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 .
Response to Amendments
Applicant did not amend the claims.
Note: This matter has been transferred to Examiner Barsky.
Response to Arguments
The Scope of Enable Rejection is withdrawn.
The Double Patenting Rejection is maintained.
The examiner responds to each of Applicant argues below in the context of his response. If Applicant has any questions, please feel free to reach out to the examiner.
Applicant argues that EAE is not a proper model for studying multiple sclerosis.
The examiner notes that this is not the case. The state of the art recognizes EAE as the proper model used to study multiple sclerosis.
The examiner cites to show the state of the art with respect to accepting EAE as the model for MS. Constantinescu et al., “Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS),” British Journal of Pharmacology 164(4):p 1079-1106, October 2011. Constantinescu teaches EAE is the most common model for studying MS and it has similar pathological features and many of the drugs in current or imminent use in MS has been developed, tested or validated on the basis of EAE studies. See Abstract.
Tian teaches homotaurine is a GABAA- receptor agonist. Oral administration of this in models of MS was sued to explore “Whether GABAA-R agonists can also inhibit processes in EAE specifically referred to as a model for MS.
Applicant argues that Tian does not described GABA-AT inhibition as promising for treating MS. Applicant further argues that Tian provides no reason to select a GABA-AT inhibitor.
The examiner notes that Tian explains that multiple drugs that inhibit GABA transaminase have been shown to inhibit EAE. Those drugs are topiramate and vigabatrin. See p2, 1st par. Tian also indicates that GABAA-R agonists have been shown to inhibit the inflammatory activity of macrophages, dendritic cells, and microglia that contribute to EAE pathogenesis. See p4, 2nd full par. Tian thus indicates that preventing the breakdown of GABA has been shown to work in treating EAE.
Even further, the examiner notes that Juncosa indicates that CPP-155 (i.e., the claimed compound) is “186 times more effective in inactivating GABA-AT than vigabatrin, the only FDA-approved drug that is an inactivator of GABAT-AT.” See Abstract. The claimed compound is 10 times more potent than CP-115. See p2, 1st par.
Silverman is merely used to show that the claimed agent can have efficacy in conditions of the brain, neurological and psychological by inhibiting GABA-AT through multiple routes of administration and dosages.
Applicant does not provide a showing or allegation of unexpected results. As such, the examiner is determining if a prima facie showing is established. The examiner believes that a prima facie showing is established that there is a reasonable and predictable expectation of success in ameliorating MS by administration of the claimed compound at a claimed and optimizable dosage for the following reasons.
The claimed agent is taught to inhibit GABA transaminsase at a level that is (186 x 10) times more potent at doing so that Vigbatrin. Further, multiple drugs that inhibit GABA transaminase have been shown to inhibit EAE. Further, Tian also indicates that GABAA-R agonists have been shown to inhibit the inflammatory activity that contributes to EAE pathogenesis. Thus, there is a reasonable basis to believes that drugs that inhibit GABA-AT as well as GABAA-R will each treat EAE. EAE is the most common and accepted model for studying MS and has been used to develop, test or validate numerous drugs for treating MS.
There is thus a reasonable expectation of success that a potent GABA-AT inhibitor will treat various types of MS and symptoms thereof by mitigating the inflammatory process and pathogenesis of the same. The nexus linking the references is multifaceted. First, the agonism of GABA directly or indirectly through inhibiting GABA-AT yields the same end-goal. Moreover, the prior art teaches GABA-AT inhibitors have been shown to treat EAE (specifically referred to as an MS model) and that GABA-AT inhibition will mitigate the inflammatory cascade that is detrimental in EAE/MS. Vigabatrin is a drug that is taught to treat EAE and is known to do so by inhibiting GABA-AT. The impact of this is GABA agonism. Not only is Vigabatrin mentioned by Tian in doing so, but Juncosa also mentions Vigabatrin in showing the enhanced potency of the claimed compound as compared thereto. The sole purpose of this comparison is to show that the claimed agent has an even better likelihood of therapeutic efficacy than one that has already been shown to work.
