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 .
Priority
The instant application 17/280,638 filed on March 26, 2021 is a 371 of PCT/US2019/054234 filed
on October 2, 2019, which claims priority to, and the benefits of U.S. Provisional Application No.
62/743,237 filed on October 9, 2018, and U.S. Provisional Application No. 62/748,875 filed on October 22, 2018.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on March 25, 2026, wherein claims 1 and 13 are amended; claims 2-4 and 19 are cancelled; and claims 5-12 and 14-18 are unchanged.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1 and 5-18 are pending and under examination.
Action Summary
Claims 1, 5-10, 12 and 14-17 rejected under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874), as evidenced by Krapf et al. (“Vulvovaginitis - Anatomy”. December, 2022. Retrieved from Internet) and Brauer et al. (Autonomic Neuroscience, 2015. Vol. 187, 2015, Pages 1-17) are maintained.
Claims 1, 5-12 and 14-17 remain rejected under 35 U.S.C. 103 as being unpatentable Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Tang et al. (Mediators of inflammation, 2018: 2380319) are maintained.
Claims 1, 5-12 and 14-18 rejected under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Chen et al. (Inflammation, 2015. Vol. 38(2):534-545.) are maintained.
Claims 1, 5-10, and 12-18 rejected under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Serhan et al. (US 2018/0256597 A1; referred to herein as “‘597 application:”) are maintained, but revisited and modified in light of the claim amendments that changes the transitional term from “comprising” to “consisting essentially of”.
Claim Interpretation
The claimed term “a secondary irritation-causing stimulation” in claim 7, when reasonably construed in light of page 2, line 16-17 of the specification, is taken to include intercourse and tampon usage.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5-10, 12 and 14-17 remain rejected under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874), as evidenced by Krapf et al. (“Vulvovaginitis - Anatomy”. December, 2022. Retrieved from Internet) and Brauer et al. (Autonomic Neuroscience, 2015. Vol. 187, 2015, Pages 1-17).
Serhan et al. teaches a method comprising administering a therapeutically effective amount of a particle to a subject in need of treatment for inflammation, wounds, or pain (see e.g., [0122]; [0097]; [0124]; abstract); wherein the particle can comprise at least one component of a cellular-derived microparticle (see e.g., [0066]), or the particle can comprise at least one component of a cellular-derived microparticle and at least one agent (see e.g., [0147]). Serhan et al. further teaches the at least one component of a cellular-derived microparticle is selected from the group consisting of, inter alia, Resolvin D2, Resolvin D3, Resolvin D5, Maresin 1, Protectin D1, Lipoxin A4, 18-hydroxyeciosapentaenoic acid (HEPE) (see e.g., [0008];[0159]). Please note the cellular-derived microparticle taught by Serhan et al. is a pro-resolving mediator. Serhan et al. further teaches the inflammatory conditions can include inflammation of mucous membrane, such as vulvovaginitis (see e.g., [0129]). Serhan et al. further teaches the term "inflammation" includes any cellular process that leads to the production of pro-inflammatory cytokines, inflammation mediators and/or the related downstream cellular events resulting from the actions of the cytokines thus produced, for example, fever, fluid accumulation, swelling, abscess formation, and cell death; and the pro-inflammatory cytokines and inflammation mediators include, inter alia, IL-6 and TNF-alpha (see e.g., [0126]). Serhan et al. further teaches the administration is topical, for example, as a cream and ointment (see e.g., [0031]; [0099]). Serhan et al. further teaches the pharmaceutical composition comprising the particle can be formulated for intravaginal administration, for example, as a pessary, cream or foam (see e.g., [0099]). Please note intravaginal administration taught by Serhan et al. is an administration to the subject’s vagina (i.e., lower genital tract) as claimed in claim 9. Serhan et al. further teaches the particle can be administered to a subject alone, or optionally in combination with one or more pharmaceutically active agents (see e.g., [0103]). Serhan et al. further teaches the patient can be administered a therapeutic amount of a composition comprising a particle, such as 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, or 50 mg/kg (see e.g., [0101]). Serhan et al. further teaches the “therapeutic effective amount” refers to an amount that provide therapeutic benefit in the treatment, prevention, or management of inflammation (see e.g., [0046]). Serhan et al. further teaches the dosing schedule are administered daily, twice daily, three times daily (see e.g., [0102]). Serhan et al. further teaches in some embodiments, the agent is selected from the group consisting of anti-inflammatory agents, anti-infective agents, antibiotics, pro-resolving drugs; and antinociceptives (see e.g., [0023]). Serhan et al. further teaches in some embodiments, the agent can be an anti-infective agent or an antibiotic; an antibiotic is further intended to include, inter alia, an antimicrobial agent (see e.g., [0074]). Please note the antibiotics taught by Serhan et al. is an antimicrobial agent and an antiviral agent. Serhan et al. further teaches in some embodiments, the agent is a lipid mediator selected from the group consisting of, inter alia, Resolvin D2, Resolvin D3, Resolvin D5, Maresin 1, Protectin D1, Lipoxin A4, and 18-hydroxyeciosapentaenoic acid (HEPE) (see e.g., [0022]). Please note the lipid mediator taught by Serhan et al. is a second pro-resolving mediator. Serhan et al. further teaches the cellular derived microparticle is generated in vitro by cellular activation and has a pro-resolving microparticle phenotype (see e.g., [0006]). Serhan et al. further teaches the term "administering," refers to the placement of a particle as described herein into a subject by a method or route which results in at least partial localization of the agents at a desired site (see e.g., [0052]).
Serhan et al. does not teach pain or pruritus associated with localized provoked vulvodynia as claimed in claim 1. Serhan et al. also does not teach vulvar vestibule as claimed in claim 8. Serhan et al. also does not teach external vulva in claim 10. Serhan et al. also does not teach perivaginal administration in claim 17.
