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 .
Claims 1-9 and 11-14, submitted on 22 March 2023, represent all claims currently under consideration.
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.
Priority
This application is a 371 of PCT/US2021/052857, filed on 30 September 2021, which claims priority to provisional US 63/086,467, filed 1 October 2020. The effective filing date is 1 October 2020.
Specification
The use of the terms CYMBALTA, SAVELLA, LYRICA, and NEURONTIN, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 7 and 8 are objected to because of the following informalities: There is no comma between “vision problems” and “numbness” in the list of conditions of Claims 7 and 8. Appropriate correction is required.
Claims 7 and 8 are objected to because of the following informalities: There is an unnecessary comma in between “digestive problems” and “including irritable bowel syndrome and bladder disorders”. Appropriate correction is required.
Claims 7, 8 and 13 objected to because of the following informalities: The claims claim “skin sensitives and rashes”. The Examiner believes this is a typographical error and should be “skin sensitivities and rashes”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 13 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. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 recites the broad recitation “antidepressants”, and the claim also recites “serotonin reuptake inhibitor antidepressants” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 7 and 8 are 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 7 and 8 claim “digestive problems including irritable bowel and bladder disorders”. The phrase "including" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention or merely exemplary. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7 and 8 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 7 and 8 depend on Claim 4, which claims the fibromyalgia is associated with a symptom selected from chronic pain, allodynia, hyperalgesia, and fatigue, and the treating of fibromyalgia comprises treating at least one of chronic pain allodynia, hyperalgesia, and fatigue. Claims 7 and 8 expand the symptoms which are treated, broadening the scope of Claim 4, which does not further limit the method of Claim 4. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-9, 11, 12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Levin (WO 2021/067089; Publication Date: 8 April 2021, Priority to 30 September 2019) in view of Pomares (Pain, Jan 2020, Volume 161, Number 1).
Levin discloses compositions containing isomerically pure forms of neurosteroids that permit preferential modulation of different subtypes of GABAA receptors, as well as methods of treating GABAA disorders using such compositions (Abstract). The invention provides compositions that contain an isomerically pure form of a compound of Formula (I):
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(Page 2, Lines 13-18). This compound is identical to the compound which is claimed in the examined application. The invention includes the finding that this compound is considerably more active on α4β3d GABAA receptors than on α1β2γ2 GABAA receptors (Page 2, Lines 18-19). The invention also provides pharmaceutical compositions containing an isomerically pure form of a compound of Formula (I) (Page 3, Lines 4-5). The invention also provides a method for treating a GABAA disorder by providing to a subject a pharmaceutical composition comprising an isomerically pure form of a compound of Formula (I) (Page 3, Lines 11-13). The composition may be effective for treatment of a GABAA disorder. The GABAA disorder may be any disease, disorder, or condition associated with altered GABAA receptor function or any disorder, disease, or condition that can be ameliorated by altered GABAA receptor function (Page 6, Lines 24-27). The composition may be formulated for a single daily dosage. The composition may be formulated for multiple daily dosages, e.g., two, three, four, five, six, or more daily dosages (Page 7, Lines 15-16).
Levin does not teach that the GABAA disorder is fibromyalgia.
Pomares studied the GABAA receptor in fibromyalgia. An imbalance between excitatory and inhibitory neurotransmission has been linked to fibromyalgia. Fifty-one postmenopausal women underwent assessments of pain sensitivity, attention and memory, psychological status and function, as well as PET imaging using a tracer for GABAA receptors. Patients showed increased pain sensitivity, impaired immediate memory, and increased cortical GABAA receptor concentration in the attention and default-mode networks. GABAA receptor concentration correlated positively with functional scores and current pain in areas overlapping with regions of increased GABA receptor A concentration. The study shows increased GABAA receptor concentration in fibromyalgia, associated with pain symptoms and impaired function. The changes were widespread and not restricted to pain-processing regions. These findings suggest that the GABAergic system is altered, possibly indicating an imbalance between excitatory and inhibitory neurotransmission (Abstract).
Levin and Pomares are considered analogous to the claimed invention as all are involved in studying the involvement of GABAA receptors in disorders and disease. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to use the compositions and methods of Levin to treat fibromyalgia, as Pomares demonstrates that fibromyalgia is a disorder linked with dysregulated GABAA signaling. Levin states that the disclosed compositions and methods can be used to treat any disease, disorder or condition associated with alter GABAA receptor function, and Pomares has demonstrated that fibromyalgia is associated with alterations in GABAA receptor function. The use of the compounds and methods of Levin to treat fibromyalgia is prima facie obvious combining of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)); the compounds and compositions of Levin are known to be useful for the treatment of GABAA-mediated conditions, and Pomares demonstrates that fibromyalgia is a disorder which is mediated by GABAA receptors. The artisan would recognize this, and would arrive at the claimed invention with a reasonable expectation of success as Levin shows the efficacy of this compound in modulating GABAA.