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 nonobviousness.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Tian, J. (Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis), Nature – Scientific Reports, Vol. 8, pp. 1-8 (Year: 2020), in view of Juncosa, J.I. Design and Mechanism of (S)‑3-Amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ‑Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction, Journal of the American Chemical Society, Vol. 140, no. 6, pp. 2151-216 (Year: 2018), and further in view of Silverman, R., et. al. (US Publication No. US-20210238120-A1; Published 08/05/2021).
Tian teaches that homotaurine, a GABAA-R specific agonist capable of crossing the blood-brain barrier, reduced experimental autoimmune encephalomyelitis (EAE) symptoms in mice (See Page 2; Results and Discussion – Figure 1B). EAE is a widely used animal model for studying multiple sclerosis.
Tian further provides the following recitation:
“Control mice displayed classical relapsing-remitting EAE. Homotaurine-treated mice exhibited a reduced mean EAE severity throughout the observation period compared to those given plain water, and eventually displayed almost complete remission (Fig. 1B). Histological analysis of their brains and spinal cords revealed reduced mononuclear cell infiltration and areas of myelin loss in the cerebellum and spinal cords of homotaurine-treated mice
(Fig. 1C). Thus, treatment with homotaurine after the clinical onset of EAE inhibited disease progression in both monophasic and relapsing-remitting mouse models of MS. Previous studies using GABA to inhibit T1D and RA in mouse models could not distinguish the contributions of GABAA-Rs versus GABAB-Rs to those observations. Our results using homotaurine point directly to GABAA-R-mediated pathways as major components of GABA’s anti-inflammatory effects” (See Page 2; Results and Discussion).
Through this recitation, Tian provides a nexus between homotaurine, it’s mechanism of action as a selective GABAA receptor agonist, and the anti-inflammatory effects observed to directly reduce myelin loss in the brain, along with directly showing clinical improvements in EAE mouse models of multiple sclerosis. At this point, one having ordinary skill in the art, would have had teaching, suggestion, or motivation to pursue treatment of multiple sclerosis with other agents known to directly or indirectly increase GABAA receptor agonism.
While Tian does not teach the Applicant’s claimed compound, Juncosa teaches that (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329), the Applicant’s claimed compound, is a highly selective GABA-AT inhibitor, and through its action of reducing GABA-AT mediated GABA breakdown, raises GABA levels (See Page 2152; Scheme 1 and Paragraph 1).
While Juncosa largely teaches alternative applications for the Applicant’s compound, one having ordinary skill in the art, drawing from Tian’s teachings as previously set forth, and Juncosa’s teaching of the mechanism of the Applicant’s compound, would see the relevance of the Applicant’s compound to treating multiple sclerosis.
It is noted that Tian teaches direct GABAA receptor agonism with a selective agonist of this receptor subtype, while Juncosa introduces the Applicant’s compound as an inhibitor of GABA-AT, an enzyme that breaks down GABA, such that administration of the Applicant’s compound would result in elevation of endogenous GABA, an agonist of all GABA receptors.
However, one having ordinary skill in the art would appreciate that the Applicant’s compound as taught by Juncosa has “favorable pharmacokinetic properties and low off-target activities”(See Page 1; Abstract) and based on these favorable intrinsic pharmacological properties, would have motivation to try the Applicant’s compound in a method of treating multiple sclerosis, as GABA is able to agonize the target receptor GABA-A as elucidated by Tian.
