SANOFI PASTEUR LIMITED et al.

Patent Trials and Appeals Board

Apr 1, 2020

14402678 - (D) (P.T.A.B. Apr. 1, 2020)

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.
14/402,678 11/20/2014 Stephen Anderson 0171.0004-US 6254
39878 7590 04/01/2020
MH2 TECHNOLOGY LAW GROUP, LLP
TIMOTHY M. HSIEH
1951 KIDWELL DRIVE
SUITE 310
TYSONS CORNER, VA 22182
EXAMINER
HORNING, MICHELLE S
ART UNIT PAPER NUMBER
1648
NOTIFICATION DATE DELIVERY MODE
04/01/2020 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):
docketing@mh2law.com
doreen@mh2law.com
lgalvin@mh2law.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STEPHEN ANDERSON, SIMON DELAGRAVE,
JOHN HAMBERGER, QINGLIAN LI, SOPHIA MUNDLE,
and NAUSHEEN RAHMAN

Appeal 2019-006608
Application 14/402,678
Technology Center 1600
Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and JAMIE T. WISZ,
Administrative Patent Judges.

WISZ, Administrative Patent Judge.

DECISION ON APPEAL

Appeal 2019-006608
Application 14/402,678

2
STATEMENT OF THE CASE
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1–12, 16–19, 24–28, and 33–47. We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
CLAIMED SUBJECT MATTER
The Specification describes compositions comprising an infectious
herpesvirus and methods of preparing such compositions such that they are
stabilized and retain an infectious titre following storage. Spec. 3. Claims 1
and 34, the two independent claims, are illustrative of the claimed subject
matter and are reproduced below:
1. A composition comprising:
a live, attenuated or genetically modified herpes simplex
virus type-2 (HSV-2) or herpes simplex virus type-1 (HSV-1),
at least two or more pharmaceutically acceptable
excipients, at least one of which is 1 mM to 50 mM histidine
and at least one of which is sucrose or trehalose, and
glutamate,
wherein the composition does not contain peptone and
has a pH of about 6.5 to 7.5.
Appeal Br. i (Claims App.).

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. Appellant identifies the real parties in interest as Sanofi
Pasteur Biologics, LLC and Sanofi Pasteur Limited. Appeal Br. 3.
Appeal 2019-006608
Application 14/402,678

3
34. A composition comprising:
a live, attenuated or genetically modified herpes simplex
virus type-2 (HSV-2) or herpes simplex virus type-1 (HSV-1),
at least two pharmaceutically acceptable excipients,
wherein one of the excipients is an amino acid consisting
of 1 mM to 50 mM histidine and optionally glutamine,
wherein one of the excipients is sucrose or trehalose, and
glutamate, and
wherein the composition has a pH of about 6.5 to 7.5.
Id. at iv–v (Claims App.).
REJECTIONS
The Examiner rejected claims 1–12, 16–19, 24–28, and 33–47 under
35 U.S.C. § 103(a) as obvious over Loudon,2 Bedu-Addo,3 Vellom,4 Da
Costa,5 and Johnston.6
The Examiner provisionally rejected claims 1–12, 16–19, 24–28, and
33–47 on the ground of nonstatutory double patenting as being unpatentable
over claims 14–29 of copending Application No. 15/155,951.

2 Loudon et al., US 6,258,362 B1, issued July 10, 2001 (“Loudon”).
3 Frank Kofi Bedu-Addo, Understanding Lyophilization Formulation
Development, Pharmaceutical Technology, 10–18 (2004) (“Bedu-Addo”).
4 Vellom et al., US 9,132,184 B2, issued Sept. 15, 2015 (“Vellom”).
5 Xavier Da Costa et al., Construction, Phenotypic Analysis, and
Immunogenicity of a UL5/UL29 Double Deletion Mutant of Herpes Simplex
Virus 2, 74 (17) Journal of Virology 7963–7971 (2000) (“Da Costa”).
6 Johnston et al., US 6,267,967 B1, issued July 31, 2001 (“Johnston”).
Appeal 2019-006608
Application 14/402,678

