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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 20, 2025 has been entered.
Priority
The instant application is a divisional of Application No. 16/936,705 filed on July 23, 2020 which claims priority to domestic Provisional Application No. 62/877,614 filed on July 23, 2019.
Status of Claims
Acknowledgement is made of previously presented (21-24, 26) amended (1, 21-24), cancelled (2-8, 19-20, 25, 27), and withdrawn (9-18), claims filed on October 20, 2025. Claims 1, 9-18, 21-24 26 are pending in instant application. Claims 1, 21-24, 26 are presently examined.
Information Disclosure Statement
The information disclosure statement filed on October 20, 2025 has been considered.
Response to Arguments
The following rejections/objections have been withdrawn due to claim amendments:
Objection of claims 1, 19-27.
The following rejections have been maintained, but modified:
35 USC § 103 Rejection over WO 2015/143201 A2 in view of Gui et. al.1 and Thakker et. al.2
Non-Statutory Double Patenting Rejections over U.S. Patent Nos. 10,723,757; 10,174,070; 9,636,348; 9,422,324; 9,364,486; 8,629,130 and 8,168,621, all in view of WO’201, Gui, and Thakker.
Applicant's arguments filed October 20, 2025 have been fully considered but they are not persuasive.
Regarding Non-Statutory Double Patenting Rejections (see 10/20/25 Remarks at p. 7), The Examiner notes that the prior action inadvertently listed an incomplete set of claims in the NSDP rejection headings (1, 3, 4, 19-24) while the rejection body addressed the intended claims and their limitations (1, 19-27); this has been corrected below to accurately reflect the claims subject to the rejections in light of claim amendments (1, 21-24, 26).
Regarding Applicant’s argument that the prior art does not recite NDC-1308 (see 10/20/25 Remarks at p. 8), WO'201 teaches NDC-1308 as Compound 21 (see WO'201 at p. 16).
Regarding Applicant’s argument that the prior art is silent regarding “switching, polarizing, or altering” (see 10/20/25 Remarks at p. 8-9), Thakker teaches E2 suppresses M1 microglia polarization while enhancing M2 microglia polarization in the hippocampus after GCI (see Thakker at p. 6 right col.), reading on the “switching, polarizing, or altering” limitation.
Regarding Applicant’s argument that Thakker does not teach an effect on basal microglial polarization states (see 10/20/25 Remarks at p. 9), the instant claims are not drawn to administering to basal microglial cells, but specify "contacting a microglial cell or a macrophage cell having a pro-inflammatory phenotype" (see instant claim 1). More relevantly, Thakker teaches M1 is a proinflammatory phenotype (see Thakker at p. 6 right col.), and after global cerebral ischemia M1 markers were elevated in the hippocampus (cells were pro-inflammatory phenotype), but treatment with E2 after global cerebral ischemia M1 markers were suppressed and M2 were enhanced, reading on administering E2 to pro-inflammatory phenotype cell (M1 markers elevated post-insult) resulting in switching, polarizing, or altering to an anti-inflammatory phenotype (M2 markers elevated) (see Thakker at p. 7 Figure 3). Moreover, Thakker examines administering E2 directly to BV2 microglial cells, and states:
“our in vitro studies indicate that E2 could directly act on the microglia cells to regulate their activation and M1/M2 polarization via suppression of M1 phenotype markers and proinflammatory cytokines and elevation of M2 phenotype markers and antiinflammatory cytokines.” (emphasis added) (see Thakker at p. 9 right col. ¶2)
Regarding Applicant’s argument that the prior art does not disclose a feature of expressing inflammatory genes or reparative genes (10/20/25 Remarks at p. 9), Thakker teaches gene expression of M1 markers, TNF-α, CD68, and IL-1β (see Thakker at p. 7 left col. ¶1) and M2 markers, Arginase1, CD206, and Ym1 (see Thakker at p. 7 left col. ¶1) which are examined when determining the effect of E2 on microglial polarization (see Thakker at p. 7 Figure 3). Thakker thus teaches administration of E2 results in down-regulation of pro-inflammatory genes (M1 markers) and up-regulation of the anti-inflammatory genes (M2 markers) in microglial cells (see id, see also Claim Interpretation). Moreover, as stated in the previous office action, the limitations of claims 23 and 24 do not require any alterations to the active step of contacting NDC-1308 to a microglial cell or macrophage cell with a pro-inflammatory phenotype capable of expressing LPL and/or ApoC2, and are understood to be the result of performing the active step (see 5/19/25 Office Action at p. 19 ¶3).
