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
This application is a CIP of 16/799,787 filed 02/24/2020 which is a CIP of 16/749,960 filed 01/22/2020 which claims domestic benefit to provisional application No. 62/822,752 filed 03/22/2019. Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119 (e) as follows:
The later-filed application must be an application for a patent for an invention
which is also disclosed in the prior application (the parent or original nonprovisional
application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the
requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112,
except for the best mode requirement. See Transco Products, Inc. v. Performance
Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, PRO 62/822,752 filed 03/22/2019 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The limitations of the instant claims 13 – 16, 18 and 19 do not appear in the provisional. Accordingly, claims 13 – 16, 18 and 19 are not entitled to the benefit of the prior applications and the effective filing date is 05/02/2022 as the limitation in claims 13 – 16, 18 and 19 are supported by 17/734,777 filed 05/02/2022.
Claims 1 – 12, 17 and 20 have appropriate support in provisional application
No. 62/822,752 and have been awarded the filing date of 03/22/2019.
Information Disclosure Statement
The Information Disclosure Statements filed on 05/02/2022 has been
acknowledged and considered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3 and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 3 and 18 recite the limitation “derivative” in line 1. The breadth of derivatives of compounds can vary greatly depending on the specific context, the nature of the compound and the derivatization process. Derivatives can be broad in terms of the range of possible structural modifications, the diversity of their properties, and the scope of their applications. Although, the specification (¶ [0015], pg.3) provides an example of retigabine derivative, there is no evidence that the specification contemplates any other modification of retigabine that leads to the claimed function or method of use.
Given the broad scope of the claim limitation, applicant has not provided sufficient written description that would allow one skilled in the art to recognize the necessary modifications to retigabine that allows for the claimed method of use.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 3 and 18 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 3 and 18 recite the limitation “derivative” in line 1. It is unclear whether
the derivatives encompass a structural and or functional relationship. The scope of the limitation is unclear.
Claim 4 depends from rejected claim 3 and is similarly rejected.
Claim 12, line 1 recites “The method of claim 12”. It is unclear what claim number claim 12 depends from. For examination purposes, claim 12 will depend from claim 1 because all the other claims depend from it.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 – 3, 5, 6, 10, 12 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vigil et al. (J Neurotrauma., Published July 7 – 12, 2017) (hereinafter Vigil).
Vigil teaches “Novel Drugs that Augment KCNQ (KV7, m-type) Potassium Channels as a Post-event Treatment for Traumatic Brain Injury” (title, left column, pg. A-114). This anticipates claim 1 and 2. Vigil tested the hypothesis that reducing neuronal excitability before the process of epileptogenesis commences, moderates or prevents post-TBI deleterious effects. Using a model of blunt TBI, Vigil pharmacologically enhanced currents from M-type K+ channels, which play a dominant role in limiting neuronal excitability. Vigil tested such effects with the anti-convulsant drug, Retigabine (RTG), which enhances M current. Mice subjected to TBI were administered RTG or vehicle 30 minutes after injury. This anticipates claims 3, 5, 10, 12 and 20.
Regarding claim 6, the active step of administering a therapeutically effective amount of an M-channel opener to a subject, after the subject experiences a traumatic brain injury, which leads to a reduction in neuronal excitability will necessarily result in the reduction in cellular energy demand in the brain.
Claims 1 – 3, 10 and 12 – 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sanchez et al. (Biophysical Journal, Published Feb. 19, 2018) (hereinafter Sanchez).
Sanchez teaches that enhancing KCNQ (‘‘M-type’’) K+ currents silences neurons and prevents seizures, such as via the M-channel ‘‘opener’’ and anti-convulsant drug, retigabine (RTG). Sanchez used a controlled closed-cortical impact (CCCI) model of TBI to test whether RTG administration soon after TBI prevents post-TBI dysfunction. Mice were subjected to CCCI TBI, followed by RTG (i.p. 1 mg/kg) or vehicle within 30 minutes post-TBI (right column, pg. 309a). This anticipates claims 1 – 3, 10 and 12 – 14.
Claims 1 and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tornoee et al. (WO 2006/092143 A1, Sep. 08, 2006) (hereinafter Tornoee).
Tornoee teaches the use of retigabine for the treatment of neurodegenerative disorders such as… encephalopathies induced by AIDS or infection by rubella viruses, herpes viruses, borrelia and unknown pathogens; trauma-induced neurodegenerations; neuronal hyperexcitation states… (paragraph 2, pg.5). This anticipates claims 1 and 7.
