THERAPEUTIC FOR GOUT OR HYPERURICEMIA

§103 §112 §DP

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 Claims Claims 28-30, 35-41, 43-50 and 54 are pending in the instant application. Claims 29-30, 36-37 and 54 are withdrawn. Claims 28, 35, 38-41 and 43-50 are subject to examination herein. Priority Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/JP2020/022039, filed on 06/04/2020. Claim Interpretation Claim 35 is interpreted as further limiting the method of claim 28 to wherein a compound of instant formula (I) is present in an amorphous solid form, such that at least 80wt% of the compound in the solid form is amorphous. Claim 35 is not interpreted as a claim to a pure compound of instant formula (I) in amorphous form. Claim 35 is not interpreted as further limiting the method of claim 28 to wherein the pharmaceutical composition is a solid substance in which 80wt% of the substance consists of an amorphous compound of instant formula (I). Claim Rejections – Withdrawn The prior rejection of claims 28, 35, 38-41 and 43-50 under U.S.C. 103 as being unpatentable over Yoshida (U.S. Patent No. 7,598,254 B2) in view of Gunawardhana, Nasatto (Nasatto, et al.; Polymers, v7, pp777-803; 2015) and Friesen (Friesen, et al.; Molecular Pharmaceutics, v5, pp1003-1019; 2008) is withdrawn in response to Applicant’s amendment of claim 28. The prior rejection of claims 28, 35, 38-41 and 43-50 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 10-11 and 13 of U.S. Patent No. 7,598,254 B2 (hereafter referred to as “Yoshida”) in view of Gunawardhana (US 2014/0357683 A1), Nasatto (Nasatto, et al.; Polymers, v7, pp777-803; 2015) and Friesen (Friesen, et al.; Molecular Pharmaceutics, v5, pp1003-1019; 2008) is withdrawn in response to Applicant’s amendment of claim 28. 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. Claim 50 is 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. Claim 50 depends from claim 28, itself regarding a method for treating or preventing gout or hyperuricemia comprising administering the compound 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, and claim 50 requires that a daily dose of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof is not increased or is increased once within 7 weeks of the administration after the start of the administration; however, claim 28 already requires that a daily dose of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof is not increased or is increased once within 7 weeks of the administration after the start of the administration. Therefore, claim 50 does not further limit claim 28. Applicant may cancel the claim, amend the claim(s) to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim 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 28, 35, 38-41 and 43-50 are unpatentable over Yoshida in view of Gunawardhana, Nasatto, Friesen and Tanno. Claims 28, 35, 38-41 and 43-50 are rejected under 35 U.S.C. 103 as being unpatentable over Yoshida (U.S. Patent No. 7,598,254 B2) in view of Gunawardhana (U.S. PG Pub 2014/0357683 A1), Nasatto (Nasatto, et al.; Polymers, v7, pp777-803; 2015), Friesen (Friesen, et al.; Molecular Pharmaceutics, v5, pp1003-1019; 2008) and Tanno (Tanno, et al.; Drug Development and Industrial Pharmacy, v30, pp9-17; 2004). Claim 28 is drawn to a method of treating a human subject in need of treatment for gout or hyperuricemia comprising: comprising orally administering a pharmaceutical composition comprising Applicant’s Compound 141 in an amount of 10-320 mg for at least 7 days; wherein a daily dose of Applicant’s Compound 14 is not increased or is increased only once or less within 7 weeks from the start of the administration; wherein the pharmaceutical composition achieves particular results in the lowering of blood uric acid concentration after the first and seventh days, respectively, as measured in percentage relative to the initial concentration of blood uric acid. Applicant has chosen to use functional language to present the amount of compound to be included in a pharmaceutical composition. Applicant’s Specification indicates, on page 106, that the composition that achieves the results of claim 28 is a composition of 80 mg of “compound 14” (i.e., Yoshida’s “Example 48”) in “Example Formulation 1”, which is shown on page 107 of the Specification to be a solid dispersion using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the carrier. The Specification indicates on page 106 that the results of the administration of this composition are shown in Figure 9 of the application’s included drawings, shown here: PNG media_image1.png 418 636 media_image1.png Greyscale As shown in the Figure 9, blood uric acid was diminished by about 1 mg/dL on day 1 and by about 2 mg/dL on Day 7. The Specification discloses that these results correspond to a maximum rate of decrease in a blood uric acid level of about 17% after the first 12 hours of administration and a maximum blood uric acid level of about 30% after the seventh day of administration (page 106). Thus, the solid dispersion incorporating HPMCAS as the carrier and Yoshida’s “Example 48” as the xanthine oxidase inhibitor is the composition indicated by Applicant via the