DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/14/2025 has been entered.
Status of Claims
Claims 13-15 and 19-21 are pending. Claims 14-15 are withdrawn.
Priority
Instant application 17/299,584, filed 06/03/2021 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendment
The amendment filed 11/13/2024 has been entered. Claims 13 and 19-20 are amended. Claims 1-12 and 16-18 are cancelled. Claim 21 is new.
Claims 1-4, 7, and 19-20 were previously rejected under 35 U.S.C. 103. Claims 1-4, 7 have been cancelled, rendering their rejection moot. Claims 19-20 now depend from claim 13. Therefore, the rejection under 103 is withdrawn.
Claims 1-13 and 18-20 were provisionally rejected on the ground of nonstatutory double patenting over copending Application No. 18/640,607. The ‘607 application went abandoned according to the Notice of Abandonment in the application file dated 05/16/2025. Therefore, the provisional nonstatutory double patenting rejection over 18/640,607 is withdrawn.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 10,717,761
Claims 13 and 19-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 14-15 of U.S. Patent No. 10,717,761 (“the ‘761 patent”) in view of Eloranta (WO2014207310A1) and Messinger 2 (WO2006125800A1).
The ‘761 patent recites compounds of Formula (I) and (Ib):
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and recites specific embodiments in claim 11. Claim 11 recites multiple compounds which are compared with the instant claims, see for example the following:
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With respect to new claim 21, the ‘761 patent recites the compound 3-((13S,15R,E)-4-fluoro-17-(hydroxyimino)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(pyrazin-2-yl)propenamide, which has the structure:
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The difference between the compounds of the ‘761 patent and the instant claims is that in the ‘761 patent, the compounds comprise an oxime at position 17; whereas in the instant claims, the compounds comprise a pyrazole ring condensed at positions 16 and 17.
The teachings of Eloranta and Messinger 2 have been previously disclosed and at least those teachings are incorporated herein by reference. Eloranta discloses inhibitors of 17β-HSD1 (abstract, title). In particular, Eloranta discloses compounds 59 and 52 in Table 1:
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and their inhibitory activity for 17-HSD1 in Table 2:
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Eloranta is considered to provide a teaching that modifying compound 59 by replacing the oxime with a condensed pyrazole ring at the 16 and 17 positions results in an alternative compound (i.e, compound 52) with roughly equivalent 17β-HSD1 inhibitory activity.
Additionally, see Eloranta, page 3, which notes that “One of the problems associated with the known 17 -HSD1 inhibitors is the disposition, in particular the metabolic stability, of the compounds. It is therefore yet a further object of the present invention to provide compounds with improved metabolic stability.” See also the results in Table 3 demonstrating the improved metabolic stability for compounds from Eloranta.
See also Messinger 2, page 8, lines 15-19 which note that “Furthermore, an increased metabolic stability of the compounds, in particular of the C17 keto position of the steroidal core, would be desirable, in order to prevent conversion of the estron to the respective estradiol derivative, which shows less inhibitory potential on the 17β-HSD1 enzyme.” Such teachings in Eloranta and Messinger 2 highlight an explicit motivation to prepare compounds having a protective group (such as a pyrazole group) in place of the C17 keto group to improve the metabolic stability of the compounds.
Therefore, applying KSR exemplary rationale (B), it would have been prima facie obvious to substitute the oxime in the compounds of the ‘761 patent with the condensed pyrazole ring as taught by Eloranta to arrive at compounds of the instant claims. A skilled artisan would have reasonably predicted that the substitution would result in compounds having roughly equivalent 17β-HSD1 inhibitory activity and metabolic stability in view of the teachings of Eloranta and Messinger 2.
US 11,254,703
Claims 13 and 19-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,254,703 in view of Messinger 1 (WO2005047303A2), Eloranta (WO2014207310A1), and Messinger 2 (WO2006125800A1).
The ‘703 patent recites compounds of Formula (II):
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and recites specific embodiments in claim 7. Claim 7 recites multiple compounds which are compared with the instant claims, see for example the following:
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With respect to new claim 21, the ‘703 patent recites the compound 3-((13 S,15R)-4-fluoro-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(pyrazin-2-yl)propanamide, which has the structure:
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The difference between the compounds of the ‘703 patent and the instant claims is that in the ‘761 patent, the compounds comprise a carbonyl at position 17; whereas in the instant claims, the compounds comprise a pyrazole ring condensed at positions 16 and 17.
