Ex Parte Park et al

Patent Trial and Appeal Board

Apr 7, 2017

13756063 (P.T.A.B. Apr. 7, 2017)

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.
13/756,063 01/31/2013 Jae-Il Park STAN-679CON 7347
77974 7590 04/11/2017
Stanford University Office of Technology Licensing
Bozicevic, Field & Francis LLP
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
BUNNER, BRIDGET E
ART UNIT PAPER NUMBER
1647
NOTIFICATION DATE DELIVERY MODE
04/11/2017 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@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JAE-IL PARK and SHEAU YU HSU1
Appeal 2016-003990
Application 13/756,063
Technology Center 1600
Before ERIC B. GRIMES, TIMOTHY G. MAJORS, and DAVID COTTA,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to methods
of inducing labor or treating pre-eclampsia, which have been rejected as
nonenabled. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm-in-part.
STATEMENT OF THE CASE
“Relaxin is a pregnancy hormone discovered in 1926.” (Spec. 13.)
There are seven members of the relaxin family, including “relaxin H2
(RLN2),” which signals through the receptors LGR7 and LGR8. (Id. 14.)
1 Appellants identify the Real Party in Interest as the Board of Trustees of
the Leland Stanford Junior University. (Appeal Br. 1.)
Appeal 2016-003990
Application 13/756,063
The Specification discloses “relaxin analogs . . . [that] have altered receptor
specificity as compared to the reference, naturally occurring forms, e.g. wild-
type human RLN2.” (Id. 19.) The Specification states that “[t]he analogs
are useful as therapeutic agents. Conditions treatable with relaxin analogs
include . . . induction of labor, treatment of pre-eclampsia,” etc. (Id. 110.)
“Preeclampsia is a devastating pregnancy-associated disorder characterized
by the onset of hypertension, proteinuria, and edema.” (Kanasaki2 831.)
Claims 20 and 23 46 are on appeal. Claims 20, 25, and 36 are the
independent claims and read as follows:
20. A method of inducing labor or treating pre-eclampsia, comprising
administering to an individual an effective dose of a pharmaceutical
formulation comprising a purified polypeptide analog of a mammalian
relaxin 2 (RLN2) protein comprising an amino acid substitution to an amino
acid other than the wild-type at residue 23 in the A chain, wherein the analog
has increased selectivity for activation of the relaxin receptor LGR7 relative
to the wild-type protein; and a pharmaceutically acceptable excipient.
25. A method of inducing labor, comprising administering to an
individual an effective dose of a pharmaceutical formulation comprising a
purified polypeptide analog of a mammalian relaxin 2 (RLN2) protein
comprising an amino acid substitution at one or both of amino acid residues
16 and 17 to an amino acid other than the wild-type in the A chain, wherein
the analog has increased activity for activation of the relaxin receptors LGR7
or LGR8 relative to the wild type protein; and a pharmaceutically acceptable
excipient.
36. A method of treating preeclampsia, comprising administering to
an individual an effective dose of a pharmaceutical formulation comprising a
purified polypeptide analog of a mammalian relaxin 2 (RLN2) protein
comprising an amino acid substitution at one or both of amino acid residues
2 Kanasaki et al., The biology of preeclampsia, 76 Kidney Inf 1 831—837
(2009). Kanasaki is one of the references cited by the Examiner.
2
Appeal 2016-003990
Application 13/756,063
16 and 17 to an amino acid other than the wild-type in the A chain, wherein
the analog has increased activity for activation of the relaxin receptors LGR7
or LGR8 relative to the wild type protein; and a pharmaceutically acceptable
excipient.
DISCUSSION
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 112, first paragraph, for lack of enablement. We will address the claims
that encompass inducing labor (claims 20 and 23—35) separately from the
claims limited to treating pre-eclampsia (claims 36-46).
Method of inducing labor
Claims 20 and 23—35 encompass a method of inducing labor by
administering a relaxin analog. The Examiner acknowledges that the
Specification states that the disclosed relaxin analogs can be used to induce
labor, but notes that it does not provide any working examples that show
induction of labor. (Ans. 3—4.) The Examiner finds that the “relevant
literature teaches that recombinant human relaxin has no effect” in inducing
labor. {Id. at 4.) The Examiner cites Brennand,3 Kelly,4 and Weiss5 as
evidence supporting this conclusion. {Id.)
3 Brennand et al., Recombinant human relaxin as a cervical ripening agent,
104 British Journal of Obstetrics and Gynaecolgy 775—780 (1997).
4 Kelly et al., Relaxin for cervical ripening and induction of labour (Review),
Cochrane Database Systemic Reviews 2, Article No. CD003103, pages 1—32
(2001).
5 Weiss et al., A Randomized, Double-Blind, Placebo-Controlled Trial of
Relaxin for Cervical Ripening in Post-Delivery Date Pregnancies, 1160
Ann. N.Y. Acad. Sci. 385-386 (2009).