In regards to the Applicant’s limitations drawn to various dosing ranges, such as “ 0.01 mg to about 750 mg”, “0.1 mg to 600 mg”, “1 mg to 500 mg”, “administered to the subject in a twenty-four hour period is between 1 mg and 400 mg”, “administered to the subject in a twenty-four hour period is between 1 mg and 300 mg”, “administered to the subject in a twenty-four hour period is between 1 mg and 200 mg”, “administered to the subject in a twenty-four hour period is between 1 mg and 100 mg”, “administered to the subject in a twenty-four hour period is between 1 mg and 50 mg”, “administered to the subject in a twenty-four hour period is between 1 mg and 25 mg”, “administered to the subject in a twenty-four hour period is between 1 mg and 10 mg”, as seen in claims 1-10, dosing frequencies, such as “one to four times a day”, as seen in claim 11, and routes of administration, such as “oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral”, as seen in claim 12, these are routinely optimizable by one having ordinary skill in the art, as a result-effective variable has been established wherein the Applicant’s compound elevates GABA, which is known to agonize GABAA receptors and decrease inflammatory markers that cause myelin damage. (MPEP 2144.05 – II.B). This nexus between the Applicant’s compound, the elevation of GABA levels, agonism of GABAA receptors, and decrease in myelin damaging inflammatory markers, once established by Tian and Juncosa, provides adequate teaching, suggestion, and motivation to one having ordinary skill in the art to further optimize administration of the Applicant’s compound to a subject afflicted with multiple sclerosis.
Further, Silverman teaches the Applicant’s compound can be administered through the following routes: oral, transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, and / or intrathecal administration (See Page 6; Paragraph 0071).
In regards to the limitation in claim 13, requiring amelioration of one or more symptoms of multiple sclerosis in response to treating multiple sclerosis, this is an intrinsic result of treatment as defined by the Applicant in the specification through the recitation: "Treating", "treatment" or “treat” can refer to the following: reducing, improving, relieving, ameliorating, mitigating, inhibiting, reversing and/or alleviating MS in a subject, or delaying the appearance of symptoms of MS (prophylaxis) in a subject.
In regards to the limitations drawn to sub-categories of multiple sclerosis, it is not understood by one having ordinary skill in the art that these sub-categories of multiple sclerosis have a different causative mechanism, such that a compound addressing the underlying myelin damage that is known to cause multiple sclerosis, as recited in claim 1, could not address these sub-categories, recited in claims 14-20. Thus, the limitations drawn to relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, progressive-relapsing multiple sclerosis, clinically isolated syndrome multiple sclerosis, fulminant multiple sclerosis, and benign multiple sclerosis, are prima facie obvious in light of the aforementioned teachings of Tian and Juncosa.
In the instant case, Tian and Juncosa provide adequate teaching suggestion, or motivation to one having ordinary skill in the art, before the Applicant’s effective filing date, to develop a method of treating multiple sclerosis by administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329) to a subject afflicted with multiple sclerosis, at routinely optimizable doses and frequencies, choosing from a finite number of standard routes of administration as taught by Silverman, wherein the multiple sclerosis is one of a list of obvious sub-categories of multiple sclerosis.
One having ordinary skill in the art would have been motivated and have had reasonable expectation of success to combine the teaching of Tian, providing a nexus between homotaurine, it’s mechanism of action as a selective GABAA receptor agonist, and the anti-inflammatory effects observed to directly reduce myelin loss in the brain, along with directly showing clinical improvements in EAE mouse models of multiple sclerosis, and Juncosa, teaching the Applicant’s compound with a relevant, although not identical, mechanism of GABA-AT inhibition taught to increase GABA, the endogenous agonist for GABA receptors, including GABAA, to develop the Applicant’s claimed method, by further optimizing dosing, frequency, and route of administration.
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filling date of the claimed invention, to combine these teachings and develop a method to treat multiple sclerosis in a subject in need thereof, by administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329) to a subject afflicted with multiple sclerosis, at routinely optimizable doses and frequencies, choosing from a finite number of standard routes of administration, wherein the multiple sclerosis is one of a list of standard sub-categories of multiple sclerosis.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-20 is/are rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-20 of prior U.S. Patent Application No. 19/157,035. This is a provisional statutory double patenting rejection, as the patentably indistinct claims have not in fact been patented.
Conclusion
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 extension fee 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 JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. 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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