Ex Parte Lingappa et al

Patent Trial and Appeal Board

Jun 17, 2015

10911421 (P.T.A.B. Jun. 17, 2015)

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.
10/911,421 08/03/2004 Vishwanath R. Lingappa 305JP-010122US 2790
22798 7590 06/18/2015
QUINE INTELLECTUAL PROPERTY LAW GROUP, P.C.
P O BOX 458
ALAMEDA, CA 94501
EXAMINER
BOESEN, AGNIESZKA
ART UNIT PAPER NUMBER
1648
MAIL DATE DELIVERY MODE
06/18/2015 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 PATENT TRIAL AND APPEAL BOARD
____________

Ex parte VISHWANATH R. LINGAPPA,
D. THOMAS RUTKOWSKI, and RAMANUJAN S. HEGDE
____________

Appeal 2012-011797
Application 10/911,421
Technology Center 1600
____________

Before DONALD E. ADAMS, ERIC B. GRIMES, and
FRANCISCO C. PRATS, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL1
This appeal2 under 35 U.S.C. § 134(a) involves claims 16, 18, 60, and
61 (App. Br. 3). Examiner entered rejection under the written description
and enablement provisions of 35 U.S.C. § 112 and obviousness-type double
patenting. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 Appellants identify the Real Party in Interest as “The Regents of the
University of California and the University of Washington” (see App. Br. 3).
2 Appellants identify co-pending Applications 11/725,066 and 11/181,631,
as well as, Appeal No. 2009-003428 (Application 10/243,509) as related to
this Appeal (Br. 3).
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STATEMENT OF THE CASE
The claims are directed to a method for identifying the presence of
one or more conformers of a wild-type protein in a sample. Claim 16 is
representative and reproduced in the Claims Appendix of Appellants’ Brief.
Claims 16, 18, 60, and 61 stand provisionally rejected under the
judicially created doctrine of obviousness-type double patenting as being
unpatentable over claims 17, 56, and 57 of copending Application No.
11/725,066.
Claims 16, 18, 60, and 61 stand rejected under the written description
provision of 35 U.S.C. § 112, first paragraph.
Claims 16, 18, 60, and 61 stand rejected under the enablement
provision of 35 U.S.C. § 112, first paragraph.

