Ex Parte Hoerr et al

Patent Trial and Appeal Board

Jun 21, 2018

13361686 (P.T.A.B. Jun. 21, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/361,686 01/30/2012
108197 7590 06/25/2018
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
Austin, TX 78746
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Ingmar Hoerr
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.
CRVC.P0022US.Cl 9807
EXAMINER
MARVICH, MARIA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
06/25/2018 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):
docket@phiplaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte INGMAR HOERR and STEVE PASCOLO
Appeal2016-004249
Application 13/361,686
Technology Center 1600
Before DEBORAH KATZ, JOHN E. SCHNEIDER, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
SCHNEIDER, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134(a) involving claims to
method for stimulating an immune response which have been rejected as
obvious. 2 We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Appellants identify the Real Party in Interest as Cure Vac GmBH. Appeal
Br. 3.
2 Oral argument was held on June 13, 2018. A copy of the transcript will be
added to the file when it becomes available.
Appeal2016-004249
Application 13/361,686
STATEMENT OF THE CASE
Vaccines have been developed that use either DNA or messenger
RNA ("mRNA") to induce an immune response. Spec. 1-3. mRNA
vaccines have advantages over DNA vaccines in that they are more stable,
do not integrate into the host genome and no viral sequences are needed to
ensure transcription. Spec. 3--4. One disadvantage of mRNA vaccines is
that they induce only a humoral immune response (Th2 type) as opposed to a
cellular immune response (Thl type). Spec. 4--5. This limits their
effectiveness against viruses and certain bacteria. Id.
The specification describes a "novel system for gene therapy and
genetic vaccination which ensures a more effective immune response and
therefore a more effective protection, in particular against intracellular
pathogens and the diseases caused by these pathogens, or also against
tumours," Spec. 5.
Claims 22-24, 27--41, 44, and 45 3 are on appeal. Claim 29 is the sole
independent claim and reads as follows:
29. A method for stimulating an antigen-specific Th I -
type immune response in a mammal, the method comprising the
following steps:
(a) administering to the mammal at least one antigen
mRNA which codes for at least one antigen of a pathogen or
codes for at least one tumour antigen; and
(b) administering to the mammal at least one cytokine
mRNA, which encodes IL-12, thereby producing a Thl-type
immune response in a mammal specific for said at least one
antigen of a pathogen or tumour antigen.
3 Claim 26 is pending in the application but has been withdrawn from
consideration. Final Act. 1.
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The claims have been rejected as follows:
Claims 22-24, 27-32, 35--40, 44, and 45 have been rejected under 35
U.S.C. § I03(a) as unpatentable over Daley4 in view ofHorton5 and
Terman. 6
Claims 33 and 34 have been rejected under 35 U.S.C. § I03(a) as
unpatentable over Daley in view of Horton and Terman in further view of
Cannon 7, Draghia-Aldi 8 or Weiner. 9
Claim 41 has been rejected under 35 U.S.C. § I03(a) as unpatentable
over Daley in view of Horton and Terman in further view of Daly. 10
DISCUSSION
Daley Combined with Horton and Terman
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
4 Daley et al., US 5,928,649, issued July 27, 1999 ("Daley").
5 Horton et al., US 7,268,120 Bl, issued Sept. 11, 2007 ("Horton").
6 Terman, US 2005/0112141 Al, published May 26, 2005 ("Terman").
7 Cannon and Weissman, RNA Based Vaccines, 21 DNA and Cell Biology
953 (2002) ("Cannon").
8 Draghia-Akli et al., US 7,316,925 B2, issued Jan. 8, 2008 ("Draghia-
Akli").
9 Weiner et al., US 2002/0123099 Al, published Sept. 5, 2002 ("Weiner").
10 Daly, US 2004/0209274 A2, published Oct. 21, 2004 ("Daly").
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claims 22-24, 27-32, 35--40, 44, and 45 would have been obvious over
Daley combined with Horton and Terman.
The Examiner finds that Daley teaches the co-administration of a
tumor antigen and a cytokine to suppress or prevent immunosuppression of
antigenic response. Final Act. 4. The Examiner also finds that Horton and
Terman both teach the use of mRNA, including mRNA which codes for IL-
12, as immune enhancers. Id. at 4--5. The Examiner finds that Horton and
Terman teach the use of mRNA encoding for a tumor antigen along with
mRNA encoding for a cytokine. Id. The Examiner concludes:
It would have been obvious to one of ordinary skill in the
art at the time the invention was made to use mRNA as taught
by Horton et al and Terman et al in the treatment protocol of
Daley et al because Horton et al and Terman et al teach that it is
within the ordinary skill of the art to use vaccines that are
mRNA as well as cytokine mRNA for therapy. Furthermore,
Terman et al teach that association of the polynucleotide with 5'
and 3' UTRs from globin is well known in the art. Given that
expression of the mRNA is explicitly produced with the UTRs
of globin, the vector is inherently attributed with the properties
accorded the beta globin sequences. In KSR International Co. v.
Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007), the Supreme Court
particularly emphasized "the need for caution in granting a
patent based on a combination of elements found in the prior
art," (Id. At 1395) and discussed circumstances in which a
patent might be determined to be obvious. Importantly, the
Supreme Court reaffirmed principles based on its precedent that
obviousness in part is predicated on use of particular known
techniques that are recognized as part of the ordinary
capabilities of one skilled in the art. In the instant case, it is
accepted that mRNA vaccination methods are preferable as set
forth above and to this end cytokine administration after antigen
administration is preferable. Based upon the teachings of the
cited references, the high skill of one of ordinary skill in the art,
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and absent evidence to the contrary, there would have been a
reasonable expectation of success to result in the claimed
invention.
Id. at 7-8.
Appellants contend that the references do not teach or suggest the use
of both an mRNA specific to a tumor or a pathogen and an mRNA encoding
for IL-12. Br. 6. Appellants contend that one skilled in the art would not
have been motivated to combine the teachings of the references and would
not have a reasonable expectation of success. Br. 7. Appellants also
contend that there is evidence of unexpected results sufficient to overcome a
prima facie case of obviousness. Br. 9.
With respect to claim 36, Appellants contend that the references do
not teach or suggest the limitation calling for one IRES or at least one 3'
stabilizing sequence.
With respect to claims 23, 24, and 28, Appellants contend that the
references do not teach or suggest the use of an RN Ase inhibitor.
Findings of Fact
We adopt the Examiner's findings as our own, including with regard
to the scope and content of, and motivation to modify or combine, the prior
art. The following findings are included for emphasis and reference
purposes.
FF 1. Daley discloses the administration of a cytokine or a cytokine
inducer to improve the efficiency of existing live or killed vaccines. Daley
col. 3, 11. 24--25.
FF2. Daley defines a cytokine inducer as an agent that "elicits
endogenous release of production of a cytokine." Daly col. 3, 11. 55-57.
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FF3. Horton teaches the use of a polynucleotide construct encoding
for a cytokine to treat cancer. Horton col. 7, 11. 41-50.
FF4. Horton teaches "In one embodiment, the polynucleotide
sequence encoding one or more cytokines is RNA. Most preferably, the
RNA is messenger RNA (mRNA)." Horton col. 30, 11. 55-57.
FF5. Horton teaches
For the methods of the present invention, a single
polynucleotide construct containing more than one
polynucleotide sequences encoding one or more molecules, or
more than one polynucleotide constructs each containing
polynucleotide sequences encoding one or more molecules may
be co-injected or sequentially injected. For example, a single
polynucleotide construct containing one polynucleotide
encoding an interferon and another polynucleotide encoding an
additional cytokine or an immunomodulatory molecule, i.e.,
MHC class I antigen, tumor antigen, and co-stimulatory
molecule, can be injected. Alternatively, two polynucleotide
construct can be injected where one encodes a cytokine to
enhance anti-tumor efficacy of the other gene product.
Horton col. 32, 11. 32--44. ( emphasis added)
FF6. Horton teaches that IL-12 is one of the cytokines that can be
used in practice of the invention. Horton col. 29, 11. 53-55.
FF7. Terman discloses a method for treating tumors. Terman
Abstract.
FF8. Terman teaches the use of mRNA to produce tumor specific
antigens. Terman ,r 376.
FF9. Terman teaches that IL-12 is necessary for NKT activation,
which is necessary for Thl response. Terman ,r,r 19, 91, and 308.
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Principles of Law
[T]he examiner bears the initial burden, on review of the
prior art or on any other ground, of presenting a prim a f acie
case ofunpatentability. 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).
"To be particularly probative, evidence of unexpected results must
establish that there is a difference between the results obtained and those of
the closest prior art, and that the difference would not have been expected by
one of ordinary skill in the art at the time of the invention." Bristol-Myers
Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014).
Analysis
Appellants do not persuade us that a preponderance of the evidence
fails to support the Examiner's conclusion that the method recited in claims
22-24, 27-32, 35--40, 44, and 45 would have been obvious over Daley
combined with Horton and Terman. To the contrary, we agree with the
Examiner's findings of fact, and conclusion of obviousness derived
therefrom, and adopt them as our own. We include the discussion below for
emphasis.