Specification for claim 28. Yoshida discloses an invention of “an agent for treating hyperuricemia”2 in the form of a family of oxazolo- and thiazolo-hydroxypyrimidines, including Applicant’s Compound 14, identified by Yoshida as “Example 48”3, and the potassium salt of this compound4, identified by Yoshida as “Example 49”: Claim Number(s) of Instant Application Instant Application Yoshida 28 PNG media_image2.png 204 404 media_image2.png Greyscale PNG media_image3.png 240 394 media_image3.png Greyscale (Example 48) 28 PNG media_image2.png 204 404 media_image2.png Greyscale PNG media_image4.png 242 400 media_image4.png Greyscale (Example 49) Yoshida discloses that the compounds disclosed therein are inhibitors of xanthine oxidase (Col 1, lines 5-10). Yoshida further discloses that the compounds “are employable for preventing or treating hyperuricemia and gout” and that the “compound of the invention can be administered into human beings by appropriate administration methods such as oral administration and parenteral administration” (Col 16, lines 62-67). While Yoshida discloses a range of dosages of “approximately 1 to 2,000 mg/day when it is orally administered” (Col. 17, lines 12-16), Yoshida does not specify a narrower dosage range or specific dosage within 10-320 mg, and does not specify that the treatment should be provided for a period of at least 7 days. Furthermore, while Yoshida discloses that the compounds disclosed therein can be formulated in a variety of known pharmaceutical formulations, including granules and powders (Col 17, lines 1-4), Yoshida does not specify an amorphous solid dispersion formulation based on HPMCAS as the as the carrier for a xanthine oxidase inhibitor compound disclosed therein; however, a person of ordinary skill in the art would have a reasonable expectation of success in arriving at the claimed dosage, dosing interval, and amorphous dispersion formulation comprising HPMCAS as the carrier, and because methods for finding safe and efficacious formulation(s) and dosage(s) are known in the prior art: Methods for evaluation of dosages and formulations of a xanthine oxidase inhibitor with structural similarities to the compounds of the instant application, in patients having hyperuricemia, are known in the art, per the disclosure of Gunawardhana; The superior utility of hyperuricemia medication(s) formulated for modified release rather than immediate release, including formulations incorporating enteric polymers, was known in the art, per the disclosure of Gunawardhana; Compound(s) disclosed by Yoshida including Yoshida’s “Example 48” have poor water solubility, as evidenced by Yoshida’s disclosure of the need to suspend such a compound in a 1% solution of methylcellulose, a substance known for its ability to hold particles of water insoluble compounds in suspension, per the teaching of Nasatto; Spray-dried solid amorphous dispersions incorporating HPMCAS are known in the art as a proven method for improving bioavailability of molecular drug compounds, per the teaching of Friesen; HPMCAS was known in the art as an enteric polymer that is useful as a carrier in solid dispersions, per the teaching of Tanno; and Because the evaluation of safe and efficacious formulations for oral administration of drugs for hyperuricemia was known in the art, per the disclosure of Gunawardhana. Gunawardhana discloses the treatment of hyperuricemia at a variety of dosages, regimens, and formulations of febuxostat, a known xanthine oxidase inhibitor with structural similarities to the instant Formula (I). Gunawardhana evaluates febuxostat dosages from 10-240 mg at dosing frequencies of once or twice a day, in formulations of immediate and/or modifed release (“IR” for immediate release vs. “XR” for extended release, respectively), and in escalating versus non-escalating dosing regimens, across result parameters including pharmacokinetics (Table 13), plasma uric acid (Tables 3-4, occurrence of gout flares (Table 5) and percent reduction in serum urate from baseline (Table 10). Gunawardhana further discloses that the method of treatment utilizes an “initial period of administration” of variable time duration but at a minimum consisting of at least 2 weeks (paragraphs [0081] and [0111]), and additionally discloses that the methods of treatment disclosed therein are applicable to the compounds disclosed by Yoshida (paragraph [0116]). The central tenets of Gunawardhana’s disclosure are that (1) establishing and maintaining a sufficiently efficacious concentration of febuxostat over a sustained period of time provides similar efficacy in treating hyperuricemia compared to high doses of the drug (paragraph [0011]), and that (2) the drug formulation affects the drug’s pharmacodynamic behavior: “For example, an 80 mg dose of febuxostat delivered in a modified release formulation will reduce gout flares compared to an 80 mg dose of febuxostat delivered in an immediate release formulation” (paragraph [0052]). For febuxostat, as shown in the example below, achieving a steady efficacious dose is achieved by blunting the initial absorption of the drug via formulation of the drug into a mixture of immediate-release and