4
ISSUES AND ANALYSIS
The Examiner finds that Loudon describes pharmaceutical
compositions comprising an attenuated herpes virus, sugar (including
sucrose and/or trehalose), an amino acid mixture, sodium glutamate and Tris
buffer with a pH of about 7. Final Act. 3 (citing Loudon, Abstract, 3:45–51;
3:62–4:15, 6:51–7:34).
The Examiner concedes that Loudon does not explicitly teach a
composition comprising 1 to 50 mM histidine; however, the Examiner finds
that Bedu-Addo and Vellom cure this deficiency. Final Act. 3–4.
Specifically, the Examiner finds that Bedu-Addo teaches lyophilization
formulation development and discusses that “the goal of the formulations
scientist is to identify the right formulation conditions, the right excipient in
optimal quantities, and the right dosage form to maximize stability,
biological activity and safety of a product.” Id. at 4 (citing Bedu-Addo at
10). According to the Examiner, Bedu-Addo provides different excipients in
a lyophilized formulation, including a buffer that undergoes minimal pH
change during freezing (including a Tris or histidine buffer), sucrose as a
stabilizer, a bulking agent, and a tonicity adjuster. Id. (citing Bedu-Addo
12).
The Examiner also finds that Vellom teaches using lyophilization to
stabilize vaccines, including those with HSV-1 and HSV-2, and discloses
that the vaccine may include 10 mM histidine and 50 mM potassium
glutamate as buffer components. Final Act. 4 (citing Vellom 5:10–19). The
Examiner also finds that Vellom teaches that the glutamate can be either a
sodium or potassium salt. Id. (citing Vellom 5:57–61). The Examiner
concludes:
Appeal 2019-006608
Application 14/402,678

5
It would have been obvious to one of ordinary skill in the
art to modify the teachings by Loudon and use a histidine buffer
in the composition as a substitute buffer to Tris given both
buffers undergo minimal pH change during freezing as taught by
Bedu-Addo. One would have been motivated to do so for the
advantage of optimizing the formulation in order to provide
maximum stability of the solution before lyophilization.
Id. at 5. According to the Examiner, there would have been a reasonable
expectation of success in creating a stable vaccine “given the underlying
materials and methods are widely known and commonly used as evidenced
by the prior art.” Id. at 6.
Appellant argues that the viral compositions disclosed in Loudon are
stabilized by peptone, an uncharacterized mixture of amino acids and that
“[a]n undefined mixture of amino acids that may include histidine at some
variable concentration from one batch to another does not reasonably equate
with the composition of claim 1 that includes histidine in a defined amount.”
Appeal Br. 10. Appellant, therefore, argues that “Loudon fails to teach or
suggest the composition of claim 1, which includes, inter alia, 1 mM to
50 mM histidine and which expressly excludes peptone.” Id. at 11.
Appellant further asserts that “Loudon also fails to teach or suggest all
of the limitations of independent claim 34, which requires that ‘one of the
excipients is an amino acid consisting of 1 mM to 50 mM histidine and
optionally glutamine’ in addition to the other recited composition
components.” Appeal Br. 11. According to Appellant, even if the peptone
disclosed in Loudon contains some unspecified amount of histidine, it also
contains other amino acids and, thus, cannot teach or suggest an HSV-1 or
HSV-2 composition consisting of 1 mM to 50 mM histidine or optionally
glutamine, as recited in claim 34. Id.
Appeal 2019-006608
Application 14/402,678

