inhibit
intracellular kinases, particularly ITK [interleukin-2 inducible tyrosine
kinase] and BTK [Bruton's tyrosine kinase], with an IC50 of 1 μM or below
in an in vitro kinase assay.” (Spec. ¶ 07.) There are four known
crystallographic structure’s describing ITK and BTK kinases (Spec. ¶ 10).
Claims 24-48 and 51-54 are on appeal, and can be found in the Claims
Appendix of the Appeal Brief (App. Br. 47-62). Claim 26 is illustrative of
the claims on appeal, and reads as follows:
26. A method of inhibiting kinase activity, comprising contacting
an aspartate-lysine-cysteine (DKC) triad kinase with a protein kinase
inhibitor or a pharmaceutically acceptable salt thereof, whereby
kinase activity of the DKC triad kinase is inhibited, wherein the
protein kinase inhibitor binds to a DKC triad kinase active site and
wherein the protein kinase inhibitor comprises:
(a) a proton acceptor positioned within hydrogen-bonding
distance to an amino group of a lysine of a catalytic dyad in the DKC
triad kinase active site when the inhibitor is bound in the DKC triad
kinase active site;
(b) an abstractable proton in hydrogen bonding proximity to an
aspartate of the catalytic dyad in the kinase active site, wherein
removal of the abstractable proton creates a conjugated system which
electronically rearranges to an enol/enolate or thiol/thiolate or
enamine when the inhibitor is bound in the DKC triad kinase active
site;
(c) a leaving group wherein further electronic rearrangement
leads to the β-elimination of the leaving group, whereby a Michael
acceptor in the inhibitor is created, and wherein in at least one
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Application 11/750,866

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conformation of the inhibitor and the kinase is such that the Michael
acceptor moiety is within reactive distance of cysteinyl nucleophile,
causing a reaction to form a Michael adduct of the protein kinase
when the inhibitor is bound in the DKC triad kinase active site; and
(d) a kinase binding moiety with affinity for a portion of the
ATP binding site selected from the group consisting of the hinge
region of the kinase, several hydrophobic residues, hydrophilic
residues, and a combination thereof, wherein the protein kinase
inhibitor (1) inhibits interleukin-2 inducible tyrosine kinase (ITK)
with an IC50 of 0.00085 μM - 1 μM in an in vitro kinase assay; (2)
inhibits Bruton's tyrosine kinase (BTK) with an IC50 of 0.00072 μM -
1 μM in an in vitro kinase assay; or (3) inhibits interleukin-2 inducible
tyrosine kinase (ITK) with an IC50 of 0.00085 μM - 1 μM and inhibits
Bruton's tyrosine kinase (BTK) with an IC50 of 0.00072 μM - 1 μM in
an in vitro kinase assay.
The following ground of rejection is before us for review:
The Examiner has rejected claims 24-48 and 51-54 under 35 U.S.C.
§ 112, first paragraph as lacking written descriptive support.

The Issue
The Examiner takes the position that although “a skilled artisan might
be able to look at a compound and determine if it meets the claimed
functional limitations, the converse is not true. The skilled artisan cannot
simply draw a compound that can meet the functional limitations with any
reasonable expectation of success.” (Ans. 5.) “The best one can do is to
make an educated guess of a range of structures, make the potential
inhibitors, and then screen the candidates for inhibition activity. This is
more a wish to know than guidance necessary to adequately describe the
claimed compounds so as to establish possession.” (Id.) “A reading of the
functions of the inhibitor as claimed does not then make it possible for one
of ordinary skill in this art to then draw a structure that will meet those
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functions. This structure:function correlation is essential to determining what
compounds meet the limitations of the composition claims. The independent
claims describe the functions of compounds only.” (Ans. 6.)
The issue is: Does the Specification sufficiently describe structural
features common to all members of the genus?

