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 .
Status of the Application
Claims 23 and 25-34 are pending.
Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on 10/20/2025 are acknowledged. Claims under consideration in the instant office action are claims 23 and 25-34.
Applicants' arguments, filed 10/20/2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claims 23 and 25-34 are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez Lio (WO 2009/044250, as disclosed in IDS) in view of Kostikas (Blood Eosinophils as Biomarkers to Drive Treatment Choices in Asthma and COPD, Current Drugs Targets, 2018, 19(16), pp. 1882-1896, as disclosed in IDS).
Gonzalez Lio teaches compounds of formula (I):
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Gonzalez Lio teaches (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane
carboxylic acid as an exemplified compound (pg. 22, Example 4). Gonzalez Lio teaches such compounds useful for the treatment of “allergic reactions including but not limited to rhinitis, urticaria, scleroderma arthritis, and respiratory diseases like asthma and COPD.” (claim 9). Gonzalez Lio teaches “Effective doses are normally in the range of 2-2000 mg of active ingredient per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.” (pg. 18, lines 6-8). Gonzalez Lio teaches such compositions suitable for oral administration (pg. 17, lines 13-14).
Gonzalez Lio does not teach selecting a human subject having, before said treatment, a level of eosinophils in peripheral blood equal to or greater than 300 cel/μL.
Kostikas is drawn towards “the utility of blood eosinophils as a surrogate biomarker of eosinophilic airway inflammation, a common feature of specific asthma and COPD phenotypes.” (see abstract). Kostikas teaches an eosinophil level of 300 cel/μL as a predictor of asthma severity and improved outcomes (pg. 1885, 6.1.1.; see Table 1). Kostikas teaches “Mepolizumab and reslizumab are anti-IL5 MAbs that bind IL5, inhibiting eosinophilic inflammation by depleting the number of eosinophils in both sputum and blood. In a dose-ranging, efficacy and safety study (DREAM) of add-on mepolizumab in patients with severe eosinophilic asthma (≥300 cells/ μL), mepolizumab significantly reduced exacerbation rate and time to first exacerbation versus placebo (P ≤ 0.0005 for all doses). Circulating blood eosinophil levels were also significantly reduced compared with placebo, and modelling analysis confirmed that baseline blood eosinophil counts predicted treatment response to mepolizumab, with efficacy intensifying as baseline blood eosinophil counts and number of prior exacerbations increased.” (pg. 1890, left column, second paragraph).
It would have been obvious to one of ordinary skill in the art to select a human subject having, before said treatment, a level of eosinophils in peripheral blood equal to or greater than 300 cel/μL, as suggested by Kostikas, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since Kostikas teaches that an eosinophil level of 300 cel/μL as a predictor of asthma severity and improved outcomes (pg. 1885, 6.1.1.; see Table 1), and the use of such a biomarker level would improve the method of treating asthma as taught by Gonzalez Lio, with a reasonable expectation of success absent evidence of criticality of the particular steps.
Even though the range for dosages as taught by Gonzalez Lio is not the same as the claimed dosages, Gonzalez Lio does teach an overlapping range of dosages, and it has been held that in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP § 2144.05(I). Furthermore, the determination of dosages is well within the purview of those skilled in the art through routine experimentation, and it has been held that “it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05(II). It would have been obvious to one of ordinary skill in the art to optimize the dosages in order to increase the efficacy of the composition.
The amounts of active agents to be used, the pharmaceutical forms, e.g., tablets, etc; mode of administration, flavors, surfactant are all deemed obvious since they are all within the knowledge of the skilled pharmacologist and represent conventional formulations and modes of administration.
Furthermore, no unobviousness is seen in the ratio claimed because once the usefulness of a compound is known to treat a condition, it is within the skill of the artisan to determine the optimum ratio.
One of ordinary skill in the art would have been motivated to do so since it is prima facie obvious to combine components known for the same purpose for their combined additive effects, with a reasonable expectation of success absent evidence of criticality of the particular formulation. Additionally, “[T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Therefore, it would have been prima facie obvious to combine (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and mepolizumab cojointly in a formulation to treat asthma.
Regarding claims 31-32, when the composition recitations are met, the desired properties are met, as any component that materially affects the composition and its properties would have to be present in the claim to be commensurate in scope (i.e. claim 31). Additionally, when the composition is delivered in the same manner as claimed, the effects of the composition would be the same such as the therapeutic profile, as they are a direct result of the components of the composition and the mode of administration which are met by the art, whereby the resulting properties and effects would intrinsically be met. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01.
Response to Arguments
Applicant argues that “there is no objective reason to specifically select the species of Example 4, much less that a specific subgroup of patients, i.e., those having a high blood eosinophilic count before the treatment, would achieve a significant improvement when treated with the compound of formula (I).” The Examiner respectfully disagrees since Example 4 is an exemplified compound among a defined group of exemplary compounds, and one of ordinary skill in the art would have been motivated to select Example 4 as a lead compound.
Applicant also argues that “Gonzalez Lio is silent about the group of patients defined in the present set of claims. Unexpectedly applicant found that a specific subgroup of patients, i.e., those having a high blood eosinophilic count before the treatment, would achieve a significant improvement when treated with the compound of formula (I). In this respect, it is relevant that no other adenosine Al receptor antagonist has shown the same or a similar effect (such as an increase in FEVI) in a subgroup of patients having a pretreatment eosinophil count >300 cells/μL. Thus, the observed technical effect (i.e., a statistically significant decrease in FEVI) in patients with elevated blood eosinophil counts before initiating treatment with the compound of formula (I) was entirely unexpected.” The Examiner respectfully disagrees since Gonzalez Lio does teach that the entire patient population with COPD can be treated with the recited compound (see claims 1, 7, 9), which would include subpopulations such as those with an eosinophil count of >300 cells/μL as taught by Kostikas (pg. 1885, 6.1.1.; see Table 1). Additionally, Applicant has not provided a comparative basis of other adenosine A1 receptor antagonists with the recited compound regarding an improvement in treatment.
Applicant also argues that “Kostikas does not mention or suggest the use of the compound of formula (I) for the treatment of said group of patients, nor does it disclose the compound of formula (I).” The Examiner respectfully disagrees since Kostikas is relied on to demonstrate that eosinophil levels are commonly used as a biomarker in the treatment of asthma and COPD (see abstract). Here, Kostikas teaches an eosinophil level of 300 cel/μL as a predictor of asthma severity and improved outcomes (pg. 1885, 6.1.1.; see Table 1).
In response to applicant's 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).
Applicant also argues that “the outcomes from the clinical trials in the Declaration were consistent and unexpectedly revealed that not all individuals treated with the compound of formula (I) respond to said treatment in a similar manner.” The Examiner respectfully disagrees since although the Declaration establishes the efficacy of the compound of formula (I) in the improvement of pulmonary function (pp. 7-10, Declaration filed 10/20/2025), Applicant has not demonstrated that no other adenosine Al receptor antagonist has shown the same or a similar effect (such as an increase in FEVI) in a subgroup of patients having a pretreatment eosinophil count >300 cells/μL. One of ordinary skill in the art would expect that the compound of formula (I) would provide increased improvement in pulmonary function in patients with an eosinophil count >300 cells/μL, since Kostikas teaches that an eosinophil level of 300 cel/μL as a predictor of asthma severity and improved outcomes (pg. 1885, 6.1.1.; see Table 1).
Conclusion
Claims 23 and 25-34 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 ANDREW P LEE whose telephone number is (571)270-1016. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691