6
Appellant also argues that Bedu-Addo fails to remedy the deficiencies
of Loudon because it is a general review article related to lyophilized
pharmaceutical products that does not mention HSV-2 or HSV-1 and only
generally suggests potentially using a histidine buffer, among other possible
buffers, such as Tris or citrate in generic formulations. Appeal Br. 11–12.
According to Appellant, Vellom also fails to remedy the deficiencies
of Loudon because it is directed to flavivirus vaccines and flaviviruses,
which are positive-sense single stranded RNA viruses with relatively small
genomes, differ from herpesviruses, which are double-stranded DNA viruses
with more complex genomes. Appeal Br. 12 (citing Declaration of Qinglian
Li filed on November 13, 2017 (“Li Declaration”)).
Appellant also argues that one of ordinary skill in the art would not
have been motivated to modify or combine the teachings of the cited art to
arrive at the claimed compositions. Appeal Br. 13–15. Specifically,
Appellant asserts that Loudon teaches away from a composition that does
not contain peptone and, with respect to Vellom, “one of ordinary skill in the
art would not expect observations made with respect to stabilizing agents
effective for flavivirus to apply to an unrelated herpesvirus, such as HSV-2.”
Id. at 14. Appellant also argues that the examples in the Specification:
provide further evidence that as of the filing date of the instant
application, and without the benefit of the results and stability
data presented in this application, one of ordinary skill in the art
would not have been able to predict whether a specific stabilizing
solution for flavivirus or specific components thereof, as taught
by Vellom, would have been useful for formulating a HSV-2
composition that retains sufficiently high infectious titre
following storage and/or large-scale manufacturing steps, like
lyophilization.
Appeal 2019-006608
Application 14/402,678

7
Id. at 14–15. Appellant also contends that Bedu-Addo’s “passing reference”
to histidine buffer, among other possible buffers, would not have motivated
one of skill in the art to make a HSV-1 or HSV-2 composition with histidine
in an amount of 1 mM to 50 mM, sucrose or trehalose, glutamate, and
having a pH of about 6.5 to 7.5. Id. at 15.
According to Appellant, one of ordinary skill in the art would not have
had a reasonable expectation of success in producing the claimed
composition in view of the cited art. Appeal Br. 15–17. Appellant argues
that, “herpesviruses are particularly labile, and as a result, formulating a
composition to stabilize a herpesvirus vaccine, and particularly an HSV-2
vaccine, was challenging and represented a major undertaking in the
unpredictable field.” Id. at 15–16 (citing Li Declaration ¶¶ 8–9; Spec. 2–3).
Appellant contends that “[t]he inventors’ efforts to formulate a composition
to stabilize an HSV-2 vaccine was particularly challenging and required
substantial experimentation, testing a number of different formulations and
approaches before arriving at the specific composition recited in the claims.”
Id. at 16.
With respect to claims 9, 36, and 40, Appellant makes similar
arguments to those above, and asserts that “the cited art fails to teach or
suggest a specific HSV-1 or HSV-2 composition with 5 mM to 20 mM
histidine and 5% to 10% w/v sucrose (Claims 9 and 36) or 5 mM to 20 mM
histidine, 5% to 10% w/v sucrose and 25 mM to 75 mM glutamate (claim
40).” Appeal Br. 18. With respect to claims 12 and 37, Appellant also
makes similar arguments to those above and asserts that “the cited art fails to
teach or suggest a specific HSV-1 or HSV-2 composition with 10 mM
Appeal 2019-006608
Application 14/402,678