The teachings of Messinger 1, Messinger 2, and Eloranta are disclosed previously and at least those teachings are incorporated herein by reference. Messinger 1 discloses inhibitors of 17β-HSD1 (abstract, title) and discloses compounds of Formula VI (page 20, lines 25-30):
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Messinger 1 discloses multiple compounds of Formula VI which are considered relevant to the instant claims in Table 42 along with their inhibitory activity toward 17β-HSD1. For example, Messinger discloses compound 329:
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Eloranta discloses inhibitors of 17β-HSD1 (abstract, title). In particular, Eloranta discloses compound 50 in Table 1:
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and its inhibitory activity for 17-HSD1 in Table 2:
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Messinger 1 and Eloranta are considered to provide a teaching that modifying compound 329 of Messinger by replacing the carbonyl with a condensed pyrazole ring at the 16 and 17 positions results in an alternative compound (i.e., compound 50 of Eloranta) with roughly equivalent 17β-HSD1 inhibitory activity.
Additionally, see Eloranta, page 3, which notes that “One of the problems associated with the known 17B-HSD1 inhibitors is the disposition, in particular the metabolic stability, of the compounds. It is therefore yet a further object of the present invention to provide compounds with improved metabolic stability.” See also the results in Table 3 demonstrating the improved metabolic stability for compounds from Eloranta.
See also Messinger 2, page 8, lines 15-19 which note that “Furthermore, an increased metabolic stability of the compounds, in particular of the C17 keto position of the steroidal core, would be desirable, in order to prevent conversion of the estron to the respective estradiol derivative, which shows less inhibitory potential on the 17β- HSD1 enzyme” Such teachings in Eloranta and Messinger 2 highlight an explicit motivation to prepare compounds having a protective group (such as a pyrazole ring) in place of the C17 keto group to improve the metabolic stability of the compounds.
Therefore, applying KSR exemplary rationale (B), it would have been prima facie obvious to substitute the carbonyl in the compounds of the ‘703 patent with the condensed pyrazole ring as taught by Messinger 1 and Eloranta to arrive at compounds of the instant claims. A skilled artisan would have reasonably predicted that the substitution would result in compounds having improved selectivity for 17β-HSD1 inhibition and improved metabolic stability in view of the teachings of Messinger 1, Messinger 2, and Eloranta.
19/196,058
Claims 13 and 19-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 19/196,058 in view of Messinger 1 (WO2005047303A2), Eloranta (WO2014207310A1), and Messinger 2 (WO2006125800A1).
The ‘058 application recites compounds of Formula (Ib) and Formula (II):
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; and
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and recites specific embodiments in claims 11 and 19. Claim 11 recites multiple compounds which are compared with the instant claims, see for example the following:
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The difference between the compounds of the ‘058 application and the instant claims is that in the ‘058 application, the compounds comprise an oxime at position 17; whereas in the instant claims, the compounds comprise a pyrazole ring condensed at positions 16 and 17.
Claim 19 recites multiple compounds which are compared with the instant claims, see for example the following:
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The difference between the compounds of the ‘058 application and the instant claims is that in the ‘058 application, the compounds comprise a carbonyl at position 17; whereas in the instant claims, the compounds comprise a pyrazole ring condensed at positions 16 and 17.
The teachings of Messinger 1 and Eloranta are disclosed previously and at least those teachings are incorporated herein by reference. Eloranta provides a teaching that modifying compound 59 by replacing the oxime with a condensed pyrazole ring at the 16 and 17 positions results in an alternative compound (i.e, compound 52) with roughly equivalent 17β-HSD1 inhibitory activity. Messinger 1 and Eloranta provide a teaching that modifying compound 329 of Messinger by replacing the carbonyl with a condensed pyrazole ring at the 16 and 17 positions results in an alternative compound (i.e., compound 50 of Eloranta) with roughly equivalent 17β-HSD1 inhibitory activity. Further, replacement of the C17 ketone with a pyrazole ring is taught to improve metabolic stability for the compound.
Additionally, see Eloranta, page 3, which notes that “One of the problems associated with the known 17 -HSD1 inhibitors is the disposition, in particular the metabolic stability, of the compounds. It is therefore yet a further object of the present invention to provide compounds with improved metabolic stability.” See also the results in Table 3 demonstrating the improved metabolic stability for compounds from Eloranta.
See also Messinger 2, page 8, lines 15-19 which note that “Furthermore, an increased metabolic stability of the compounds, in particular of the C17 keto position of the steroidal core, would be desirable, in order to prevent conversion of the estron to the respective estradiol derivative, which shows less inhibitory potential on the 17β- HSD1 enzyme” Such teachings in Eloranta and Messinger 2 highlight an explicit motivation to prepare compounds having a protective group (such as a pyrazole ring) in place of the C17 keto group to improve the metabolic stability of the compounds.