delayed-release formulations. Thus, the dose and dosing regimen are determined in the context of appropriate formulation of the drug to achieve the desired treatment response. A particular example among Gunawardhana’s disclosures is “Example 3”, a “randomized double blind, multicenter, active-controlled study to evaluate the efficacy and safety of febuxostat 80 XR5, 40 mg XR, 80 mg IR6 and 40 mg IR in subjects with gout is designed and performed” (paragraph [0271]). A total of 200 subjects were included (paragraph [0272]). Patients had their blood drawn for measurements of serum urate (sUA) and estimated glomerular filtration rate (eGFR). Subjects started with a serum urate level >0.7 mg/dL at day -4 and an estimated glomerular filtration rate (eGFR) of ≥30 mL/min and ≤60 mL/min on day -21 for patients already on urate lowering therapy,7 whereas the same target was checked for patients not already on urate therapy on day -4 (paragraph [0274]). Patients had visits at Week 2, Month 1, 2, and 3 (final visit) for such checks, although patients were not informed of their sUA levels after the Day 4 visit (paragraph [0280]). Patients self-reported occurrences of pregnancy and adverse effects (paragraph [0281]). Patients self-administered febuxostat once daily in oral form (paragraph [0282]). Endpoints of the study included the following (paragraphs [0284-0286]): Proportion of subjects whose serum rate level is <0.6 mg/dL at Month 3 visit. Comparison of results for 40 and 80 mg XR vs. 40 and 80 mg IR. Percent reduction from baseline to Month 3 in serum rate. Percentage of subjects with gout flares. The “Example 3” study shows how routine experimentation serves to evaluate results such as efficacy (reduction of sUA) and safety (gout flares and other adverse events potentially reported). Gunawardhana further discloses “Example 4” (paragraphs [0293-0296]), wherein safety and efficacy were evaluated in the context of administering febuxostat in dose-escalating regimen with immediate release (IR) tablets in dosages of 10-20-40 mg compared to a non-dose-escalating regimen using extended release (XR) tablets of febuxostat 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. The study found that safety of the febuxostat XR tablets in the dosages listed above is within the permissible range and the proportion of subjects whose serum urate level is <6.0 mg/dL for patients dosing with the XR dosages in the non-dose-escalating regimen is almost the same or higher than that in the febuxostat 10-20-40 mg IR dose-escalating treatment regimen. Gunawardhana further discloses a variety of modified release dosage forms, including formulations that include enteric coating (paragraph [0165]), including “microencapsulation” wherein the coating is done on beads or particles containing the drug product rather than an enteric capsule, providing a drug that is “gradually released. . . into the gastrointestinal tract and provides the desired controlled release of the drug” (paragraph [0170]). Thus, Gunawardhana discloses that sustained release of a hyperuricemic drug by a drug formulation provides a superior therapy to a formulation providing immediate release, discloses formulations that provide sustained release, including formulations comprising an enteric polymer, and discloses methods for the evaluation of hyperuricemic drug formulations for safety and efficacy. Yoshida does not disclose the formulation of their compounds into a solid dispersion comprising HPMCAS; however, Yoshida’s in vitro assay for xanthine oxidase inhibition requires the initial dissolution of the test compound, in dimethylsulfoxide prior to dilution into the aqueous buffer used in the assay (Example 50, Col 41, lines 33-36). The use of dimethylsulfoxide, a polar aprotic organic solvent, rather than water, to pre-dissolve the compound evidences that the compounds are not highly soluble in water. Additionally, Yoshida’s in vivo assay for xanthine oxidase inhibition requires that the test compound is “suspended” (not dissolved) in a 1% methylcellulose aqueous solution prior to administration to the rodent subjects used in the assay. Nasatto teaches a review of methylcellulose (MC), including its properties and applications, and Nasatto specifically teaches that “MC solutions enable the control of the settling of solid particles in dispersion, avoiding sedimentation. MCs have a protective colloid effect against droplets or particles agglomeration. MCs also stabilize emulsions and foams due to their surface and interfacial tensions.” Nasatto further teaches that “MC being an amphiphilic polymer is a binder for many types of systems: pigments, cellulosic fibers, pharmaceutical products, ceramics, and others.” Thus the teaching of Nasatto evidences that the suspension of the compounds of Yoshida in a methylcellulose solution is indicative of inadequate water solubility of Yoshida’s compounds to be dissolved in aqueous solution without an agent to support their solubility. Friesen teaches that “amorphous solids and solid dispersions” are among a variety of solubilization techniques developed to enhance the oral bioavailability of molecular drugs (page 1004). Friesen elaborates on the