DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
The claim set filed January 20, 2026 has been entered. Claims 2, 4, 7-9, 12-15, 18, 20, 23-25, 28-31 and 33-84 are canceled. Claims 5-6, 10-11, 21-22 and 26-27 continue to be withdrawn from consideration as discussed in further detail in the Election/Restrictions section of the non-final rejection mailed on October 20, 2025.
Thus, claims 1, 3, 16-17, 19 and 32 as amended are examined on the merits herein.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the non-final office action on October 20, 2025:
(I) The objection of claims 1, 16-17 and 32; and
(II) The rejection of claims 1, 16-17 and 32 under 35 U.S.C. 103 are withdrawn in view of Applicant’s amendments.
Response to Arguments
The rejection of claims 1, 3, 16-17, 19 and 32 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is maintained.
Applicant argues:
(A) The treatment step of claim 1 and claim 17 are fairly narrow and no other compounds or alternatives are listed as possible treatments, only estriol-16-glucuronide is recited, see Applicant’s remarks, pg. 2, breath of claims, paragraph 1.
With respect to Applicant’s argument (A), the Examiner respectfully notes claim 1 and claim 17 are drawn to treat as recited within these claims comprising administering to the individual at least one compound to mitigate early term birth, preterm birth, or pregnancy loss as recited in claim 1; or at least one tocolytic agent compound to mitigate uterine contractions, wherein the at least one compound is estriol-16-glucuronide.
Therefore, the Examiner respectfully disagrees that claim 1 and claim 17 are fairly narrow as claim 1 and claim 17 currently recite and require only the compound estriol-16-glucuronide be administered.
However, based on the recitation of “comprising” within claim 1, line 2 and claim 17, line 2, each of these claims allow for the option where additional compounds can be administered within the recited method; the Examiner further notes said additional compounds are not explicitly recited within either claim 1 or claim 17.
(B) The specification provides sufficient guidance for the treatment methods as recited within claim 1 and claim 17, see Applicant’s remarks, pg. 2, direction and guidance provided by the specification, paragraph 1; by providing a rationale for use of estriol-16-glucuronide for treatment of pregnancy conditions related to premature uterine contractions, see Applicant’s remarks, pg. 4, second paragraph from the bottom of the page; and derived from data from a cohort of women demonstrating that biosynthesis of estriol-16-glucuronide remained at high concentrations in the blood of pregnant individuals with low variance, and then drops precipitously right before these individuals begin labor contractions, see Applicant’s remarks, pg. 4, second paragraph from the bottom of the page.
The Examiner notes the graphical depiction of this data is shown in Fig. 2 on pg. 5 of Applicant’s remarks and is also shown in Fig. 2 of the drawings filed on March 23, 2022.
With respect to Applicant’s argument (B), the Examiner respectfully notes that elevated biosynthesis of estriol-16-glucuronide is shown throughout pregnancy and a drop in estriol-16-glucuronide biosynthesis is shown within Fig. 2 stating at approximately the 40th week of pregnancy.
Although, the Examiner further notes all other biosynthesized steroid hormones measured along with estriol-16-glucuronide during the standardized 40-week pregnancy depicted in Fig 2. are also elevated during this time and drop starting at approximately the 40th week of pregnancy consistent with what is observed with estriol-16-glucuronide as discussed above.
Therefore, the Examiner fails to see how production of estriol-16-glucuronide during pregnancy as shown in Fig. 2 is evidence in support of treating the recited conditions listed in claim 1 and claim 17, wherein said claims require administering estriol-16-glucuronide to an individual in order to treat premature uterine contractions as argued by Applicant above.
The Examiner also notes the only information provided by Fig. 2 as discussed above is the level of biosynthesis of certain steroid hormones during pregnancy, and does not demonstrate what role, if any, estriol-16-glucuronide has in treating premature uterine contractions as argued by Applicant above.
(C) The specification further details that estriol-16-glucuronide reduces contractions in uterine muscle cells, see Applicant’s remarks, pg. 5, last two lines of the page; wherein the Applicant provides data presented in Fig. 4A and Fig. 4B as discussed on pg. 6 of Applicant’s remarks, paragraph 2.