Regarding Applicant’s argument over functional equivalents (see 10/20/25 Remarks at p. 10), while the derivatives may not be functional equivalents in regards to binding to estrogen receptors as stated by Applicant and taught by Yarger, WO'201 teaches estradiol derivatives are still known functional equivalents in regards to up-regulating LPL or ApoC2 (see WO'201 at p.1 [0002] and pp. 14-17, specifically compounds 4, 21, and p. 33 Table 1, see also 5/19/20 Office Action at p. 19 par 2 and p. 20 par 3), the same function instantly claimed (see instant claim 1, "expressing lipoprotein lipase (LPL) and/or apolipoprotein C2 (ApoC2)"). Accordingly, the functional equivalent sections of the rejections have been altered to include the above rationale.
Applicant’s Examples (see instant specification at pp. 31-33) disclose that it is the cell contact with NDC-1308 (which is understood to be CAS Registry No. 1227511-09-2) that up-regulates LPL, which alters microglial or macrophage cells to M2-like phenotype. No additional or special steps are identified. Therefore any prior art or patent document that discloses contacting a microglial or macrophage cell or administering CAS# 1227511-09-2 to a subject would consequently up-regulate LPL and alter microglial or macrophage cells to M2-like phenotype since it is a result of the active step of administering CAS# 1227511-09-2.
Absent unexpected results commensurate in scope with the claims, the claims are still rendered obvious by the prior art.
Claim Interpretation
Regarding “down-regulated inflammatory gene” (see in particular instant claim 23), the instant specification does not specifically define the genes encompassed, only exemplifies TNF-α, IL-6, IL-12, IL-23, IL1β, IFNγ, nitrogen monoxide via iNOS induction, and chemokines. Therefore any art-recognized inflammatory gene is encompassed in the claim scope.
Regarding “upregulated reparative gene” (see in particular instant claim 24), the instant specification does not specifically define the genes encompassed, only exemplifies anti-inflammatory cytokines, such as TGF-3, IL-4, IL-10, and IL-13, growth factors such as vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and platelet-derived growth factor (PDGF) (see instant specification at p. 7 lines 21-27). Therefore any art-recognized reparative gene is encompassed in the claim scope.
Regarding “microglial cell or macrophage cell”, exemplary reference Ginhoux et. al.3 teaches microglial cells are known in the art to be a type of macrophage cell (see Ginhoux at Abstract). Any art disclosing contacting a microglial cell is thus art disclosing contacting a macrophage cell.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 21-24, 26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/143201 A2 in view of Gui et. al.4 and Thakker et. al.5.
Claim interpretation: The claim interpretations set forth in the “claim interpretation” section above are hereby incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding claims 1, 21-24, 26 and CAS# 1227511-09-2, WO’201 claims a method of treating Alzheimer’s Disease comprising administering a compound of formula I, including CAS# 1227511-09-2 (see WO’201 at claim 4 p. 37 and claim 5 at p. 38, “(6R,8R,9S,13S,14S)-6-(6-methoxyhexyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol”).
Regarding claim 1 and a method of altering an inflammatory phenotype comprising contacting a microglial or macrophage cell having a pro-inflammatory phenotype capable of expressing LPL and/or ApoC2 with an effective amount of a compound, WO’201 claims a method of up-regulating LPL and/or ApoC2 functional activity comprising administering a compound of formula:
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(see WO’201 claim 6), including instantly elected CAS#1227511-09-2 (see WO’201 at claim 9 p. 42 and claim 10, “(6R,8R,9S,13S,14S)-6-(6-methoxyhexyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol”) (see also WO’201 at p. 33 Table 1 compound 21).
Regarding claims 23 and a down-regulated inflammatory gene and claim 24 and an upregulated reparative gene, these limitations do not require any alterations to the active step of contacting a compound of Formula I to a microglial cell or macrophage cell with a pro-inflammatory phenotype capable of expressing LPL and/or ApoC2, and are understood to be a result of performing said active step.
