Ex Parte CASTLE et al

Patent Trial and Appeal Board

May 4, 2016

13084342 (P.T.A.B. May. 4, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/084,342 04/11/2011
52059 7590 05/06/2016
LIFE TECHNOLOGIES CORPORATION
Attn: IP Department
5823 Newton Drive
Carlsbad, CA 92008
FIRST NAMED INVENTOR
JOHN CASTLE
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
LT00089.l CON 9945
EXAMINER
WOOLWINE, SAMUEL C
ART UNIT PAPER NUMBER
1637
NOTIFICATION DATE DELIVERY MODE
05/06/2016 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):
LifetechDocket@system.foundationip.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOHN CASTLE, CHRISTOPHER K. RAYMOND, and
CHRISTOPHER ARMOUR1
Appeal2013-009913
Application 13/084,342
Technology Center 1600
Before DEMETRA J. MILLS, ERIC B. GRIMES, and JACQUELINE T.
HARLOW, 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
for amplifying mRNA, which have been rejected as indefinite and obvious.
We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
The Specification discloses "methods for selectively amplifying a
target population of nucleic acid molecules (e.g., all mRNA molecules
1 Appellants identify the Real Party in Interest as Life Technologies
Corporation. (Appeal Br. 3.)
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Application 13/084,342
expressed in a cell type except for the most highly expressed mRNA
species)." (Spec. 2:28-30.) The Specification states that "[i]t is often
undesirable to amplify highly expressed RNAs (e.g., ribosomal RNAs). For
example, in gene expression experiments that analyze expression of genes in
blood cells, amplification of numerous copies of abundant globin mRNAs,
or ribosomal RN As, may obscure subtle changes in the levels of rare
mRNAs." (Id. at 2:16-19.)
Claims 43-54 are on appeal. Claims 43 and 53 are illustrative and
read as follows:
43. A method for selectively amplifying total mRNA in a sample
containing total cellular RNA, the method comprising:
(a) contacting the sample containing total cellular RNA with a
population of oligonucleotides comprising the structure P-N and a reverse
transcriptase under conditions which allow for the generation of single-
stranded cDNA molecules complementary to all of the mRNA molecules,
where P is a promoter element and N is a sequence of six nucleotides
complementary to all of the mPJ'.Jii .. molecules;
(b) converting the single-stranded cDNA molecules produced in (a) to
double-stranded cDNA molecules; and
( c) generating RNA molecules from the double-stranded cDNA
molecules by in vitro transcription.
53. A method for selectively amplifying total mRNA in a sample
containing total cellular RNA, the method comprising:
(a) contacting the sample containing total cellular RNA with a
population of oligonucleotides comprising the structure P-N and a reverse
transcriptase under conditions which allow for the generation of single-
stranded cDNA molecules complementary to all of the mRNA molecules,
where P is a promoter element and N is a sequence of six nucleotides
complementary to the members of the RNA subset;
(b) converting the single-stranded cDNA molecules produced in (a) to
double-stranded cDNA molecules; and
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( c) generating RNA molecules from the double-stranded cDNA
molecules by in vitro transcription, wherein the population of
oligonucleotides comprising the structure P-N, comprises oligonucleotides
formed by:
(i) determining all of the possible combinations of nucleotide
sequences for N;
(ii) eliminating nucleotide sequences for N with sequence
complementarity to ribosomal RNA; and
(iii) synthesizing all oligonucleotides comprising the structure P-N
oligonucleotides, where N is a sequence not eliminated in step (ii), to form
the population of oligonucleotides comprising the structure P-N.
The claims stand rejected as follows:
Claims 53 and 54 under 35 U.S.C. § 112, second paragraph, as
indefinite (Non-final Rej. 2 2) and
Claims 43-54 under 35 U.S.C. § 103(a) as obvious based on Ziman,3
Christians,4 and McClelland5 (Non-final Rej. 3).
I
The Examiner has rejected claims 53 and 54 as indefinite, on the basis
that "[c]laim 53 recites the limitation 'the RNA subset' in the last line of step
(a). There is insufficient antecedent basis for this limitation in the claim ....
It is unclear what 'the RNA subset' refers to." (Non-final Rej. 2-3.)
Appellants argue that "[i]t would be clear to one of skill in the art that
'the RNA subset' referred to in section (a) of claim 53 are the mRNA
2 Office Action mailed June 7, 2012.
3 Ziman et al., US 2004/0081978 Al, pub. Apr. 29, 2004.
4 Christians et al., US 2005/0003369 Al, pub. Jan. 6, 2005.
5 McClelland et al., WO 99/11823, pub. Mar. 11, 1999.
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molecules complementary to the N component of the oligonucleotide."
(Appeal Br. 6.)
We agree with the Examiner, however, that the claim language does
not make clear which "RNA subset" is intended. The Examiner has pointed
out that "[t]otal cellular RNA (see step 'a') would contain, in addition to
mRNA and ribosomal RNA, non-mRNA species such as transfer RNA
(tRNA), micro RNA (miRNA), and intron RNA (which is spliced out of the
original RNA transcript to leave mRNA)." (Ans. 2.) Any one or more of
these types of RNA could be considered an "RNA subset."
Although Appellants argue that those skilled in the art would
understand the claim to refer to mRNAs that are complementary to the N
component of the oligonucleotides (Appeal Br. 6), claim 53 states that "N is
a sequence of six nucleotides complementary to the members of the RNA
subset," not "complementary to mRNA." If Appellants intend a sequence of
six nucleotides complementary to mRNA, there would seem to be no reason
not to amend the claim to state that clearly, as claim 43, for example, does.
See In re Zletz, 893 F.2d 319, 321 (Fed. Cir. 1989) ("[D]uring patent
prosecution when claims can be amended, ambiguities should be recognized,
scope and breadth of language explored, and clarification imposed.").
II
Issue
The Examiner has rejected all of the claims on appeal as obvious
based on Ziman, Christians, and McClelland. The Examiner finds that
Ziman teaches "a method for amplifying RNA (preferably mRNA) using a
population of oligonucleotides to prime the amplification of said target
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nucleic acid molecules," where the oligonucleotides comprise a promoter
and a random sequence that can be six nucleotides long. (Non-final Rej. 4.)
The Examiner also finds that Ziman teaches generating single- and double-
stranded cDNAs and carrying out in vitro transcription to generate RNA.
(Id. at 5.)
The Examiner finds that Christians teaches that very abundant RNAs,
such as ribosomal RNA or globin mRNA in blood samples, should be
removed when they are not of interest for subsequent analysis. (Id. at 6.)
The Examiner finds that McClelland teaches an alternative way of depleting
unwanted nucleic acids such as ribosomal RNA in a sample, by "excluding
certain primers from a list of all possible primers, so as not to amplify any
'undesirable' nucleic acid sequences." (Id.)
The Examiner concludes that it would have been obvious "to modify
the method taught by Ziman by excluding sequences of the hybridizing
portion of the random promoter-primer that were complementary to
ribosomal RNA, as taught by McClelland" in order to avoid amplifying it,
and to exclude sequences hybridizing to globin RNA because Christians also
taught that it was problematic. (Id. at 7-8.) The Examiner found that
Christians teaches that both ribosomal RNA and globin RNA cause
problems in gene expression analysis, which is taught by Ziman, and a
skilled worker "would have realized that McClelland' s approach was also a
suitable solution." (Id. at 8.)
Appellants contend that "the core of the McClelland et al. disclosure
is directed to primer pairs designed to amplify 'related' nucleotide
sequences" (Br. 7) and that"[ o ]ne skilled in the art would consider
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individual statements in McClelland et al. in the context of the subject
matter addressed therein" (id. at 9). Appellants also argue that neither
Ziman nor Christians teach eliminating sequences complementary to
abundant nucleic acid molecules from a random sequence pool. (Id. at 11-
12.) Finally, Appellants argue that they have provided evidence of
commercial success that overcomes the Examiner's prima facie case of
obviousness. (Id. at 13-19.)
The issues presented are (a) whether the method of claim 43 would
have been obvious to a person of ordinary skill in the art based on the cited
references, and (b) whether Appellants' evidence of commercial success,
when weighed with the evidence favoring obviousness, shows that the
claimed method would have been nonobvious.
Findings of Fact
1. Ziman discloses a "random-primed reverse transcriptase-in vitro
transcription method of linearly amplifying RNA." (Ziman i-f 10.)
2. In Ziman's method, "source RNA ... , preferably, mRNA, is
converted to double-stranded cDNA using two random primers, one of
which comprises a RNA polymerase promoter sequence ('promoter-
primer'), to yield a double-stranded cDNA that comprises a RNA
polymerase promoter that is recognized by a RNA polymerase." (Id.)
3. "The double-stranded cDNA is then transcribed into RNA by the
RNA polymerase." (Id.)
4. Ziman states that its method uses "a first set of oligonucleotides,
each of which comprises a promoter sequence and a sequence from a set of
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random sequences of at least 4 nucleotides (but preferably 6 to 9 nucleotides,
more preferably 9 nucleotides)." (Id. at i-f 11.)