Therefore, applying KSR exemplary rationale (B), it would have been prima facie obvious to substitute the oxime in the compounds of the ‘058 application with the condensed pyrazole ring as taught by Eloranta to arrive at compounds of the instant claims. Similarly, it would have been obvious to substitute the carbonyl in the compounds of the ‘058 application with the condensed pyrazole ring as taught by Messinger 1 and Eloranta. A skilled artisan would have reasonably predicted that these substitutions would result in compounds having roughly equivalent or improved 17β-HSD1 inhibitory activity and metabolic stability in view of the teachings of Messinger 1, Messinger 2, and Eloranta.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
In response to the nonstatutory double patenting rejection over US 10, 717,761, applicant traverses the rejection and alleges that “[T]here is no citation or support for the assertion that substation [sic] of the C17 ketone with a pyrazole ring results in a compound with metabolic stability” (Remarks, page 7, first paragraph).
Applicant's arguments have been fully considered but they are not persuasive. Please note that the rejection points to Table 3 in Eloranta which discloses the in vitro metabolic stability of compounds having a pyrazole ring including compounds 50, 51, 53, and 55. Please also note the passage cited in Messinger 2, which teaches that an increased metabolic stability of the compounds, in particular of the C17 keto position of the steroidal core, would be desirable, in order to prevent conversion of the estron to the respective estradiol derivative, which shows less inhibitory potential on the 17β- HSD1 enzyme. Eloranta and Messinger 2 highlight an explicit motivation to prepare compounds having a protective group (such as a pyrazole ring) in place of the C17 keto group to improve the metabolic stability of the compound toward conversion to the estradiol derivative.
Additionally in the Remarks at page 7, first paragraph, Applicant points to data for compound 52 ("the compound with the C16-C17 pyrazole ring") in Table 2 of Eloranta. Applicant stated that "[a]s reflected in Table 2, the % inhibition of 17B-HSD2 at 1 uM for the compound with the C16-C17 pyrazole ring is zero. Reliance on that data teaches that opposite conclusion than that what was asserted. One of ordinary skill in the art would not be motivated to make a substitution that results in complete loss of inhibitory activity”.
Applicant’s argument is not persuasive and the assertion that making such a substitution would result in "complete loss of inhibitory activity" is misleading. Table 2 of Eloranta shows that compound 52 exhibited 94% inhibition of 17B-HSD1 at 1 uM; and 0% inhibition of 17B-HSD2 at 1 uM. Applicant's mere characterization of compound 52 as exhibiting a "complete loss of inhibitory activity" is misleading because a stated objective of both Eloranta and the '761 patent is to achieve selective inhibition of 17BHSD1 over 17BHSD2.
See Eloranta, page 3, lines 23-27, which states: “An object of the present invention is to provide compounds useful in treating disorders and diseases associated with increased level of estradiol and/or treatable by inhibition of 17-HSD1 enzyme. It is further an object of the present invention to provide compounds that show little or no inhibitory effect on 17β-HSD2 enzyme.”
See also the '761 patent, col. 2, line 64 continuing to col. 3, line 2 which states: “An object of the present invention is to provide compounds useful in treating disorders and diseases associated with increased level of estradiol and/or treatable by inhibition of 17β-HSD1 enzyme. It is further an object of the present invention to provide compounds that show little or no inhibitory effect on 17β-HSD2 enzyme.”
Eloranta's Table 2 results demonstrate that compound 52 is a selective inhibitor of 17BHSD1 over 17BHSD2. The compounds claimed in the '761 patent are also selective for 17BHSD1. Therefore, a person having ordinary skill would have expected similar properties (with respect to selective inhibition of 17BHSD1) between the compounds of the '761 patent and those resulting from modification of the oxime to a pyrazole group.
Please also note MPEP 2144.09, which states “A prima facie case of obviousness based on structural similarity is rebuttable by proof that the claimed compounds possess unexpectedly advantageous or superior properties.” Applicant is invited to provide or point to evidence that the claimed compounds possess unexpectedly advantageous or superior properties beyond those which are taught by the cited references.
In response to the nonstatutory double patenting rejection over US 11,254,703, applicant traverses the rejection and reiterates the arguments set forth in response to the rejection over the '761 patent above. Applicant's arguments are not persuasive for the same reasons set forth above. Applicant's mere characterization of compound 52 as exhibiting a "complete loss of inhibitory activity" is misleading because a stated objective of both Eloranta and the '703 patent is to achieve selective inhibition of 17BHSD1 over 17BHSD2.
See the '703 patent, col. 3, lines 6-12 which states: “An object of the present invention is to provide compounds useful in treating disorders and diseases associated with increased level of estradiol and/or treatable by inhibition of 17β-HSD1 enzyme. It is further an object of the present invention to provide compounds that show little or no inhibitory effect on 17β-HSD2 enzyme.”
Please also note MPEP 2144.09, which states “A prima facie case of obviousness based on structural similarity is rebuttable by proof that the claimed compounds possess unexpectedly advantageous or superior properties.” Applicant is invited to provide or point to evidence that the claimed compounds possess unexpectedly advantageous or superior properties beyond those which are taught by the cited references.
Conclusion
Claims 13 and 19-21 are rejected. Claims 14-15 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 8:30 am - 5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621