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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 29, 2026, has been entered.
Response to Arguments
Applicant’s argument that carbamazepine works primarily through voltage gated channel blocking rather than as a GABA agonist is persuasive. Applicant argues that TGN is treated different than other types of neuropathic pain.
Each of Applicant’s arguments are moot in view of the teachings of new prior art cited below. In response to Applicant’s arguments, the examiner cites: Dieb et al., “Mechanism of GABA involvement in post-traumatic trigeminal neuropathic pain: Activation of neuronal circuitry composed of PKCγ interneurons and pERK1/2 expressing neurons,” European J Pain (2014) 1-12.
Dieb teaches that a decrease of GABA transmission constituted a key factor in the activation of this neuronal circuitry, which opens the gate for non-noxious stimuli to reach nociceptive projection neurons in lamina I. Dieb investigated the implication of GABA in trigeminal dynamic mechanical allodynia (DMA) obtained after chronic constriction of the infraorbital nerve (CCI-IoN), and explored the cellular and molecular mechanisms by which GABA dysfunction induced DMA. Abstract.
The present study demonstrates for the first time the down-regulation of GABA cell markersGAD67 and parvalbumin in CCI-IoN. This low expression constituted a major factor that induced DMA. Moreover, under pathological conditions (CCI-IoN), GABA tonic input becomes deficient, opening the gate for non-noxious tactile information to reach nociceptive cells in lamina I and produce DMA. The polysynaptic circuitry com posed by PKCγ-interneurons and pERK1/2-expressing cells is silent under physiological conditions (tonic GABAergic inhibition) and is activated under neuropathic condition (low GABAergic inhibition).
Dieb explained that VGB treatment decreased allodynia and elevated the expression of all GABA cell markers. Elevated GABA alone was sufficient to reverse the allodynic behavior. See p8, last par. The GABAergic system could constitute a therapeutic target for the treatment of trigeminal neuro pathic pain. See p11.
The examiner notes that Nielson teaches and claims that compound 1 reverses mechanical allodynia after acute and chronic treatment. This includes after surgery and on mechanical allodynia chronic constriction injury.
In view of Nielson teaching the claimed compound to treat mechanical allodynia as a GABA receptor modulator and a positive allosteric modulator of GABA for treating neuropathic pain; and Dieb teaching that trigeminal dynamic mechanical allodynia a can be treated with GABA alone, which can reverse allodynic behavior and mitigate the deficient tonic input that opens the gate for noxious information to reach nociceptive cells in lamina I, thereby mitigating DMA. Further, Dieb explains that the model of DMA used was caused by chronic constriction injury of the infraorbital nerve. See Abstract.
Status of the Claims
Claims 1, 2, 4-10, 12, 13, 17, 19, and 23 are pending.
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.
Claims 1, 2, 4-10, 12, 13, 17, 19, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Nielsen et al., (WO2020/053377 A1) (cited in ISR), in view of Xie et al., (US2016/0347810), in view of Piomelli et al., (US2009/0082435), in view of Vickers et al., “Neuropathic Orofacial Pain Part 1- Prevalence and Pathophysiology,” Australian Endodontic Journal February 11, 2010 (Abstract), in view of Dieb et al., “Mechanism of GABA involvement in post-traumatic trigeminal neuropathic pain: Activation of neuronal circuitry composed of PKCγ interneurons and pERK1/2 expressing neurons,” European J Pain (2014) 1-12.
Nielson teaches treatment of neuropathic pain with the claimed compound. See Abstract. The compound can treat pain, neuropathic pain, and/or itch. See p1, lines 7-8. The compound can be used to prevent, treat, and alleviate neuropathic pain. See p3, lines 12-13. Compositions may be administered orally as well as buccally and sublingually, and by inhalation, e.g. See p7-8, bridging par. An oral dose can range from 1 microgram or .001 mg to 100 mg/kg/day orally. See p9, lines 28-29. Symptoms of neuropathic pain including burning, tingling, electricity, pins and needles, hyperalgesia, and many other characterizations. See p10, lines 23-28. Administration of an API is taught after surgery. Further, chronic administration of was shown to maintain effects indicating a lack of tolerance. See Figure 3, e.g. It is not apparent that the type of surgery would impact the ability to mitigate and/or treat pain and itch resulting therefrom.
Nielson also teaches intravenous administration as an acceptable route of administration. See p8, line 1. A most preferred dose includes about 10 to 500 mg. See p9, line 24. An upper limited of the dosage range for IV administration is considered to be about 10 mg/kg. See p9, line 27.
With regard to claims directed to administration for a number of days prior to an operation, the examiner notes that Nielson teaches after 7 days of chronic treatment, a significant analgesic effect of all doses tested was maintained. As such, when prevention is intended, a starting point for dosage regimen optimization would be considered to be 7 days prior to surgery, e.g. Chronic and acute administration are both effective. See Example 4, among others.
Nielson does not teach facial pain in particular.
