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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/04/2026 has been entered.
Status of the Application
Claims 23, 25-30, and 32-36 are pending.
Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on 06/04/2026 are acknowledged. Claims under consideration in the instant office action are claims 23, 25-30, and 32-36.
Applicants' arguments, filed 06/04/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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, 25-30, and 32-36 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 claim 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 32). 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 “the predictive value of blood eosinophils in Kostikas is mechanism-dependent, not a general property of airway-disease therapy. Every instance in which Kostikas reports that baseline eosinophils predict treatment response is tied to an agent that acts directly on the eosinophilic or Th2 inflammatory cascade including anti-IgE therapy (omalizumab), anti-IL5 therapies (mepolizumab, reslizumab, benralizumab), anti-IL4/IL13 therapy (dupilumab), and inhaled corticosteroids. Kostikas provides no example in which the eosinophil count predicts response to an agent acting outside that pathway. A selective adenosine Al receptor antagonist such as the compound of formula (I) acts by an entirely different mechanism, and Kostikas supplies no basis to expect that an eosinophil-defined subgroup would respond differentially to it.” The Examiner respectfully disagrees since although Kostikas discloses specific pathways to target eosinophil recruitment, Kostikas does teach eosinophilic inflammation is a common feature of asthma and COPD (see abstract), and “Several studies have examined the ability of baseline blood eosinophils to predict treatment response; others have assessed their potential as predictors of asthma severity or future exacerbations” (pg. 1885, right column, 2nd paragraph). Given that the claimed compound is known in the art to treat asthma and COPD as taught by Gonzalez Lio (see claim 9), it would have been obvious to one of ordinary skill in the art to utilize eosinophil levels as a biomarker for treatment.
Applicant also argues that “the threshold is not even transferable among the eosinophil-targeted agents themselves. The thresholds reported in Kostikas vary with the agent and study-approximately 150 cells/μL for mepolizumab, 400 cells/μL for reslizumab, 300 cells/μL for benralizumab, and others-and Kostikas expressly acknowledges that the appropriate threshold "remained a topic of debate" and required further refinement. If a single, transferable threshold cannot be identified even among biologics designed specifically to target eosinophilic inflammation, the prior art provides no rational basis to predict that 300 cells/μL would identify responders to a mechanistically unrelated small molecule.” The Examiner respectfully disagrees since although there are a number of baseline eosinophil levels that serve as a threshold as taught by Kostikas (pg. 1891, bridging paragraph), it would have been obvious to one of ordinary skill in the art to select a patient population wherein the eosinophil level is ≥ 300 cells/μL since such a level is commonly employed as an indicator of moderate to severe asthma and improved treatment response as taught by Kostikas (pp. 1890-1891, bridging paragraph; see pg. 1891, right column, 1st paragraph).
Applicant also argues that “Kostikas shows that the biomarker fails to stratify even within the anti-Th2 biologics. Kostikas reports that, unlike other agents targeting eosinophils, dupilumab produced benefit "not only in the subgroup of patients with ~00 cells/μL" but also in the overall population and in patients below that threshold (pg. 1891, 6.1.4). Thus, even an agent acting squarely on the Th2 pathway need not exhibit an eosinophil-defined differential response. This directly refutes any inference that an eosinophil cutoff would predictably define a responder population for the compound of formula (I).” The Examiner respectfully disagrees since efficacy of an active agent in other subgroups does not preclude other criteria for patient selection depending on other considerations. It would have been obvious to one of ordinary skill in the art to select a patient population wherein the eosinophil level is ≥ 300 cells/μL as discussed above.
Applicant also argues that “Kostikas would have discouraged the skilled artisan from expecting that selecting COPD patients by baseline eosinophil count would yield a differential pulmonary-function benefit-least of all with a previously untested adenosine Al antagonist.” The Examiner respectfully disagrees since it would have been obvious to one of ordinary skill in the art to select a patient population wherein the eosinophil level is ≥ 300 cells/μL as discussed above.
Applicant also argues that “The prior art was therefore entirely devoid of human clinical data from which a person of ordinary skill in the art could have predicted that an adenosine Al antagonist as a class - let alone a compound of formula (I) specifically - would significantly reduce blood eosinophils or improve lung function in subjects with an airway disease, let alone preferentially so in a subgroup defined by baseline blood eosinophil levels equal to or greater than 300 cells/μL.” The Examiner respectfully disagrees since the prior art is not required to disclose clinical data to teach or suggest a limitation of the claimed invention, and it would have been obvious to one of ordinary skill in the art to select a patient population wherein the eosinophil level is ≥ 300 cells/μL as discussed above.
Conclusion
Claims 23, 25-30, and 32-36 are rejected.
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
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