Ex Parte Shaaltiel et al

Patent Trial and Appeal Board

Feb 26, 2019

14375472 (P.T.A.B. Feb. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/375,472 07/30/2014
67801 7590 02/28/2019
MARTIN D. MOYNIHAN d/b/a PRTSI, INC.
P.O. BOX 16446
ARLINGTON, VA 22215
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Yoseph Shaaltiel
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.
59974 2570
EXAMINER
WORLEY, CATHY KINGDON
ART UNIT PAPER NUMBER
1662
NOTIFICATION DATE DELIVERY MODE
02/28/2019 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):
usptomail@ipatent.co.il
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte YOSEPH SHAAL TIEL, URI HAN ANIA, TALI KIZHNER,
YULIA MATIUHIN, LIAT FUX, and A VIDOR SHULMAN 1
Appeal2018-002109
Application 14/375,472
Technology Center 1600
Before RICHARD M. LEBOVITZ, JEFFREY N. FRED MAN, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
SCHNEIDER, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal2 under 35 U.S.C. § 134 from the Examiner's
rejection of claims to a recombinant human DNase I protein which have
been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Appellant identifies the Real Party in Interest as PROT ALIX, Ltd. Appeal
Br. 2.
2 We have considered and herein refer to the Specification of July 30, 2014
("Spec."); Final Office Action of Jan. 11, 2017 ("Final Act."); Appeal Brief
of Aug. 3, 2017 ("Appeal Br."); Examiner's Answer of Oct. 20, 2017
("Ans."); and Reply Brief of Dec. 19, 2017 ("Reply Br.").
Appeal2018---002109
Application 14/375,472
STATEMENT OF THE CASE
"The principal therapeutic use ofhmnan DNase has been to reduce the
viscoelasticity of pulmonary secretions (including mucus) in such diseases
as pneumonia and cystic fibrosis (CF), thereby aiding in the clearing of
respiratory airways." Spec. 1. "Recombinant human DNase I for
therapeutic use (domase alfa; Pulmozyme®) is currently produced in
mammalian cells (CHO cells)." Spec. 2. The Specification describes "an
isolated polynucleotide comprising a nucleic acid sequence encoding a
human DNase I protein, wherein said human DNase I protein is
translationally fused at the N-terminus to a plant endoplasmic reticulum
targeting signal peptide." Spec. 3.
Claims 24--28 are on appeal. 3 Claim 24 is the sole independent claim
on appeal and reads as follows:
24. An isolated plant expressed, secreted recombinant
human DNase I protein wherein the amino acid residue at
position 1 at the N-terminus of said human DNase I protein
consists of Glycine.
3 Claims 1, 12, 13, 19, 20, 22, 32-34, 37, 38, 40, and 42--45 are pending in
the application but have been withdrawn from consideration as directed to a
non-elected species. Final Act. 2.
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Application 14/375,472
Claims 24--28 have been rejected under 35 U.S.C. § 103(a) as
unpatentable over Shak4 in view of Gonda 5, Whitelam 6, Chrispeels 7,
Worley8 and Varshavsky. 9
DISCUSSION
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner's conclusion that the subject matter of
the claims would have been obvious over Shak combined with Gonda,
Whitelam, Chrispeels, Worley and Varshavsky.
The Examiner finds that Shak teaches the sequence of human DNase I
which is the same as SEQ ID NO: 5 of the present disclosure with the
exception that the sequence in Shak does not have glycine at the N-terminus.
Final Act. 6. The Examiner finds that Gonda teaches that the presence of
4 Steven Shak et al., RECOMBINANT HUMAN DNASE I REDUCES THE VISCOSITY
OF CYSTIC FIBROSIS SPUTUM, 87 Proc. Nat'l Acad. Sci. USA 9188
(1990)("Shak").
5 David Gonda et al., UNIVERSALITY AND STRUCTURE OF THEN-END RULE,
264 J. Bio. Chem. 16700 (1989) ("Gonda").
6 Gary C. Whitelam, THE PRODUCTION OF RECOMBINANT PROTEINS IN
PLANTS, 68 J. Sci. Food Agric. 1 (1995).
7 Maarten J. Chrispeels & Loic Faye, THE PRODUCTION OF RECOMBINANT
GLYCOPROTEINS WITH DEFINED NON-IMMUNOGENIC GLYCANS, in Transgenic
plants: a production system for industrial and pharmaceutical proteins
(Owen MRL, Pen J. (eds.) 1996) ("Chrispeels").
8 Cathy Kingdon Worley et al., ENGINEERING IN VIVO INST ABILITY OF
FIREFLY LUCIFERASE AND ESCHERICHIA COLI B-GLUCURONIDASE IN HIGHER
PLANTS USING RECOGNITION ELEMENTS FROM THE UBIQUITIN PATHWAY, 37
Plant Molecular Bio. 337 (1998) ("Worley").