(D) Estriol-16-glucuronide is a tocolytic compound that reduces uterine contractions as demonstrated in human smooth muscle cells and mouse uterine muscle tissue, see Applicant’s remarks, pg. 7, paragraph 3.
(E) Administration of estriol-16-glucuronide can reconstitute the loss of this compound to prevent further contractions from occurring, see Applicant’s remarks, pg. 7, paragraph 5.
(F) Progesterone can be used for treatment of recurrent pregnancy loss. The serum concentration profile of estriol-16-glucuronide during pregnancy follows the same pattern as progesterone, therefore, esteriol-16-glucuronide can find utility in treating recurrent pregnancy loss, see Applicant’s arguments, pg. 7, paragraph 7.
(G) Because estriol-16-glucuronide has a very particular serum concentration pattern over the course of pregnancy, deficiency of this compound can be monitored, and when discovering that estriol-16-glucuronide is deficient during pregnancy, that compound can be administered to restore their serum levels mitigating the chance of premature contractions, see Applicant’s remarks, pg. 7, last paragraph of the page – pg. 8, first paragraph.
(H) Fig. 6B shows treatment of LPS-induced preterm labor in mice treated with estriol-16-glucuronide extended pregnancy beyond control-treated mice, and although this improvement is slight it does show utility, see Applicant’s remarks, pg. 8, working examples in the specification, paragraph 1.
(I) Estriol-16-glucuronide extends the gestation when experiencing preterm labor, and further considering this data in context with estriol-16-glucuronide’s ability to reduce contractions in human uterine smooth muscle cells and the fact that estriol-16-glucuronide was highly abundant within the sera of human pregnant individuals, a skilled artisan would find this data supports the ability of estriol-16-glucuronide in treating pregnancy conditions involving premature uterine contractions, such as recited within claim 1 and claim 17, see Applicant’s remarks, pg. 8, working examples in the specification, paragraph 2.
With respect to Applicant’s arguments (C)-(I), the Examiner respectfully disagrees with Applicant’s argument that the specification demonstrates estriol-16-glucuronide reduces contractions in uterine muscle cells.
The Examiner respectfully notes the drawings filed March 23, 2022 depict Figure 4A which shows image results of administering estriol-16-glucuronide 1 hour after administering oxytocin to human uterine smooth muscle cells to stimulate contractions.
The Examiner notes the results in Figure 4A representing estriol-16-glucuronide correspond to C3; wherein the Examiner notes the physical results of the administered estriol-16-glucuronide on human uterine muscle cells contractions after stimulation by oxytocin as depicted within Fig. 4A are reasonably interpreted by the Examiner to be visually comparable to when oxytocin alone is administered.
The Examiner notes the results of Fig. 4A are graphically represented in Fig. 4B shown in Applicant’s remarks on pg. 6 and in the drawings filed March 23, 2022.
The Examiner notes the graphical results within Fig. 4B show the vehicle which contains the administered oxytocin to result in collagen covering approximately 37.5% of the well area, as estimated by the Examiner, and C3 (e.g. the administered estriol-16-glucuronide) to result in collagen covering approximately 55% of the well area, which the Examiner respectfully notes is approximately 1.5 times more area than oxytocin administered alone.
However, the Examiner also respectfully notes within Fig. 5A of the drawings, Fig. 5A depicts the results of a myographic experiment testing uterine muscle strips from pregnant wild-type (WT) mice at D18 incubating with oxytocin, and 1 micromolar estriol-16-glucuronide (e.g. C3).
The Examiner respectfully notes Fig. 5A only demonstrates a slightly smaller contraction of estriol-16-glucuronide when compared to oxytocin.
Additionally, the Examiner respectfully notes the error bars within Fig. 5A associated with estriol-16-glucuronide seem to encompass the graphical difference between oxytocin and estriol-16-glucuronide; and therefore, the error bars seem to encompass the difference in uterine contraction observed within the myographic experiment discussed above.
Moreover, within Fig. 6B of the drawings, Fig. 6B displays results of compound treatment in mouse models of moderate preterm birth, where lipopolysaccharides (LPS) were administered to stimulate labor in the test mice. The Examiner notes the specification discusses the results of Fig. 6B and does not state or even suggest the administration of estriol-16-glucuronide resulted in prolonged gestation in vivo, see paragraph [0115], pg. 32, first paragraph.
Moreover, after reviewing Fig. 6B the Examiner notes when LPS+C3 (e.g. C3 is estriol-16-glucuronide) was administered there was only a slight increase in the time until delivery when compared to LPS+con (e.g. con is reasonably interpreted by the Examiner to mean “control”).
Furthermore, the Examiner also notes the error bars depicted within Fig. 6B and associated with LPS+con seem to encompass the graphical difference between LPS+con and LPS+C3 (e.g. estriol-16-glucuronide), therefore, the error bars seem to encompass the difference in time until delivery observed within the mouse treatment models as discussed above.
Therefore, based on the results of Figs. 4A-4B, 5A and 6B as a whole, the specification at best demonstrates inconsistent results regarding the role of estriol-16-glucuronide in inhibiting uterine muscle cell contractions, which the Examiner notes is particularly important as Applicant argues inhibiting said contractions is the mechanism of action in treating the conditions recited within claim 1 and claim 17 by administering estriol-16-glucuronide.
Consequently, the Examiner notes Applicant’s argument seems to be supported by an outside importance of the level of biosynthesis of estriol-16-glucuronide during pregnancy and the extrapolation any decrease in the level of estriol-16-glucuronide during pregnancy may result in premature uterine contractions, wherein said contractions result in the listed conditions recited within claim 1 and claim 17.
Accordingly, the Examiner respectfully notes the specification as a whole does not suggest nor guide one of ordinary skill in the art in how estriol-16-glucuronide treats premature uterine muscle cell contractions other than the results provided within Figs. 4A-4B, 5A and 6B.
Thus, Applicant’s arguments (C)-(I) rely on the observed level of biosynthesis of estriol-16-glucuronide during pregnancy and Applicant’s position of the importance said level of synthesis of estriol-16-glucuronide may have within a pregnant individual to inhibit premature uterine contractions, which the Examiner respectfully notes are not particularly persuasive arguments in view of the evidence as a whole provided within Figs. 4A-4B, 5A and 6B of the specification as discussed above.
(J) A skilled artisan would find that the quantity of further experimentation required is routine, not exhaustive, see Applicant’s remarks, pg. 8, further experimentation, paragraph 1.
(K) The data provided within the specification establishes that estriol-16-glucuronide is a tocolytic agent, see Applicant’s remarks, pg. 9, paragraph 1.
(L) The only further experimentation required would be the assessment of administering estriol-16-glucuronide within human patients, see Applicant’s remarks, pg. 9, paragraph 1.
(M) Further preclinical experimentation has already been performed establishing the ease of preforming experimentation to confirm the tocolytic ability of estriol-16-glucuronide, where a new batch of estriol-16-glucuronide was purchased and administered to mouse models of uterine contractility or of preterm labor, see Applicant’s remarks, pg. 9, paragraph 2; wherein myographic analysis of said experiment is shown in Figure A on pg. 9 of Applicant’s arguments, see Applicant’s remarks, pg. 9, paragraph 2.
(N) The results of Fig. A demonstrate that esteriol-16-glucuronide yields a dose-dependent response in uterine contractility, see Applicant’s remarks, pg. 9, paragraph 3.
With respect to Applicant’s remarks (J)-(N), the Examiner respectfully reiterates the previous Examiner’s notations as discussed above.
Additionally, the Examiner respectfully notes when reviewing Fig. A on pg. 9 of Applicant’s remarks a dose-dependent response is shown attributable to the concentration of estriol-16-glucuronide regarding uterine contractility.
However, when comparing the control to estriol-16-glucuronide there is only a slight difference, approximately at most a 0.1 reduction compared to the control between these two measurements when considering the error bars for the concentrations of estriol-16-glucuronide examined within Fig. A.
Moreover, the Examiner respectfully notes Fig. A does not test oxytocin as compared to Figure 5A in the specification, which the Examiner respectfully notes Figure 5A administered oxytocin to stimulate spontaneous contraction, see specification, paragraph [0111]; and is therefore reasonably interpreted by the Examiner to be a key consideration in treating the listed conditions recited within claim 1 and claim 17.
Furthermore, the Examiner respectfully notes neither claim 1 nor claim 17 require a particular concentration of estriol-16-glucuronide be administered to the pregnant individual. Consequently, the Examiner reasonably interprets claim 1 and claim 17 encompass the broad scope of administering any amount of estriol-16-glucuronide to a pregnant individual in treating the conditions listed within claim 1 and claim 17.
Thus, the Examiner respectfully notes Applicant’s results shown within Fig. A do not seem be commensurate in scope with the scope of the subject matter recited within either claim 1 or claim 17 as discussed above; and/or the experiment conducted which corresponds to the results shown within Fig. A as discussed above do not seem to assess the ability of estriol-16-glucuronide in treating premature uterine contractions when said contractions are stimulated, for example by oxytocin, within a pregnant individual.
(O) In a second experiment, LPS-induced contractility of pregnant mice induced into preterm labor via LPS and were either treated with estriol-16-glucuronide or vehicle; wherein treatment of preterm mice with estriol-16-glucornide extended gestation to near the average gestation of healthy mice (Fig. B), see Applicant’s remarks, pg. 9, last paragraph of the page and pg. 10, Fig. B.
With respect to Applicant’s argument (O), the Examiner respectfully notes within Fig. B as discussed above provides an observation of a prolonged gestational period of approximately 45 hours (e.g. approximately 2 days) in preterm mice when treated with estriol-16-glucuronide when compared to preterm mice treated with vehicle.
However, the Examiner respectfully notes claim 1 is drawn to recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss; and claim 17 is drawn to early term birth, spontaneous preterm birth or spontaneous abortion, which as evidenced by the specification is the opening of the cervix weeks before full term, see paragraph [0004].
The Examiner also respectfully notes the time scale for treating these conditions as recited within claim 1 and claim 17 range from at least 2 weeks and up to 20 weeks as evidenced by the specification in paragraph [0004].
Therefore, the Examiner reasonably interprets the data presented within Fig. B of Applicant’s remarks is not commensurate in scope with the timeframe of treating conditions as recited within claim 1 and claim 17.
Moreover, Applicant’s do not provide any evidence demonstrating estriol-16-glucuronide can prolong labor for the timeframe required for treating the conditions recited within claim 1 and claim 17.
Furthermore, this newly presented data is not particularly persuasive in view of the data already presented in Fig. 6B within the specification as discussed above.
Thus, Applicant’s arguments (A)-(O) have been fully considered but are not found persuasive.
New Claim Rejections
The following are new ground(s) or modified rejections necessitated by Applicant's amendment, filed on January 20, 2026, where the limitations in pending claims 1, 3, 16-17, 19 and 32 as amended now have been changed.
Therefore, rejections from the previous Office Action, dated October 20, 2025, have been modified and are listed below.
35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 16-17, 19 and 32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for administering tetrahydrodeoxycorticosterone, androsterone sulfate, androsterone, or androstane-3,17-diol in treating recurrent preterm birth, recurrent early term birth, early term birth, and spontaneous preterm birth, does not reasonably provide enablement for administering estriol-16-glucuronide, dehydroisoandrosterone sulfate (DHEA-S), or pregnenolone sulfate in treating any condition recited in either claim 1 or claim 17 or in administering tetrahydrodeoxycorticosterone, androsterone sulfate, androsterone, or androstane-3,17-diol in treating either recurrent pregnancy loss required in claim 1 or spontaneous abortion required in claim 17. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Applicant's attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the invention: The claimed invention is drawn to treating a pregnant individual for recurrent preterm birth, recurrent early term birth or recurrent pregnancy loss comprising administering to the individual at least one compound to mitigate recurrent preterm birth, recurrent early term birth or recurrent pregnancy loss wherein the at least one compound is estriol-16-glurcuronide, see claim 1.
Additionally, claim 16 recites administering at least one compound to the pregnant individual who is deficient in at least one metabolite, wherein the metabolite is at least dehydroisoandrosterone sulfate (DHEA-S) or pregnenolone sulfate.
Moreover, the claim set recites a method of treating a pregnant individual for early term birth, spontaneous preterm birth or spontaneous abortion comprising administering at least one tocolytic compound to mitigate uterine contractions, wherein the at least one compound is estriol-16-glurcuronide, see claim 17.
Furthermore, claim 32 recites administering at least one compound to the pregnant individual who is deficient in at least one metabolite, wherein the metabolite is at least dehydroisoandrosterone sulfate (DHEA-S).
Finally, the Examiner respectfully notes the specification defines “to treat” to mean to ameliorate at least one symptom of a disorder to be treated or to provide a beneficial physiological effect, for example one such amelioration of a symptom could be reduction of risk of spontaneous preterm labor, spontaneous abortion, recurrent preterm birth, early term birth or recurrent pregnancy loss, see pg. 20, paragraph [0083].
Therefore, in order to be enabled for the full scope of treatment as recited in independent claim 1 or independent claim 17, one skilled in the art must reasonably be able to ascertain which agents are effective, obtain said agents, and successfully use said agents for treating recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion in a pregnant individual.
The state of the prior art: The state of the art does not provide an expectation that administering estriol-16-glurcuronide or estradiol 17β-D-glucuronide treats (e.g. including to reduce the risk of) recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion; or in administering tetrahydrodeoxycorticosterone in treating (including to reduce the risk of) recurrent pregnancy loss or spontaneous abortion.
Attention is drawn to Omori (Published 20 May 1982, Folia Endocrinologica Japonica, Vol. 58, Issue 5, pp. 689-705, PTO-892 mailed 10/20/2025) which teaches dynamics of estriol-16-glucuronide (E3-16-G) in early pregnancy and its prognostic value in complicated pregnancy, see pg. 689, title.
Omori teaches E3-16-G in normal pregnant women increased as pregnancy progressed and was over the level in non-pregnant women after 6 weeks gestation. Omori observed the levels of E3-16-G were lower in complicated pregnancies, namely threatened abortion, intrauterine fetal death, ectopic pregnancy, anencephalus and so on; and decreases of urinary E3-16-G in threatened abortion were more rapid than those of urinary hCG which Omori considered a useful prognostic indicator in those cases. See pg. 689, abstract.
Omori discloses the possibility that E3-16-G is produced by the fetus in in vitro experiments where 14C-E3 was incubated with various tissues in early pregnancy. Omori teaches 14C-E3 (e.g. estriol) was conjugated to be E3-16-G by homogenate of the fetal tissue in 8 weeks gestation, and by the liver and by the kidney in 13 weeks gestation but not by chorionic tissue. Omari therefore suggests these results indicated that the conjugation process of E3, though perhaps not entirely, proceeds in the fetus and the urinary determination of E3-16-G might give us good information about the fetus in pregnant women. See Abstract.
Therefore, Omori does not teach estriol-16-glucornide can be used to treat any pregnancy-related condition recited within claim 1 or claim 17, rather Omori teaches estriol-16-glucuronide may have a role as a prognostic indicator of fetal health within a pregnant individual.
Additionally, Olsen et al. (Published 18 June 2013, The Journal of Maternal-Fetal & Neonatal Medicine, Vol. 27, Issue 4, pp. 376-380, PTO-892 mailed 10/20/2025) teaches elevated maternal serum estriol was significantly associated with preterm birth and concluded elevated second trimester maternal serum unconjugated estriol is independently associated with a higher rate of spontaneous preterm birth, see abstract, results and conclusion. Olsen also teaches a direct correlation between the level of estriol concentrations and gestational age at time of delivery, see abstract, results.
Moreover, Jackson (Published 09 June 1998, US-5763431-A, PTO-892 mailed 10/20/2025) teaches regulating the levels of neuropeptide hormones in the blood of human patients by using neuroactive steroids, see Col. 3, lines 3-6.