8
histidine, 10% w/v sucrose, 160 mM NaCl, and 50 mM potassium
glutamate.” Id. at 19.
We find that the Examiner has the better position. Loudon discloses
compositions that include attenuated herpes virus, sugar (including sucrose
and/or trehalose), glutamate, and a buffer, wherein the composition has a pH
of about 7. Loudon, Abstract, 3:62–4:15, 6:51–7:34. While Loudon
discloses the use of a Tris buffer, rather than a histidine buffer, Bedu-Addo
lists these buffers as equivalents and discloses that histidine buffers undergo
minimal pH change during freezing. Bedu-Addo 12. Vellom also teaches
stabilizing vaccines (including HSV-1 and HSV-2 vaccines) by
lyophilization, and discloses that the vaccine may include 10 mM of
histidine and 50 mM of potassium glutamate as buffer components. Vellom
5:10–19. Therefore, one of ordinary skill in the art would have been
motivated to substitute the Tris buffer in the compositions disclosed by
Loudon for 10mM of histidine buffer, as disclosed in Bedu-Addo and
Vellom, with a reasonable expectation of success.
We are not persuaded by Appellant’s argument that Loudon discloses
the use of peptone and, therefore, teaches away from claim 1. We agree
with the Examiner that there is no teaching away because Loudon states that
dextran or another polysaccharide with a molecular weight above about
5,000 can be substituted for the peptone. Loudon 3:52–55. Furthermore, the
HSV-2 composition in Example 2 of Loudon, which includes sodium
glutamate and sucrose, does not include any peptone. Id. at 7:10–18.
With regard to Appellant’s argument that Loudon does not disclose
the use of 1 mM to 50 mH histidine, we do not find this argument persuasive
because Appellant is arguing the reference individually. “Non-obviousness
Appeal 2019-006608
Application 14/402,678

9
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 discussed above, Bedu-Addo discloses the
beneficial use of histidine buffers in lyophilized formulations because they
undergo minimal pH change during freezing and Vellom discloses the use of
10 mM histidine in vaccines, including with herpes viruses.
We are also not persuaded by Appellant’s arguments regarding
Vellom being directed to flaviviruses, which are different than herpes
viruses. As pointed out by the Examiner, Vellom specifically states that the
disclosed compositions can be used with herpes viruses (including HSV-1
and HSV-2). Vellom 7:9–17. We have considered the Li Declaration;
however, we do not find it persuasive because it does not address this
specific disclosure of herpes viruses in Vellom (and in fact does not discuss
the Vellom reference at all).
We are also not persuaded by Appellant’s argument that one of
ordinary skill in the art would not have had a reasonable expectation of
success in producing the claimed composition because herpes viruses are
particularly labile and the inventors’ efforts to formulate a composition to
stabilize an HSV-2 vaccine required substantial experimentation. We find
that, based on the disclosures in the cited prior art, one of skill in the art
would have been motivated to optimize the ingredients and ranges of the
different vaccine components in order to develop a stable composition (as
discussed in Bedu-Addo). See In re Aller, 220 F.2d 454, 456 (CCPA 1955)
(“[W]here the general conditions of a claim are disclosed in the prior art, it is
Appeal 2019-006608
Application 14/402,678

10
not inventive to discover the optimum or workable ranges by routine
experimentation.”)
Furthermore, in reviewing the data in the current Specification (e.g.,
Tables 4 and 7), it is not clear that the optimized formulations are
commensurate in scope with the claims. For example, independent claims 1
and 34, which recite a 1 mM to 50 mM range for histidine and no specific
ranges for the other excipients would encompass a broad range of
compositions. “It is well established that the objective evidence of
nonobviousness must be commensurate in scope with the claims.” In re
Lindner, 457 F.2d 506, 508 (CCPA 1972). Therefore, we are not convinced
that there are unexpected results associated with these claims. In other
words, Appellant has not shown that there is a “nexus” between the results in
the Specification and the limitations recited in the present claims. See In re
GPAC Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995) (“For objective evidence [of
nonobviousness] to be accorded substantial weight, its proponent must
establish a nexus between the evidence and the merits of the claimed
invention.”).
We are also not persuaded by Appellant’s arguments with respect to
claims 9, 36, and 40, which recite HSV-1 or HSV-2 compositions with 5 mM
to 20 mM histidine and 5% to 10% w/v sucrose (Claims 9 and 36) or 5 mM
to 20 mM histidine, 5% to 10% w/v sucrose and 25 mM to 75 mM glutamate
(claim 40). For the reasons discussed above, we find that these claims
would have been obvious to one of skill in the art. Furthermore, Loudon
discloses compositions with herpes virus including 5% sucrose and Vellom
discloses vaccine compositions with 10 mM histidine and 50 mM potassium
glutamate. Loudon 6:52–65; Vellom 5:11–19. For the reasons discussed
Appeal 2019-006608
Application 14/402,678