The prior art differs from the claims as follows: While WO’201 teaches administering compounds of instant CAS#1227511-09-2 for up-regulating LPL and/or ApoC2 functional activity and treating Alzheimer’s, WO’201 does not specify i) contacting a microglial or macrophage cell or ii) altering an inflammatory phenotype.
Regarding claims 1, 21, 22, 26 and contacting a microglial or macrophage cell, including a macrophage cell with a pro-inflammatory M1 phenotype, one skilled in the art would appreciate that administering a compound of CAS#1227511-09-2 to a subject will inevitably contact a microglial or macrophage cell, including M1 phenotypes (see also relevant diseases for treatment in instant spec at p. 2 lines 14-20).
Nevertheless,
Instant CAS#1227511-09-2 belongs to a class of compounds called estradiols. Gui teaches 17β-Estradiol up-regulates ApoCs in a dose-dependent manner, including ApoC2 (see Gui at p. 142 right col. section 3.1.3 and p. 144 Figure 3D-F). Gui also teaches ApoC2 is a co-factor of lipoprotein lipase (LPL) (see Gui at p. 147 right col. par. 2 and at p. 148 Table 2). These teachings parallel those of WO’201, which teaches the 6-substituted estradiol derivative compound 4 up-regulates LPL and ApoC2 (see WO’201 at p. 33 Table 1). Gui and WO’201 thus teaches 17β-Estradiol and compounds of Formula I are structurally similar, functional equivalents.
17β-Estradiol, “E2”
WO’201 Compound 4
CAS#1227511-09-2
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Thakker teaches M1 is a proinflammatory phenotype (see Thakker at p. 6 right col.), and after global cerebral ischemia M1 markers were elevated in the hippocampus (cells were pro-inflammatory phenotype), but treatment with E2 after global cerebral ischemia M1 markers were suppressed and M2 were enhanced, reading on administering to pro-inflammatory phenotype cell (M1 markers elevated post-insult) resulting in switching, polarizing, or altering to an anti-inflammatory phenotype (M2 markers elevated, M1 markers suppressed) (see Thakker at p. 7 Figure 3). Moreover, Thakker examines administering E2 directly to BV2 microglial cells, and states:
our in vitro studies indicate that E2 could directly act on the microglia cells to regulate their activation and M1/M2 polarization via suppression of M1 phenotype markers and proinflammatory cytokines and elevation of M2 phenotype markers and antiinflammatory cytokines. (emphasis added) (see Thakker at p. 9 right col. ¶2)
Thakker also teaches a neuroprotective role for E2 has also been suggested in neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis (see Thakker at p. 1 right col. ¶1), an overlapping utility with WO’201’s CAS#1227511-09-2 Alzheimer’s treatment (see WO’201 at Title).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to one skilled to substitute one known structurally similar, functionally equivalent estradiol Alzheimer treatment known to up-regulate LPL and/or ApoC2 (compounds of Formula I and CAS#1227511-09-2 taught by WO’201) for another estradiol Alzheimer treatment known to up-regulate LPL and/or ApoC2 (17β-Estradiol taught by Gui) with a reasonable expectation of altering macrophage or microglial phenotype because the prior art teaches a known estradiol alters macrophage phenotypes from pro-inflammatory M1 phenotypes to an anti-inflammatory M2 phenotypes (as taught by Gui and Thakker) (see also MPEP § 2144.06(II)).
Furthermore, it is well-within the ordinary skill in art to identify relevant mechanisms (including M1 and M2 phenotypes) of known treatments for the same purpose as taught by the prior art (administering a compound of Formula I to alter phenotypes). Furthermore it is well-within the ordinary skill in the art to substitute one functional equivalent for another for purposes taught in the prior art.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Accordingly, claims 1, 21-24, 26 are obvious over WO’201 in view of Gui and Thakker.
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.
Claims 1, 21-24, 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent Nos. 8,168,6216 in view of WO’201, Gui and Thakker.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding claim 1 and CAS# 1227511-09-2, US’621 claims compounds encompassed by instant Formula I (see below).