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.
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.
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 8, 11 and 16 – 18 are rejected as being unpatentable under 35 U.S.C 103 over Sanchez et al. (Biophysical Journal, Published Feb. 19, 2018) (hereinafter Sanchez) as applied to claims 1 – 3, 10 and 12 – 14 above, in view of Bierbower et al. (J Neurosci., Published Feb. 04, 2015) (hereinafter Bierbower).
The teachings of Sanchez are discussed above and are incorporated hereinafter.
Sanchez does not teach a method wherein administering is delivered intravenously, intramuscularly, subcutaneously, transdermally, orally, or nasally or a method wherein administering the therapeutically effective amount of the compound is performed within 1 hour of the subject experiencing the at least one traumatic brain injury event or within six hours after the traumatic brain injury or wherein the subject is experiencing or at risk of experiencing metabolic exhaustion in cells of a brain.
However, Bierbower teaches a therapeutic time window of effectiveness for M-channel openers in stroke-induced brain injury by injecting retigabine into the tail vein at various time after stroke (Figure 3, pg.2105). This helps to teach claim 8. Bierbower also teaches that RTG administered 6 h after the stroke had reduced efficacy compared with RTG administered at 0, 1, or 3 h poststroke, but still significantly less than control animals, indicating a critical time window closer to 3 h than 6 h (left column, pg. 2105). This helps to teach claims 11 and 16.
Bierbower further teaches that an obvious improvement was shown in M-channel opener-treated mice in the reduction of brain injury and functional impairment… working model assumes that by decreasing the excitability of, or “silencing,” neurons, we can rescue neurons in the penumbral region that are metabolically compromised but not yet damaged beyond repair (left column, pg. 2109). This helps to teach claim 17.
As discussed above, retigabine reduces neuronal excitability soon after TBI which helps prevent seizures. It would have been obvious to one of ordinary skill in the art, before the effective filing date, to administer retigabine within 6 hours of a brain injury. One would have been motivated to take advantage of the therapeutic time window because Bierbower demonstrates that effectiveness of retigabine to reduce neuronal excitability and prevent metabolic exhaustion diminishes severely after 6 hours.
Claim 4 is rejected as being unpatentable under 35 U.S.C 103 over Vigil et al. (J Neurotrauma., Published July 7 – 12, 2017) (hereinafter Vigil) as applied to claims 1 – 3, 5, 6, 10, 12 and 20 above, in view of Kumar et al. (Mol Pharmacol., Published Mar. 22, 2016) (hereinafter Kumar).
The teachings of Vigil are discussed above and are incorporated hereinafter.
Vigil does not teach a method wherein the M-channel opener is RL648_81 or a pharmaceutically acceptable salt thereof.
However, Kumar teaches the synthetic modification of several moieties of the KCNQ2–5 channel activator, retigabine. Kumar generated Ethyl (2-amino-3-fluoro-4-((4-(trifluoromethyl)benzyl)amino)phenyl)carbamate (RL648_81), a new KCNQ2/3-specific activator that is 15 times more potent and also more selective than retigabine. Kumar suggests that RL648_81 is a promising clinical candidate for treating or preventing neurologic disorders associated with neuronal hyperexcitability (abstract). Kumar also teaches that recent data have shown severe side effects associated with retigabine, including urinary retention, blue skin discoloration, and retinal abnormalities (right column, pg.667).
It would have been obvious to one of ordinary skill in the art, before the effective filing date, to use RL648_81 as an M-channel opener. One would have been motivated take advantage of its increased potency and selectivity as compared to retigabine and the lack of undesirable side effects associated with retigabine as taught by Kumar.
Claim 15 is rejected as being unpatentable under 35 U.S.C 103 over Vigil et al. (J Neurotrauma., Published July 7 – 12, 2017) (hereinafter Vigil) as applied to claims 1 – 3, 5, 6, 10, 12 and 20 above, in view of Dekmak et al. (Behav Brain Res., Published Dec. 30, 2016) (hereinafter Dekmak).
The teachings of Vigil are discussed above.
Vigil does not teach a method further comprising administering a second therapy for treatment of the traumatic brain injury to the subject, the second therapy comprising stem cell therapy, hardware implantation, ultrasound therapy, or a therapeutically effective amount of a compound comprising an adenosine A3 receptor agonist, an anticonvulsant, a coma-inducing drug, or a diuretic.