3
Appeal 2016-003990
Application 13/756,063
We agree with the Examiner that a preponderance of the evidence of
record supports a conclusion that relaxin does not induce labor, and
therefore using a relaxin analog to do so would require undue
experimentation. Brennand states that “porcine relaxin had some therapeutic
benefit as a cervical ripening agent in women. . . . The development of
recombinant human relaxin . . . has provided an agent that could have
superior cervical ripening properties in women and has stimulated further
research in this field.” (Brennand 775, right col.)
Brennand “reports the results of the UK double-blind, three-centre
study investigating the effect of recombinant human relaxin, administered as
an intravaginal gel, on cervical ripening in pregnant women at term with an
unfavourable cervix.” {Id.) More specifically, Brennand’s study compared
a placebo to recombinant human relaxin at 1, 2, or 4 mg, administered in a
gel vehicle. {Id. at 776, left col.)
Brennand states that
this study has not demonstrated any cervical ripening effect of
recombinant human relaxin. This may simply be due to incorrect
choice of dosage. However, it seems more likely that the route
of administration for this large polypeptide hormone was
inappropriate. The intravenous route may be more suitable and
deserves to be investigated before we can discard relaxin as a
ripening agent.
{Id. at 779, right col.)
Weiss reports a study in which subjects received intravenously
administered relaxin at a dose of 75 pg/kg/day. (Weiss 385—386, bridging
paragraph.) Weiss concluded that “human relaxin infusion is safe, has
positive effects on blood pressure and renal function, and does not advance
cervical ripening and induce labor.” {Id. at 386, left col.)
4
Appeal 2016-003990
Application 13/756,063
Kelly provides a summary of several “[c]linical trials comparing
relaxin used for third trimester cervical ripening or labour induction with
placebo/no treatment or other methods.” (Kelly 1 (Selection criteria).) The
trials studied by Kelly included Brennand. {Id. at 7, left cols.) Kelly found
that “[currently available data do not show any significant difference
between relaxin and placebo for induction of labour.” {Id. at 6, right col.)
Kelly concluded that “[t]he place of relaxin, either purified porcine or
recombinant human, as an induction or cervical priming agent is unclear and
its use outside of clinical trials should be discouraged.” {Id. at 6, right col.)
Thus, the three references cited by the Examiner provide experimental
evidence showing that relaxin is not effective in inducing labor in pregnant
women.
Appellants state that “[i]t is also known in the art that LGR7 is
involved in induction of labor.” (Appeal Br. 4.) In support, Appellants cite
Hsu6 and state that it was “previously made of record,” although they do not
indicate when. {Id.) The Examiner states that, “contrary to Appellant’s
assertion, the Hsu et al. paper has not been submitted for independent review
by the Examiner.” {Id. at 8.) Appellants did not file a Reply Brief to clarify
if or when Hsu was made of record. We have therefore not considered it.
Appellants also argue that “human relaxin has currently been tested in
a Phase II clinical trial for cervical ripening during the process of inducing
labor, for example as described in US Clinical trials NCT00259103,
sponsored by Corthera, Inc (previously submitted).” {Id. at 5.) Appellants
6 295 Science 671 (2002).
5
Appeal 2016-003990
Application 13/756,063
argue that “[o]ne of skill in the art would reasonably expect to substitute the
more active or more selective polypeptides of the present invention for a
known use of relaxin.” (Id.)
The Clinical Trials reference summarizes a study in which relaxin was
administered to determine its effect on “[c]ervical ripening” and
“[progression to active labor and delivery” i.e., induction of labor. (Clinical
Trials 1, primary and secondary outcomes, respectively.) As the Examiner
points out (Ans. 9), however, the reference does not report the results of the
clinical trial. Rather, it merely describes the patients and procedures of the
clinical trial. And, as the Examiner also points out (Ans. 9), the trial
described bears a striking resemblance to the trial described by Weiss, which
found that relaxin does not induce labor.
In summary, we conclude that a preponderance of the evidence of
record supports the Examiner’s conclusion that relaxin is not effective in
inducing labor, and therefore practicing the full scope of claims 20 and 25
would require undue experimentation. We therefore affirm the rejection of
claims 20 and 25 for lack of enablement.
Claims 23, 24, and 26—35 have not been argued separately and
therefore fall with claims 20 and 25. 37 C.F.R. § 41.37(c)(l)(iv).
Method of treating preeclampsia
Claims 36-46 are directed to treating preeclampsia by administering a
relaxin analog. The Examiner acknowledges that the Specification states
that the disclosed relaxin analogs can be used to treat preeclampsia, but
notes that it does not provide any working examples that show treating
preeclampsia. (Ans. 3—4.) The Examiner finds that the “relevant literature
6
Appeal 2016-003990
Application 13/756,063
teaches that the pathophysiological mechanisms underlying the onset of pre­
eclampsia are not yet fully known and defined.” {Id. at 5.) The Examiner
cites Cemaro,7 Kanasaki,8 and Unemori9 as evidence supporting this
conclusion. {Id.) In responding to Appellants’ arguments, the Examiner
also cites Lafayette.10 {Id. at 12—13.)