5. Ziman states that "[i]n general, it is preferable for the RNA-
containing sample to contain purified poly-A+ RNA (mRNA). In one
embodiment, a random promoter-primer is hybridized with an initial mRNA
(poly-A+ RNA) sample." (Id. at i-f 41.)
6. Christians teaches that "[ o ]ften complex samples are comprised of
high levels of some nucleic acids that are not of interest for subsequent
analysis. Removal of these unwanted nucleic acids from the sample by
depletion ... may be used to generate an amplified sample for analysis."
(Christians i-f 4 7.)
7. Christians describes a "method for depleting RNA species from
nucleic acid samples." (Id. at i-f 48.) "[T]he method may be used to remove
globin mRNAs from samples derived from human blood. Applications
include, for example, methods to increase the relative abundance of protein-
encoding RNAs (mRNAs) by depleting the very abundant RNAs, such as
ribosomal RNA." (Id.)
8. McClelland discloses "a method of determining a set of primer
pairs for amplifying a group of related nucleotide sequences." (McClelland
3: 14--16.) McClelland states that "related nucleotide sequences" include
those having common structural features, or "a common feature such as
being involved in DNA repair or ... the common feature of being expressed
in a particular human cell." (Id. at 6:30 to 7:3.)
9. McClelland states that
[a] computer process can compile a list of all possible primers
composed of short nucleotide sequences that can function as
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Application 13/084,342
PCR primers. . . . The computer process provides an advantage
in that a large number of possible primers can be considered .. .
and the primers can be restricted by specific criteria, such as .. .
restricted to exclude matches to undesirable nucleotide
sequences, for example, ribosomal RNA sequences.
(Id. at 11 :33 to 12: 11.)
10. McClelland states that "[a]bundant nucleotide sequences such as
mitochondrial DNA and ribosomal RNA ... can lead to high background if
primers in the set hybridize to these sequences during PCR. Thus, primers
that match such abundant sequences can be eliminated from the compiled
list of possible primers." (Id. at 13:5-11.)
11. McClelland states that "[r]emoval of background contributed by
the abundant mRNA sequences ... would increase the likelihood of
detecting amplified products from the less abundant mRNA sequences." (Id.
at 14:33 to 15:5.)
Principles of Law
"An examiner bears the initial burden of presenting a prima facie case
of obviousness. Once the examiner establishes a prima facie case of
obviousness, the burden shifts to the applicant to rebut that case." In re
Huai-Hung Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011) (citation omitted).
"[T]he Patent and Trademark Office (PTO) ... must consider
objective evidence of nonobviousness - e.g. commercial success." In re
Huang, 100 F.3d 135, 139 (Fed. Cir. 1996).
"In the ex parte process of examining a patent application, however,
the PTO lacks the means or resources to gather evidence which supports or
refutes the applicant's assertion that the sales constitute commercial
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success .... Consequently, the PTO must rely upon the applicant to provide
hard evidence of commercial success." Id. at 139-140.
Commercial success "is relevant in the obviousness context only if
there is proof that the sales were a direct result of the unique characteristics
of the claimed invention - as opposed to other economic and commercial
factors unrelated to the quality of the patented subject matter." Id. at 140.
"In other words, a nexus is required between the sales and the merits of the
claimed invention." Id.
Prima facie Obviousness
We agree with the Examiner that Ziman, Christians, and McClelland
would have made obvious the method of claim 43. Ziman, in fact, discloses
a method that includes all three of the steps of the claimed method (FF 1-
FF 4 ). Ziman differs from claim 43, however, in disclosing that its promoter-
primers have a random primer sequence (FF2); thus, its primers would be
expected to collectively include every sequence of a given length, which
would amplify all of the RNA in a sample, rather than "selectively
amplifying total mRNA in a sample," as recited in claim 43.
Christians discloses that the presence of abundant RN As, such as
globin mRNA or ribosomal RNA, in a sample decreases the relative
abundance of mRNAs of interest (FF6, FF7). Christians suggests removing
the unwanted nucleic acids from the sample (FF6), and McClelland suggests
restricting primers to exclude those that match undesirable nucleotide
sequences such as ribosomal RNA (FF9). McClelland states that removal of
the background caused by amplified abundant mRNAs and ribosomal RNA
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increases the likelihood of detecting amplified products from less abundant
mRNAs (FFlO, FFl 1).
Based on these teachings, it would have been obvious to modify
Ziman' s method by eliminating primer sequences that match undesired
abundant RNA species such as ribosomal RNA. McClelland provides a
reason to make such a modification because it states that eliminating those
primers reduces background and increases the likelihood of detecting
amplified products from the less abundant mRNAs of interest.