9 Alexander Varshavsky, The N-end rule: Functions, mysteries, uses, 93
Proc. Nat'l Acad. Sci. 12142 (1996) ("Varshavsky").
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Appeal2018---002109
Application 14/375,472
leucine at the N-tenninal location significantly reduces the half-life of a
protein whereas the presence of glycine does not. Final Act. 6-7. The
Examiner finds that Whitelam teaches the production of recombinant
proteins in plants. Final Act. 7. The Examiner finds that Chrispeels also
teaches the production of recombinant proteins in plants. Id. The Examiner
finds that Worley teaches the N-end rule applies in plants and that leucine is
a very de-stabilizing terminal amino acid residue. Id. The Examiner finds
that Varshavsky teaches the applicability of the N-end rule for almost all
living organisms; that leucine is a de-stabilizing N-terminal residue; and that
glycine is a stabilizing reside. Final Act. 7-8.
The Examiner concludes
At the time the invention was made, it would have been
obvious and within the scope of one of ordinary skill in the art
to add a glycine to the N-terminus of human DNase I to
increase the half-life of the recombinant protein so that it could
accumulate to higher levels and have a longer half-life in vivo.
Because the N-End Rule has been shown to be universal (see
Gonda et al and Varshavsky et al), one would have had an
expectation of success in increasing the half-life by changing
the N-terminal amino acid to one of the "stabilizing" amino
acids (valine, methionine, glycine, or pro line).
At the time the invention was made, it would have been
obvious and within the scope of one of ordinary skill in the art
to express a human DNase I with a glycine at the N-terminus in
a plant system and target the recombinant DNase I for
secretion. Because Gonda et al and Worley et al and
Varshavsky each teach that leucine is a highly de-stabilizing N-
terminal amino acid residue that will lead to a very short half-
life, one would have been motivated to add a stabilizing amino
acid, such as glycine, to the N-terminus of the DNase I taught
by Shak et al. One would have been motivated to grow this
recombinant protein in a plant system, because Whitelam and
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Application 14/375,472
Chrispeels et al both teach advantages of plant systems over
other recombinant protein production systems. One would have
been motivated to target the protein for secretion because
Whitelam teaches that this increases the yield that can be
achieved. One would have had an expectation of success in
growing a recombinant protein in a plant system, because
Whitelam provides numerous examples of such success; and
one would have had an expectation of increasing the stability
by altering the N-terminal amino acid residue because Gonda et
al teach that the N-end Rule is universal, and Worley et al
demonstrate that the N-end Rule functions in plant systems, and
Varshavsky teaches the N-end Rule functions both with and
without the ubiquitin pathway.
Final Act. 8-9.
Principles of Law
[T]he examiner bears the initial burden, on review of the prior
art or on any other ground, of presenting a prima facie case of
unpatentability. If that burden is met, the burden of coming
forward with evidence or argument shifts to the applicant.
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992) (citation omitted).
Analysis
We adopt the Examiner's findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer regarding this rejection. We find the Examiner has established that
the matter of the claims would have been obvious to one of ordinary skill in
the art at the time the invention was made over Shak combined with Gonda,
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Application 14/375,472
Whitelam, Chrispeels, Worley and Varshavsky. Appellants have not
produced evidence showing, or persuasively argued, that the Examiner's
determinations on obviousness are incorrect. Only those arguments made by
Appellants in the Briefs have been considered in this Decision. Arguments
not presented in the Briefs are waived. See 37 C.F.R. § 4I.37(c)(l)(iv)
(2015). We have identified claim 24 as representative; therefore, all claims
fall with claim 24. We address Appellants' arguments below.
Appellants contend that the Examiner improperly applied hindsight in
making the rejection. Appeal Br. 6. Appellants argue that the Examiner has
not shown why one skilled in the art would combine the teachings of the
references to produce the claimed invention. Id. Appellants point to two
alleged errors in the rejection. Id.
The first alleged error cited by Appellants is that Worley teaches the
production of recombinant peptide in the peroxisome and not in the apoplast
as taught by the instant specification. Appeal Br. 6-7. Appellants contend
that the recombinant peptide in an apoplast would not see the same harsh
conditions found in the peroxisome and therefore stability of the peptide
would not be an issue. Appellants argue that the limitation in claim 24
calling for the peptide to be secreted links the peptide to production in the
apoplast. Appeal Br. 7. Appellants contend that a peptide created in the
apoplast would not see the same hostile environment in the peroxisome. Id.
Appellants contend that argument based on the change in activity of a
peptide produced in the peroxisome is applicable to a peptide produced in
the apoplast. Id.
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Application 14/375,472
We have considered Appellants' arguments and are not persuaded.