US’621 Claim 1
US’621 Claim 2 CAS# 1092659-75-0
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The instantly claimed compound CAS# 1227511-09-2 differs from the patented genus by repeating -(CH2)- segments.
Regarding claim 1 and a method, US’621 claims a pharmaceutical composition comprising aforementioned compounds (US’621 claim 3). Per MPEP §804(II)(B)(1), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010). In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. US’621 discloses the utility of binding to estrogen receptors to impact cell proliferation (col 44 lines 39-43) and treating cancer (see US’621 at col. 6 lines 11-15).
The patented claims differ from instant claims as follows: While US’621 claims structurally same and similar compounds for treating cancer, US’621 does not discuss altering macrophage phenotypes.
However,
Regarding altering microglial or macrophage types, Thakker teaches M1 is a proinflammatory phenotype (see Thakker at p. 6 right col.), and after global cerebral ischemia M1 markers were elevated in the hippocampus (cells were pro-inflammatory phenotype), but treatment with estradiol derivative E2 after global cerebral ischemia M1 markers were suppressed and M2 were enhanced, reading on administering to pro-inflammatory phenotype cell (M1 markers elevated post-insult) resulting in switching, polarizing, or altering to an anti-inflammatory phenotype (M2 markers elevated, M1 markers suppressed) (see Thakker at p. 7 Figure 3). Moreover, Thakker examines administering E2 directly to BV2 microglial cells, and states:
our in vitro studies indicate that E2 could directly act on the microglia cells to regulate their activation and M1/M2 polarization via suppression of M1 phenotype markers and proinflammatory cytokines and elevation of M2 phenotype markers and antiinflammatory cytokines. (emphasis added) (see Thakker at p. 9 right col. ¶2)
Regarding CAS#1227511-09-2, instant CAS#1227511-09-2 belongs to a class of compounds called estradiols. Gui teaches 17β-Estradiol up-regulates ApoCs in a dose-dependent manner, including ApoC2 (see Gui at p. 142 right col. section 3.1.3 and p. 144 Figure 3D-F). Gui also teaches ApoC2 is a co-factor of lipoprotein lipase (LPL) (see Gui at p. 147 right col. par. 2 and at p. 148 Table 2).
These teachings parallel those of WO’201, which teaches the 6-substituted estradiol derivatives (see WO’201 pp. 14-17), including compounds 4 and 21 (CAS#1227511-09-2) which differ by repeating -(CH2)- units, up-regulate LPL and ApoC2 (see WO’201 at p. 33 Table 1). Gui and WO’201 thus teaches 17β-Estradiol, compounds of Formula I such as CAS#1227511-09-2, and compounds of US’621 claim 1 are structurally similar, functional equivalents.
17β-Estradiol, “E2”
WO’201 Compound 4
WO’201 Compound 21
CAS#1227511-09-2
US’621 Claim 1
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Therefore, it would have been obvious to one of ordinary skill in the art, based on the previous patent, to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to one skilled to substitute one known structurally similar, functionally equivalent ApoC2/LPL regulating estradiol structure of US’621 claims 1-3 for another ApoC2/LPL regulating 17β-Estradiol (as taught by Gui and WO’201) with a reasonable expectation of altering macrophage or microglial phenotype because the prior art teaches the known estradiol alters macrophage phenotypes from pro-inflammatory M1 phenotypes to an anti-inflammatory M2 phenotypes (17β-Estradiol taught by Thakker) (see also MPEP § 2144.06(II)).
Accordingly, the claims are not patentably distinct.
Claims 1, 21-24, 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 8,629,130 B27 in view of WO’201, Gui, and Thakker et. al.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding compounds of Formula I, US’130 claims compounds encompassed by instant Formula I (US’130 claim 1) including CAS# 1025495-78-6 (US’130 claim 4) (see below).
US’130 Claim 1
US’130 Claim 4 CAS# 1025495-78-6
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Instantly claimed compound CAS# 1227511-09-2 differs only by repeating -(CH2)- segments from US’130’s CAS# 1025495-78-6 (US’130 claims 4 and 5).
Regarding a method, US’130 claims methods of treating cancer (US’130 claims 1-4) including breast cancer (US’130 claim 2).