Findings of Fact
1. The Specification provides that the target kinase forms the adduct
with the inhibitory compounds using the following steps:
(1) The catalytic lysine N-H is positioned within
hydrogen bonding distance (approximately 1.8 - 4.0
Angstroms) of a hydrogen bond acceptor Y in the compound
that exists in the form of a C=Y (Y=O, S, NOR) functionality.
Polarization of the C=Y bond results in increasing the acidity of
the proton (HA) at a carbon atom alpha to the C=Y group.
(2) Acting as a base, the aspartate of the catalytic dyad
extracts the acidic proton HA, leaving behind a conjugated
carbanion that forms for Y = 0, an enol, H-bonded enolate
through standard electronic rearrangement. For Y = S, it would
form a thioenol or H-bonded thioenolate, and for Y = NOR, it
would form an alkoxy (R = alkyl), aryloxy (R=aryl) or hydroxy
(R=H) enamine.
(3) The formation of the enol/thioenol/enamine facilitates
the elimination of the leaving group attached at a carbon beta to
C=Y, through a process known as "β-elimination." The leaving
group, attached to the compound through protonatable
heteroatom Z, may optionally be additionally tethered to the
rest of the compound.
(4) Being a strong nucleophilic species, the sulfhydryl
group of the neighboring cysteine residue reacts with the newly
formed electrophilic elimination product. This addition reaction
(thioalkylation) forms the covalent adduct to the kinase
resulting in its irreversible inhibition and abrogation of activity.
(Spec. ¶ 57.)
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2. The Specification provides that:
[C]ompounds which inhibit tyrosine kinases, particularly
Tec (e.g., ITK, BTK), Src (Src, Lck, etc.) and EGFR kinases
(e.g., EGFR1, Her 2, Her 4), and Jak kinase (e.g., Jak3), having
structures that exploit a discrete mechanistic rationale described
herein. This mechanism provides for the utilization of the
kinase catalytic machinery, described in the ITK
crystallographic structures as the acid-base pair residues
Lys391 and Asp500 (herein referred to as the "catalytic dyad"),
to trigger a transformation that activates the proposed inhibitory
compounds within the enzyme active site. This transformation
involves the elimination of a leaving group, resulting in the in
situ formation of an electrophilic intermediate capable of
forming a covalent adduct with an active site cysteine residue
thereby irreversibly inhibiting the function of the target
enzyme. This cysteine residue is identifiable as Cys442 in the
ITK crystallographic structure.
(Spec. ¶ 55.)
Principle of Law
[T]he hallmark of written description is disclosure…. [T]he test
requires an objective inquiry into the four corners of the
specification from the perspective of a person of ordinary skill
in the art. Based on that inquiry, the specification must
describe an invention understandable to that skilled artisan and
show that the inventor actually invented the invention claimed.
Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1351 (Fed.
Cir. 2010).
“The written description requirement . . . ensures that when a patent
claims a genus by its function or result, the specification recites sufficient
materials to accomplish that function - a problem that is particularly acute in
the biological arts.” Id. at 1352-53.
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Thus, a “sufficient description of a genus . . . requires the disclosure
of either a representative number of species falling within the scope of the
genus or structural features common to the members of the genus so that one
of skill in the art can ‘visualize or recognize’ the members of the genus.” Id.
at 1350 (quoting Regents of the University of California v. Eli Lilly & Co.,
119 F.3d 1559, 1568-69 (Fed. Cir. 1997)).

Analysis
With regard to claims 40-48, Appellants contend that the “structural
features is shown in the structural formulae recited in each of [these]
claims.” (Reply Br. 6.) Appellants further contend that the Specification
provides approximately 18 compounds meeting the structural requirements
of formula II (App. Br. 36); approximately 39 compounds meeting the
structural requirements of formula III (id.); approximately 51 compounds
meeting the structural requirements of formula IV (id.); approximately 6
compounds meeting the structural requirements of formula V (id.);
approximately 3 compounds meeting the structural requirements of formula
VI (id. at 37); approximately 8 compounds meeting the structural
requirements of formula VII (id.); approximately 2 compounds meeting the
structural requirements of formula VIII (id.); approximately 3 compounds
meeting the structural requirements of formula IX (id.); approximately 14
compounds meeting the structural requirements of formula XI (id.).
We find that Appellants have the better position. Claims 40-48 are
directed to kinase inhibitors having core structural formulas set out in
formulas II-IX and XI. Here the Specification provides examples of
approximately 144 compounds that have the requisite kinase inhibiting
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activity and possess one of the recited formulaic core structures. The
Examiner acknowledges that one of ordinary skill in the art can take an
inhibitor compound and determine if it meets the functional requirements as
set out in the independent claims (Ans. 5). We find that for claims 40-48,
the claims recite a formulaic structure that provides an adequate structural
guide for the recited inhibitor. See Ariad, 598 F.3d at 1350. Accordingly,
we find that Appellants’ Specification has sufficiently disclosed the
structure-function relationship between the kinase inhibitor and the enzyme
binding pocket to meet the written description requirement for claims 40-48.