11
above, it would have been obvious for one of ordinary skill in the art to
substitute 10 mM histidine into the compositions of Loudon and to
maximize the amount of glutamate in order to stabilize the compositions.
We are also not persuaded by Appellant’s arguments with respect to
claims 12 and 37, which recite HSV-1 or HSV-2 compositions with 10 mM
histidine, 10% w/v sucrose, 160 mM NaCl, and 50 mM potassium
glutamate. For the reasons discussed above, we find that these claims would
have been obvious to one of skill in the art. Furthermore, Loudon discloses
that its compositions can include 2–12% w/v sucrose, which encompasses
the 10 w/v sucrose recited in the claims. Loudon 5:59–62. It is well
established that a prior art reference which discloses a range encompassing
or overlapping a claimed range is sufficient to establish a prima facie case of
obviousness. See In re Peterson, 315 F.3d 1325, 1329–30 (Fed. Cir. 2003).
Furthermore, Loudon also discloses the use of 138 mM sodium chloride in
its compositions. Loudon 6:61–62. “[A] prima facie case of obviousness
exists when the claimed range and the prior art range do not overlap but are
close enough such that one skilled in the art would have expected them to
have the same properties.” In re Peterson, 315 F.3d at 1329.
For the reasons described herein and those already of record, we
sustain the Examiner’s rejection of independent claims 1 and 34 under 35
U.S.C. § 103(a) as being obvious over Loudon, Bedu-Addo, Vellom, Da
Costa, and Johnston. We also affirm the Examiner’s rejection of claims 9,
12, 36, 37, and 40. Claims 2–8, 10–11, 16–19, 24–28, 33, 35–36, 38–39,
and 41–47 are not argued separately and, therefore, fall with independent
claims 1 and 34. See 37 C.F.R. § 41.37(c)(1)(iv).

Appeal 2019-006608
Application 14/402,678

12
Provisional Obviousness-type Double Patenting of Claims 1–12, 16–19, 24–
28, and 33–47
The Examiner provisionally rejected claims 1–12, 16–19, 24–28, and
33–47 on the ground of nonstatutory double patenting as being unpatentable
over claims 14–29 of copending Application No. 15/155,951. We note that
copending Application No. 15/155,951 issued on July 30, 2019 as U.S.
Patent No. 10,363,304 (“the ’304 patent”) with the last amendment to the
claims occurring before the Examiner’s Answer was mailed in the instant
appeal. Thus, the rejection is considered on appeal to no longer be
provisional as the Examiner determined that the claims issued in the ‘304
patent were a proper basis for the rejection by not withdrawing the
provisional rejection based on the same claims in the Examiner’s Answer.
We also note that Appellant has not made any arguments regarding this
rejection and has not filed an appropriate terminal disclaimer to obviate the
rejection; therefore, we affirm the Examiner’s rejection.
CONCLUSION
For the reasons described herein and those already of record, we
affirm the Examiner’s rejection of claims 1–12, 16–19, 24–28, and 33–47.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–12, 16–19,
24–28, 33–
47
103 Loudon, Bedu-
Addo, Vellom, Da
Costa, Johnston
1–12, 16–19,
24–28, 33–
47

Appeal 2019-006608
Application 14/402,678

13
1–12, 16–19,
24–28, 33–
47
Provisional
Obviousness-type
Double Patenting
1–12, 16–19,
24–28, 33–
47

Overall
Outcome
1–12, 16–19,
24–28, 33–
47

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). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED