PREVENTION OF PRETERM BIRTH (PTB) BY INHIBITION OF FKBP51

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 . Continued Examination Under 37 CFR 1.114 A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 17, 2026 has been reviewed by the examiner and entered of record in the file. 3. Claim 1 is amended. Claims 9 and 10 are cancelled. 4. Applicant previously elected without traverse the single FK506 binding protein 51 (FKBP51) inhibitor “15-deoxy-D12,14-prostaglandin J2” and the species of progesterone. The non-elected species (i.e., small interfering RNA (siRNA)) remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter. 5. Claims 1, 3-7 and 9-11 are under examination with the elected species and are the subject of this office action. Drawings 6. The drawings submitted December 13, 2021 are objected to because in Figures 7, 8, and 11, the label on the Y-axis is misspelled as “Weigth,” but should be spelled as “Weight.” Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Maintained Claim Rejections - 35 USC § 103 The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. 7. Claims 1, 3-7 and 11 remain rejected under 35 U.S.C. 103 as being unpatentable over Pirianov et al., Endocrinology (2009), in view of Kallen, Bengt, Eur Respir J (2013), and in view of Rode et al., Acta Obstetricia et Gynecologica (2009), and further in view of Zannas et al., Neuropsycho-pharmacology Reviews (2016). 8. This rejection has been modified as a result of Applicant’s amendment to claim 1. Claim 1, as amended, is drawn to a method of preventing or treating fetal growth restriction in a pregnant mammal comprising administering a progesterone supplement (more specifically, progesterone) and a composition comprising an inhibitor of FK506 binding protein 51 (FKBP51), (more specifically, 15-deoxy-D12,14-prostaglandin J2) to the pregnant mammal, wherein the pregnant mammal has an increased level of IL-8 or does not have an increased level of IL-6 prior to administration of the composition as compared to a pregnant mammal that is not administered the supplement and composition, and wherein the inhibitor of FKBP51 enhances progesterone receptor activity in the pregnant mammal as compared to a pregnant mammal that is not administered the composition, and wherein the gestation period of the pregnant mammal is extended as compared to a pregnant mammal that is not administered the composition (claim 6), and wherein the likelihood of preterm birth (PTB) is reduced as compared to a pregnant mammal not administered the composition (claim 7). 9. Pirianov et al. teach that the administration of 15-deoxy-D12,14-prostaglandin J2 (“15d-PGJ2,” the same compound recited by Applicant) successfully delays preterm birth in a murine model of inflammation-assisted preterm delivery, when compared with a control group in the same model, who did not receive 15d-PGJ2 (see abstract and page 701, right column, under “15d-PGJ2 delays LPS-induced preterm delivery”). Pirianov et al. suggest the clinical use of 15d-PGJ2 to delay or prevent preterm delivery in woman at high risk of preterm birth, i.e., “[t]]he ability of 15d-PGJ2 to both delay preterm delivery and reduce fetal mortality makes it an attractive candidate for the clinical prevention of preterm labor in women at high risk” (page 705, right column, second paragraph). Pirianov et al. teach that “15d-PGJ2 stocks were prepared in dimethylsulfoxide and then administered as 10% (vol/vol) dimethyl-sulfoxide in saline,” which meets the limitation of a composition comprising 15d-PGJ2 (see page 700, right column, under “Mouse model of intrauterine inflammation”). One of skill in the art before the effective filing date of the claimed invention would reasonably expect that by administering a composition comprising 15-deoxy-D12,14-prostaglandin J2 to prevent preterm delivery, one is necessarily extending the gestation period. 10. Kallen et al. teach that IUGR (fetuses with impaired intrauterine growth aka fetal growth restriction) is significantly related to preterm birth, such that, “[i]t is therefore difficult to study the two phenomena independently,” (page 674, paragraph in left column). Thus, one skilled in the art before the effective filing date of the claimed invention would have reasonably expected that by virtue of administering a composition comprising 15d-PGJ2 to delay preterm delivery in a pregnant mammal in need thereof, one is necessarily treating fetal growth restriction. 11. And, Zannas et al. teach the mechanism by which FKBP51 inhibits progesterone receptor activity: “FKBP5 interacts with steroid receptors … including the MR, progesterone (PR), estrogen (ER), and androgen (AR) receptors. Similar to its effects on GR, FKBP5 inhibits MR and PR activity (Barent et al, 1998; Gallo et al, 2007; Hubler et al, 2003),” [emphasis added] (page 263, left column, first paragraph). FKBP51 is also known as FKBP5 (see Abstract). Therefore, one of skill in art before the effective filing date of the claimed invention would have reasonably expected that by virtue of administering 15dPGJ2 to a pregnant mammal, thereby blocking FKBP5/ FKBP51, then PR activity would necessarily be enhanced. 12. As such, Pirianov et al. suggest administering a composition comprising 15dPGJ2 as a therapeutic agent in the management of preterm labor in a pregnant mammal at high risk of preterm delivery, wherein said administration prevents or treats fetal growth restriction, but do not teach the administration of progesterone. 13. Yet, Rode et al. summarize studies of exogenous progesterone supplementation on the reduction in rate of preterm delivery, wherein progesterone treatment: “showed a positive effect … on the risk of birth before 37 weeks (39% in the progesterone group vs. 59% in the placebo group). The main effect was found before 32 weeks as 2/74 women (2.7%) delivered before 32 weeks in the progesterone group compared to 18/74 (24.3%) in the placebo group,” (page 1182, right column, under “Results,” second full paragraph). Rode et al. demonstrate that progesterone extends the gestation period to full term (i.e., 37 weeks), reduces the risk of preterm birth before 37, 35 and 32 weeks of gestation, and significantly reduces the relative risk of low birth weight, thereby treating fetal growth restriction (see Table II at page 1184, and page 1188, left column, under Conclusion). 14. Therefore, one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat fetal growth restriction and preterm birth in a pregnant mammal in need thereof, by administering both a progesterone supplement and a composition comprising 15dPGJ2 to the pregnant mammal, wherein each treatment independently reduces the rate of preterm birth and treats fetal growth restriction. And, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law, please see In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings). Furthermore, MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. 15. In the instant case, two known therapeutic strategies which individually demonstrate the ability to reduce the rate of preterm delivery and treat fetal growth restriction, could be combined in order to achieve an additive effect for reducing the rate of preterm birth and treating/ preventing fetal growth restriction in a pregnant mammal in need thereof. 16. Please refer to MPEP 2144.06 “I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE” wherein Kerkhoven is specifically referenced: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). 17. As stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976); see also: Merck v. Biocraft (874 F.2d 804, 807 (Fed. Cir. 1989), indicating that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands; Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008): a claimed invention is obvious is it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined; Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 (1945): indicating that “[r]eading a list and selecting a known component to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle.” 18. Regarding the level of IL-8, Pirianov et al. additionally teach that in their murine model of inflammation-assisted preterm delivery, in which inflammation is induced by LPS administration, the expression level of several labor-associated genes is elevated, including CXCLI (which is the mouse equivalent of human IL-8), (page 702, right column, under “15dPGJ2 inhibits LPS-induced COX-2, CCL2 and CXCL1 production in mouse myometrium” and see Figure 5, page 704). Thus, one skilled in the art would reasonably consider administering the combination of progesterone and a composition comprising 15dPGJ2 as a therapeutic modality in the management of preterm labor in a pregnant mammal having increased levels of IL-8. 19. Regarding the level of IL-6, neither Pirianov et al. nor Rode et al. require that any such pregnant mammal receiving treatment in the form of 15dPGJ2 or progesterone, has an elevated level of IL-6. One skilled in the art would have been motivated before the effective filing date of the claimed invention to treat fetal growth restriction and preterm birth in a pregnant mammal in need thereof by administering the combination of progesterone and a composition comprising 15dPGJ2 to the pregnant mammal, and wherein said mammal does not demonstrate increased levels of IL-6. 20. Therefore, one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat fetal growth restriction and preterm birth in a pregnant mammal in need thereof by administering the combination of progesterone and a composition comprising 15dPGJ2 to the pregnant mammal, and wherein said mammal has either increased levels of IL-8 or does not have elevated levels of IL-6 prior to said treatment. As such, claims 1, 6 and 7 are prima facie obvious. Claim 3 is drawn to claim 1, wherein the PR activity is PR-mediated gene transcription. Claim 4 is drawn to claim 1, wherein 15-deoxy-D12,14-prostaglandin J2 blocks glucocorticoid-induced FKBP51 gene expression, wherein the glucocorticoid is dexamethasone (DEX) (claim 5). 21. The combined prior art of record motivates one of skill in the art to treat fetal growth restriction and preterm birth in a pregnant mammal in need thereof, by administering both a progesterone supplement and a composition comprising 15dPGJ2 to the pregnant mammal. Claims 3 and 4 are drafted in terms of the intended outcome of the administration of the progesterone supplement and composition comprising 15d-PGJ2 of claim 1: “...wherein 15-deoxy-D12,14-prostaglandin J2 enhances progesterone receptor (PR) activity wherein the PR activity is PR-mediated gene transcription” (claim 3) or “…wherein 15-deoxy-D12,14-prostaglandin J2 blocks glucocorticoid-induced FKBP51 gene expression,” (claim 4). However, a claimed composition maybe obvious because it was suggested by, or structurally similar to, a prior art composition even though a particular benefit of the claimed composition asserted by patentee is not expressly disclosed in the prior art. It is the differences in fact in their respective properties which are determinative of nonobviousness. If the prior art composition does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, Applicant's recognition of the benefit is not in itself sufficient to distinguish the claimed composition from the prior art, In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1991). In this case, enhancing PR-mediated gene transcription and blocking glucocorticoid-induced FKBP51 gene expression are considered latent properties of the compositions disclosed by Pirianov et al. and Rode et al. and the alleged unexpected results do not confer patentability. The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). As such, claims 3-5 are prima facie obvious. Claim 11 is drawn to claim 1, wherein the pregnant mammal does not have an increased level of TNF-a prior to administration of the composition as compared to a pregnant mammal that is not administered the composition. 22. The combined prior art of record motivates one of skill in the art to treat fetal growth restriction and preterm birth in a pregnant mammal in need thereof, by administering both a progesterone supplement and a composition comprising 15dPGJ2 to the pregnant mammal. Neither Pirianov et al. nor Rode et al. require that any such pregnant mammal receiving treatment in the form of 15dPGJ2, or progesterone, has an elevated level of TNF-a. 23. Thus, one skilled in the art would have been motivated before the effective filing date of the claimed invention to treat fetal growth restriction and preterm birth in a pregnant mammal in need thereof by administering the combination of progesterone and a composition comprising 15dPGJ2 to the pregnant mammal, and wherein said mammal does not demonstrate increased levels of TNF-a. As such, claim 11 is prima facie obvious. Response to Arguments 24. Applicant traverses the previous obviousness rejection and argues that amended claim 1 is further distinguished between the recited invention and the cited references, because Pirianov, Kallen, or Rode, alone or in combination do not teach or suggest the the administration of 15d-PGJ2 as an inhibitor of FKBP51 in combination with a progesterone supplement for the prevention or treatment of fetal growth restriction in a pregnant mammal who has an increased level of IL-8 or does not have an increased level of IL-6 prior to administration, as compared to a pregnant mammal who has not been administered the combination. Applicant argues the following points: (i) Applicant argues that Pirianov does not teach or suggest all of the limitations of amended claim 1, in particular, the administration of 15d-PGJ2 as an inhibitor of FKBP51 in combination with a progesterone supplement for the prevention or treatment of fetal growth restriction (FGR) in a pregnant mammal, who has an increased level of IL-8 or does not have an increased level of IL-6 prior to administration, as compared to a pregnant mammal who has not been administered the combination. Applicant alleges that the instant specification further shows that inhibiting FKBP51 prolongs the gestational length of the stressed animals (See FIG. 3), wherein the data demonstrate that inhibition of FKBP51 can extend gestational periods in stressed pregnant mammals, wherein the stressed pregnant mammals are identified as having non-increased IL-6 levels and increased IL-8 levels. Further, the specification teaches that the siRNA and 15dPGJ2 can inhibit the expression of FKBP51. 25. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Pirianov teaches the clinical use of 15d-PGJ2 to delay or prevent preterm delivery in woman at high risk of preterm birth, wherein Kallen is relied upon for teaching the “strong interaction between gestational duration and IUGR” (page 674, left column, first paragraph). Pirianov additionally teaches in their murine model of inflammation-assisted preterm delivery, in which inflammation is induced by LPS administration, the expression level of several labor-associated genes is elevated, including CXCLI (which is the mouse equivalent of human IL-8), (page 702, right column, under “15dPGJ2 inhibits LPS-induced COX-2, CCL2 and CXCL1 production in mouse myometrium” and Figure 5, page 704). Thus, one skilled in the art would reasonably consider administering a composition comprising 15dPGJ2 as a therapeutic modality in the management of preterm labor in a pregnant mammal having increased levels of IL-8. 26. Rode demonstrates that progesterone supplementation extends the gestation period to full term (i.e., 37 weeks), reduces the risk of preterm birth before 37, 35 and 32 weeks of gestation, and significantly reduces the relative risk of low birth weight, thereby treating fetal growth restriction. Regarding the level of IL-6, neither Pirianov et al. nor Rode et al. require that any such pregnant mammal receiving treatment in the form of 15dPGJ2 or progesterone, has an elevated level of IL-6. 27. Zannas is relied upon for teaching that FKBP5/ FKBP51 inhibits PR activity; therefore, by administering 15dPGJ2 to a pregnant mammal, thereby blocking FKBP5/ FKBP51, one skilled in the art would reasonably expect that PR activity to necessarily be enhanced. Thus absent a demonstration of unexpected results, Applicant’s amendment to claim 1 is insufficient to differentiate from the teachings of the combined prior art of record. One of skill in the art would reasonably expect that the administration of 15d-PGJ2 delays or prevents preterm birth in woman at high risk of preterm birth, wherein 15dPGJ2 inhibits FKBP5/ FKBP51, thereby enhancing PR activity and treating intrauterine growth restriction in said pregnant mammal, wherein said pregnant mammal has increased levels of IL-8 or does not have elevated levels of IL-6. (ii) Applicant argues that Rode likewise fails to disclose or suggest the limitations of amended claim 1, which recites administration of an inhibitor of FKBP51, such as 15d-PGJ2, in combination with a progesterone supplement to prevent or treat fetal growth restriction (FGR). Applicant alleges that Rode discusses the administration of progesterone to women with a history of spontaneous preterm birth, it is silent with respect to the use of any FKBP51 inhibitor, either alone or in combination with progesterone. Applicant contends that the Office's reliance on Rode to supplement Pirianov is misplaced because Rode simply does not address or suggest the combination therapy required by the amended claims, nor does it contemplate modulation of FKBP51 as a therapeutic strategy in pregnant mammals who have an increased level of IL-8 or does not have an increased level of IL-6 prior to administration of the progesterone supplement and the composition. Applicant argues that the teachings of Rode are directed to a distinct clinical objective of preventing spontaneous preterm birth, not to the prevention or treatment of fetal growth restriction. Applicant argues that the data in Rode reflect that treatment with progesterone alone may be associated with adverse effects such as increased incidence of gestational diabetes mellitus. (Rode, page 1185), wherein Applicant alleges this observation teaches away from the use of progesterone or enhancing PR activity in the current application and would further discourage a person skilled in the art from modifying existing progesterone protocols absent compelling data supporting a benefit from combination with an FKBP51 inhibitor. 28. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In this case, the primary reference, Pirianov teaches the clinical use of 15d-PGJ2 to delay or prevent preterm delivery in woman at high risk of preterm birth, wherein Kallen links shortened gestational duration to intrauterine growth restriction. Rode demonstrates that progesterone supplementation extends the gestation period to full term (i.e., 37 weeks), reduces the risk of preterm birth before 37, 35 and 32 weeks of gestation, and significantly reduces the relative risk of low birth weight, thereby treating fetal growth restriction. While Rode reports that in their study, 12.9% of gestational diabetes mellitus (GDM) was reported, Rode also notes that 4.9% of women in the control group also developed GDM, accounting for a risk increase of only 8%. 29. Pirianov additionally teaches in their murine model of inflammation-assisted preterm delivery, in which inflammation is induced by LPS administration, the expression level of several labor-associated genes is elevated, including CXCLI (which is the mouse equivalent of human IL-8), (page 702, right column, under “15dPGJ2 inhibits LPS-induced COX-2, CCL2 and CXCL1 production in mouse myometrium” and Figure 5, page 704). Regarding the level of IL-6, neither Pirianov et al. nor Rode et al. require that any such pregnant mammal receiving treatment in the form of 15dPGJ2 or progesterone, has an elevated level of IL-6. Thus, one skilled in the art would reasonably consider administering the combination of 15d-PGJ2 and a composition comprising 15dPGJ2 as a therapeutic modality in the management of preterm labor in a pregnant mammal having increased levels of IL-8, or not having elevated levels of IL-6. 30. Regarding Applicant’s argument that Rode teaches away from the claimed invention, the examiner refers to MPEP 2141.02 VI, Allied Erecting v. Genesis Attachments, 825 F.3d 1373,1381,119 USPQ2d 1132,1138 (Fed. Cir. 2016) ("Although modification of the movable blades may impede the quick change functionality disclosed by Caterpillar, ‘[a] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine,’" (quoting Medichem, SA. v. Rolabo, S.L., 437 F.3d 1157,1165, 77 USPQ2d 1865,1870 (Fed Cir. 2006) (citation omitted)). And, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed."). PNG media_image1.png 18 19 media_image1.png Greyscale (iii) Applicant argues that Kallen acknowledges that FGR and preterm birth often co-occur and may share certain clinical features, yet correlation or co-occurrence does not equate to causation or therapeutic equivalence. Applicant alleges that the fact that FGR is statistically associated with preterm birth does not establish that a treatment which delays preterm labor necessarily prevents or treats FGR, and that Kallen does not teach or suggest that delaying labor will inherently resolve impaired fetal growth, nor do they disclose or imply that administration of 15d-PGJ2 alone addresses the molecular or physiological drivers of FGR. Applicant argues that Zannas does not teach pregnancy treatment, does not identify 15dPGJ2 or siRNA as FKBP51 inhibitors for use in pregnant subjects, does not disclose co-administration with progesterone for fetal growth restriction, and does not suggest that inhibiting FKBP51 would enhance progesterone receptor activity in a way sufficient to prevent or treat fetal growth restriction in pregnant mammals who have an increased level of IL-8 or does not have an increased level of IL-6 prior to administration of the progesterone supplement and the composition. 31. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In this case, the combined teachings of Rode and Pirianov motivate one skilled in the art to administer both progesterone and 15d-PGJ2 to treat fetal growth restriction and reduce the risk of preterm birth in a pregnant mammal, wherein said mammal has increased levels of IL-8 or does not have increased levels of IL-6, prior to administration, as compared to a pregnant mammal that is not treated with the recited combination. Kallen is additionally relied upon for linking shortened gestational duration to IUGR/ fetal growth restriction (FGR). And in view of Zannas, one would expect that in administering 15dPGJ2 to a pregnant mammal, thereby blocking FKBP5/ FKBP51, PR activity would necessarily be enhanced. Conclusion 32. Claims 1, 3-7 and 11 are present in the application. Claims 1, 3-7 and 11 are rejected. No claim is presently allowed. 33. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JANET L COPPINS/Examiner, Art Unit 1628 /AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628