Appellants argue that neither Ziman nor Christians "contain disclosure
related to the elimination of sequences complementary to abundant nucleic
acid molecules from the random sequence pool." (Br. 12.) While true, this
argument does not address the basis of the Examiner's rejection, which
relies on McClelland' s disclosure of eliminating primers containing
sequences complementary to abundant nucleic acids.
With regard to McClelland, Appellants argue that its method is
directed to using primer pairs to amplify related nucleotide sequences, and
that "one skilled in the art would focus consideration of McClelland et al. on
primer pairs designed to amplify structurally related nucleic acid
molecules." (Id. at 8.)
Again, however, Appellants are not addressing the rationale
underlying the Examiner's rejection, which relies on the basic method of
Ziman, and cites McClelland as providing a reason to modify Ziman's
method in the manner required by claim 43. As discussed above,
McClelland discloses removing primer sequences that are complementary to
abundant RNA sequences such as ribosomal RNA, and provides a reason to
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incorporate that feature in Ziman' s method. Whether McClelland' s
remaining disclosure would have suggested other aspects of the method of
claim 43 is not germane to the basis of the rejection.
Commercial Success
Appellants argue that they have provided evidence of commercial
success that supports patentability of the claimed method, which
"encompasses processes used in the Life Technologies product known as the
'Ambion® WT Expression Kit."' (Br. 14.) Appellants argue that "the
Ambion® WT Expression Kit has been optimized for use with Affymetrix®
GeneChip® Human, Mouse, and Rat 1.0 ST Arrays" (id.) and is the subject
of a "co-marketing arrangement between Affymetrix and Ambion" (id. at
16, citing the Bittick/Setterquist Declaration6). Appellants also argue that
"Affymetrix recommends the use of the Ambion® WT Expression Kit for
use with their GeneChip® WT Terminal Labeling and Controls Kit and
provides on their website a direct link to Ambion's website for ordering the
product." (Id., citing the Bittick Declaration.7)
Appellants argue that, compared to prior methods, the "methods
claimed in the captioned application eliminate the need for rRNA depletion
and enables faster, more sensitive, and reproducible results." (Id. at 14.)
Appellants point to the Bittick Declaration as evidence that the Ambion®
WT Expression Kit generated about $3 .3 million in sales in 2010. (Id. at
6 Combined Declarations of Tom Bittick and Robert Setterquist under 37
C.F.R. § 1.132, signed Oct. 3 and 4, 2011.
7 Declaration of Thomas Bittick under 37 C.F.R. § 1.132, signed Feb. 11,
2011.
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16. 8) Appellants estimate that the Ambion® WT Expression Kit has a 7 5-
80% share of the "total market of products which can be used or adapted for
use with the Affymetrix® GeneChip Human, Mouse, and Rat 1. 0 ST
Arrays" but also note that the size of this market is "difficult to quantify."
(Id.)
Appellants cite the Baldwin Declaration9 as evidence that a customer
"switched from the Affymetrix kit to the Ambion kit while the Affymetrix
kit was still on the market," based on the advantages of the Ambion kit. (Id.
at 17.) Appellants also argue that Life Technologies bought a package of
intellectual property that included the instant application based largely on
the perceived value of the patent family of the application on appeal. (Id.,
citing the Second Setterquist Declaration. 10)
We conclude that Appellants' evidence is inadequate, when weighed
with the evidence provided by Ziman, Christians, and McClelland, to show
that the claimed method would have been nonobvious. Appellants have
provided evidence that the Ambion® WT Expression Kit had sales of
$682,016 in the last half of 2009 and $3,277,485 in 2010. (Bittick
Declaration i-f 3.) However, "evidence related solely to the number of units
sold provides a very weak showing of commercial success." In re Huang,
8 Appellants also allege sales figures for 2011 and 2012, but concede that the
Bittick Declaration does not provide evidence to support the argument. (Id.
at 16, n.4.)
9 Declaration of Donald A. Baldwin under 37 C.F.R. § 1.132, signed Sept.
19, 2011.
10 Declaration of Robert Setterquist under 37 C.F.R. § 1.132, signed Feb. 10,
2011.
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100 F.3d 135, 140 (Fed. Cir. 1996). Appellants also state that they "estimate
that the size of the 2011 market (i.e., reagents for the preparation of samples
for use with the Affymetrix® GeneChip Human, Mouse, and Rat 1.0 ST
Arrays) is about $5 million with the Ambion® WT Expression Kit
encompassing about 7 5% to 80% of that market." (Bittick/Setterquist
Declaration i-f 11.)
We do not give this evidence much weight, however, for two reasons.
First, Appellants have not presented evidence of the 2011 sales of the
Ambion kit that would support an estimate that its sales make up 7 5-80% of
the relevant market. Appellants present arguments in their brief that allege
certain sales figures for 2011 and 2012, but attorney argument is not
evidence. In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) ("Attorney's
argument in a brief cannot take the place of evidence."). Second, Appellants
have provided no data to support their estimate of the size of the relevant
market or of other products that are also sold in that market. Appellants
acknowledge, in fact, that the market share is "difficult to define" but
provide no explanation of how they attempted to define it anyway.
(Bittick/Setterquist Declaration i-f 10.) Because the estimate of 75-80% of
the relevant 2011 market is supported by no data whatsoever, it is entitled to
little, if any, weight as evidence of nonobviousness.
In addition, commercial success "is relevant in the obviousness
context only if there is proof that the sales were a direct result of the unique
characteristics of the claimed invention - as opposed to other economic and
commercial factors unrelated to the quality of the patented subject matter."
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In re Huang, 100 F .3d at 140. "In other words, a nexus is required between
the sales and the merits of the claimed invention." Id.
The Bittick Declaration states that "[ c ]ustomer have [sic, has?]
indicated to me that the WT Expression Kit streamlines their work flow in
that fewer sample preparation steps are required .... I have also been told
that the lower amount of total RNA that is required, as compared to previous
methods they have used, is another positive feature." (Bittick Declaration
i-f 6.) These vague statements about anecdotal reports are entitled to little
weight as evidence, however. See In re Huang, 100 F.3d at 140 ("[T]he
applicant must submit some factual evidence that demonstrates the nexus
between the sales and the claimed invention - for example, an affidavit from
the purchaser explaining that the product was purchased due to the claimed
features.").
The Baldwin Declaration does provide evidence that one customer
switched from the Affymetrix kit to the Ambion kit based on two technical
features: the ability to use smaller samples and production of reproducible
amounts of copy RNA when similar samples are used. (Baldwin Deel. i-fi-12,
3.) However, the Baldwin Declaration also states that another reason for the
switch was "due to [the] cost effectiveness of the Ambion product." (Id. at
i-f 4.) In other words, using the Ambion product was cheaper than using the
Affymetrix product.
In addition to the evidence of "cost effectiveness," Appellants'
evidence also shows that the Ambion product is co-marketed with
Affymetrix (Bittick Deel. i-f 4) and that Affymetrix promotes the Ambion kit
for use with its exon arrays (id. at i-f 5). Appellants have also stated that
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Affymetrix provides on its website a direct link to the Ambion product for
ordering it. (Br. 16.) These factors suggest that part of the success of the
Ambion kit is due to marketing and the convenience with which it can be
purchased, rather than its technical merits.
Thus, considering the evidence of commercial success as a whole, we
conclude that it lacks probative value as to the extent of the market share and
is ambiguous as to the extent that the sales of the Ambion kit are due to
technical aspects of the claimed method rather than to price, marketing, and
ease of purchase. As such, the evidence of commercial success is entitled to
little weight as evidence of nonobviousness.
Appellants also cite the Second Setterquist Declaration as evidence
that Life Technologies acquired the patent family that includes the instant
application because they thought it would be valuable. (Br. 17.) It is
unclear, however, why Appellants' after-the-fact recognition of the
advantages of the claimed method should be taken as evidence that the
method would not have been obvious to a person of ordinary skill in the art
at the time it was actually made. The Second Setterquist Declaration
therefore is entitled to little or no weight as evidence of nonobviousness.
Finally, Appellants present an "Invention 'Timeline"' as evidence that
"[t]he difference in time between filing of Appellants['] earliest priority
application date (October 27, 2005) and June 2, 2002 is about three and a
half years." (Br. 20.) Even Appellants acknowledge, however, that "three
and a half years is not an exceptionally long period of time." (Id.) To the
extent Appellants are trying to show a long-felt but unsolved need, "long-felt
need is analyzed as of the date of an articulated identified problem and
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evidence of efforts to solve that problem." Texas Instruments, Inc. v.
International Trade Comm., 988 F.2d 1165, 1178 (Fed. Cir. 1993).
Appellants have not provided evidence to show that the present invention
solves a long-felt but previously unsolved need.
Conclusion of Law
The method of claim 43 would have been obvious to a person of
ordinary skill in the art based on the cited references. Appellants' evidence
of commercial success, when weighed with the evidence favoring
obviousness, does not show that the claimed method would have been
nonobvious.
Claims 44--54 have not been argued separately and therefore fall with
claim 43. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm both of the rejections on appeal.
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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