Ex Parte 5241060 et al

Patent Trial and Appeal Board

Jun 26, 2015

90012361 (P.T.A.B. Jun. 26, 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.
90/012,361 06/15/2012 5241060 LT00682 REX 3726
31013 7590 06/26/2015
KRAMER LEVIN NAFTALIS & FRANKEL LLP
INTELLECTUAL PROPERTY DEPARTMENT
1177 AVENUE OF THE AMERICAS
NEW YORK, NY 10036
EXAMINER
KUNZ, GARY L
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
06/26/2015 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
____________

ENZO DIAGNOSTICS, INC.
Patent Owner and Appellant
____________

Appeal 2015-004280
Reexamination Control 90/012,361
Patent U.S. 5,241,060
Technology Center 3900
____________

Before ROMULO H. DELMENDO, JAMES T. MOORE, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on an appeal by Patent Owner, Enzo Diagnostics
(“Enzo”), from the Patent Examiner’s final rejection of claims 1 and 3 in this
ex parte reexamination proceeding. The Board’s jurisdiction for this appeal
is under 35 U.S.C. §§ 6(b), 134(b), and 306. We affirm.

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I. STATEMENT OF THE CASE
This appeal involves US 5,241,060 (“the ’060 patent”) which issued
August 31, 1993. The patent owner and real party in interest is Enzo
Diagnostics, Inc. Appeal Br. 1.
A Request for Ex Parte Reexamination of the ’060 patent was filed by
a Third Party Requester, Life Technologies Corporation, on June 15, 2012,
under 35 U.S.C. §§ 302–307 and 37 C.F.R. § 1.501, requesting
reexamination of claims 1, 2, and 3. Reexamination was ordered.
A Final Rejection confirming the patentability of claim 2 and rejecting
claims 1 and 3 was mailed by the Examiner on Nov. 8, 2013. Claims 1 and
3 stand rejected under 35 U.S.C. § 102(b) as anticipated by David E. Draper
and Larry Gold, “A Method for Linking Fluorescent Labels to
Polynucleotides: Application to Studies of Ribosome-Ribonucleic Acid
Interactions,” Biochemistry 19(9): 1774 - 1781 (1980) (hereinafter “Draper
(1980)”). Patent Owner appeals from the determination that claims 1 and 3
are unpatentable in view of Draper (1980). Appeal Br. 19, 21.
The ’060 patent expired on August 31, 2010 before the
Reexamination began. Appeal Br. 8. No amendment, other than the
cancellation of claims, can be incorporated into a patent by a certificate
issued after the expiration of the patent. 37 C.F.R. § 1.530(j).
According to Enzo, the ’060 patent is an asserted patent in two actions
currently pending in the Southern District of New York. Appeal Br. 2.

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II. CLAIMS
Claims 1 and 3 read as follows:
l. A nucleotide having the formula PM-SM-BASE-Sig wherein
PM is a phosphate moiety, SM is a sugar moiety, BASE is a
pyrimidine, purine or 7-deazapurine moiety, PM being attached
at the 3' or the 5' position of SM when the nucleotide is a
deoxyribonucleotide and at the 2', 3' or 5' position when the
nucleotide is a ribonucleotide, BASE being attached to the 1'
position of SM from the N1 position when BASE is a
pyrimidine or the N9 position when BASE is a purine or a 7-
deazapurine, and Sig is covalently attached to BASE at a
position other than the C5 position when BASE is a pyrimidine,
at a position other than the C8 position when BASE is a purine
and at a position other than the C7 position when BASE is a 7-
deazapurine and wherein Sig represents a detectable moiety.