Appellants' argument is an attack on the individual teaching of Worley and
not on the combined references. "Non-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references. . . . [The reference] must be read,
not in isolation, but for what it fairly teaches in combination with the prior
art as a whole." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
As the Examiner points out, the N-end rule generally, and the
destabilizing effect of leucine has been shown in a number of different
organisms and in different organelles. Ans. 8. Appellants have not
persuasively demonstrated that the rule would not be applicable in the
apoplast compared with the other environments tested. Appellants have only
presented attorney argument about the conditions in the apoplast verses the
peroxisome and have not offered any evidence to support that argument. See
Appeal Br. 7. "Attorneys' argument is no substitute for evidence."
Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989).
We also note that the claim is drawn to the protein product, and not to
the method by which the protein was produced. Claim 24 does not even
have any product-by-process limitations. Thus, the argument regarding the
location of production is not drawn to a limitation of the claim. But even if
we treated this as a limitation, the process of making is only relevant "if the
process by which a product is made imparts 'structural and functional
differences' distinguishing the claimed product from the prior art"
Greenliant Systems, Inc. v. Xicor LLC, 692 F.3d 1261, 1268 (Fed. Cir.
2012). See In re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985) ("even though
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Application 14/375,472
product-by-process claims are limited by and defined by the process,
determination of patentability is based on the product itself;" "[t]he
patentability of a product does not depend on its method of production;" and
"[i]f the product in a product-by-process claim is the same as or obvious
from a product of the prior art, the claim is unpatentable even though the
prior product was made by a different process.")
The second error alleged by Appellants is that the Examiner
misapprehended the teachings of Worley. Appeal Br. 7. Appellants argue
that Worley teaches that other pathways unrelated to the n-terminal amino
acid may be the cause of the peptide instability. Id. Appellants contend that
this ambiguity of Worley negates the Examiner's reasoning regarding a
motivation to modify the peptide by adding a glycine residue. Appeal Br. 8.
Appellants contend that ubiquitin dependent degradation occurs in the
plant nucleus and not in the apoplast. Id. Appellants argue that one skilled
in the art would not be motivated to add a glycine to a peptide produced in a
region where ubiquitin dependent degradation does not occur. Appeal Br. 8.
Appellants argue that the Examiner's contentions that one skilled in the art
would been motivated to make the change to increase the half-life of the
recombinant protein is insufficient. Appeal Br. 9.
Appellants' arguments have been considered and are unpersuasive.
That the authors in Worley presented several possibilities of what
could case the reduction in activity, this does not detract from Worley's
teaching that the presence of leucine at the N-terminus results in less activity
when compared with other N-terminus amino acids. Ans. 9. This teaching
would provide the motivation to avoid leucine at the N-terminal amino acid.
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With respect to Appellants' argument concerning the ubiquitin
pathway, we agree with the Examiner that the references teach that the N-
end rule applies even in organisms and organelles where the ubiquitin
pathway does not exist. Ans. 10. For example, Varshavsky teaches that
leucine causes instability in E. coli where the ubiquitin pathway does not
occur. Varshavsky Table 1 and 12144. The overall teachings of the
reference is that the presence of leucine reduces the half-life of recombinant
peptides regardless of the organism involved and the location in the cell
where the peptide is produced. See, e.g., Gonda 16703, Table 1; Worley
341, Figure 2C; and Varshavsky 12143 Table 1. We agree with the
Examiner that this would lead one skilled in the art to introduce a stabilizing
amino acid such as glycine at the N-terminus. Ans. 10-11.
Appellants conclude by arguing that the Examiner improperly used
the claimed invention as an instruction manual or template to piece together
the invention from the individual references. Appeal Br. 9. We are
unpersuaded by this argument.
The court in McLaughlin explained that:
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level
of ordinary skill at the time the claimed invention was made
and does not include knowledge gleaned only from applicant's
disclosure, such a reconstruction is proper.
In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). As discussed above,
the Examiner's rejection is based on the teachings of the references which
show that the human DNase I has leucine at the N-terminus and that leucine
at that position causes instability. We agree with the Examiner that these
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Application 14/375,472
teachings would have led on skilled in the art to modify the human DNase I
to include a more stable amino acid, such as glycine at the N-terminus. Ans.
9. All of these teachings are found in the references.
Appellants have not pointed to any specific knowledge gleaned from
the instant disclosure that has been used to support the rejection. The
Examiner has used the claims as part of the rejection, this is not improper
hindsight. It is required for a proper analysis under 35 U.S.C. § 103(a). In
re Ochiai, 71 F.3d 1565, 1572 (Fed. Cir. 1995).
Conclusion of Law
We conclude that a preponderance of the evidence supports the
Examiner's conclusion that the subject matter of claim 24 would have been
obvious over Shak combined with Gonda, Whitelam, Chrispeels, Worley
and Varshavsky.
Claims 25-28 have not been argued separately and therefore fall with
claim 24. 37 C.F.R. § 4I.37(c)(l)(iv).
SUMMARY
We affirm the rejection under 35 U.S.C. § 103(a).
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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