Obviousness-type Double Patenting:
Appellants contend that “a Terminal Disclaimer regarding the ’066
application [was filed] on 11 August 2010 to obviate the non-statutory
provisional double patenting rejection,” which “they consider . . . irrelevant
to the present Appeal” (App. Br. 3). As Examiner explains, however,
Appellants’ Terminal Disclaimer was not approved (see Ans. 26).
Therefore, the obviousness-type double patenting rejection is summarily
affirmed.
FACTUAL FINDINGS (FF)
FF 1. This Application is a divisional of Application 09/739,179, filed
December 15, 2000, now US 6,821,742, issued November 23, 2004. Thus,
Appellants’ effective filing date is December 15, 2000.
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FF 2. Appellants define the term “conformers” to mean “proteins having at
least substantially the same amino acid sequence, but different physical
topology or topography,” wherein “topology” refers to “the different
placement of the protein, e.g. C-cytosolic as compared to N-cytosolic” and
“[t]opography . . . refers to proteins of substantially the same or similar
amino acid sequence but different three dimensional shapes due to
differences in folding/conformation” (Spec. 15: 6–8 and 11–13).
FF 3. Appellants disclose that “the signal sequence affects the
conformation of the protein” (id. at 16: 23).
FF 4. Appellants disclose that “[t]he proteins of interest are proteins, which
have a signal sequence and are subject to processing in the endoplasmic
reticulum” (id. at ll. 16–17; see Ans. 7 (“a ‘conformer’ of the present
invention could be any protein”)).
FF 5. Appellants disclose that “conformers may be mobile or immobile
proteins, being bound to membranes or free in solution” (id. at 19: 7–8).
FF 6. “Without being bound by any theory,” Appellants disclose that “the
signal sequence directs whether the ribosome forms a tight, loose or
intermediate junction with the endoplasmic reticulum (ER) and the selection
of the channel and accompanying processing proteins through which the
translated protein is translocated and processed” (id. at 16: 24–27; see
generally Ans. 5 and 13).
FF 7. Appellants disclose that “[b]y using signal sequences having
different degrees of junction tightness, the conformation of the resulting
protein can be modified” and “used in a number of ways” (id. at 17: 9–11).
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FF 8. Appellants disclose that
conformers serve to differentiate between individual hosts, who
produce the conformers in different ratios, normally or under
different environments. One of the environments is the
presence of a compound, particularly a drug, and the binding
affinity and/or modulation of activity of a target physiologically
active compound, usually a protein, such as a membrane
receptor, channel, enzyme, transcription factor, housekeeping
protein, cytoskeletal protein, membrane protein, and the like.
(Id. at 19: 2–7.)
FF 9. Appellants disclose that “conformers may be used for the production
of antibodies, either antisera or preferably monoclonal antibodies,” using
conventional techniques, to “distinguish between . . . conformers” (id. at 17:
11–19).
FF 10. Appellants disclose that “it may be desirable to use two or more
antibodies, where the conformer may be defined by steric inhibition of
binding, different affinity constants, or the like” (id. at 18: 8–10).
FF 11. Appellants disclose that “conformers can be distinguished by
oligomers, particularly . . . oligopeptides, [which] . . . may serve for
identifying . . . different conformers” (id. at ll. 11–13).
FF 12. Appellants disclose that “oligopeptides can be used in competitive
assays for identifying other oligopeptides[,] which compete for the site or
other compounds, particularly small organic compounds, natural or
synthetic, of less than 5 kDal, usually less than about 2.5 kDal which bind to
the conformer” (id. at ll. 13–16).
FF 13. Appellants disclose that:
[O]ne may vary the signal sequences for other proteins having
signal sequences, where the protein is suspected of being
associated with a diseased state or lowered performance. One
could then determine whether the protein can be produced in
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varying conformations. If different conformers are found . . .
the presence of the different conformers is established in
healthy normal patients as compared to patients who have the
disease or reduced performance. Drugs would then be screened
. . . against the undesired conformer.
(Id. at 20: 14–20.)
FF 14. Appellants exemplify “prion protein (PrP)” as an
example of a substrate with complex and highly regulated
translocation . . . [, wherein] PrP is simultaneously synthesized
in three alternate topological forms at the ER. . . . One of these
forms, termed secPrP, is fully translocated across the ER
membrane [while] . . . the other two forms of PrP are made as
singly-spanning membrane proteins in opposite orientations
with either the N- or C-terminus in the ER lumen (termed
NtmPrP and CtmPrP respectively).
(Id. at 36: 1–11).
FF 15. Appellants exemplify the use of “standard techniques” to prepare
variant PrP constructs, wherein the signal sequence of PrP is replaced with
the signal sequence of various non-PrP proteins; Appellants found that they
could control conformer synthesis using various signal sequences, known to
direct their native protein to a secretion pathway or to a pathway resulting in
C- or N-terminal expression of the native protein in a membrane, resulting in
PrP secretion, or either C- or N-terminal membrane expression (id. at 36:
21– 42: 11; see also Lingappa Dec.3 ¶ 8 (“I and the co-inventors developed
an hypothesis that different conformers of a protein can be synthesized
directly by altering the signal sequence of the gene that expresses the
corresponding wild-type (i.e., native) protein”); see also Lingappa Dec.
¶¶ 9–14; Ans. 5–6 and 12–13).

3 Lingappa Declaration executed Mar. 17, 2009.
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FF 16. Appellants disclose that “[p]rion diseases can be infectious, sporadic
and genetic,” wherein “elevated CtmPr[P] causes neurodegeneration” (id. 49:
11 and 26–27).
FF 17. Appellants disclose antibodies that can distinguish between two PrP
variants (see id. at 56: 13–15).
FF 18. According to Appellants, “[i]f signal sequences play the
hypothesized regulatory role in protein folding, in part through the nature of
the ribosome-membrane junction they establish, then swapping the signal
sequence of two different secretory proteins should have a dramatic
consequence” (id. at 60: 6–8).
FF 19. Dr. Lingappa directs attention to the post-filing date work of Marzi4
to “describe[] how different signal sequences control the production of two
Ebola glycoprotein conformers and thereby govern the infectivity of the
virus” (Lingappa Dec. ¶ 16).
FF 20. Dr. Lingappa directs attention to the unpublished, non-dated, work of
Alpert5 to “demonstrate[] that PAcP [prostatic acid phosphatase] is not a
single protein, but a family comprising three protein forms having identical
mature amino acid sequences; yet profoundly different physiological
functions, sub-cellular location, and biochemical properties . . . due, at least
in part, to differences in three-dimensional folding” (Lingappa Dec. ¶ 17).

4 Andrea Marzi et al., The Signal Peptide of the Ebolavirus Glycoprotein
Influences Interaction with the Cellular Lectins DC-SIGN and DC-SIGNR,”
80(13) J. Virology 6305–6317 (2006).
5 Evgenia Alpert et al., Multifunctionality of Prostatic Acid Phosphatase in
Prostate Cancer Pathogenesis, unpublished and undated manuscript.
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FF 21. Dr. Lingappa directs attention to the unpublished, non-dated, work of
Saghafi6, “which reports the use of the conformer-specific monoclonal
antibody ‘19C3’, specific for [C]tmPrP . . . [and] demonstrate[s] that
conformers of a protein can be detected using monoclonal antibodies”
(Lingappa Dec. ¶ 18).
FF 22. Examiner finds that Appellants’ “[S]pecification discloses one
species representing the genus of the claimed conformers, a prion protein”
(Ans. 10).
FF 23. Examiner finds that Appellants’ “[S]pecification does not provide a
structure and function correlation with regard to the structures of the
conformers and the ligands binding the conformers versus the ligands
binding the wild-type protein” (id. at 10).
FF 24. Examiner finds that Appellants’ “[S]pecification does not provide
support for the genus of ligands that bind the conformers” or “a
representative number of species for the ligands that must be used in the
claimed methods” (id. at 10–11; see id. at 25).
FF 25. Examiner finds that a “skilled artisan cannot envision the detailed
structures of molecules that are encompassed by the genus of ligands”
encompassed by the scope of Appellants’ claims (id. at 12).
FF 26. Examiner finds that “[b]esides the two species, the pre-beta-
lactamase, and preprolactin, which facilitate the conversion of the wild type
prion protein into a conformer, the present specification does not disclose[]
any other signal sequences that contribute to the formation of conformers of
any other proteins” (id. at 13; see generally id. at 24–25).

6 Sam Saghafi et al., Bifunctional Roles for Two Topological Conformers of
the Cellular Prion Protein, unpublished and undated manuscript.
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FF 27. Examiner relies on Hegde7 to teach “that signal sequences within the
translocating chain of a protein can elicit dramatic and reversible structural
changes in a protein” (id. at 13; see Hegde 217: Summary).
FF 28. Examiner finds that Appellants’ Specification fails to provide
working examples of, inter alia, the “identification of a conformer using
ligands having more or less than 5kDa” (Ans. 5).
FF 29. Examiner finds that Bennion8 “teaches that separate antibodies are
required for detection of various conformations of prion proteins” (Ans. 6).
FF 30. Examiner finds that “altered binding” of a ligand to a “protein could
be an indication of a mutation within the protein, an addition of a small
molecule, carbohydrate, or lipid molecule to the protein or improper protein
folding during protein expression,” therefore, a “skilled artisan would be
unable to automatically conclude that an altered binding of a . . . [ligand] to
a protein is an indication of a presence of a conformer” (Ans. 7).

Written Description:
ISSUE
Does the preponderance of evidence on this record support
Examiner’s finding that Appellants’ Specification fails to provide written
descriptive support for the claimed invention?

7 Ramanujan S. Hegde, Sequence-Specific Alteration of the Ribosome-
Membrane Junction Exposes Nascent Secretory Proteins to the Cytosol, 85
Cell 217–228 (1996).
8 Brian J. Bennion et al., Protein Conformation and Diagnostic Tests: The
Prion Protein, 48:12 Clinical Chemistry 2105–2114 (2002).
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ANALYSIS
Examiner finds that Appellants’ “[S]pecification does not provide
adequate written description for the genus of ligands including the ligands
that are more or less than 5 kDa” or “for the genus [of] signal sequences
used in the claimed methods to make the chimeric gene” (Ans. 10; see
generally id. at 23–25). Therefore, we are not persuaded by Appellants’
contention “that the rejection at issue in this appeal is focused on the
question of whether sufficient written description is provided for ligands
smaller than 5 kDa,” which fails to account for the word “including” in
Examiner’s finding (App. Br. 21; cf. Ans. 10; App. Br. 24 (“Examiner
asserted that . . . ‘contrary to Appellant’s [sic] assertions . . . the present
claims are rejected for lack of written description and enablement regarding
all ligands including those of less than 5kDa and not just for the ligands that
are less than 5 kDa”) (emphasis added)).
Appellants contend that their examples, relating exclusively to PrP,
“demonstrate th[at] Applicants were in possession of the [full scope of the]
invention at the time the application was filed” (App. Br. 25; see generally
Reply Br. 6). We are not persuaded. Appellants’ examples are limited in
scope to three conformers of PrP (FF 14–17). Based on their observations
with PrP, Appellants attempt to expand the scope of their PrP observations
to encompass “other proteins having signal sequences” asserting that “[o]ne
could . . . determine whether the protein can be produced in varying
conformations” and “[i]f different conformers are found” determine whether
a difference in conformers exists between “healthy normal patients as
compared to patients who have the disease or reduced performance” (FF 13
(emphasis added); see also FF 18 (“[i]f signal sequences play the
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hypothesized regulatory role in protein folding . . . then swapping the signal
sequences of two different secretory proteins should have a dramatic
consequence” (emphasis added)); see FF 4 (“[t]he proteins of interest are
proteins, which have a signal sequence and are subject to processing in the
endoplasmic reticulum”). “The description requirement of the patent statute
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 1559, 1568 (Fed. Cir. 1997).
As Examiner explains, Appellants’ prion example is not
representative of the class of proteins and ligands encompassed by
Appellants’ claimed invention (FF 22 and 24). In addition, Examiner finds
that Appellants’ Specification fails to provide a correlation between structure
and function of the conformers and ligands (FF 23). In this regard,
Examiner finds that a “skilled artisan cannot envision the detailed structures
of molecules that are encompassed by the genus of ligands” encompassed by
the scope of Appellants’ claims (FF 25). This is particularly relevant when,
as here, Appellants’ Specification discloses that one has to experiment to
determine if a conformer for any particular protein could, in fact, be
produced, let alone be distinguishably identified by a ligand (see FF 13).
Notwithstanding Appellants’ contentions to the contrary:
[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.
Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1350 (Fed.
Cir. 2010). “[M]erely drawing a fence around the outer limits of a purported
genus[, as Appellants have done on this record,] is not an adequate substitute
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for describing a variety of materials constituting the genus and showing that
one has invented a genus and not just a species” (id.).
We recognize Appellants’ contention “that the claims are not drawn to
a genus of signal sequences, broadly or otherwise; the claims on appeal read
on a method for detecting conformers” (App. Br. 25). Appellants’
contention reads the requirements of the method steps out of the claimed
method. For clarity, the claimed method comprises: (1) making a
conformer of a wild-type protein by expression of a chimeric gene that
comprises a signal sequence other than said wild-type signal sequence; (2)
combining a sample with a ligand for the wild-type protein9 and (3)
detecting altered binding of the ligand to a conformer in the sample relative
to binding of the ligand to wild-type protein (see Appellants’ Claim 16).
Notwithstanding Appellants’ contention to the contrary, the first step
of Appellants’ claimed method requires the expression of a construct that
comprises a signal sequence other than the wild-type signal sequence (id.).
Appellants’ Specification discloses that the signal sequence may be selected
from a genus of potential signal sequences (see e.g., FF 7 and 13). Further,
for each potential conformer within the genus of conformers encompassed
by Appellants’ claim 16, at least one ligand must be able to distinguish
between the conformer and the wild-type protein (see Appellants’ Claim 16).
Therefore, Appellants’ claim 16 also encompasses a genus of ligands. For
the foregoing reasons, we are not persuaded by Appellants’ contention that
their Specification provides written descriptive support for the claimed