Jackson teaches this class of compounds acts at receptors for the inhibitor neurotransmitter GABA; and these compounds can either enhance or reduce ongoing inhibition exerted by GABA. Jackson teaches by acting on the membranes of neurosecretory nerve terminals, neuroactive steroids will reduce the secretion of neuropeptides, thereby reducing release of the neuropeptide oxytocin which has value in controlling premature labor. See Col. 3, lines 9-15.
Jackson teaches the preferred compounds for enhancing the inhibitory effect of GABA at the neurosecretory nerve terminal include 5α-androstan-3α,17β-diol, tetrahydrodeoxycorticosterone and androsterone, see Col. 4, lines 2-12.
Jackson further teaches the preferred compounds for reducing the inhibitory effect of GABA at the neurosecretory nerve terminal include 17β-estradiol, DHEAS and pregnenolone sulfate, see Col. 4, lines 13-18.
Therefore, Jackson teaches 17β-estradiol, DHEAS and pregnenolone sulfate reduce the inhibitory effect of GABA and would therefore result in an increased release of the neuropeptide oxytocin which stimulates labor as taught by Jackson above.
Finally, Coomarasamy et al. (Published 26 November 2015, The New England Journal of Medicine, Vol. 373, No. 22, pp. 2141-2148, PTO-892 mailed 10/20/2025) teaches recurrent miscarriage, which is defined as the loss of three or more pregnancies, affects approximately 1% of couples who attempt to have a child. Coomarasamy teaches even after comprehensive investigations a cause for recurrent miscarriage is identified in less than half of these couples and various therapeutic strategies to increase the rate of live births among these women have been evaluated but no effective treatment has been identified. See pg. 2142, left column, paragraph 1.
Therefore, in view of the state of the art as a whole based on the disclosures of Omori, Olsen and Jackson, none of these references suggest using estriol-16-glucuronide or estradiol 17β-D-glucuronide in a treatment method for recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion, to the contrary, rather the disclosure of Olsen suggests that unconjugated estriol is independently associated with a higher rate of spontaneous preterm birth. Additionally, Jackson teaches 17β-estradiol reduces the inhibitory effect of GABA at the neurosecretory nerve terminal resulting in GABA’s decreased inhibitory effect in reducing release of the neuropeptide oxytocin in controlling premature labor.
Thus, the Examiner reasonably considers it an open question as to how estriol or 17β-estradiol via a glucuronidation reaction resulting in estriol-16-glucuronide or estradiol 17β-D-glucuronide respectively treats any condition recited in claim 1 or claim 17; to the contrary, the disclosures of Olsen and Jackson discuss these compounds would have the opposite effect in treating conditions related to preterm or early term birth as disclosed by Olsen for estriol and as disclosed by Jackson for 17β-estradiol as discussed above.
Furthermore, Coomarasamy discloses no medications are currently available for treating recurrent miscarriages. Therefore, the Examiner considers it an open question as to how estriol-16-glucuronide or any compound recited within claim 16 or claim 32, in view of the disclosure of Coomarasamy above, treats recurrent pregnancy loss or spontaneous abortion (e.g. miscarriages).
Thus, in view of the state of the art as a whole and based on the combined disclosures of Omori, Olsen, Jackson and Coomarasamy above its currently unclear what the actual use of administering estriol-16-glucuronide has in treating (e.g. including to reduce the risk of) recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion in a pregnant individual in need thereof.
Also, based on the disclosure of Coomarasamy above its currently unclear what the actual use of tetrahydrodeoxycorticosterone, androsterone sulfate, androsterone, or androstane-3,17-diol has in treating (e.g. including to reduce the risk of) recurrent pregnancy loss or spontaneous abortion in a pregnant individual in need thereof.
The relative skill in the art: The relative skill of those in the art is high.
The predictability or lack thereof in the art: As discussed above, the use of estriol-16-glucuronide, estradiol 17β-D-glucuronide, dehydroisoandrosterone sulfate (DHEA-S) or pregnenolone sulfate in treating recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion; or the use of tetrahydrodeoxycorticosterone, androsterone sulfate, androsterone, or androstane-3,17-diol in treating recurrent pregnancy loss or spontaneous abortion in a pregnant individual is currently unknown.
Moreover, the disclosures of Omori, Olsen, Jackson and Coomarasamy do not suggest using estriol-16-glucuronide, estradiol 17β-D-glucuronide, dehydroisoandrosterone sulfate (DHEA-S) or pregnenolone sulfate within a treatment method of recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion. As a result, at the time of the invention the field of use of estriol-16-glucuronide, estradiol 17β-D-glucuronide, dehydroisoandrosterone sulfate (DHEA-S) or pregnenolone sulfate for treating (e.g. including to reduce the risk of) recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion were limited.
Additionally, the disclosure of Coomarasamy does not suggest any known therapeutic method to treat recurrent miscarriages. As a result, at the time of the invention the field of use of tetrahydrodeoxycorticosterone, androsterone sulfate, androsterone, or androstane-3,17-diol for treating (e.g. including to reduce the risk of) recurrent pregnancy loss or spontaneous abortion were limited.
Thus, at the time of the invention the field of therapeutic use as discussed above was relatively underdeveloped and unpredictable.
The breadth of the claims: The scope of the claims is extremely broad by specifically including treating (e.g. including to reduce the risk of) recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion by administering at least estriol-16-glucuronide.
Additionally, the Examiner respectfully notes claim 1 and claim 17 are currently drawn to treat the recited conditions within these claims comprising administering to the individual at least one compound to mitigate early term birth, preterm birth, or pregnancy loss as recited in claim 1; or at least one tocolytic agent compound to mitigate uterine contractions, wherein the at least one compound is estriol-16-glucuronide.
Therefore, the Examiner respectfully notes claim 1 and claim 17 currently require only the compound estriol-16-glucuronide be administered, but claim 1 and claim 17 as a whole both allow the option for additional compounds to be administered within the recited method; wherein the Examiner respectfully notes said additional compounds are not explicitly recited within either claim 1 or claim 17.
The amount of direction or guidance presented: The specification discloses treating in a pregnant individual for recurrent preterm birth, recurrent early term birth or recurrent pregnancy loss by administering estriol-16-glucuronide, see paragraph [0007], pp. 2-3; or treating a pregnant individual for early term birth, spontaneous preterm birth or spontaneous abortion by administering estriol-16-glucuronide, see pg. 4, paragraph [0011].
The specification discloses exemplary methods and experiments performed related to uterine contractions and gestational progress (i.e. time until delivery) indicating that various compounds can be utilized to treat individuals having a menstrual or gestational complication, see pg. 27, paragraph [0102].
The specification discloses various metabolites help maintain an appropriate gestational timeline and prevent premature uterine contractions, see pg. 25, paragraph [0096].
The presence or absence of working examples: The specification discloses one example of preterm birth in Example 4 where compound treatment in mouse models of preterm birth were examined. Applicants depict in Fig. 6B results of compound treatment in mouse models of moderate pre-term birth where pregnant C57BL/6 mice were intraperitoneally administered 2mg/kg LPS or PBS (e.g. control), see pg. 31, example 4, paragraph [0115] and Fig. 6B.
Fig. 6B shows the time until delivery after LPS treatment measured in hours (h), where LPS + vehicle (con) showed less than 50 hours, potentially less than 12.5 hours, before delivery occurred; however, when compared with LPS + C3 (e.g. estriol-16-glucuronide), the LPS + C3 is only slightly higher than LPS + vehicle (con) as discussed above showing less than 50 hours but potentially as much as 25 hours, see Fig. 6B.
Additionally, Applicants suggest in data shown in Fig. 6B that DEHA-S, THDOC, androstane-3,17-diol, androstane-3,17-diol + progesterone combined or DHEA-S + androstane-3,17-diol + progesterone combined prolonged gestation in vivo; and full-term live pups were birthed from preterm model females treated with DHEA-S, androstane-3,17-diol, or androstane-3,17-diol + progesterone combined. See paragraph [0115], pg. 32.
However, the Examiner notes each of these compound treatments depicted in Fig. 6B show at least a two-fold increase in the amount of time until delivery then the amount of time elicited when treated with estriol-16-glucuronide, see Fig. 6B. Additionally, the Examiner respectfully notes estradiol 17β-D-glucuronide was not tested in this model.