The patented claims differ from instant claims as follows: While US’130 claims structurally same and similar compounds for treating cancer, US’130 does not discuss altering macrophage phenotypes.
However,
Regarding altering microglial or macrophage types, Thakker teaches M1 is a proinflammatory phenotype (see Thakker at p. 6 right col.), and after global cerebral ischemia M1 markers were elevated in the hippocampus (cells were pro-inflammatory phenotype), but treatment with estradiol derivative E2 after global cerebral ischemia M1 markers were suppressed and M2 were enhanced, reading on administering to pro-inflammatory phenotype cell (M1 markers elevated post-insult) resulting in switching, polarizing, or altering to an anti-inflammatory phenotype (M2 markers elevated, M1 markers suppressed) (see Thakker at p. 7 Figure 3). Moreover, Thakker examines administering E2 directly to BV2 microglial cells, and states:
our in vitro studies indicate that E2 could directly act on the microglia cells to regulate their activation and M1/M2 polarization via suppression of M1 phenotype markers and proinflammatory cytokines and elevation of M2 phenotype markers and antiinflammatory cytokines. (emphasis added) (see Thakker at p. 9 right col. ¶2)
Regarding CAS#1227511-09-2, instant CAS#1227511-09-2 belongs to a class of compounds called estradiols. Gui teaches 17β-Estradiol up-regulates ApoCs in a dose-dependent manner, including ApoC2 (see Gui at p. 142 right col. section 3.1.3 and p. 144 Figure 3D-F). Gui also teaches ApoC2 is a co-factor of lipoprotein lipase (LPL) (see Gui at p. 147 right col. par. 2 and at p. 148 Table 2).
These teachings parallel those of WO’201, which teaches the 6-substituted estradiol derivatives (see WO’201 pp. 14-17), including compounds 4 (CAS# 1025495-78-6, the same compound as US’130 claim 4) and 21 (CAS#1227511-09-2, the same compound as instant claims) which differ by repeating -(CH2)- units, up-regulate LPL and ApoC2 (see WO’201 at p. 33 Table 1). Gui and WO’201 thus teach 17β-Estradiol, compounds of Formula I such as CAS#1227511-09-2, and US’130 CAS# 1025495-78-6 are structurally similar, functional equivalents.
17β-Estradiol, “E2”
WO’201 Compound 4
WO’201 Compound 21
CAS#1227511-09-2
US’130 Claim 4 CAS# 1025495-78-6
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Therefore, it would have been obvious to one of ordinary skill in the art, based on the previous patent, to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to one skilled to substitute one known structurally similar, functionally equivalent ApoC2/LPL regulating estradiol structure of US’130 claims 1-5 for another ApoC2/LPL regulating 17β-Estradiol (as taught by Gui and WO’201) with a reasonable expectation of altering macrophage or microglial phenotype because the prior art teaches the known estradiol alters macrophage phenotypes from pro-inflammatory M1 phenotypes to an anti-inflammatory M2 phenotypes (17β-Estradiol taught by Thakker) (see also MPEP § 2144.06(II)).
Accordingly, the claims are not patentably distinct.
Claims 1, 21-24, 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9,364,486 B28 in view of WO’201, Thakker, and Gui.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding compounds of Formula I, US’486 claims compounds encompassed by instant Formula I (US’130 claim 1-3, 6, 7, 8) including CAS# 1025495-78-6 (US’130 claims 4, 5, 9, 10, 15-16 “(6R,8R,9S,13S,14S)-6-(methoxymethyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol”).
US’486 Claim 1
US’486 Claims 4-5, 9-10, 15-16
CAS# 1025495-78-6
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Regarding claims 25 and 26, instantly claimed compound CAS# 1227511-09-2 differs only by repeating –(CH2)- segments from US’486 CAS#1025495-78-6.
Regarding a method, US’486 claims methods of treating demyelination in an axon of a nerve cell in need of remyelination (US’486 claim 1), including wherein the cells are glial cells (US’486 claim 17), and demyelinating disorders, including multiple sclerosis and Alzheimer’s (US’486 claims 11, 12, 13, 14).
The patented claims differ from instant claims as follows: While US’486 claims structurally same and similar compounds for treating demyelination or Alzheimer’s, US’486 does not discuss altering macrophage or microglial phenotypes.