properties and advantage of solid, spray-dried amorphous dispersions, showing the following attributes:8 Enhance the oral absorption of poorly water-soluble compounds by attaining and sustaining a supersaturated concentration of drug in the gastrointestinal (GI) fluid; Provide a physically stable drug form (avoiding crystallization or phase separation of amorphous drug) that enables processing of the dispersion into solid dosage forms for shipment and usage; Provide a solid drug form that can be manufactured via a reproducible, controllable, and scalable process; Provide a technology that is applicable to structurally diverse insoluble compounds across a wide range of physicochemical properties. Friesen further teaches the reasons why HPMCAS is a particularly suitable polymer for use as a binder in solid, spray-dried amorphous dispersions (SDDs):9 HPMCAS has a high Tg (glass transition temperature) in its un-ionized state. This high Tg directly correlates to the drug having low mobility, which is responsible for the excellent physical stability of HPMCAS SDDs. HPMCAS is highly soluble in volatile organic solvents, such as acetone and methanol, allowing for economical and controllable processes for forming SDDs. When at least partially ionized, as it is at any pH above about 5, the charge on the polymer minimizes formation of large polymer aggregates, allowing drug/polymer colloids (for example, amorphous nanostructures) to remain stable. The amphiphilic nature of HPMCAS allows insoluble drug molecules to interact with the hydrophobic regions of the polymer, whereas the hydrophilic regions allow these structures to remain as stable colloids in aqueous solution. Friesen teaches the methods for preparing SDDs based on HPMCAS (page 1009). Friesen shows that powder x-ray diffraction of four different drug compounds rendered into amorphous SDDs based on HPMCAS exhibit >95 wt% amorphous character in each SDD.10 Tanno teaches an evaluation of HPMCAS as a carrier in solid dispersions in comparison to other candidate polymers including hypromellose, hypromellose phthalate, methacrylic acid ethyl acrylate copolymer and povidone, using nifedipine as an exemplary drug compound (Abstract). Tanno teaches that HPMCAS is an enteric coating agent (Abstract). Tanno tests the dissolution of nifedipine from solid dispersions mixed into simulated gastric (pH 1.2), simulated intestinal (pH 6.8) and unbuffered water solutions (page 11, section: “Dissolution Study” and page 15, Figure 6), and shows that formulation into HPMCAS solid dispersion results in much higher dissolution in intestinal solution than in gastric solution or in unbuffered water. A person of ordinary skill in the art would understand from the teachings of Friesen and Tanno that HPMCAS, a known enteric polymer useful in solid dispersion formulations, can provide both the delayed absorption recommended by Gundawardhana and an improved solubility that Yoshida’s disclosure indicates as needed to support dissolution of Yoshida’s compounds. Applicant’s invention is unpatentable over the disclosure of Yoshida in view of the disclosure of Gundawardhana and the teachings of Nasatto, Friesen and Tanno, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in in treating hyperuricemia in a patient in need thereof by administering a pharmaceutical composition comprising Yoshida’s compound 48 (i.e., Applicant’s Compound 14) in an amorphous dispersion comprising HPMCAS as the solid carrier at the claimed dosage and dosing regimen, for the following reasons: Because the safe and efficacious dosage and dosing regimen of a xanthine oxidase inhibitor are result-effective variables, and the determination of these result-effective variables was known in the art per the disclosure of Gunawardhana; and it was known in the art that a drug given for treating hyperuricemia and formulated in a modified/delayed release at sufficiently efficacious concentration provides similar efficacy compared to higher doses of the drug, per the disclosure of Gundawardhana; Because the safe and efficacious formulation of a poorly water-soluble drug for oral administration is a result-effective variable, and it was known in the art that Yoshida’s compound 48 is a poorly water-soluble drug, per the disclosure of Yoshida and the teaching of Nasatto; and it was known in the art that amorphous solid dispersions based on HPMCAS as the carrier are a safe and efficacious formulation for poorly water-soluble drugs, per the teachings of Friesen; and it was known in the art that HPMCAS is an enteric polymer that, when formulated with a drug compound into a solid dispersion, provides greater intestinal than gastric dissolution of a drug compound, and thus constitutes a delayed release formulation, per the teaching of Tanno; and because the evaluation of drug formulations for safety and efficacy, specifically for patients with hyperuricemia, was known in the art, per the methods disclosed by Gunawardhana. Thus, the invention was prima facie obvious at the time of filing. Claim 35 further limits the method of claim 28 to wherein the instant Compound 14 is present in an amorphous solid form, such that at least 80wt% of the compound