Regarding Claim 14, the selection of treating a human female patient is prima facie obvious as the artisan would know that women are affected by fibromyalgia at a higher rate than men, and this is known in the art of fibromyalgia management and treatment.
Claims 1-9 and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Martinez Botella (WO 2016/061527; Publication Date: 21 April 2016) in view of Hoffman (US 2020/0281943; Publication Date: 10 September 2020) and Pomares (Pain, Jan 2020, Volume 161, Number 1).
Martinez Botella discloses neuroactive steroids which are GABA modulators, as well as pharmaceutical compositions comprising a compound of the invention and methods of use and treatment (Abstract). One compound disclosed is
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(Page 21) (Compound 121, Page 150), which is identical to the compound claimed in the examined application. This compound has a 35S-TBPS Radioligand displacement IC50 of between 10 and 50 nM (Table 1, Page 217). Compound 121 displayed efficacy of greater than 500% against two isoforms of GABA (Table 2, Page 229). In one aspect, provided is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient (Page 38). In an embodiment, the compound is administered in combination with another therapeutic agent (Page 38). In one aspect, provided is a method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of a compound of formula (I) (Page 39). In one aspect, provided is a method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof (Page 39). In an embodiment, the compound is administered orally (Page 40). With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regiments (Paragraph 110, Page 70). Compounds of the present invention are generally designed to modulate GABA function, and therefore act as neuroactive steroids for the treatment of CNS-related conditions in subject (Page 75, Paragraph 0133). Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders (e.g., insomnia), mood disorders (e.g., depression), anxiety disorders (e.g., generalized anxiety disorder, social anxiety disorder), stress, disorders of memory and/or cognition, pain (e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain), and tinnitus (Page 76, Paragraph 0134).
Martinez Botella does not specifically disclose the treatment of fibromyalgia.
Hoffmann discloses a compound for the treatment of CNS related disorders and methods of improving the effectiveness of the administration of the compound for treating CNS related disorders (Abstract). The disclosure relates to the use of the compound
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which differs from the compound of the examined application by the presence of a methyl group, as well as the stereochemistry of one of the hydrogen atoms. This compound is a neuroactive steroid that has been shown to be a positive allosteric modulator of GABAA receptors (Paragraph 0004). Compound 1 can be used for example as an analgesic or other agent for pain control. In some embodiments, the compound of formula I can be used as an analgesic or other agent for pain control to treat inflammatory pain, neuropathic pain, fibromyalgia, or peripheral neuropathy (Paragraph 0218). Symptoms which can be treated include but are not limited to, behavioral, emotional, and sleep-related symptoms, including but not limited to, fatigue, poor memory, anxiety, depression, emotional lability, lack of concentration, attention difficulties, and dry skin (Paragraph 0155). The composition can be provided in a single dose per day (Paragraph 0027). The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration (Paragraph 0134).
Pomares, as described previously, teaches that fibromyalgia is a disorder linked with aberrant GABAA receptors.
Martinez Botella, Hoffmann, and Pomares are considered analogous to the claimed invention as all are involved in the treatment of disorders and diseases associated with aberrant activity of GABAA receptors. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to apply the compound, compositions, and methods of Martinez Botella to the treatment of fibromyalgia, as Hoffmann discloses the treatment of fibromyalgia with a compound of similar structure, and Pomares describes how fibromyalgia is linked with aberrant activity of GABAA receptors. The substitution of the compound of Martinez Botella into the method of Hoffmann to treat fibromyalgia is prima facie obvious simple substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)); Compound 121 is shown to be a potent GABA positive allosteric modulator, which differs only slightly in structure from the compound of Hoffmann, and as such, the artisan would not expect there to be a significant difference in the activity of this compound in the treatment of fibromyalgia as both compounds are potent GABA positive allosteric modulators. The artisan would have both a motivation to select, and a reasonable expectation of success in choosing Compound 121 due to the potent activity of this compound, which is described previously.
Regarding Claim 13, the additional active agents are known in the art to be useful for the treatment and/or management of the symptoms of fibromyalgia. Thus, their use in combination with Compound 121 is prima facie obvious combination of equivalents known for the same purpose (See MPEP § 2144.06 I). Hoffmann teaches that their method can comprise an additional therapeutic agent, and it flows from this teaching that agents which are useful for the management or treatment of fibromyalgia would be combined with the neurosteroid which is being used in treatment.
Regarding Claim 14, the selection of treating a human female patient is prima facie obvious as the artisan would know that women are affected by fibromyalgia at a higher rate than men, and this is known in the art of fibromyalgia management and treatment.
Conclusion
Claims 1-9 and 11-14 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625