Appellants contend that the references, either alone or in combination
do not teach the combined administration of an mRNA specific to tumor or a
pathogen antigen with an mRNA coding for IL-12. Br. 6. Appellants argue
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that Daley does not teach the use of tumor antigens let alone mRNA
encoding for a tumor antigen but rather is directed to pathogens. Br. 8.
Appellants argue that Horton uses cytokines as direct anti-tumor effectors
and is not directed to a tumor vaccine. Id. With respect to Terman,
Appellants argue that the compositions used include a SAgs antigen in
combination with tumor antigens and cytokines. Id. Appellants contend that
there is nothing in Terman to suggest the use of a tumor antigen and a
cytokine alone. Id.
Appellants also contend that there is evidence of unexpected results to
overcome a prima facie case of obviousness. In support of this contention
Appellants rely on the Declaration of Dr. Hoerr, 11 which reports a series of
experiments that appear to show that administration of an mRNA encoding
for a tumor antigen alone induces a Th2 response whereas the co-
administration of the same mRNA with and mRNA encoding for IL-12
induces a Thl response. Br. 9-10. Hoerr Deel. ,r 12.
We have considered Appellants' arguments as well as the Declaration
of Dr. Hoerr and find them unpersuasive in outweighing the evidence of
obviousness on this record. Appellants' arguments appear to be an attack on
the individual references and not on the combination of the references
advanced by the Examiner. "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,
11 Declaration Under 37 C.F.R. § 1.132, filed January 7, 2014 ("Hoerr
Deel.").
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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, Daley is directed to use of a pathogen
antigen and a cytokine to induce an enhanced immune response. Ans. 11.
As seen from claim 22 above, the claimed method embraces mRNAs
encoding for either a tumor antigen or a pathogen antigen. Thus the method
of Daley is relevant to the method recited in the claims.
With respect to Appellants' argument that Horton is not directed to a
vaccine, the rejected claims do not refer to vaccine but only call for the
administration of the two types of mRNAs. Moreover, as the Examiner
points out, Daley teaches the preparation of a vaccine. Ans. 12. The
Examiner cited Horton for teaching the benefits of using mRNA encoding
for cytokines. Id. Horton also teaches the use of mRNA encoding for a
cytokine in combination with an mRNA which encodes for another cytokine
or an immunomodulatory molecule which includes a tumor antigen. FF5.
Thus Horton teaches the use of two mRNAs, one encoding for a cytokine
such as IL-12 and the other for a tumor antigen. One skilled in the art would
have been motivated to use the mRNAs of Horton in the method of Daley
because it is preferable to use mRNA as it avoids problem associated with
using the antigens themselves. Final Act. 4--5.
Turning to Terman, we agree with the Examiner that combining the
teachings of Terman with Daly is also proper. Terman includes SAg
antigens which are pathogen antigens, similar to those used on Daley. Ans.
12. In addition, Terman also teaches the use of mRNA encoding for a tumor
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antigen. FF8. The combined teachings of the reference would have led one
skilled in the art to create the claimed method.
Appellants' evidence of unexpected results is also unpersuasive.
Appellants' principle argument is that the inducement of a Thl response by
the combination of an mRNA encoding for a pathogen antibody (influenza
hemagglutinin) and mRNA encoding for IL-12, was unexpected. Br. 9-10.
As the Examiner points out, the inducement of a THI response from
the co-administration of an mRN A encoding for IL-12 was not unexpected.
Ans. 12-14. The inducement of a Thl response using mRNA encoding for
IL-12 is taught by Terman. FF9. In addition, the data in the Hoerr
declaration only reports a Thl response for co-administration of an mRNA
encoding for a pathogen and an mRNA encoding for IL-12. Hoerr Deel. ,r 5.
Appellants do not direct us to data or evidence that a combination of an
mRNA encoding for a tumor antigen with an mRNA encoding for IL-12
would produce the same response. Thus, even if the results were
unexpected, they are not commensurate with the scope of the claims. "The
evidence presented to rebut a prima facie case of obviousness must be
commensurate in scope with the claims to which it pertains." In re Dill, 604
F.2d 1356, 1361 (CCPA 1979).
With respect to claim 36, Appellants argue that the references do not
teach or suggest a cytokine mRNA with an IRES and a poly(A) sequence.
Br. 13. We are unpersuaded. Horton teaches the use of transcription control
sequences in mRNAs such as IRES. Horton col. 43, 11. 1-17. Terman
teaches the use of cap structure such as poly(A). Terman ,r 1249.
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Appellants argue that the references do not teach or suggest the
administration of an RN Ase inhibitor along with the antigen mRNA as
required by claims 23, 24, and 28. Br. 14. Again, we are unpersuaded. As
the Examiner points out, this teaching is provided by Terman. Ans. 14,
Terman ,r 1254.