With regard to claims 24-39 and 51-54, Appellants contend that “[t]he
inhibitors . . . have structural features that permit the inhibitors to form a
covalent bond with a DKC triad kinase active site.” (App. Br. 38.) The
mechanism by which the compounds inhibit kinase activity is disclosed (FF
1; App. Br. 38), in addition, the Specification provides numerous
compounds that employ this mechanism (App. Br. 38; Reply Br. 6).
Appellants contend that the present claims can be distinguished from Noelle
v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004) because the kinase’s “three-
dimensional structure [is] known in atomic detail.” (App. Br. 40; Reply
Br. 6.)
The Examiner finds that the claims at best allow the ordinary artisan
“to make an educated guess of a range of structures, make the potential
inhibitors, and then screen the candidates for inhibition activity. This is
more a wish to know than guidance necessary to adequately describe the
claimed compounds so as to establish possession.” (Ans. 5.)
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We find that the Examiner has the better position. The independent
claims 24-26 and 32 are claiming a genus of inhibitors that are recited by
their functional features such as having “a proton acceptor,” “an abstractable
proton,” “creating a Michael acceptor in the inhibitor,” and “a kinase
binding moiety.” What is missing from the claims are the requisite
structural identifiers that can guide the ordinary artisan to the claimed
inhibitor compound.
We are not persuaded by Appellants’ contention that having the
crystal structure of the kinase distinguishes the present claims over Noelle.
The Noelle court has recognized that if you have a fully characterized
antigen the applicant can claim an antibody by its binding affinity to that
described antigen. Noelle, 355 F.3d at 1349. However, the present claims
are not directed to an antibody and antigen relationship. Antibodies are
specialized immune proteins, with an art-recognized generic structure, made
by a vertebrate animal’s B-cells in response to an antigen, which is usually a
foreign molecule. Because of this special relationship, if in possession of an
antigen, the ordinary artisan will be able to obtain an antibody. This is not
the case for an enzyme inhibitor binding relationship such as we have
before us in the present claims.
Even though the protein kinase of the claims has been fully
characterized down to the atomic level by crystallographic structure, the
structure of the inhibitor that fits into the aspartate-lysine-cysteine (DKC)
triad kinase active site has not been described by structural limitations in the
claims. The claims provide no description of the molecule that fits into the
space of the active site. “[A] patentee of a biotechnological invention cannot
necessarily claim a genus after only describing a limited number of species
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because there may be unpredictability in the results obtained from species
other than those specifically enumerated.” Noelle, 355 F.3d at 1350.
Appellants contend that the Specification provides the structure of the active
site and compounds that “exploit a discrete mechanistic rationale.” (App.
Br. 38). A review of the cited portion of the Specification (FF 1) reveals that
this section describes the mechanism of adduct formation in the kinase
binding pocket but does not provide any structural details required by the
inhibitor. The crystal structure of the enzyme provides a description of the
volume of space available in the active site. Here the Specification has
provided kinase inhibitors having core structures recited formulas II-IX and
XI that also possess the recited functional requirements. These formulas
represent a diverse structural group with no common generic structure
linking all groups. However, even with all this information the ordinary
artisan could not draw a structure based on the functional recitation in the
claim alone because more guidance is required by the Specification to arrive
at the inhibitor structure. We agree with the Examiner’s position that “[t]his
is more a wish to know than guidance necessary to adequately describe the
claimed compounds so as to establish possession.” (Ans. 5.)
As recognized in Rochester, “[e]ven with the three-dimensional
structures of enzymes such as COX-1 and COX-2 in hand, it may even now
not be within the ordinary skill in the art to predict what compounds might
bind to and inhibit them.” University of Rochester v. G.D. Searle & Co.,
Inc., 358 F.3d 916, 925 (Fed. Cir. 2004). Our reviewing court has thus
recognized that being in possession of the crystal structure of the enzyme
might not necessarily be enough to allow the ordinary artisan to draw the
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structure of a compound that meets the functional requirements as recited in
the claims.
The claims are directed to the function or mechanism of inhibition of
the compound. Merely describing the mechanism does not allow the
ordinary artisan to come up with a structure that can satisfy the inhibition
mechanism even though the crystal structure of the enzymes is known. The
written description requirement “requires a description of an invention, not
an indication of a result that one might achieve if one made that invention.”
Regents of the University of California v. Eli Lilly & Co., 119 F.3d at 1568.
Indeed, to comply with the written description requirement, an applicant
must “describe[] the invention, with all its claimed limitations, not that
which makes it obvious . . . .” Id. at 1566 (citation omitted.) The claims are
directed to claiming the compounds based on the function of the inhibitor in
the binding pocket of the enzyme, however, this does not provide any
structural information that can be used by the ordinary artisan to draw the
structure of the compound. Thus, we agree with the Examiner that the
ordinary artisan reading the claims in light of the Specification could not
envision and draw a structural formula of a compound that will meet the
functional claim language as recited.
In sum, Appellants’ arguments do not persuade us, for the reasons
discussed, that a preponderance of the evidence fails to support the
Examiner's prima facie case of lack of written description as to claim 26. We
therefore affirm the Examiner's rejection of that claim, as well as claims 24,
25, 27-39, and 51-54, which were not argued separately. See 37 C.F.R.
§41.37(c)(1)(vii).

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SUMMARY
We affirm the rejection of claims 24-39 and 51-54 under 35 U.S.C. §
112 first paragraph as lacking written descriptive support.
We reverse the rejection of claims 40-48 under 35 U.S.C. § 112 first
paragraph as lacking written descriptive support.

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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