in the solid form is amorphous (i.e., not crystalline), and is met by the rejection above. Claim 38 further limits the method of claim 28 to the administration of a pharmaceutical composition that is a solid dispersion containing a hypromellose derivative, and is met by the rejection above. Claim 39 further limits the method of claim 38 to wherein the weight ratio of the instant Compound 14 to hypromellose is from 1:0.1 to 1:25, and is met by the rejection above. Claim 40 further limits the method of claim 38 to wherein the hypromellose derivative is hypromellose acetate succinate, and is met by the rejection above. Claim 41 further limits the method of claim 28 to the administration of a pharmaceutical composition that is a solid preparation, and is met by the rejection above. Claims 43-46 further limit the method of claim 28, each to a pharmaceutical composition that includes a distinct range of allowable quantity of the active agent, and each including Applicant’s elected quantity of 80 mg, and each is met by the rejection above. Claims 47 and 48 further limit the method of claim 28 to the administration of a pharmaceutical composition that achieves particular results in the lowering of blood uric acid concentration after the first and seventh days, respectively, as measured in milligrams/deciliter (mg/dL) units of blood uric acid, and each is met by the rejection above. Claims 49 and 50 depend from claim 28 and require that the daily dose is not escalated within 3 weeks of administration after the start of administration (claim 49) or is not increased or is increased only once within 7 weeks after the start of the administration (claim 50), and each is met by the rejection above. Applicant’s invention is unpatentable over the disclosure of Yoshida in view of the disclosure of Gunawardhana and the teachings of Nasatto and Friesen because a person of ordinary skill in the art would have a reasonable expectation of success in treating hyperuricemia in a patient in need thereof by administering a pharmaceutical composition comprising Yoshida’s compound 48 (i.e., Applicant’s Compound 14) in an amorphous dispersion comprising HPMCAS as the solid carrier at the claimed dosage and dosing regime, for the following reasons: because the safe and efficacious dosage and dosing regimen of a xanthine oxidase inhibitor are result-effective variables, and the determination of these result-effective variables was known in the art per the disclosure of Gunawardhana; because the utility of modified release drug formulations in hyperuricemia treatment, including with enteric polymers for delayed release, was known in the art per the disclosure of Gundawardhana; because the safe and efficacious formulation of a poorly water-soluble drug for oral administration is a result-effective variable, and Yoshida’s compound 48 was readily recognizable as a poorly water-soluble drug per the disclosure of Yoshida and the teaching of Nasatto; because the effective formulation of poorly-water soluble drugs via amorphous dispersion using HPMCAS as the carrier was known in the art per the teaching of Friesen; because the utility of HPMCAS as an enteric polymer was known in the art per the teaching of Tanno; and because the evaluation of safe and efficacious formulation of drugs for patients with hyperuricemia was known in the art per the disclosure of Gunawardhana. Thus, the invention was prima facie obvious at the time of filing. Double Patenting The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. Claims 28, 35 and 38-41 and 43-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 10-11 and 13 of U.S. Patent No. 7,598,254 B2 (hereafter referred to as “Yoshida”) in view of Gunawardhana (US 2014/0357683 A1), Nasatto (Nasatto, et al.; Polymers, v7, pp777-803; 2015), Friesen (Friesen, et al.; Molecular Pharmaceutics, v5, pp1003-1019; 2008) and Tanno (Tanno, et al.; Drug Development and Industrial Pharmacy, v30, pp9-17; 2004). The limitations of claims 28, 35 and 38-41 and 43-50, the disclosures of Yoshida and Gunawardhana, and the teachings of Nasatto, Friesen and Tanno are discussed in the rejection above and hereby incorporated into the instant rejection. Claim 13 of Yoshida is drawn to “An agent for treating hyperuricemia containing as an active ingredient a compound or a salt thereof according to claim 1 and a suitable excipient or diluent.” Claim 1 of Yoshida describes a genus of thiazolopyrimidines, designated as “formula (I)” with additional substituents and limitations and encompasses instant Compound 1411 as shown in the table below: Claim Number(s) of Instant Application Instant Application Yoshida, formula (I) of claim 1: 28 PNG media_image2.png 204 404 media_image2.png Greyscale PNG media_image5.png 214 606 media_image5.png Greyscale wherein: Claims 4-8 and 10-11 of Yoshida significantly narrow the genus of Yoshida’s formula (I), including limiting the reference genus to only thiazolopyrimidine compounds, requiring the hydroxyl group at the 7-position12, requiring the X position to be an oxygen atom, requiring the R1 group to be a phenyl group, and limiting the substituent at R2 to cyano and/or nitro. While reference claim 13 of Yoshida does not include limitations or steps on how to use an “agent for treating hyperuricemia” with regard to the dosage and dosing regimen requirements of instant claim 28 (e.g., 10-320 mg/day, for at least 7 days, not increased or increased only once or less within 7 weeks from the start), and does not include dosing and formulation requirements that achieve the claimed results of instant claim 28 (i.e., an 80 mg daily dose of an amorphous dispersion using HPMCAS as the carrier), a person of ordinary skill in the art would have a reasonable expectation of success in administering a compound disclosed by Yoshida at the instantly claimed dose and dosing regimen, for the following reasons: Methods for evaluation of dosages and formulations of a xanthine oxidase inhibitor with structural similarities to the compounds of the instant application, in patients having hyperuricemia, are known in the art, per the disclosure of Gunawardhana; The superior utility of hyperuricemia medication(s) formulated for modified release rather than immediate release, including formulations incorporating enteric polymers, was known in the art, per the disclosure of Gunawardhana; Compound(s) disclosed by Yoshida including Yoshida’s “Example 48” have poor water solubility, as evidenced by Yoshida’s disclosure of the need to suspend such a compound in a 1% solution of methylcellulose, a substance known for its ability to hold particles of water insoluble compounds in suspension, per the teaching of Nasatto; Spray-dried solid amorphous dispersions incorporating HPMCAS are known in the art as a proven method for improving bioavailability of molecular drug compounds, per the teaching of Friesen; HPMCAS was known in the art as an enteric polymer that is useful as a carrier in solid dispersions, per the teaching of Tanno; and Because the evaluation of safe and efficacious formulations for oral administration of drugs for hyperuricemia was known in the art, per the disclosure of Gunawardhana. Gunawardhana discloses the treatment of hyperuricemia at a variety of dosages, regimens, and formulations of febuxostat, a known xanthine oxidase inhibitor with structural similarities to the instant Formula (I). Gunawardhana evaluates febuxostat dosages from 10-240 mg at dosing frequencies of once or twice a day, in formulations of immediate and/or modifed release (“IR” for immediate release vs. “XR” for extended release, respectively), and in escalating versus non-escalating dosing regimens, across result parameters including pharmacokinetics (Table 13), plasma uric acid (Tables 3-4, occurrence of gout flares (Table 5) and percent reduction in serum urate from baseline (Table 10). Gunawardhana further discloses that the method of treatment utilizes an “initial period of administration” of variable time duration but at a minimum consisting of at least 2 weeks (paragraphs [0081] and [0111]), and additionally discloses that the methods of treatment disclosed therein are applicable to the compounds disclosed by Yoshida (paragraph [0116]). The central tenets of Gunawardhana’s disclosure are that (1) establishing and maintaining a sufficiently efficacious concentration of febuxostat over a sustained period of time provides similar efficacy in treating hyperuricemia compared to high doses of the drug (paragraph [0011]), and that (2) the drug formulation affects the drug’s pharmacodynamic behavior: “For example, an 80 mg dose of febuxostat delivered in a modified release formulation will reduce gout flares compared to an 80 mg dose of febuxostat delivered in an immediate release formulation” (paragraph [0052]). For febuxostat, as shown in the example below, achieving a steady efficacious dose is achieved by blunting the initial absorption of the drug via formulation of the drug into a mixture of immediate-release and delayed-release formulations. Thus, the dose and dosing regimen are determined in the context of appropriate formulation of the drug to achieve the desired treatment response. A particular example among Gunawardhana’s disclosures is “Example 3”, a “randomized double blind, multicenter, active-controlled study to evaluate the efficacy and safety of febuxostat 80 XR13, 40 mg XR, 80 mg IR14 and 40 mg IR in subjects with gout is designed and performed” (paragraph [0271]). A total of 200 subjects were included (paragraph [0272]). Patients had their blood drawn for measurements of serum urate (sUA) and estimated glomerular filtration rate (eGFR). Subjects started with a serum urate level >0.7 mg/dL at day -4 and an estimated glomerular filtration rate (eGFR) of ≥30 mL/min and ≤60 mL/min on day -21 for patients already on urate lowering therapy,15 whereas the same target was checked for patients not already on urate therapy on day -4 (paragraph [0274]). Patients had visits at Week 2, Month 1, 2, and 3 (final visit) for such checks, although patients were not informed of their sUA levels after the Day 4 visit (paragraph [0280]). Patients self-reported occurrences of pregnancy and adverse effects (paragraph [0281]). Patients self-administered febuxostat once daily in oral form (paragraph [0282]). Endpoints of the study included the following (paragraphs [0284-0286]): Proportion of subjects whose serum rate level is <0.6 mg/dL at Month 3 visit. Comparison of results for 40 and 80 mg XR vs. 40 and 80 mg IR. Percent reduction from baseline to Month 3 in serum rate. Percentage of subjects with gout flares. The “Example 3” study shows how routine experimentation serves to evaluate results such as efficacy (reduction of sUA) and safety (gout flares and other adverse events potentially reported). Gunawardhana further discloses “Example 4” (paragraphs [0293-0296]), wherein safety and efficacy were evaluated in the context of administering febuxostat in dose-escalating regimen with immediate release (IR) tablets in dosages of 10-20-40 mg compared to a non-dose-escalating regimen using extended release (XR) tablets of febuxostat 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. The study found that safety of the febuxostat XR tablets in the dosages listed above is within the permissible range and the proportion of subjects whose serum urate level is <6.0 mg/dL for patients dosing with the XR dosages in the non-dose-escalating regimen is almost the same or higher than that in the febuxostat 10-20-40 mg IR dose-escalating treatment regimen. Gunawardhana further discloses a variety of modified release dosage forms, including formulations that include enteric coating (paragraph [0165]), including “microencapsulation” wherein the coating is done on beads or particles containing the drug product rather than an enteric capsule, providing a drug that is “gradually released. . . into the gastrointestinal tract and provides the desired controlled release of the drug” (paragraph [0170]). Thus, Gunawardhana discloses that sustained release of a hyperuricemic drug by a drug formulation provides a superior therapy to a formulation providing immediate release, discloses formulations that provide sustained release, including formulations comprising an enteric polymer, and discloses methods for the evaluation of hyperuricemic drug formulations for safety and efficacy. Yoshida does not disclose the formulation of their compounds into a solid dispersion comprising HPMCAS; however, Yoshida’s in vitro assay for xanthine oxidase inhibition requires the initial dissolution of the test compound, in dimethylsulfoxide prior to dilution into the aqueous buffer used in the assay (Example 50, Col 41, lines 33-36). The use of dimethylsulfoxide, a polar aprotic organic solvent, rather than water, to pre-dissolve the compound evidences that the compounds are not highly soluble in water. Additionally, Yoshida’s in vivo assay for xanthine oxidase inhibition requires that the test compound is “suspended” (not dissolved) in a 1% methylcellulose aqueous solution prior to administration to the rodent subjects used in the assay. Nasatto teaches a review of methylcellulose (MC), including its properties and applications, and Nasatto specifically teaches that “MC solutions enable the control of the settling of solid particles in dispersion, avoiding sedimentation. MCs have a protective colloid effect against droplets or particles agglomeration. MCs also stabilize emulsions and foams due to their surface and interfacial tensions.” Nasatto further teaches that “MC being an amphiphilic polymer is a binder for many types of systems: pigments, cellulosic fibers, pharmaceutical products, ceramics, and others.” Thus the teaching of Nasatto evidences that the suspension of the compounds of Yoshida in a methylcellulose solution is indicative of inadequate water solubility of Yoshida’s compounds to be dissolved in aqueous solution without an agent to support their solubility. Friesen teaches that “amorphous solids and solid dispersions” are among a variety of solubilization techniques developed to enhance the oral bioavailability of molecular drugs (page 1004). Friesen elaborates on the properties and advantage of solid, spray-dried amorphous dispersions, showing the following attributes:16 Enhance the oral absorption of poorly water-soluble compounds by attaining and sustaining a supersaturated concentration of drug in the gastrointestinal (GI) fluid; Provide a physically stable drug form (avoiding crystallization or phase separation of amorphous drug) that enables processing of the dispersion into solid dosage forms for shipment and usage; Provide a solid drug form that can be manufactured via a reproducible, controllable, and scalable process; Provide a technology that is applicable to structurally diverse insoluble compounds across a wide range of physicochemical properties. Friesen further teaches the reasons why HPMCAS is a particularly suitable polymer for use as a binder in solid, spray-dried amorphous dispersions (SDDs):17 HPMCAS has a high Tg (glass transition temperature) in its un-ionized state. This high Tg directly correlates to the drug having low mobility, which is responsible for the excellent physical stability of HPMCAS SDDs. HPMCAS is highly soluble in volatile organic solvents, such as acetone and methanol, allowing for economical and controllable processes for forming SDDs. When at least partially ionized, as it is at any pH above about 5, the charge on the polymer minimizes formation of large polymer aggregates, allowing drug/polymer colloids (for example, amorphous nanostructures) to remain stable. The amphiphilic nature of HPMCAS allows insoluble drug molecules to interact with the hydrophobic regions of the polymer, whereas the hydrophilic regions allow these structures to remain as stable colloids in aqueous solution. Friesen teaches the methods for preparing SDDs based on HPMCAS (page 1009). Friesen shows that powder x-ray diffraction of four different drug compounds rendered into amorphous SDDs based on HPMCAS exhibit >95 wt% amorphous character in each SDD.18 Tanno teaches an evaluation of HPMCAS as a carrier in solid dispersions in comparison to other candidate polymers including hypromellose, hypromellose phthalate, methacrylic acid ethyl acrylate copolymer and povidone, using nifedipine as an exemplary drug compound (Abstract). Tanno teaches that HPMCAS is an enteric coating agent (Abstract). Tanno tests the dissolution of nifedipine from solid dispersions mixed into simulated gastric (pH 1.2), simulated intestinal (pH 6.8) and unbuffered water solutions (page 11, section: “Dissolution Study” and page 15, Figure 6), and shows that formulation into HPMCAS solid dispersion results in much higher dissolution in intestinal solution than in gastric solution or in unbuffered water. A person of ordinary skill in the art would understand from the teachings of Friesen and Tanno that HPMCAS, a known enteric polymer useful in solid dispersion formulations, can provide both the delayed absorption recommended by Gundawardhana and an improved solubility that Yoshida’s disclosure indicates as needed to support dissolution of Yoshida’s compounds. Applicant’s invention is unpatentable over the disclosure of Yoshida in view of the disclosure of Gundawardhana and the teachings of Nasatto, Friesen and Tanno, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in in treating hyperuricemia in a patient in need thereof by administering a pharmaceutical composition comprising Yoshida’s compound 48 (i.e., Applicant’s Compound 14) in an amorphous dispersion comprising HPMCAS as the solid carrier at the claimed dosage and dosing regimen, for the following reasons: Because the safe and efficacious dosage and dosing regimen of a xanthine oxidase inhibitor are result-effective variables, and the determination of these result-effective variables was known in the art per the disclosure of Gunawardhana; and it was known in the art that a drug given for treating hyperuricemia and formulated in a modified/delayed release at sufficiently efficacious concentration provides similar efficacy compared to higher doses of the drug, per the disclosure of Gundawardhana; Because the safe and efficacious formulation of a poorly water-soluble drug for oral administration is a result-effective variable, and it was known in the art that Yoshida’s compound 48 is a poorly water-soluble drug, per the disclosure of Yoshida and the teaching of Nasatto; and it was known in the art that amorphous solid dispersions based on HPMCAS as the carrier are a safe and efficacious formulation for poorly water-soluble drugs, per the teachings of Friesen; and it was known in the art that HPMCAS is an enteric polymer that, when formulated with a drug compound into a solid dispersion, provides greater intestinal than gastric dissolution of a drug compound, and thus constitutes a delayed release formulation, per the teaching of Tanno; and because the evaluation of drug formulations for safety and efficacy, specifically for patients with hyperuricemia, was known in the art, per the methods disclosed by Gunawardhana. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice. /W.J.Y./Examiner, Art Unit 1629 /JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629 1 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine 2 Col. 3, lines 4-6. 3 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine – see Col 40, lines 50-67. 4 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine potassium salt– see Col 41, lines 1-23. 5 Extended release formulation. 6 Immediate release formulation. 7 Indicating moderate renal impairment. Renal impairment is common among patients with hyperuricemia. – see paragraph [0175]. 8 Page 1005. 9 Page 1008. 10 See “Solid-State Properties” section on page 1010 and Figure 3 on page 1011. 11 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine 12 N.b., The compound numbering system in Yoshida differs from the instant number system in that the 4-position of structures in Yoshida matches to the 7-position in the numbering of the instant application. This is because in Yoshida the structure is numbered starting at the “Y” atom as 1 and going clockwise around the bicyclic ring core, whereas in the instant application the compounds are numbered starting at the Nitrogen atom of the oxazolo or thiazolo ring and proceeding counterclockwise around the core structure. 13 Extended release formulation. 14 Immediate release formulation. 15 Indicating moderate renal impairment. Renal impairment is common among patients with hyperuricemia. – see paragraph [0175]. 16 Page 1005. 17 Page 1008. 18 See “Solid-State Properties” section on page 1010 and Figure 3 on page 1011.