Appellants contend that the simultaneous administration of the two
mRNAs as called for in claims 27 and 45 is not taught by the references. Br.
18. We are not persuaded. Horton teaches that the two mRNAs can be co-
injected. FF5.
Finally, Appellants argue that none of the references teach or suggest
that an untranslated region ("UTR") could be added to an RN A sequence to
enhance stability. Br. 17. Appellants contend that Terman teaches that the
UTR sequences should be reduced rather than increased. Id. Again, we find
this argument unpersuasive. As the Examiner points out, Terman
specifically teaches the use of a 3 'UTR from the Xenopus B-globin gene
combined with a polyA tail to improve the stability of the mRNA. Ans. 15,
Terman ,r 492.
Conclusion
We conclude that a preponderance of the evidence supports the
Examiner's conclusion that the subject matter of claims 22-24, 27, 28, 36,
44, and 45 would have been obvious over Daley combined with Horton and
Terman. Claims 29-32, 35, and 37--40 have not been argued separately and
therefore fall with claim 22.
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Daley combined with Horton, Terman, Cannon, and Draghia-Akli or Weiner
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
claims 33 and 34 would have been obvious over Daley combined with
Horton, Terman, Cannon, and Draghia-Akli or Weiner.
Claims 33 and 34 depend from claim 29 and add the limitation that
the GC or AU content of the antigen mRNA be increased in the ribosome
binding sequence. Br. 21 (Claims App 'x).
The Examiner reiterates the analysis of Daley, Horton, and Terman
discussed above. The Examiner goes on to find that Cannon teaches codon
optimization can be used to improve vaccine performance. Final Act. 8.
The Examiner also finds that Draghia-Akli teaches that increasing GC
content can increase mRNA stability. Id. The Examiner goes on to find that
Weiner teaches that the environment of the ribosome binding site is
improved by the presence of an AT rich sequence. Id. The Examiner
concludes:
It would have been obvious to one of ordinary skill in the
art at the time the invention was made to improve vaccination
by improving conditions such as mRNA stability according to
the methods of Draghia-Akli and Weiner et al to alter
nucleotide content to improve the stability or to decrease
RNAse in the cell. In KSR International Co. v. Teleflex Inc., 82
USPQ2d 1385 (U.S. 2007), the Supreme Court particularly
emphasized "the need for caution in granting a patent based on
a combination of elements found in the prior art," (Id. At 1395)
and discussed circumstances in which a patent might be
determined to be obvious. Importantly, the Supreme Court
reaffirmed principles based on its precedent that obviousness in
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part is predicated on use of particular known techniques that are
recognized as part of the ordinary capabilities of one skilled in
the art. In the instant case, it is accepted that generation of
increased stability of mRNA is done by known methods in the
art. As well, it is within the ordinary skill of the art to use
available methodologies to modify mRNA stability and one
would have been motivated to do so in order as the ability do so
by applying conventional methodologies. Based upon the
teachings of the cited references, the high skill of one of
ordinary skill in the art, and absent evidence to the contrary,
there would have been a reasonable expectation of success to
result in the claimed invention.
Final Act. 9.
In addition to the arguments discussed above, Appellants contend that
neither Draghia-Akli nor Weiner provide any guidance as to the use of
increased GC content or increased AU content in the ribosome binding
sequence. Br. 16.
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 subject matter of the claims would have been obvious to one skilled in
the art at the time the invention was made in view Daley combined with
Horton, Terman, Cannon, and Draghia-Akli or Weiner. Appellants have not
directed us to 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 address Appellants' arguments below.
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Appellants contend that neither Draghia-Akli nor Weiner provide any
guidance as to the use of increased GC content or AU content. Br. 16. We
find this argument unpersuasive. As the Examiner points out, Draghia-Akli
specifically teaches that increased GC content improves mRNA stability.
Ans. 15, Draghia-Akli ,r 67. Similarly, Weiner teaches that an AT rich
sequence in the ribosome binding region improved the environment on the
ribosome binding site. Ans. 15, Weiner ,r 62. We agree with the Examiner
that the cited evidence would have encouraged one skilled in the art to either
increase GC content or increase AU content with a reasonable expectation of
success.
Conclusion
We conclude that a preponderance of the evidence supports the
Examiner's conclusion that claims 33 and 34 would have been obvious over
Daley combined with Horton, Terman, Cannon, and Draghia-Akli or
Weiner.
Daley combined with Horton, Terman, and Daly
Appellants argue that Daly does not remedy the deficiencies of the
references. Br. 16. As discussed above, we do not find the teachings of
Daley, Horton, and Terman to be deficient. We therefore do not find
Appellants' argument persuasive and affirm this rejection.
SUMMARY
We affirm the rejections 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).
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AFFIRMED
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