Hesselink et al. teaches in patients suffering from vulvodynia, increased concentration of mast cells has been found in vulvar biopsies; and vulvodynia has been recognized as a cytokine-mediated pain syndrome, characterized by increases in proinflammatory cytokines, such as IL-8, and decreases in anti-inflammatory cytokines, such as IL-10 (see e.g., p. 758, right column, “(Neuro)inflammatory component” section). Hesselink et al. further teaches the autacoid palmitoylethanolamide could inhibit the positive feedback loop of overactive mast cells producing neurotrophic growth factor (NGF), which is a major biological actor that was first identified in pain and inflammation (see e.g., p. 759, right column, last paragraph to p.760, left column, 1st paragraph). Hesselink et al. further teaches mast cells also produce prostaglandin E2, an enhancer of neurogenesis, and this metabolite can activate the TRPV1 receptor, and then NGF can subsequently promote the insertion of TRPV1 into the cell surface membrane (see e.g., p.760, left column, 4th paragraph). Hesselink et al. further teaches other compounds from the autacoid classes of lipoxins, maresins, protectins, and resolvins are candidates that can be added to analgesic creams for the treatment of localized provoked vulvodynia (LPV) given their therapeutic roles in restoring neuroimmunological homeostasis (see e.g., p.760, “Rationale for topical treatment with baclofen-palmitoylethanolamide” section, 1st paragraph; p. 761, “Discussion” section). Hesselink et al. further teaches localized provoked vulvodynia (LPV) is a clinical diagnosis and is defined by a characteristic pattern of mechanical allodynia localized to the vulvar vestibule upon stimulation (see e.g., 2nd paragraph under “Introduction” section). Please note the vulvar vestibule taught by Hesselink et al. is part of the vulva according to female anatomy, as evidenced by Krapf et al. Hesselink et al. further teaches most LPV cases can be regarded as a manifestation of a (localized) neuropathic pain disorder because vulvodynia is described by patients as burning, stinging, irritation, and/or rawness, and thus has comparable pain characteristics as postherpetic neuralgia and complex regional pain syndrome (see e.g., 3rd paragraph under “Introduction” section). Hesselink et al. further teaches topical treatment of vulvodynia may bring relief from pain by targeting local components of the vaginal epithelium, such as free nerve endings of nociceptors, immunocompetent cells, and epithelial cells (see e.g., p. 760, “Rationale for topical treatment with baclofen-palmitoylethanolamide”).
Ji et al. teaches protectin D1 (PD1) is useful for inhibiting TRPV1 and TNF-α signaling, preventing glial activation and neuropathic pain, and reducing established inflammatory pain and neuropathic pain (see e.g., p. 34, Table 1, Mediator “PD1”). Ji et al. further teaches peri-surgical treatment with PD1 completely prevented mechanical allodynia in a mouse model of neuropathic pain; and post-treatment via spinal intrathecal route also reversed nerve injury-induced mechanical allodynia for several hours (see e.g., p. 11, line 3-8). Ji et al. further teaches pain is one of the cardinal features of inflammation; and it is well established that inflammatory mediators released locally after tissue injury — including classic mediators (e.g., bradykinin, prostaglandins, H+, ATP, nerve growth factor), pro-inflammatory cytokines and chemokines as well as emerging mediators (bacterial N-formylated peptides15 and microRNAs16) — can directly stimulate and cause sensitization of pain-sensing nociceptors located at nerve fibers of primary afferent neurons in peripheral tissues (see e.g., p. 2, line 3-9).
Schwab et al. teaches LXA4, RvE1 and Protectin D1 (PD1) each regulated release of chemokine/cytokine during phagocytosis, reducing IFN-γ and IL-6 (see e.g., p. 2, 3rd paragraph; Figure 2C).
Regarding claims 1, 9, and 12, in the present case, Serhan et al. teaches a method of treating inflammation or pain in a subject in need thereof comprising topically administering a therapeutically effective amount of a pharmaceutical composition formulated for intravaginal administration, wherein the pharmaceutical composition comprising a particle comprising at least one component of a cellular-derived microparticle selected from the group consisting of, inter alia, Protectin D1 and Maresin 1; and further teaches that "inflammation" includes any cellular process that leads to the production of pro-inflammatory cytokines and inflammation mediators, including IL-6. The difference between the method of Serhan et al. and the claimed method is that the prior art does not teach the pain in the subject is associated with localized provoked vulvodynia. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Serhan et al. by selecting protectin 1 of Ji et al. as the at least one component of a cellular-derived microparticle for treating pain in a subject with localized provoked vulvodynia, as taught by Hesselink et al. One would have been motivated to do so, because Hesselink et al. teaches vulvodynia has been recognized as a cytokine-mediated pain syndrome characterized by increases in proinflammatory cytokines, and other compounds from the autacoid class, including protectins, can be added to the analgesic creams for treating localized provoked vulvodynia by restoring neuroimmunological homeostasis and inhibiting the positive feedback loop of overactive mast cells that activates the TRPV1 receptor in the cell surface membrane; and Ji et al. teaches protectin D1 can inhibit TRPV1 and TNF-α signaling, preventing glial activation and neuropathic pain, and reducing established inflammatory pain and neuropathic pain; and Schwab et al. teaches Protectin D1 (PD1) reduces cytokines IL-6. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that topically administering a therapeutically effective amount of a pharmaceutical composition comprising Protectin D1 as the at least one component of a cellular-derived microparticle to the vagina of a subject having localized provoked vulvodynia would have successfully reduce the pain by inhibiting TRPV1 and TNF-α signaling, and decreasing the production of pro-inflammatory cytokines and inflammation mediators, including IL-6.
Regarding the limitation of “wherein the pro-resolving mediator is administered at 0.0001 mg/kg – 100 mg/kg” in claim 5, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. sets forth above by incorporating 0.5 mg/kg as the therapeutic amount. One would have been motivated to do so, because Serhan et al. teaches the therapeutic amount of the composition comprising the particle useful for the treatment of inflammation or pain, includes 0.5 mg/kg. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering 0.5 mg/kg as the therapeutic amount would successfully treat the inflammation or pain.
Regarding the limitation of “wherein the pro-resolving mediator is administered once a week” in claim 6, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. sets forth above by administering the pharmaceutical composition once daily. One would have been motivated to do so, because Serhan et al. teaches the dosing schedule includes daily administration. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the pharmaceutical composition sets forth in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. above once daily would successfully treat the inflammation or pain.
Regarding the limitation of “wherein the pro-resolving mediator is administered before the subject is exposed to a secondary irritation-causing stimulation” in claim 7, the claimed limitation is drawn to the order of performing the administration step. The claimed language “a secondary irritation-causing stimulation”, when construed in light of page 2, line 15-17 of the instant specification, is taken to include intercourse and tampon usage. It would have been prima facie obvious to one of ordinary skill in art at the time the application was filed to administer the pharmaceutical composition sets forth in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. above before the subject is exposed to intercourse and tampon usage, because one would have reasonably recognized that intercourse and/or tampon insertion would interfere with the absorption of the pharmaceutical composition, and therefore, decreasing the efficacy of the pharmaceutical composition. One would have been motivated to do so in order to ensure effective topical administration of the pharmaceutical composition. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the pharmaceutical composition sets forth in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. above before the subject is exposed to intercourse and tampon usage would have successfully treat the inflammation or pain.
Regarding the limitation of “wherein the treatment site comprises the vulvar vestibule” in claim 8, and the limitation of “wherein the treatment site comprises the external vulva” in claim 10, and the limitation of “perivaginal administration” in claim 17, each of these claimed limitations is drawn to the treatment site where the topical application of the pharmaceutical composition takes place. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. sets forth above to further administer the pharmaceutical composition to the vulvar vestibule taught by Hesselink et al. One would have been motivated to do so, because Hesselink et al. teaches localized provoked vulvodynia is characterized by mechanical allodynia localized to the vulvar vestibule upon stimulation, and topical treatment bring relief from pain by targeting local components of the vaginal epithelium, such as free nerve endings of nociceptors, immunocompetent cells, and epithelial cells. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that topically administering the pharmaceutical composition sets forth in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. above to vulvar vestibule as the desired site would successfully reduce pain or inflammation by targeting the site affected by localized provoked vulvodynia. Please note that by administering the pharmaceutical composition to the vulvar vestibule, it would necessarily deliver said pharmaceutical composition to the external vulva, because the vulvar vestibule taught by Hesselink et al. is part of the vulva according to female anatomy, as evidenced by Krapf et al. Please also note that the administration of pharmaceutical composition to the vulvar vestibule is a perivaginal administration, because the vulvar vestibule taught by Hesselink et al. is part of the perivaginal tissue, as evidenced by Brauer et al. (see e.g., p. 4, right column, lines 17-20).
Regarding the limitation of “further comprising administering a second therapeutic agent to the subject” in claim 14, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. sets forth above to further administer a second therapeutic agent. One would have been motivated to do so, because Serhan et al. teaches the particle can be administered to a subject alone, or optionally in combination with one or more pharmaceutically active agents. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that combining the pharmaceutical composition sets forth in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. above with one or more pharmaceutically active agents can successfully treat the inflammation or pain.
Regarding the limitation of “wherein the second therapeutic agent is a second pro-resolving mediator” in claim 15, and the limitation of “wherein the second therapeutic agent is an antimicrobial agent or an antiviral agent” in claim 16, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. sets forth above to further administer a second therapeutic agent. One would have been motivated to do so, because Serhan et al. teaches the particle can be administered in combination with one or more pharmaceutically active agents, including lipid mediator such as Maresin-1, pro-resolving drugs, and antibiotics such as antimicrobial. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that combining the pharmaceutical composition sets forth in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. above with an antimicrobial or Maresin-1 as the one or more pharmaceutically active agents can successfully treat the inflammation or pain. Please note the lipid mediator maresin-1 taught by Serhan et al. renders obvious the limitation of “pro-resolving mediator”.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1, 5-12 and 14-17 remain rejected under 35 U.S.C. 103 as being unpatentable Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Tang et al. (Mediators of inflammation, 2018: 2380319).
The teachings of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. are sets forth above and applied as before.
Serhan et al., Hesselink et al., Ji et al. and Schwab et al. sets forth above does not teach maresin-1 in claim 11.
Tang et al. further teaches maresin 1 dose-dependently inhibited TRPV1 currents in neurons, blocked capsaicin-induced inward currents, and reduced both inflammation-induced and chemotherapy-induced neuropathic pain in mice (see e.g., p. 6, line 5-10). Tang et al. further teaches maresins, which are biosynthesized from docosahexaenoic acid (DHA) by macrophages, display strong anti-inflammatory and proresolving activity (see e.g., abstract), and counterregulate the proinflammatory cytokines such as IL-1β, IL-6, and TNF-α (see e.g., p. 4, left column, line 22-24). Tang et al. further teaches Maresin 1 counterregulates proinflammatory chemical mediators, and controls pain and enhances tissue regeneration (see e.g., Table 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. sets forth above by substituting the protectin D1 with maresin-1 as the at least one component of a cellular-derived microparticle. One would have been motivated to do so, because Serhan et al. teaches a list of the at least one component of a cellular-derived microparticle, including Maresin 1 and Protectin D1, that can be interchanged to treat the inflammation or pain; and Tang et al. further teaches maresin 1 can inhibits TRPV1 currents in neurons, counterregulates proinflammatory chemical mediators such as IL-6, and controls pain and enhances tissue regeneration. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that maresin 1 would have exert the same or substantially similar anti-inflammatory effect and inhibiting effect against TRPV1 signaling as protectin D1 for treating the inflammation or pain.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1, 5-12 and 14-18 remain rejected under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Chen et al. (Inflammation, 2015. Vol. 38(2):534-545.).