However, Dekmak teaches “Stem Cells and Combination Therapy for the Treatment of Traumatic Brain Injury” (title). Dekmak further explains that a strong rationale for the use of combination therapies is brought upon by the complexity of the TBI insult. Moreover, the success of this approach for other medical conditions presents another driving force for exploring combination therapies in TBI (left column, pg. 56). Additionally, Dekmak teaches that a number of combination therapies were undertaken in TBI with positive effects (right column, pg. 56).
Dekmak provides the benefits of combination therapy for the treatment of traumatic brain injury. It would have been obvious to one of ordinary skill in the art, before the effective filing date, to add on a second therapy for the treatment of traumatic brain injury because combination therapy leads to better patient outcomes in TBI as taught by Dekmak.
Claim 19 is rejected as being unpatentable under 35 U.S.C 103 over Vigil et al. (J Neurotrauma., Published July 7 – 12, 2017) (hereinafter Vigil) as applied to claims 1 – 3, 5, 6, 10, 12 and 20 above, in view of Villoslada et al. (WO 2021/211867 A1 Oct. 21, 2021) (hereinafter Villoslada).
The teachings of Vigil are discussed above.
Vigil does not teach a method wherein administering the therapeutically effective amount of the compound to the subject prevents the occurrence of traumatic brain injury-induced hypersomnia in the subject.
However, Villoslada discloses a method for treating a sleep disorder in a patient in need thereof, comprising the step of administering a therapeutically effective amount of a potassium channel modulator to the patient to control the excitability of Hcrt/Orx neurons. In particular embodiments, the potassium channel modulator modulates a Kv7 member of voltage-gated potassium channels… the neuronal Kv7 activator is a flupirtine or retigabine or a derivative thereof, or any combination thereof (¶ [033], pg.11 – 12). Non-limiting examples of a sleep disorder include insomnia, hypersomnia, parasomnia, sleep apnea, jet lag, restless leg syndrome, sleepwalking (somnambulism or noctambulism), narcolepsy, night terrors, rhythmic movement disorder, sleep paralysis, sundowning, and rapid eye movement sleep behavior disorder (¶ [063], pg.25).
As discussed above, traumatic brain injury is linked to altered neuronal excitability that is controlled with retigabine. One of ordinary skill in the art before the effective filing date would expect a reasonable expectation of success in using retigabine to prevent traumatic brain injury-induced hypersomnia because Villoslada teaches that sleep disorders are linked to altered neuronal excitability and retigabine is used as a potassium channel modulator in controlling neuronal excitability.
Claim 9 is rejected as being unpatentable under 35 U.S.C 103 over Zhao et al. (Eur Rev Med Pharmacol Sci. Published Dec. 22, 2018) in view of Price et al. (CRC Press/Taylor and Francis Group, Published 2016).
Price teaches that tight junctions are composed of claudins, occludins, and other transmembrane proteins held together by zona occludens proteins that scaffold these complexes to the cytoskeleton (paragraph 3, pg. 1) and permeability of the BBB is largely regulated by the expression of certain tight junction proteins on microvessel endothelial cells. TBI disrupts expression of tight junction proteins (paragraph 4, pg. 2).
Price does not teach the method of preserving permeability of a blood brain barrier of a brain of the subject via exposure to the M-channel opener.
However, Zhao teaches the tight connection between adjacent endothelial cells is a crucial functional unit for the maintenance of the integrity of the blood-brain barrier and a key factor determining the permeability (right column, pg.8509). Retigabine can up-regulate the expression levels of claudin-5, occludin, and ZO-1 as well as their protein expression levels, and restore the intact structure of tight junctions. Therefore, it was believed that retigabine may reduce the blood-brain barrier permeability through the paracellular pathway by affecting the distribution and expressions of claudin-5, occludin, and ZO-1 (left column, pg.8516).
It would have been obvious to one of ordinary skill in the art, before the effective filing date, to use retigabine to preserve permeability of the blood brain barrier. One would have been motivated to do so because disruption of tight junction protein is a hallmark of TBI and retigabine restores the intact structure of tight junctions thereby preserving the permeability of the blood brain barrier as taught by Zhao.
Conclusion
Claims 1 – 20 are rejected.
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Faidat Jyoti whose telephone number is (571)272-0120. The examiner can normally be reached Monday -Friday 10am - 7pm.
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/Faidat Jyoti/Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
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