Regarding altering microglial or macrophage types, Thakker teaches M1 is a proinflammatory phenotype (see Thakker at p. 6 right col.), and after global cerebral ischemia M1 markers were elevated in the hippocampus (cells were pro-inflammatory phenotype), but treatment with estradiol derivative E2 after global cerebral ischemia M1 markers were suppressed and M2 were enhanced, reading on administering to pro-inflammatory phenotype cell (M1 markers elevated post-insult) resulting in switching, polarizing, or altering to an anti-inflammatory phenotype (M2 markers elevated, M1 markers suppressed) (see Thakker at p. 7 Figure 3). Moreover, Thakker examines administering E2 directly to BV2 microglial cells, and states:
our in vitro studies indicate that E2 could directly act on the microglia cells to regulate their activation and M1/M2 polarization via suppression of M1 phenotype markers and proinflammatory cytokines and elevation of M2 phenotype markers and antiinflammatory cytokines. (emphasis added) (see Thakker at p. 9 right col. ¶2)
Regarding CAS#1227511-09-2, instant CAS#1227511-09-2 belongs to a class of compounds called estradiols. Gui teaches 17β-Estradiol up-regulates ApoCs in a dose-dependent manner, including ApoC2 (see Gui at p. 142 right col. section 3.1.3 and p. 144 Figure 3D-F). Gui also teaches ApoC2 is a co-factor of lipoprotein lipase (LPL) (see Gui at p. 147 right col. par. 2 and at p. 148 Table 2).
These teachings parallel those of WO’201, which teaches the 6-substituted estradiol derivatives (see WO’201 pp. 14-17), including compounds 4 (CAS# 1025495-78-6, the same compound as US’486 claim 4) and 21 (CAS#1227511-09-2, the same compound as instant claims) which differ by repeating -(CH2)- units, up-regulate LPL and ApoC2 (see WO’201 at p. 33 Table 1). Gui and WO’201 thus teaches 17β-Estradiol, compounds of Formula I such as CAS#1227511-09-2, and compounds of US’486 CAS# 1025495-78-6 are structurally similar, functional equivalents.
17β-Estradiol, “E2”
WO’201 Compound 4
WO’201 Compound 21
CAS#1227511-09-2
US’486
Claims 4-5, 9-10, 15-16
CAS# 1025495-78-6
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Therefore, it would have been obvious to one of ordinary skill in the art, based on the previous patent, to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to one skilled to substitute one known structurally similar, functionally equivalent ApoC2/LPL regulating estradiol structure of US’486 (CAS# 1025495-78-6) for another ApoC2/LPL regulating 17β-Estradiol such as CAS#1227511-09-2 (as taught by Gui and WO’201) with a reasonable expectation of altering macrophage or microglial phenotype because the prior art teaches the known estradiol alters macrophage phenotypes from pro-inflammatory M1 phenotypes to an anti-inflammatory M2 phenotypes (17β-Estradiol taught by Thakker) (see also MPEP § 2144.06(II)).
Accordingly, the claims are not patentably distinct.
Claims 1, 21-24, 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 9,422,324 B29 in view of WO’201, Gui, and Thakker.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding compounds of Formula I, US’324 claims compounds encompassed by instant Formula I (US’324 claims 1-20) wherein instant Z is always H, whereas instant Z is H or Me, including CAS# 1365658-89-4 (US’324 claim 20, “(6R,8S,9S,14S,17S)-6-(methoxymethyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol”).
US’324 Claim 1
US’324 Claim 20 CAS# 1365658-89-4
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Instantly claimed compound CAS# 1227511-09-2 differs only by repeating -(CH2)- segments from US’324 CAS# 1365658-89-4.
Regarding a method, US’324 claims methods of treating pain (US’324 claim 1) in a human (US’324 claim 21) wherein the compound selectively binds to the ER-β receptor (US’324 claim 22).
The patented claims differ from instant claims as follows: While US’324 claims structurally same and similar compounds for treating pain, US’324 does not discuss altering macrophage phenotypes.
However,
Regarding altering microglial or macrophage types, Thakker teaches M1 is a proinflammatory phenotype (see Thakker at p. 6 right col.), and after global cerebral ischemia M1 markers were elevated in the hippocampus (cells were pro-inflammatory phenotype), but treatment with estradiol derivative E2 after global cerebral ischemia M1 markers were suppressed and M2 were enhanced, reading on administering to pro-inflammatory phenotype cell (M1 markers elevated post-insult) resulting in switching, polarizing, or altering to an anti-inflammatory phenotype (M2 markers elevated, M1 markers suppressed) (see Thakker at p. 7 Figure 3). Moreover, Thakker examines administering E2 directly to BV2 microglial cells, and states:
our in vitro studies indicate that E2 could directly act on the microglia cells to regulate their activation and M1/M2 polarization via suppression of M1 phenotype markers and proinflammatory cytokines and elevation of M2 phenotype markers and antiinflammatory cytokines. (emphasis added) (see Thakker at p. 9 right col. ¶2)
Regarding CAS#1227511-09-2, instant CAS#1227511-09-2 belongs to a class of compounds called estradiols. Gui teaches 17β-Estradiol up-regulates ApoCs in a dose-dependent manner, including ApoC2 (see Gui at p. 142 right col. section 3.1.3 and p. 144 Figure 3D-F). Gui also teaches ApoC2 is a co-factor of lipoprotein lipase (LPL) (see Gui at p. 147 right col. par. 2 and at p. 148 Table 2).
These teachings parallel those of WO’201, which teaches the 6-substituted estradiol derivatives (see WO’201 pp. 14-17), including compounds 33 (CAS# 1365658-89-4, the same compound as US’324 claim 20) and 21 (CAS#1227511-09-2, the same compound as instant claims) which differ by -(CH2)- units, up-regulate LPL and ApoC2 (see WO’201 at p. 33 Table 1 and p. 3 ¶[0008]). Gui and WO’201 thus teaches 17β-Estradiol, compounds of Formula I such as CAS#1227511-09-2, and US’324 CAS#1365658-89-4 are structurally similar, functional equivalents.
17β-Estradiol, “E2”
WO’201 Compound 33
WO’201 Compound 21
CAS#1227511-09-2
US’324 Claim 20
CAS# 1365658-89-4
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Therefore, it would have been obvious to one of ordinary skill in the art, based on the previous patent, to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to one skilled to substitute one known structurally similar, functionally equivalent ApoC2/LPL regulating estradiol structure of US’324 CAS#1365658-89-4 for another ApoC2/LPL regulating 17β-Estradiol such as CAS#1227511-09-2 (as taught by Gui and WO’201) with a reasonable expectation of altering macrophage or microglial phenotype because the prior art teaches the known estradiol alters macrophage phenotypes from pro-inflammatory M1 phenotypes to an anti-inflammatory M2 phenotypes (17β-Estradiol taught by Thakker) (see also MPEP § 2144.06(II)).
Accordingly, the claims are not patentably distinct.
Claims 1, 21-24, 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 9,636,348 B210 in view of WO’201, Gui, and Thakker.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding compounds of Formula I, US’348 claims compounds of Formula I (US’348 claims 1-10) including CAS# 1025495-78-6 (US’348 claims 5,6, 9,10) “(6R,8R,9S,13S,14S)-6-(methoxymethyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol”).
US’348 Claim 1
US’348 Claims 5-6, 9-10
CAS# 1025495-78-6
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Instantly claimed compound CAS# 1227511-09-2 differs only by repeating –(CH2)- segments from US’348 CAS#1025495-78-6.
Regarding methods, US’348 claims methods of treating myelination in an axon of a nerve cell (US’486 claim 1), treating a demyelination disorder (US’348 claim 6), such as multiple sclerosis or Alzheimer’s (US’348 claims 11, 12, 13, 14)
The patented claims differ from instant claims as follows: While US’348 claims structurally same and similar compounds for treating demyelination or Alzheimer’s, US’348 does not discuss altering macrophage or microglial phenotypes.