The teachings of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. are sets forth above and applied as before.
Serhan et al., Hesselink et al., Ji et al. and Schwab et al. does not teach eicosapentaenoic acid or arachidonic acid in claim 18.
Chen et al. teaches eicosapentaenoic acid (EPA) exerted a more potent anti-inflammatory effect when compared with eicosatrienoic acid (ETrA), which is a rare naturally occurring n-3 polyunsaturated
fatty acid (see e.g., abstract). Chen et al. further teaches EPA suppresses PGE2 and IL-6 production by LPS-stimulated macrophages (see e.g., Fig. 5; p. 543, left column, line 7-9).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the pharmaceutical composition sets forth in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. above to further comprise eicosapentaenoic acid as the at least one agent. One would have been motivated to do so, because Serhan et al. teaches the particle can comprise at least one component of a cellular-derived microparticle and at least one agent, and
the agent is selected from the group consisting of anti-inflammatory agents; and Chen et al. teaches eicosapentaenoic acid has an anti-inflammatory effect useful for suppressing PGE2 and IL-6 production. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the pharmaceutical composition further comprising eicosapentaenoic acid would have successfully treat inflammation or pain by suppressing PGE2 and IL-6 production.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1, 5-10, and 12-18 remain rejected under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Serhan et al. (US 2018/0256597 A1; referred to herein as “‘597 application:”).
The teachings of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. are set forth above and applied as before.
Serhan et al., Hesselink et al., Ji et al. and Schwab et al. does not teach the mixture consisting essentially of DHA, 14-HDHA, 17-HDHA, and 18-HEPE in claim 13.
’597 application teaches a composition comprising omega-3 (e.g., EPA and/or DHA), 17-HDHA and 18-HEPE (see e.g., [0125]). ‘597 application further teaches the composition further comprises 14-HDHA (see e.g., [0129]). ‘597 application further teaches a composition LM03-3:
PNG
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860
488
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(see e.g., [0285]; table 3). Please note the composition LM03-3 of ‘597 application is a mixture comprising DHA, 14-HDHA, 17-HDHA, 18-HEPE, and EPA. ‘597 application further teaches the composition further comprise an acceptable carrier or excipient can administer by variety of route, for example, topical and vaginal (see e.g., [0171]). ‘597 application further teaches a method for treating and resolving inflammation in a subject having a disease with an inflammatory component by administering to the subject an effective amount of the composition in an amount effective to activate resolution mechanism and thus resolve local inflammation (see e.g., [0247]).
Regarding the limitation of “a composition comprising a pro-resolving mediator topically to a treatment site of the subject’s lower genital tract, wherein the pro-resolving mediator is…. (ii) a mixture consisting essentially of DHA, 14-HDHA, 17-HDHA, and 18-HEPE” in claim 13, according to MPEP 2111.03 I, the transitional term “comprising”, which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). In other words, even though the transitional term “consisting essentially of” is used in the context of pro-resolving mediator mixture, the composition as a whole recited “comprising” language that does not exclude additional and unrecited elements to said composition. In addition, according to MPEP 2111.03 III, “[f]or the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355”. Applying same logic to the instant case, the “consisting essentially of” recites in the instant claim language is reasonably construed as equivalent to “comprising”. In the present case, Serhan et al. clearly teaches that the at least one component of a cellular-derived microparticle can be 18-hydroxyeciosapentaenoic acid (HEPE). It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine the least one component of a cellular-derived microparticle sets forth in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. with the composition LM03-3 taught by ‘597 application to arrive at the claimed invention. One would have been motivated to do so, because Serhan et al. teaches the at least one component of a cellular-derived microparticle can combined with at least one agent, including anti-inflammatory agents, to arrive at the particle contains in the pharmaceutical composition, and ’597 application teaches LM03-3, which comprises DHA, 14-HDHA, 17-HDHA, 18-HEPE, and EPA, is useful for treating and resolving inflammation in a subject. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the combination of the least one component of a cellular-derived microparticle with LM03-3 of ‘597 application as the anti-inflammatory agents would have successfully treat the inflammation or pain.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on March 25, 2026 with respect to the rejection of claims 1, 5-10, 12 and 14-17 under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874), as evidenced by Krapf et al. (“Vulvovaginitis - Anatomy”. December, 2022. Retrieved from Internet) and Brauer et al. (Autonomic Neuroscience, 2015. Vol. 187, 2015, Pages 1-17); the rejection of claims 1, 5-12 and 14-17 under 35 U.S.C. 103 as being unpatentable Serhan et al. (US 2014/0079631 A1), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Tang et al. (Mediators of inflammation, 2018: 2380319); the rejection of claims 1, 5-12 and 14-18 under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Chen et al. (Inflammation, 2015. Vol. 38(2):534-545.); and the rejection of claims 1, 5-10, and 12-18 under 35 U.S.C. 103 as being unpatentable over Serhan et al. (US 2014/0079631 A1; cited in IDS filed on 06/07/2021), in view of Hesselink et al. (Journal of pain research, 2016. 9, 757–762; cited in the IDS filed on 6/7/2021), Ji et al. (Nat Rev Drug Discov, 2014. Vol. 13(7): 533-48) and Schwab et al. (Nature, 2007. Vol. 447(7146): 869–874) as applied to claims 1, 5-10, 12 and 14-17 above, and further in view of Serhan et al. (US 2018/0256597 A1; referred to herein as “‘597 application:”) have been fully considered, but they are not persuasive for the reasons set forth herein.
Applicant amends claim 1 from the recitation of “(ii) a mixture comprising DHA, 14-HDHA, 17-HDHA, and 18-HEPE” to the recitation of “(ii) a mixture consisting essentially of DHA, 14-HDHA, 17-HDHA, and 18-HEPE”; and amends claim 13 from the recitation of “the pro-resolving mediator is the mixture that comprises DHA, 14-HDHA, 17-HDHA, and 18-HEPE” to the recitation of “the pro-resolving mediator is the mixture that consist essentially of DHA, 14-HDHA, 17-HDHA, and 18-HEPE”. Therefore, the rejection on the record has been revisited and modified in light of the claim amendments.
In summary, Applicant argues the cited prior arts either alone or in combination does not renders the claimed invention obvious, because the inflammatory condition vulvovaginitis taught by Serhan et al. is completely different than localized provoked vulvodynia (LPV). Specifically, applicant argues LPV is not an inflammatory condition by redirecting attention to the declaration under 37 CFR 1.132 filed on August 25, 2025 and September 8, 2025. Applicant further argues Hesselink et al. does not teach that LPV is an inflammatory disease, and the teachings of Hesselink et al. that recites “[v]ulvodynia has been recognized as a cytokine-mediated pain syndrome, characterized by increases in proinflammatory cytokines, such as IL-8, and decreases in anti-inflammatory cytokines, such as IL-10” is a mischaracterization of Baker et al. and Gerber et al. (see p. 5 of the reply). Applicant argues there were conflicting findings in terms of which cytokines were upregulated and downregulated in patients with vestibulodynia, which is a form of vulvodynia; and while cytokines are biomarkers associated with vulvodynia, it is unclear whether these cytokines regulate vulvodynia or if inhibition of such cytokines would improve this condition; and therefore, one would not have been motivate to combine Serhan et al. and Hesselink et al. based on the fact that Baker et al. cited by Hesselink et al. teaches IL-6 and TNF-[Symbol font/0x61] are significantly down-regulated in the vestibulodynia patients. Applicant further argues Hesselink et al. fails to explain the details of each subtype of vulvodynia, let alone LPV; and does "not differentiate between the local and the generalized variety of vulvodynia and ... [uses] the term vulvodynia to cover all primary and secondary or generalized varieties" (see page 6, 2nd paragraph of the reply). Applicant further argues Baker et al. supports the notation that the cause of vulvodynia is unknown; and given that the cause and mechanisms of action for vulvodynia are complex, unknown, and different among the different types of vulvodynia, one would not have had a motivation or expectation of success to reduce lower genital tract pain or pruritus associated with LPV by reducing a pro-inflammatory cytokine, such as IL-6. Hesselink et al. provides no support that any of the claimed pro-resolving mediators could be used to reduce lower genital tract pain or pruritus associated with LPV.
Applicant further argues Ji et al., Schwab et al., Tang et al., Chen et al., and the '597 application, are each silent about LPV; and Krapf et al. and Brauer et al. are each silent about the claimed method. Applicant argues Tang et al. teaches the role of pro-resolving lipid mediators in inflammatory-related diseases; However, the claimed LPV is not an inflammatory condition.
Applicant further argues the amendment to claims 1 and 13, which changes the transitional term “comprising” to “consisting essentially of” (see "mixture consisting essentially of DHA, 14-HDHA, 17-HDHA, and 18-HEPE") overcomes the rejection further in view of the '597 application. Applicant argues the '597 application is silent that composition LM03-3 is useful for treating any gynecologic conditions; and the mere fact that the '597 application teaches vaginal delivery would not lead one of skill in the art to arrive at the claimed method.
In response, applicant’s argument is not found persuasive for the reasons set forth below:
First, Applicant presents several 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). It is respectfully noted that the rejection on the record is form using the combination of prior arts rather than using each prior art individually. In other words, Ji et al., Schwab et al., Tang et al., Chen et al., and the '597 application, are not applied individually to teach localized provoked vulvodynia (LPV) or the claimed method. For instance, applicant argues Ji et al. teaches spinal intrathecal route rather than topical administration, it is noted that the rejection on the record is form on the basis that Serhan et al. established topical administration (see e.g., [0031]; [0099]) of at least one component of a cellular-derived microparticle, including Protectin D1, for treating pain or inflammation; rather than applying Ji et al. alone to teach topical administration. In addition, Krapf et al. and Brauer et al. are evidentiary references solely applied to teach the female anatomy of lower genital tract, specifically, applied to teach the “vulvar vestibule” taught by Hesselink et al. is part of the external vulva and part of the perivaginal tissue rather than applied individually to teach the claimed method.
Second, the declaration under 37 CFR 1.132 filed on August 25, 2025 and September 8, 2025 has been considered and addressed in the previous Non-Final Office Action mailed on January 27, 2026. It may well be true that Serhan et al. teaches vulvovaginitis as an exemplary inflammatory condition of mucous membranes that is contemplate for use in the method of treating inflammation, wounds, or pain; However, according to MPEP 2123 II, “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)”. In other words, the mere fact that Serhan et al. teaches vulvovaginitis as an example of inflammatory condition does not constitute a teaches away from treating any other conditions that leads to the production of pro-inflammatory cytokines, because such disclosure does not criticize, discredit or otherwise discourage treating other conditions. In fact, Serhan et al. clearly teaches "inflammation" can includes any cellular process that leads to the production of pro-inflammatory cytokines, inflammation mediators and/or the related downstream cellular events resulting from the actions of the cytokines thus produced, for example, fever, fluid accumulation, swelling, abscess formation, and cell death; and the pro-inflammatory cytokines and inflammation mediators include, inter alia, IL-6 and TNF-alpha (see e.g., [0126]).
Furthermore, it may also well be true that Hesselink et al. does not expressly state that the localized provoked vulvodynia is an inflammatory condition; However, Hesselink et al. clearly teaches the pathogenesis of vulvodynia includes (neuro)inflammatory component (see e.g., p. 758, “Pathogenesis of vulvodynia”, 1st paragraph), and further teaches “[a]n exaggerated response to inflammation due to decreased ability to downregulate the inflammatory activity is currently seen as a cornerstone in disease pathogenesis. Vulvodynia has been recognized as a cytokine-mediated pain syndrome, characterized by increases in proinflammatory cytokines, such as IL-8, and decreases in anti-inflammatory cytokines, such as IL-10. Blood samples from patients with vestibulodynia have shown enhanced induction of a proinflammatory cytokine (IL-1[Symbol font/0x62]) and decreased production of anti-inflammatory mediator (IL-1 receptor antagonist) as compared with controls” (see e.g., p. 758, right column, last paragraph to p. 759, left column, line 4). In other words, one of ordinary skill in the art would have reasonably recognized that the elevated level of proinflammatory cytokine, caused by an decrease ability to downregulate the inflammatory activity, is a characteristic of inflammation even though Hesselink does not expressly states it. Additionally, according to Ji et al., pain is one of the cardinal features of inflammation, and it is well established that the local release of inflammatory mediators (including pro-inflammatory cytokines) can directly stimulate and sensitizes pain-sensing nociceptors (see e.g., p. 2, line 3-9). While applicant asserts localized provoke vulvodynia is not an inflammatory condition, it is respectfully noted that the working examples (e.g., Example 5-6) upon which applicant relies in the arguments expressly disclosed pain and inflammatory endpoints of localized provoked vulvodynia are reduced in the treatment (see e.g., p. 9, 2nd paragraph of the reply); and that appears to be conflicting with applicant’s assertion that the localized provoke vulvodynia is not a “inflammation”. In view of the foregoing, applicant’s argument is not found persuasive, because it is not apparent that localized provoked vulvodynia is not a condition caused by elevated level of proinflammatory cytokine, and the pain of localized provoked vulvodynia is not caused by local release of inflammatory mediators, including pro-inflammatory cytokines.
Third, Baker et al. and Gerber et al. that applicant relies upon are acknowledged by the Examiner. It is respectfully noted that the rejection on the record does not rely on Baker et al. and Gerber et al., respectively, to teach localized provoked vulvodynia, and the pathogenesis and treatment of said condition. Solely to rebut applicant’s argument that there were conflicting findings in terms of which cytokines were upregulated and downregulated in patients with vestibulodynia (a form of vulvodynia; also known as “vulvar vestibulitis syndrome”), it may well be true that disease presentation vary wildly across different people with the same condition, for instance, increased proinflammatory cytokines interleukin-1-[Symbol font/0x62] levels are reported in patients with vestibulodynia and are also decreased in patients with the same condition (see e.g., p. 5, last paragraph of the reply); However, just because some patients do not have elevated proinflammatory cytokines (e.g., interleukin-1-[Symbol font/0x62]), it does not mean one of ordinary skill in the art would not have a reasonable expectation of success to treat patients with elevated proinflammatory cytokines.
In response to applicant’s argument that there is no teachings, suggestion, or motivation to combine the references for treating localized provoked vulvodynia, because the cause and mechanisms of action are complex, unknown, and different among the different types of vulvodynia. It is noted that the feature upon which applicant relies (“etiology of vulvodynia”) is not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In other words, the instant claim(s) does not limit the “localized provoke vulvodynia” with specific etiology; and therefore, the etiology of localized provoked vulvodynia is considered irrelevant for the rejected claims. Solely to rebut this argument, according to MPEP 2141.02, VI, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984)”. In instant case, it may well be true that Hesselink et al. recognizes the cause of vulvodynia is unknown in the introduction shown below (see p. 757, 1st paragraph):
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; However, it does not mean the pathogenesis of vulvodynia taught by Hesselink et al. is incapable of forming a rational therapy for treating localized provoked vestibulodynia or vulvodynia; instead, Hesselink et al. clearly suggest the pathogenesis of vulvodynia discussed therein can supports new treatment modality, see the last two lines cited above.
It may also well be true that the term “vulvodynia” used by Hesselink et al. covers all primary and secondary or generalized varieties and does not differentiate between local and the generalized variety of vulvodynia; However, it does not mean the pathogenesis of vulvodynia and the topical treatment taught by Hesselink et al. is inapplicable in localized provoked vulvodynia. Instead, Hesselink et al. clearly noted that the classification of localized provoked vestibulodynia or vulvodynia remains in flux and said condition is included in the teachings (see e.g., p. 757, 2nd paragraph to p. 758, left column, line 6); and further teaches other compounds from the autacoid classes of lipoxins, maresins, protectins, and resolvins can be added to analgesic creams for the treatment of localized provoked vulvodynia (LPV) shown below (see shaded) (see e.g., p. 760, right column, “Rationale for topical treatment with baclofen-palmitoylethanolamide”):
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.
Even though Hesselink et al. does not exemplify topical administration of a compound from the autacoid classes of lipoxins, maresins, protectins, and resolvins in the treatment of localized provoked vulvodynia, it does not constitute a teaching away from administering any of these alternatives. According to MPEP 2143.02, I, “[c]onclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019)”. In short, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. 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), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Applying the same logic to the instant process claim(s), one of ordinary skill in the art would have a reasonable expectation of success to administer compounds from the autacoid classes of lipoxins, maresins, protectins, and resolvins for treating localized provoked vulvodynia even though Hesselink et al. does not expressly exemplify them.
In response to applicant’s argument that Hesselink et al. fails to teach the specific pro-resolving mediator or mixture of pro-resolving mediators instantly claimed, the rejection on the record is from using the combination of prior art(s) rather than Hesselink et al. alone. It is respectfully noted that the rejection on the record further relies on Ji et al. to teach teaches protectin D1 can inhibit TRPV1 and TNF-α signaling, preventing glial activation and neuropathic pain, and reducing established inflammatory pain and neuropathic pain; and Schwab et al. to teach Protectin D1 (PD1) reduces pro-inflammatory cytokines IL-6. It may well be true Hesselink et al. does not expressly teach the compound species from the autacoid classes of lipoxins, maresins, protectins, and resolvins for the treatment of LPV; However, Hesselink et al. clearly teaches the therapeutic role of autacoid in the pathogenesis of vulvodynia. Specifically, Hesselink et al. teaches autacoid inhibits the positive feedback loop of overactive mast cells producing neurotrophic growth factor (NGF), which is a major biological actor that was first identified in pain and inflammation (see e.g., p. 759, right column, last paragraph to p.760, left column, 1st paragraph); and these overactive mast cells also produce prostaglandin E2, an enhancer of neurogenesis, and this metabolite can activate the TRPV1 receptor, and then NGF can subsequently promote the insertion of TRPV1 into the cell surface membrane (see e.g., p.760, left column, 4th paragraph). In light of the mechanism of autacoid taught by Hesselink et al., and the fact that protectin D1 can reduces pro-inflammatory cytokines IL-6, and inhibits TRPV1 and TNF-α signaling for reducing neuropathic pain and inflammatory pain (see Ji et al. and Schwab et al. above), one would have a reasonably expected that protectin D1 as the at least one component of a cellular-derived microparticle in the composition of Serhan et al. can successfully reduce pain of localized provoke vulvodynia by decreasing production of pro-inflammatory cytokines, including IL-6 and inhibiting TRPV1 and TNF-α signaling, in the absence of evidence to the contrary.
Furthermore, applicant’s argument that amendment to claims 1 and 13, which changes the transitional term “comprising” to “consisting essentially of” overcomes the rejection further in view of the '597 application is not found persuasive, according to MPEP 2111.03 I, the transitional term “comprising”, which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). In other words, even though the transitional term “consisting essentially of” is used in the context of pro-resolving mediator mixture, the composition as a whole recited “comprising” language that does not exclude additional and unrecited elements to said composition. In addition, according to MPEP 2111.03 III, “[f]or the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355”. Thus, applying same logic to the instant case, the “consisting essentially of” recites in the instant claim language is reasonably construed as equivalent to “comprising”. In addition, the rejection further in view of the '597 application is form on the basis that Serhan et al. teaches the at least one component of a cellular-derived microparticle (e.g., Protectin D1) can combined with anti-inflammatory agents (see e.g., [0023]); and ’597 application teaches LM03-3, which comprises DHA, 14-HDHA, 17-HDHA, 18-HEPE, and EPA, is useful for treating and resolving inflammation in a subject. In other words, one would have a reasonable expectation of success to combine the cellular-derived microparticle of Serhan et al. with LM03-3 of ’597 application as the anti-inflammatory agents for treating pain or inflammation in the method of Serhan et al., Hesselink et al., Ji et al. and Schwab et al. set forth in the rejection above.
Applicant further argues the claimed method exhibits unexpected results, including the reduction of cytokines such as IL-6 and PGE-2, and treating pain in patients with LPV, by directing attention to (i) the previously filed response dated August 25, 2025; (ii) page 8, lines 9-12 of the specification: “[t]his invention is based, at least in part, on unexpected discoveries that fibroblasts isolated and cultured from sites of pain in LPV patients produce very high levels of pro- inflammatory and pro-pain mediators compared to ‘pain free’ sites and that a class of molecules called pro-resolving mediators are effective against LPV”; and (iii) Example 5-6 of the specification. In sum, Applicant argues Example 5 demonstrate 67% of allodynia-induced mice topically treated with a high dose of LIPINOVA recovered from allodynia; and Example 6 demonstrates the effect of treatment were sustained greater than 7 weeks in the LIPINOVA high group, and concludes that “LIPINOVA is effective in promoting the resolution of inflammation and reducing pain in a mouse model of vulvodynia”.
In response, applicant argument with respect to unexpected results is not found persuasive. According to MPEP 716.02(d), “[w]hether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
As stated in the previous Non-Final Office Action mailed on January 27, 2026, applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention. In the previously reply filed on August 25, 2025, Applicant argued unexpected results are demonstrated in the declarations under 37 CFR 1.132 filed on September 8, 2025, and Examples 2-3 of the specification. Specifically, Example 2 demonstrates Lipoxin A4, Resolvin D2, Maresin 1 and epi-Maresin 1 significantly reduced prostaglandin E2 (PGE2; FIG. 5A) and interleukin-6 (IL-6; Figure 5B) production by both vestibular and external vulvar fibroblasts in the in vitro LPV model (see e.g., p. 28); and similar results are obtained from other SPMs, including Resolvin D3, Resolvin D4, Resolvin D5, Resolvin E1, Protectin D1, and Protectin DX (see e.g., p. 28, line 25 to p. 29, line 6); Example 3 demonstrates Maresin 1 or RvD2 significantly suppressed the enhanced PGE2 responses following IL-1[Symbol font/0x62] treatment in vitro by culturing mouse vulvar explants (see e.g., p. 29, line 27-28); and the declaration demonstrates RvD2, 7-epi-Maresin-1, Maresin-1, LXA4, Protectin DX, RvD5, Protectin D1, RvD4, RvE1, RVD3 reduces IL-6 and PGE-2 in the fibroblast isolated and cultured from sites of pain in LPV patients (see e.g., page 2). However, as noted in the previous Non-Final Office Action mailed on mailed on January 27, 2026, the declaration and Example 2-3 of the specification do not include the treatment results of DHA alone nor a mixture consisting essentially of DHA, 14-HDHA, 17-HDHA, and 18-HEPE; and the effective amount administered to the subject is also not disclosed therein.
In contrast, instant claims recite administering a broad effective amount of a composition comprising a pro-resolving mediator topically to a broad genus of treatment site of a subject’s lower genital tract for reducing lower genital tract pain or pruritus associated with LPV, wherein the pro-resolving mediator is (i) selected from the group consisting of Resolvin D2, Resolvin D3, Resolvin D4, Resolvin Ds, Resolvin E1, Maresin-1, epi-Maresin-1, Lipoxin A4, Protectin D1, Protectin DX, and docosahexaenoic acid (DHA); or (ii) a mixture consisting essentially of DHA, 14-HDHA, 17-HDHA, and 18-HEPE. Please note even though the transitional term “consisting essentially of” is used in the context of pro-resolving mediator mixture, the composition as a whole recited “comprising” language that does not exclude additional and unrecited elements to said composition; and therefore, “consisting essentially of" is construed as equivalent to "comprising".
In view of the foregoing, Applicant only demonstrates the unexpected results (“reduces a level of IL-6 or PGE-2”) in an in vitro model, specifically, in the vestibular and external vulvar fibroblasts using the following pro-resolving mediators: Resolvin D2, Resolvin D3, Resolvin D4, Resolvin D5, Resolvin E1, Maresin-1, epi-Maresin-1, Lipoxin A4, Protectin D1, and Protectin DX. The disclosure and the declaration do not provide adequate basis for concluding that similar results would be obtained for other pro-resolving mediators, such as docosahexaenoic acid, or a mixture comprising DHA, 14-HDHA, 17-HDHA, and 18-HEPE. In addition, the disclosure and the declaration also do not adequate basis for concluding that similar results would be obtained in any other fibroblasts obtained from the subject as well as at any effective amount of a composition comprising the pro-resolving mediator.
In the present case, while applicant further directs attention to page 8, lines 9-12, and Example 5-6 of the specification in the reply filed on March 25, 2026 to support additional unexpected results (“It was also unexpected that pro-resolving mediators could be used to treat pain in patients with LPV”, see p. 8 of the reply), these disclosures do not describe DHA alone or a mixture consisting essentially of DHA, 14-HDHA, 17-HDHA, and 18-HEPE “reduces a level of IL-6 or PGE-2” as required by the instant claim(s). In addition, Examples 5-6 administered a highly purified fish oil product “LIPINOVA” that contains ~40% docosahexaenoic acid (DHA) by volume with additional specialized pro-resolving mediator (SPM) precursor molecules (14-HDHA, 17-HDHA, and 18-HEPE) to the treatment groups (see p. 34, line 2-3 of the specification), including LIPINOVA cream high dose (1.9% LIPINOVA by volume; 12 mice) and LIPONOVA low dose (0.7 % LIPINOVA by volume, 12 mice) (see p. 33, line 31-33 of the specification). Said product “LIPINOVA” was topically apply to the vulvar area of mice at different percent volume, i.e., 1.9% or 0.7% by volume(see p. 35, line 27 of the specification), twice daily from Monday through Friday and single daily application on Saturday and Sundays for a total of 4 weeks in Example 5 and for a period of 17 weeks in Example 6 (see p. 34, line 4-6 of the specification). Example 5-6 only exemplifies the topical administration of 0.7% and 1.9% of “LIPINOVA” by volume, and does not disclose the amount of 14-HDHA, 17-HDHA, and 18-HEPE contains therein aside from a broad recitation that “LIPINOVA” contains ~40% docosahexaenoic acid (DHA) by volume with additional 14-HDHA, 17-HDHA, and 18-HEPE. Thus, it is not commensurate in scope to encompass any effect amount of a composition comprising the pro-resolving mediator. Further according to the disclosure of Example 5 (see p. 34, line 17-18 of the specification), “[t]hese data suggest that recovery was influenced by LIPINOVA dose, with higher doses being more effective”. In other words, the additional unexpected results upon which applicant relies appears to be dose-dependent, and that also does not provide adequate basis for concluding that similar results would be obtained by administering any effective amount of any composition comprising any of the claimed pro-resolving mediator. Furthermore, Example 5-6 only exemplified the unexpected results using a specific dosing regimen (“twice daily from Monday through Friday and single daily application on Saturday and Sundays”), and that is not commensurate in scope to include any dosing regimen as broadly encompassed by the claim(s).
In addition, the unexpected results (“reduces a level of IL-6 or PGE-2” and “treat pain”) upon which applicant relies would have been expected, as noted in the rejection above, the cellular-derived microparticle taught by Serhan et al., for example, Protectin D1, is known in the art to be capable of reducing pro-inflammatory cytokines, including IL-6, as taught by Schwab et al.; and it is known in the art to be capable of inhibiting TRPV1 and TNF-α signaling, preventing glial activation and neuropathic pain, and reducing established inflammatory pain and neuropathic pain, as taught by Ji et al. Therefore, one would have reasonably expected that the administration of protectin D1 as the claimed cellular-derived microparticle would have successfully reduce pro-inflammatory cytokines IL-6 and inhibiting TRPV1 and TNF-α signaling for reducing the pain.
Therefore, applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention for the reasons set forth herein.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
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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.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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