Furthermore, Applicants do not provide any working examples where estriol-16-glucuronide was administered in models to treat recurrent pregnancy loss or spontaneous abortion.
Therefore, in total, the Examiner respectfully notes the working examples presented by Applicants suggest that estriol-16-glucuronide may slightly increase time until delivery when administered to pregnant mice as compared to administration of oxytocin which stimulates uterine contractions.
However, in view of the disclosure of Olsen and Jackson above and the results of example 4 disclosed by Applicant above, the Examiner also reasonably interprets the role of estriol-16-glucuronide in treating preterm birth in mice within Example 4 of Applicants disclosure is at least inconclusive as to the therapeutic benefit of administering estriol-16-glucuronide to treat preterm birth, let alone recurrent pregnancy loss or spontaneous abortion as claimed by Applicants above.
Thus, the Examiner respectfully notes the data presented within Applicants specification does not support the claim that administration of estriol-16-glucuronide prolongs gestation in vivo, to the contrary, the data presented by Applicants at most may suggest estriol-16-glucuronide provides a slight benefit in prolonging gestation, if any at all given the inconclusiveness of the data provided by Applicants in Fig. 6B, when this data is compared to the information contained within the disclosures of Olsen and Jackson as discussed above.
As a result, the Examiner respectfully notes the data presented by Applicants do not provide a reasonable expectation of success that estriol-16-glucuronide treats spontaneous preterm birth, early term birth, recurrent preterm birth and recurrent early term birth; let alone in treating a pregnant individual for spontaneous abortion or recurrent pregnancy loss as discussed above.
Additionally, the absent of a working example presented by Applicants of administering tetrahydrodeoxycorticosterone, androsterone sulfate, androsterone, or androstane-3,17-diol to a pregnant individual to treat recurrent pregnancy loss or spontaneous abortion works against Applicants claim these compounds treat these conditions, especially in view of the disclosure of Coomarasamy which explicitly discloses no effective treatment method has been identified to treat the same conditions disclosed by Applicants.
Thus, based on Applicants data presented within the disclosure the specification does not provide support with a reasonable expectation of success that estriol-16-glucuronide, estradiol 17β-D-glucuronide, dehydroisoandrosterone sulfate (DHEA-S) or pregnenolone sulfate is effective in treating (e.g. including to reduce the risk of) recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion; or that tetrahydrodeoxycorticosterone, androsterone sulfate, androsterone, or androstane-3,17-diol is effective in treating (e.g. including to reduce the risk of) recurrent pregnancy loss or spontaneous abortion.
Note that lack of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art such as the treatment of (e.g. including to reduce the risk of) recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion as recited in either independent claim 1 or independent claim 17 respectively. See MPEP 2164.
The quantity of experimentation required: Thus, in order to practice the invention of treating (e.g. including to reduce the risk of) recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion, one of ordinary skill in the art would be required to undertake a novel and extensive research program to show that administration of at least estriol-16-glucuronide treats the conditions discussed above in pregnant individuals. Because this research would need to be exhaustive, and because it would involve such a wide scope of conditions and involve treatment options of these conditions that are outside the scope of what is already known in the art, it would constitute an undue and unpredictable search and experimental burden.
Genentech, 108 F.3d at 1366, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors, as discussed above, particularly the breadth of the claims, the nature of the invention, and the lack of working examples, Applicants fail to provide information sufficient to practice the claimed invention of treating (e.g. including to reduce the risk of) recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, early term birth, spontaneous preterm birth or spontaneous abortion in a pregnant individual by administering estriol-16-glucuronide, estradiol 17β-D-glucuronide, dehydroisoandrosterone sulfate (DHEA-S) and/or pregnenolone sulfate; or by administering tetrahydrodeoxycorticosterone, androsterone sulfate, androsterone, or androstane-3,17-diol in combination with estriol-16-glucuronide in treating (e.g. including to reduce the risk of) recurrent pregnancy loss or spontaneous abortion in a pregnant individual as recited in either independent claim 1 or independent claim 17 respectively.
Conclusion
No claims are allowed in this action.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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