Regarding altering microglial or macrophage types, Thakker teaches M1 is a proinflammatory phenotype (see Thakker at p. 6 right col.), and after global cerebral ischemia M1 markers were elevated in the hippocampus (cells were pro-inflammatory phenotype), but treatment with estradiol derivative E2 after global cerebral ischemia M1 markers were suppressed and M2 were enhanced, reading on administering to pro-inflammatory phenotype cell (M1 markers elevated post-insult) resulting in switching, polarizing, or altering to an anti-inflammatory phenotype (M2 markers elevated, M1 markers suppressed) (see Thakker at p. 7 Figure 3). Moreover, Thakker examines administering E2 directly to BV2 microglial cells, and states:
our in vitro studies indicate that E2 could directly act on the microglia cells to regulate their activation and M1/M2 polarization via suppression of M1 phenotype markers and proinflammatory cytokines and elevation of M2 phenotype markers and antiinflammatory cytokines. (emphasis added) (see Thakker at p. 9 right col. ¶2)
Regarding CAS#1227511-09-2, instant CAS#1227511-09-2 belongs to a class of compounds called estradiols. Gui teaches 17β-Estradiol up-regulates ApoCs in a dose-dependent manner, including ApoC2 (see Gui at p. 142 right col. section 3.1.3 and p. 144 Figure 3D-F). Gui also teaches ApoC2 is a co-factor of lipoprotein lipase (LPL) (see Gui at p. 147 right col. par. 2 and at p. 148 Table 2).
These teachings parallel those of WO’201, which teaches the 6-substituted estradiol derivatives (see WO’201 pp. 14-17), including compounds 4 (CAS# 1025495-78-6, the same compound as US’348 claims 5-6, 9-10) and 21 (CAS#1227511-09-2, the same compound as instant claims) which differ by repeating -(CH2)- units, up-regulate LPL and ApoC2 (see WO’201 at p. 33 Table 1). Gui and WO’201 thus teaches 17β-Estradiol, compounds of Formula I such as CAS#1227511-09-2, and compounds of US’348 CAS# 1025495-78-6 are structurally similar, functional equivalents.
17β-Estradiol, “E2”
WO’201 Compound 4
WO’201 Compound 21
CAS#1227511-09-2
US’348 Claims 5-6, 9-10
CAS# 1025495-78-6
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Therefore, it would have been obvious to one of ordinary skill in the art, based on the previous patent, to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to one skilled to substitute one known structurally similar, functionally equivalent ApoC2/LPL regulating estradiol structure of US’348 (CAS# 1025495-78-6) for another ApoC2/LPL regulating 17β-Estradiol such as CAS#1227511-09-2 (as taught by Gui and WO’201) with a reasonable expectation of altering macrophage or microglial phenotype because the prior art teaches the known estradiol alters macrophage phenotypes from pro-inflammatory M1 phenotypes to an anti-inflammatory M2 phenotypes (17β-Estradiol taught by Thakker) (see also MPEP § 2144.06(II)).
Accordingly, the claims are not patentably distinct.
Conclusion
Claims 1, 21-24, 26 are rejected.
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/S.R./ Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
1 Gui et. al. "17-β-estradiol up-regulates apolipoprotein genes expression during osteoblast differentiation in vitro" BioScience Trends, 2016, 10, 2, 140-151. DOI: 10.5582/bst.2016.01007
2 Thakker et. al. "17β-Estradiol Regulates Microglia Activation and Polarization in the Hippocampus Following Global Cerebral Ischemia" Oxidative Medicine and Cellular Longevity, 2018, 248526, 1-19. DOI: 10.1155/2018/4248526. Hereinafter Thakker.
3 Ginhoux et. al. "Origin and differentiation of microglia" Front. Cell. Neurosci. 2013, 7, 45, 1-14. DOI: 10.3389/fncel.2013.00045.
4 Gui et. al. "17-β-estradiol up-regulates apolipoprotein genes expression during osteoblast differentiation in vitro" BioScience Trends, 2016, 10, 2, 140-151. DOI: 10.5582/bst.2016.01007
5 Thakker et. al. "17β-Estradiol Regulates Microglia Activation and Polarization in the Hippocampus Following Global Cerebral Ischemia" Oxidative Medicine and Cellular Longevity, 2018, 248526, 1-19. DOI: 10.1155/2018/4248526. Hereinafter Thakker.
6 Filed June 4, 2008
7 Filed April 30, 2012.
8 Filed March 21, 2012
9 Filed March 21, 2012
10 Filed June 10, 2016