3. An oligo- or polyribonucleotide comprising at least one
nucleotide in accordance with claim 1.

III. CLAIM INTERPRETATION
A. The Claims
Claim 1 of the ’060 patent is directed to a nucleotide of the formula
PM-SM-BASE-Sig, where PM is a phosphate moiety, SM is a sugar moiety,
BASE is pyrimidine, purine, or 7-deazapurine, and Sig represents a
detectable moiety. The claimed nucleotide is a mononucleotide and not a
residue within an oligonucleotide or polynucleotide. Appeal Br. 11-12. As
explained in the ’060 patent, the detectably labeled nucleotides are attached
to or incorporated into nucleic acid, such as DNA and RNA, making them
useful for many purposes, such as for hybridization probes and as immune-
stimulating agents. ’060 patent, col. 2, ll. 60–62; col. 27, ll. 14–29.
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Enzo contends that the claimed nucleotide must be capable of
attachment or incorporation into a DNA or other nucleic acid. Appeal Br.
14. This interpretation is reasonable in view of its dependence on claim 3
which is directed to an oligo- or polyribonucleotide comprising a nucleotide
of claim 1 and teachings in the ’060 patent that the claimed nucleotides are
“suitable for attachment to or incorporation into DNA or other nucleic acid
material.” ’060 patent, col. 2, ll. 60–62.
Claim 3 is directed to an “oligo- or polyribonucleotide comprising at
least one nucleotide in accordance with claim 1.” Thus, this claim requires
that a labeled mononucleotide according to claim 1 is incorporated into
RNA.
Enzo contends that the claims require the oligo- or polyribonucleotide
to be suitable for use as a hybridization probe. Appeal Br. 22. Specifically,
relying on the declaration by Steven E. Rokita, Ph.D.1 (“Rokita Decl.”),
Enzo argues:
[T]he ’060 patent . . . requires that the labeled nucleotides “are
capable of incorporation into nucleic acids and once
incorporated in nucleic acids the modified nucleotides do not
significantly interfere with the formation or stabilization of
the double helix formed of the resulting nucleic acids [i.e.,
when the oligo of claim 3 is used a a probe and hybridized to a
nucleic acid having a complementary sequence] containing the

1 Enzo provided a declaration by Dr. Rokita in support of the patentability of
claims 1 and 3 (dated May 6, 2013). Dr. Rokita has a Ph.D. in chemistry
and was a Professor of Chemistry at Johns Hopkins University at the time
his declaration was executed. Dr. Rokita testified that his research focuses
on nucleic acid chemistry. Rokita Decl. ¶ 1.

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modified nucleotides” (col. 2, line 65–col. 3, line 2). (See
Rokita Decl. ¶¶ 11–12).
Id. at 23 (emphasis added).
Enzo bases this interpretation on disclosure in the ’060 patent that
“[i]n accordance with the practices of this invention nucleotides are
modified . . . preparatory for the preparation therefrom of nucleotide probes
suitable for attachment to or incorporation into DNA or other nucleic acid
material” (’060 patent, col. 2, lines 57-62) and that “[a] particularly
important and useful aspect of the special nucleotides of this invention is the
use of such nucleotides in the preparation of DNA or RNA probes” (id. at
col. 25, lines 11-13). Reply Br. 1-2. See also Rokita Decl. ¶¶ 8, 11.

B. Legal standard
The ’060 patent has expired. The “Board’s review of the claims of an
expired patent is similar to that of a district court’s review, Ex Parte Papst-
Motoren, 1 U.S.P.Q.2d 1655, 1655–56 (B.P.A.I. Dec. 23, 1986); see also
MPEP § 2258 I.G (directing Examiners to construe claims pursuant to
Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en banc), during
reexamination of an expired patent).” In re Rambus, Inc., 694 F.3d 42, 46
(Fed. Cir. 2012). As explained in Phillips:
[C]laims “must be read in view of the specification, of which
they are a part.” [Markman v. Westview Instruments, Inc., 52
F.3d 967, 979 (Fed. Cir. 1995) (en banc), aff’d, 517 U.S. 370
(1996)]. [The] specification “is always highly relevant to the
claim construction analysis. Usually, it is dispositive; it is the
single best guide to the meaning of a disputed term.” [Vitronics
Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir.
1996).].
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Phillips, 415 F.3d at 1315.
Even under the mode of claim interpretation applicable in district
courts, it is inappropriate to import limitations appearing as preferred
embodiments into a claim. See, e.g., Silicon Graphics, Inc. v. ATI Techs.,
Inc., 607 F.3d 784, 792 (Fed. Cir. 2010) (“A construing court’s reliance on
the specification must not go so far as to import limitations into claims from
examples or embodiments appearing only in a patent’s written description
unless the specification makes clear that the patentee intends for the claims
and the embodiments in the specification to be strictly coextensive.”
(internal quotation marks omitted)).

C. Discussion
The weight of the evidence before us does not support Enzo’s
contention that the claims “require” the nucleotides of claim 1 to not
“significantly interfere with the formation or stabilization of the double helix
formed of the resulting nucleic acids containing the modified nucleotides.”
Appeal Br. 23 (quoting Draper (1980), col. 2, l. 65–col. 3, l. 2).
As mentioned by Enzo, the ’060 patent teaches:
In the practices of this invention nucleotides, i.e. nucleic acids,
preferably are modified in a non-disruptive manner such that
the resulting modified nucleotides are capable of incorporation
into nucleic acids and once incorporated in nucleic acids the
modified nucleotides do not significantly interfere with the
formation or stabilization of the double helix formed of the
resulting nucleic acids containing the modified nucleotides.
’060 patent, col. 2, l. 62–col. 3, l. 2 (emphasis added).
This statement indicates a preference for nucleic acids, formed from
the nucleotides of claim 1, which form stable double-helix arrangements.
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However, the claims are not explicitly recited to be limited to nucleic acid
“probes” which stably hybridize to complementary nucleic acids. We have
not been directed to verbiage in the claim which would require such an
interpretation.
In addition to the disclosure in the ’060 patent of probes with
sequences that substantially match DNA or RNA to be located or identified
(id. at col. 25, ll. 11-27), the patent expressly teaches that the
polynucleotides “have many uses and utilities.” Id. at col. 27, ll. 22–23.
Specifically, the patent teaches “[f]or example, the nucleotides of this
invention and polynucleotides containing the nucleotides of this invention
are useful as immune-stimulating agents, as adjuvants in vaccines, as agents
for the stimulation or induction from competent cells, such as lymphocytes,
for the production of l[y]mphokines, cytokines or cytokinins, interferon or
other cellular products.” Id. at col. 27, ll. 23–29. The ’060 patent further
teaches that single-stranded RNA is useful:
Of special interest in the practices of this invention
improved polynucleotides incorporating the special nucleotides
of this invention are provided as inducers or stimulating agents
for the production of interferon. Such polynucletoides [sic]
would be singl[e]-stranded or double-stranded ribonucleotides,
dsRNA.
Id. at col. 28, l. 62–67.
In addition to this, the cited Draper (1980) publication describes
making fluorescently labeled single-stranded RNA to study interactions
between the RNA and ribosomal proteins. Draper (1980) 1774, 1780 (col. 2,
section titled “Conclusion”). Thus, Draper (1980) provides evidence of a
well-established utility of single-stranded RNA as a binding partner to
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ribosomal proteins to study ribosome-RNA interactions, which does not
require nucleic acid hybridization. See M.P.E.P. § 2107 (a claim complies
with utility requirement of 35 U.S.C. § 101 when it has a well-established
utility).
In sum, while the ’060 patent expresses a preference for nucleic acids
which form stable double-stranded nucleic acid materials when used as
“probes,” the patent expressly covers other utilities and specifically
mentions single-stranded ribonucleotides as useful, a fact corroborated by
Draper (1980). Consequently, the evidence does not support Enzo’s
contention that the claims “require” that the claimed mononucleotides of
claim 1 cover only modified nucleotides which, when incorporated into a
nucleic acid, “do not significantly interfere with the formation or
stabilization of the double helix formed of the resulting nucleic acids
containing the modified nucleotides.” Appeal Br. 23.
Enzo also contends that claim 1 requires the recited nucleotide to be a
substrate for polymerase. Appeal Br. 20. However, Enzo has not pointed to
specific language in the claim that would warrant this narrow interpretation.
See Answer 10. At column 2, lines 57–62 of the ’060 patent, Enzo
acknowledges that it is disclosed that the nucleotides must be “suitable for
attachment or incorporation into DNA or other nucleic acid material.”
Appeal Br. 17.
However, such disclosure does limit the incorporation or attachment
to be accomplished using a polymerase. Indeed, as acknowledged by Enzo,
the patent teaches that “various techniques may be employed in the practices
of this invention for the incorporation of the special nucleotides of this
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invention into DNA and related structures.” ’060 patent, col. 25, ll. 41–44.
The patent also teaches that “[o]ne particularly useful technique referred to
hereinabove involves the utilization of terminal transferase.” Id. at col. 25,
ll. 44–46.
In addition, the patent discloses that, in one procedure, “small
molecules are bound to the nucleotide using the allyl amine side chain.
These nucleotides are then incorporated into specific nucleic acids using a
DNA or RNA polymerase or ligase reaction or a chemical linkage.” Id. at
col. 26, ll. 15–19 (emphasis added). In view of this broad disclosure of
various methods of attaching or incorporating nucleotides into nucleic acids,
and the lack of limiting language in the claim, we will not read the claim in
the narrow way advocated by Enzo.
While it is apparent that the primary purpose of the claimed
nucleotides described in the ’060 patent is as part of nucleic acid
hybridization probes to detect and identify nucleic acid sequences of interest,
this is not a license to import such a substantial purpose into the claim when
the claim language, itself, does not warrant it. It is improper to import
limitations from the specification into the claims. “For example, a particular
embodiment appearing in the written description may not be read into a
claim when the claim language is broader than the embodiment.”
Superguide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875 (Fed. Cir.
2004); Silicon Graphics, 607 F.3d at 792. As indicated above, non-
hybridization utilities are disclosed in the patent and are well-established in
the art. Thus, nucleotides for hybridization probes is not the only purpose
for which the claimed subject matter could be used.
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IV. ANTICIPATION BY DRAPER
The Examiner found that Draper (1980) describes a fluorescently
labeled mononucleotide “NBF-CMP” which meets all the structural
limitations of claim 1. Answer 3–4. See also Declaration of John F. W.
Keana, Ph.D.2 ¶¶ 16, 18. With respect to claim 3, the Examiner found that
Draper (1980) describes a polyribonucleotide which had been chemically
labeled with a fluorescent label (Answer 5).
Enzo contends that Draper (1980) does not describe the claimed
nucleotide because its NBF-CMP “could not have been a polymerase
substrate and one skilled in the art would have expected the linker and label
to interfere with hybridization.” Appeal Br. 20.
Enzo’s argument is not supported by persuasive evidence. First, the
claims do not require the recited nucleotide to be a polymerase substrate.
Answer 10–11. See also supra at p. 8. Second, even if the claims were so
limited, Enzo did not provide adequate objective evidence that Draper
(1980)’s nucleotide would not be a polymerase substrate. Enzo has not
otherwise structurally distinguished the claimed nucleotide from the
nucleotide described in Draper (1980).
Enzo also argues that the labeled nucleotides of Draper (1980)
destabilize polynucleotides from complexing with complementary
sequences. Rokita Decl. ¶ 12; Appeal 22. Enzo contends that such reduced
stability “would render the polynucleotides useless for the purposes of the

2 The declaration by Dr. Keana was submitted in the related litigation in
district court by defendant Amersham PLC.
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’060 patent, which . . . requires that the labeled nucleotides ‘are capable of
incorporation into nucleic acids and once incorporated in nucleic acids the
modified nucleotides do not significantly interfere with the formation or
stabilization of the double helix formed of the resulting nucleic acids
containing the modified nucleotides’ (col. 2, line 65-col. 3, line 2).”
This argument is based on a restrictive, unduly narrow, interpretation
of claims 1 and 3 to require that the nucleotides, when incorporated into a
polyribonucleotide, do not substantially interfere with duplex formation. As
explained in the claim interpretation section, the claimed nucleotide and
polyribonucleotide have other uses that do not involve probe hybridization.
Claims 1 and 3 are directed to compositions of matter, i.e., a
nucleotide and polyribonucleotide. Enzo attempts to distinguish the
compositions of matter from Draper (1980), arguing that “Draper (1980)
does not first prepare a labeled mononucleotide and then incorporate the
labeled mononucleotide into a probe as required by the claims of the ’060
patent.” Appeal Br. 21. Enzo did not provide adequate persuasive evidence
that the claim is limited to such an embodiment. Specifically, Enzo did not
identify language in the claim that would support its interpretation, which
imports process steps into a claim drawn to a composition of matter.
Enzo states that Draper (1980) teaches that cytosine would be
converted to uracil and that in some cases “up to 93% of the cytosine
residues were deaminated.” Appeal Br. 23-24. Based on this teaching, Enzo
concludes:
Thus, those of skill in the art would not have expected Draper
(1980)’s constructs would not [sic?] be useful as hybridization
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probes because deamination of cytosine (C) to uracil (U) would
preclude stable binding to the intended sequence.
Id. at 24.
Table 1, referenced by Enzo, shows that at certain conditions,
“deamination is heavily favored and the cytosine is completely consumed in
less than 24 h.” Draper (1980) 1776 (col. 2). However, Draper (1980) also
teaches conditions in which deamination to uracil does not substantially
occur, e.g., at pH 7.2. Id. Draper (1980) teaches: “By adjusting the reaction
conditions, we can prepare polynucleotides with any proportion of cytosine,
uracil, and N4-(3-aminopropyl)cytosine.” Id. Enzo’s argument, therefore,
has no merit because it overlooks explicit teachings in Draper (1980) of how
deamination of cytosine to uracil would be avoided.
To the extent that Enzo relies on David E. Draper, “Attachment of
reporter groups to specific, selected cytidine residue in RNA using a
bisulfite-catalyzed transmission reaction,” Nucleic Acids Research, 12(2):
989-1002 (1984) (hereinafter “Draper (1984)”), we shall not consider such
arguments since its publication date is after the filing date of the ’060 patent
and, therefore, its teaching were not available at the time of the invention.
Nonetheless, Enzo made several unsubstantiated arguments about alleged
deficiencies in Draper (1980) when discussing Draper (1984).
Enzo states “Draper (1980)’s methods would not be expected to be
useful for making hybridization probes because natural RNAs cannot be
labeled with the method of Draper (1980).” Appeal Br. 25 (emphasis
added). Enzo cited Draper (1984) to support this statement. Id. at 24-25.
However, Draper (1984) did not state that natural RNAs “cannot” be
labeled.
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The actual statement, as quoted by Enzo in the Appeal Brief, is as
follows: “Unfortunately none of these reaction schemes is well-suited for
placement of reporter groups in natural RNAs: either the reaction is very
slow and quantitative cytidine modification is difficult to achieve [footnote
to Draper (1980)] or the pyrimidine-bisulfite adduct is formed irreversibly.”
Draper (1984) 990 (Footnotes omitted.) Thus, Draper (1984) did not
characterize Draper (1980) as teaching that “RNAs cannot be labeled”
(Appeal Br. 25), rather that “the reaction is very slow and quantitative
cytidine modification is difficult to achieve.” Draper (1984) 990.
In addition to this, Enzo argues that “non-specific site modification
methods taught by Draper (1980) (as confirmed by Draper (1984)) would
not result in a useful hybridization probe for this additional reason because,
as Dr. Rokita explains, substantial homogeneity of labeling is required for a
hybridization probe to be useful.” Appeal Br. 25 (citing Rokita Decl. ¶ 15).
However, we have reviewed paragraph 15 of Dr. Rokita’s declaration, which
was referenced by Enzo for this statement, but do not find objective
evidence to substantiate his opinion.
Even if we assume arguendo that a proper construction of claims 1
and 3 requires the nucleotides to not interfere with hybridization to another
nucleotide sequence, we still are not persuaded that Draper (1980) does not
anticipate the claimed subject matter. The Examiner provided adequate
evidence that all the structures recited in claims 1 and 3 are described in
Draper (1980). The main argument against anticipation is that Draper
(1980) is said to “unambiguously teach[ ] that its polynucleotides destabilize
complexes with complementary sequences, stating that the Poly(C,NBF-C)
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derivatives will have ‘lower stability than Poly(C).’ (p. 1778).” Rokita Decl.
¶ 12. Based on this teaching, Dr. Rokita testified that probes containing the
Draper (1980) nucleotides would be “useless” for the purposes of the ’060
patent. Id.
However, the claims do not require any specific amount of stability,
and even if hybridization is less efficient, Dr. Rokita does not introduce
sufficient evidence that nucleic acids comprising a labeled nucleotide of
Draper (1980) would be unable to hybridize to a complement. To the
contrary, Draper (1980), at page 1778, specifically indicates that its labeled
poly(C, NBF-C) forms a double-helix with polyI. The ’060 patent, at
column 29, lines 51–66, describes poly rC:rI dsRNA. Enzo did not provide
evidence that the double-helix formed in Draper (1980) from the
poly(C,NBF-C) and poly(I) does not possess the same properties described
for it in the ’060 patent.
For the foregoing reasons, we conclude that the preponderance of the
evidence supports the Examiner’s determination that claims 1 and 3 are
anticipated by Draper (1980).
Requests for extensions of time in this ex parte reexamination
proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f).

AFFIRMED

peb

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PATENT OWNER:

KRAMER LEVIN NAFTALIS & FRANKEL LLP
Intellectual Property Department
1177 Avenue Of The Americas
New York, NY 10036

THIRD PARTY REQUESTOR:

Karen R. Zachow, Ph.D.
LIFE TECHNOLOGIES CORP., ATTN: IP DEPT.
5791 Van Alllen Way
Carlsbad, CA 92008