9 We note that Appellants’ claim 16 does not require the conformer made in
the first step of the method to be present in the sample (see Appellants’
claim 16).
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method, because the Specification provides generic methodology as to how
one might attempt to collect the necessary reagents to practice the claimed
method throughout its full scope (App. Br. 25). “The written description
requirement [serves to] . . . ensure[] that when a patent claims a genus by its
function or result, the specification recites sufficient materials to accomplish
that function.” Ariad, 598 F.3d at 1352. In this regard, the written
description requirement requires “more than a ‘wish’ or ‘plan’ for obtaining”
the claimed invention. Id. at 1350.
For the foregoing reasons, we are not persuaded by Appellants’
contention that:
App[ellants] are not claiming chemical compounds or
mechanical devices, but rather methods for detecting
conformers, the question is not whether detailed structural
descriptions are provided or lists of compounds for genuses
[sic]. The question is whether the routineer would recognize
that the App[ellants] possessed the invention as claimed, i.e.,
the invention described by the claims to the method for
detecting conformers on appeal here.
(App. Br. 26–27.)
We recognize, but are not persuaded by, Appellants’ contention that
“each of the limitations of the claims at issue in this Appeal has ipsissima
verba support in the Specification as filed” (App. Br. 23). “[G]eneric claim
language appearing in ipsis verbis in the original specification does not
satisfy the written description requirement if[, as here,] it fails to support the
scope of the genus claimed.” Ariad, 598 F.3d at 1350.
We recognize, but are not persuaded by, the post-filing date Marzi
reference, as well as the unpublished, non-dated, manuscripts of Alpert and
Saghafi, cited in the Lingappa Declaration (FF 19–21). “[A]ctual
‘possession’ or reduction to practice outside of the specification is not
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enough. Rather . . . it is the specification itself that must demonstrate
possession.” Ariad, 598 F.3d at 1352.
CONCLUSION OF LAW
The preponderance of evidence on this record supports Examiner’s
finding that Appellants’ Specification fails to provide written descriptive
support for the claimed invention. The rejection of claim 16 under the
written description provision of 35 U.S.C. § 112, first paragraph is affirmed.
Claims 18, 60, and 61 are not separately argued and fall with claim 16 (see
App. Br. 5 (“[c]laims 16, 18, 60, and 61 stand or fall together”).

Enablement:
ISSUE
Does the evidence of record support Examiner’s conclusion that
undue experimentation would be required to practice the claimed invention?
ANALYSIS
Examiner finds that Appellants’ Specification fails to “provide
sufficient enabling disclosure for the scope of the: 1) ligands used in
identification of a presence of a conformer and 2) signal sequences used to
generate the chimeric gene” (Ans. 4). Examiner’s rationale can be distilled
down to two major themes: (1) Appellants’ Specification does not provide
working examples for proteins other than prions and (2) it would require
undue experimentation to make and screen for conformers and ligands
encompassed by the genus set forth in Appellants’ claimed invention (see
Ans. 4–9 and 15–19). We are not persuaded.
Working examples are not required to satisfy the enablement
provision of 35 U.S.C. § 112, first paragraph. In re Strahilevitz, 668 F.2d
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1229, 1232 (CCPA 1982). Further, the fact “that some experimentation is
necessary does not preclude enablement; the amount of experimentation,
however, must not be unduly extensive.” Atlas Powder Co., v. E.I. DuPont
De Nemours & Co., 750 F.2d 1569, 1576 (Fed. Cir. 1984). Further, to the
extent that Examiner may be concerned that Appellants’ claimed invention
encompasses inoperative embodiments, the question is not whether
inoperative embodiments are encompassed by the scope of the claim, but
rather “if the number of inoperative combinations becomes significant, and
in effect forces one of ordinary skill in the art to experiment unduly in order
to practice the claimed invention.” Id.
“[T]he PTO bears an initial burden of setting forth a reasonable
explanation as to why it believes that the scope of protection provided by
that claim is not adequately enabled by the description of the invention
provided in the specification of the application.” In re Wright, 999 F.2d
1557, 1561–62 (Fed. Cir. 1993). Examiner, however, failed to establish a
factual basis on this record to support a finding that undue experimentation
would be required to practice Appellants’ claimed invention (see FF 28–30;
see generally Ans. 4–9 and 15–19; App. Br. 13–20; Reply Br. 2–5).
CONCLUSION OF LAW
The evidence of record fails to support Examiner’s conclusion that
undue experimentation would be required to practice the claimed invention.
The rejection of claims 16, 18, 60, and 61 under the enablement provision of
35 U.S.C. § 112, first paragraph is reversed.

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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
KRH