Appellants argue, among other things, that
[b]ecause reducing blood pressure in women with hypertension
has been shown to prevent the progression to severe
hypertension, maternal complications such as cerebrovascular
hemorrhage, and heart failure, and to improve fetal maturity by
prolonging pregnancy, pharmacological intervention with
relaxin analogs can be used for the treatment of preeclampsia by
decreasing blood pressure and vascular resistance while
increasing cardiac output and placental perfusion.
7 Cemaro et al., Relaxin: New Pathophysiological Aspects and
Pharmacological Perspectives for an Old Protein, 34 Medicinal Research
Reviews 77—105 (2014).
8 Cited supra, footnote 2.
9 Unemori et al., Scientific Rationale and Design of a Phase I Safety Study of
Relaxin in Women with Severe Preeclampsia, 1160 Ann. N.Y. Acad. Sci.
381-384 (2009).
10 Lafayette et al., Serum relaxin levels and kidney function in late
pregnancy with or without preeclampsia, 75 Clinical Nephrology 226—232
(2011).
7
Appeal 2016-003990
Application 13/756,063
(Appeal Br. 6.) Appellants cite Conrad,11 Davison,12 Sasser,13 and
Gooi14 as evidence supporting their position.
We agree with Appellants that a preponderance of the evidence shows
that relaxin is likely to be effective in, at least, lowering blood pressure in
patients suffering from preeclampsia. Several of the references state that
hypertension is a symptom of preeclampsia. Kanasaki states that
“[p]reeclampsia is a devastating pregnancy-associated disorder characterized
by the onset of hypertension, proteinuria, and edema.” (Kanasaki 831, right
col.) Cemaro states that “preeclampsia [is] a pathological condition defined
by the development of arterial hypertension associated with proteinuria or
edema or both, due to pregnancy or to the influence of a recent pregnancy.”
(Cemaro 82.) Davison states that “[t]he term preeclampsia refers to the new
onset of hypertension (>140/90 mmHg) and proteinuria after 20 wk of
gestation in previously normotensive, nonproteinuric women.” (Davison
2440, left col.)
Several of the references also state that relaxin reduces blood
pressure. Weiss states that “human relaxin infusion is safe, has positive
11 Conrad et al., The renal circulation in normal pregnancy and
preeclampsia: is there a place for relaxin? 306 Am. J. Renal Physiol.
FI 121—F1135 (2014).
12 Davison et al., New Aspects in the Pathophysiology of Preeclampsia, 15 J.
Am. Soc. Nephrol. 2440—2448 (2004).
13 Sasser et al., Relaxin Ameliorates Hypertension and Increases Nitric
Oxide Metabolite Excretion in Angiotensin II But Not Na-Nitro-L-Arginine
Methyl Ester Hypertensive Rats, 58 Hypertension 197—204 (2014).
14 Gooi et al., Enhanced Uterine Artery Stiffness in Aged Pregnant Relaxin
Mutant Mice is Reversed with Exogenous Relaxin Treatment, 89 Biology of
Reproduction 1—11 (2013).
8
Appeal 2016-003990
Application 13/756,063
effects on blood pressure and renal function, and does not advance cervical
ripening and induce labor.” (Weiss 386, left col., emphasis added.) Sasser
states that “the antihypertensive and renoprotective effects of relaxin are
dependent on a functional NOS system.” (Sasser 200, left col., emphasis
added.) Sasser also states: “our data indicate that relaxin is a potential
therapeutic agent for the treatment of hypertension.” (Id. at 203, left col.)
Cemaro states that “in the 1980s the first findings were published about
relaxin’s ability to induce, if administered, a decrease in blood pressure.”
(Cemaro 80.)
Finally, Unemori expressly suggests that relaxin should help in
treating preeclampsia by lowering blood pressure. Unemori states that
“[rjegardless of a potential relaxin deficiency in preeclampsia, the
pharmacological effects of relaxin demonstrated in previous clinical trials
and in nonclinical studies suggest that it may have a beneficial effect on
blood pressure, renal function, and fetal perfusion in women with
preeclampsia.” (Unemori 383, bridging paragraph.)
The Examiner points to Lafayette’s statement that “serum relaxin
levels do ‘not appear to influence BP [blood pressure], renal vascular
resistance, renal blood flow, or GFR [glomerular filtration rate] in late
pregnancy or in women with pre-eclampsia.’” (Ans. 12—13, quoting
Lafayette 226 (abstract).) However, Lafayette is referring to endogenous
levels of relaxin. ft does not address the effect of administering relaxin to
women with preeclampsia.
9
Appeal 2016-003990
Application 13/756,063
In summary, we conclude that a preponderance of the evidence does
not support the Examiner’s conclusion that the claimed method of treating
preeclampsia would require undue experimentation.
SUMMARY
We affirm the rejection for nonenablement as applied to claims 20 and
23—35 but reverse it as applied to claims 36-46.
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-IN-PART
10