Xie teaches neuropathic pain to include: trigeminal neuralgia (par. 92), postoperative pain (prior claim 16); and migraine or tension headache (par. 189).
Piomelli teaches neuropathic pain to include: trigeminal neuralgia, post-surgical pain, atypical facial neuralgia after tooth extraction, mononeuropathy, and others. See par.’s 19 and 48.
Vickers teaches orofacial pain is neuropathic pain and those predisposed may include those suffering from cluster or migraine headaches. See Abstract. This is common at the dentist and is common after endodontic treatments.
Dieb teaches that a decrease of GABA transmission constituted a key factor in the activation of this neuronal circuitry, which opens the gate for non-noxious stimuli to reach nociceptive projection neurons in lamina I. Dieb investigated the implication of GABA in trigeminal dynamic mechanical allodynia (DMA) obtained after chronic constriction of the infraorbital nerve (CCI-IoN), and explored the cellular and molecular mechanisms by which GABA dysfunction induced DMA. Abstract.
The present study demonstrates for the first time the down-regulation of GABA cell markersGAD67 and parvalbumin in CCI-IoN. This low expression constituted a major factor that induced DMA. Moreover, under pathological conditions (CCI-IoN), GABA tonic input becomes deficient, opening the gate for non-noxious tactile information to reach nociceptive cells in lamina I and produce DMA. The polysynaptic circuitry com posed by PKCγ-interneurons and pERK1/2-expressing cells is silent under physiological conditions (tonic GABAergic inhibition) and is activated under neuropathic condition (low GABAergic inhibition).
Dieb explained that VGB treatment decreased allodynia and elevated the expression of all GABA cell markers. Elevated GABA alone was sufficient to reverse the allodynic behavior. See p8, last par. The GABAergic system could constitute a therapeutic target for the treatment of trigeminal neuro pathic pain. See p11.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of Nielson, Xie, Piomelli, Vickers, and Dieb. One would be motivated to do so because the claimed API is taught to treat neuropathic pain at claimed dosages and through a same route of administration. Moreover, Xie, Piomelli, and Vickers collectively teach that trigeminal neuralgia, postoperative pain, atypical facial neuralgia, orofacial pain, migraines, and tension headaches are forms of neuropathic pain. In view of Nielson teaching the claimed compound to treat mechanical allodynia as a GABA receptor modulator and a positive allosteric modulator of GABA for treating neuropathic pain; and Dieb teaching that trigeminal dynamic mechanical allodynia a can be treated with GABA alone, which can reverse allodynic behavior and mitigate the deficient tonic input that opens the gate for noxious information to reach nociceptive cells in lamina I, thereby mitigating DMA. Further, Dieb explains that the model of DMA used was caused by chronic constriction injury of the infraorbital nerve. See Abstract. As such, a POSA would have a reasonable and predictable expectation of success in treating trigeminal neuralgia by administering an agent known to treat DMA at dosages taught to prevent and treat neuropathic pain when administered by a claimed route of administration at a claimed dosage.
As such, no claim is allowed.
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, 2, 4-10, 12, 13, 17, 19, and 23 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,396,510, in view of Dieb et al., “Mechanism of GABA involvement in post-traumatic trigeminal neuropathic pain: Activation of neuronal circuitry composed of PKCγ interneurons and pERK1/2 expressing neurons,” European J Pain (2014) 1-12.
The ‘510 patent is sets forth all that is described above with respect to the Nielson reference. Further, the claims of the ‘510 patent include administering the claimed compound to treat allodynia as a form of neuropathic pain.
Dieb teaches that a decrease of GABA transmission constituted a key factor in the activation of this neuronal circuitry, which opens the gate for non-noxious stimuli to reach nociceptive projection neurons in lamina I. Dieb investigated the implication of GABA in trigeminal dynamic mechanical allodynia (DMA) obtained after chronic constriction of the infraorbital nerve (CCI-IoN), and explored the cellular and molecular mechanisms by which GABA dysfunction induced DMA. Abstract.
The present study demonstrates for the first time the down-regulation of GABA cell markersGAD67 and parvalbumin in CCI-IoN. This low expression constituted a major factor that induced DMA. Moreover, under pathological conditions (CCI-IoN), GABA tonic input becomes deficient, opening the gate for non-noxious tactile information to reach nociceptive cells in lamina I and produce DMA. The polysynaptic circuitry com posed by PKCγ-interneurons and pERK1/2-expressing cells is silent under physiological conditions (tonic GABAergic inhibition) and is activated under neuropathic condition (low GABAergic inhibition).
Dieb explained that VGB treatment decreased allodynia and elevated the expression of all GABA cell markers. Elevated GABA alone was sufficient to reverse the allodynic behavior. See p8, last par. The GABAergic system could constitute a therapeutic target for the treatment of trigeminal neuro pathic pain. See p11.
As such, it would have been obvious to arrive at the instant claims in view of Nielsen and Dieb for the reasons set forth above.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 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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/JARED BARSKY/Primary Examiner, Art Unit 1628
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