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 Claims 29-30, 36-37 and 54 are withdrawn pursuant to a prior Election of Species. 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Claim Rejections - 35 USC § 112(d) – Withdrawn
The prior rejection of claim 42 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the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is withdrawn in response to Applicant’s cancellation of claim 42.
Claim Rejections - 35 USC § 103 – Withdrawn
The prior rejection of claims 28, 41-46 and 49-50 under 35 U.S.C. 103 as being unpatentable over Yoshida (Yoshida, et al.; US Patent 7,598,254 B2) in view of Gunawardhana (Gunawardhana, et al.; US 2014/0357683 A1) is withdrawn in response to Applicant’s amendment of claim 28 and cancellation of claim 42.
The prior rejection of claims 28, 35 and 38-52 under 35 U.S.C. 103 as being unpatentable over Yoshida in view of Gunawardhana and further in view of 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et al.; Polymers, v7, pp777-803; 2015) and Friesen (Friesen, et al.; Molecular Pharmaceutics, v5, pp1003-1019; 2008) is withdrawn in response to Applicant’s amendment of claim 28 and cancellation of claims 42 and 51-52.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
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 and Friesen.
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, Nasatto (Nasatto, et al.; Polymers, v7, pp777-803; 2015) and Friesen (Friesen, et al.; Molecular Pharmaceutics, v5, pp1003-1019; 2008).
Claim 28 is drawn to a method of treating a human subject in need of treatment for gout or hyperuricemia comprising orally administering a pharmaceutical composition comprising Applicant’s Compound 141 in an amount of 10-320 mg for at least 7 days, and 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:
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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:
Claim Number(s) of Instant Application
Instant Application
Yoshida
(Example 48)
28
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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 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, because these are all result-effective variables, 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;
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; 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 extended release (“IR” vs. “XR”, 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 XR4, 40 mg XR, 80 mg IR5 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,6 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 discloses two types of formulated febuxostat that can be mixed in varying proportion to achieve modified release/absorption of the drug:
“Immediate release” (IR) formulation, wherein the drug is admixed with hypromellose (hydroxypropyl methylcellulose) and the mixture is coated onto sugar spheres;
“Delayed release” (DR) formulation, wherein the IR beads are enterically coated with a pH dependent polymer: “methacrylic acid copolymer”.
Gunawardhana prepares “extended release” (XR) capsules containing a mixture of the IR and DR beads, and studies the safety and efficacy of dosing this formulation in the “Example 3” study discussed in the rejection above. Thus Gunawardhana shows that formulated pharmaceutical compositions can be studied for safety and efficacy. Although Gunawardhana does not employ a solid dispersion comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), a person of ordinary skill in the art would have a reasonable expectation of success in studying any formulation of a xanthine oxidase inhibitor following the example shown by Gunawardhana.
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, including Example 48 discussed in the rejections above, 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 compound is 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:7
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):8
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.9
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 an amount of 80 mg/day for a period of at least 7 days, 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 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 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 further limit the method of claim 28 to 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 an amount of 80 mg/day for a period of at least 7 days, 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 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, and 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 and 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 – Withdrawn
The prior rejection of claim 28 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) is withdrawn in response to Applicant’s amendment of claim 28.
The prior rejection of claims 28 and 38-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-9, and 11-13 of U.S. Patent No. 11,234,984 B2 (hereafter referred to as “Itai”) in view of Gunawardhana (US 2014/0357683 A1) is withdrawn in response to Applicant’s amendment of claim 28.
Double Patenting – Necessitated by Amendment
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) and Friesen (Friesen, et al.; Molecular Pharmaceutics, v5, pp1003-1019; 2008).
The limitations of claims 28, 35 and 38-50 and the disclosure of Gunawardhana and the teachings of Nasatto and Friesen 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 1410 as shown in the table below:
Claim Number(s) of Instant Application
Instant Application
Yoshida, formula (I) of claim 1:
28
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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-position11, 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), 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 in an amount within 80 mg/day for a period of at least 7 days, for the following reasons:
Because safe and efficacious dose and dosing regimen are result-effective variables, and the determination of safe and efficacious dose and dosing regimen were known in the art at the effective time of filing, per the disclosure of Gunawardhana;
Because a person of ordinary skill in the art would recognize the poor water-solubility of Yoshida’s compounds, including Yoshida’s compound 48 corresponding to the compound of instant claim 28, per the disclosure of Yoshida and the teaching of Nasatto;
Because 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; 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 extended release (“IR” vs. “XR”, 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 XR12, 40 mg XR, 80 mg IR13 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,14 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 discloses two types of formulated febuxostat that can be mixed in varying proportion to achieve modified release/absorption of the drug:
“Immediate release” (IR) formulation, wherein the drug is admixed with hypromellose (hydroxypropyl methylcellulose) and the mixture is coated onto sugar spheres;
“Delayed release” (DR) formulation, wherein the IR beads are enterically coated with a pH dependent polymer: “methacrylic acid copolymer”.
Gunawardhana prepares “extended release” (XR) capsules containing a mixture of the IR and DR beads, and studies the safety and efficacy of dosing this formulation in the “Example 3” study discussed in the rejection above. Thus Gunawardhana shows that formulated pharmaceutical compositions can be studied for safety and efficacy. Although Gunawardhana does not employ a solid dispersion comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), a person of ordinary skill in the art would have a reasonable expectation of success in studying any formulation of a xanthine oxidase inhibitor following the example shown by Gunawardhana.
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, including Example 48 discussed in the rejections above, 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 compound is 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:15
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):16
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.17
Thus, the instant claims are not patentably distinct from the reference claims.
Claims 28, 35, 38-41 and 43-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-9, and 11-13 of U.S. Patent No. 11,234,984 B2 (hereafter referred to as “Itai”) in view of Gunawardhana, Nasatto and Friesen.
The limitations of claims 28, 35 and 38-50 and the disclosure of Gunawardhana and the teachings of Nasatto and Friesen are discussed in the rejection above and hereby incorporated into the instant rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons:
Itai’s claims 1 claims a solid dispersion comprising a compound of a genus that encompasses instant Compound 14 and a hypromellose derivative selected from hypromellose acetate and hypromellose succinate, while Itai’s claims 2-4 further narrow the genus in ways that continue to encompass Compound 14 and Itai’s claim 11 further limits the genus to precisely the same compound as instant Compound 14;
Itai’s claim 8 narrows the solid dispersion of claim 1 to a pharmaceutical composition comprising said dispersion, while Itai’s claim 9 further narrows the pharmaceutical composition of claim 8 to a solid preparation;
While reference claim 11 is not drawn to a method of treating hyperuricemia, it would be obvious to a person of ordinary skill in the art that the pharmaceutical composition comprising the same compound, explicitly disclosed in US 11,234,984 B2 as an agent for treating hyperuricemia (see Industrial Applicability18 statement by Applicant, just above reference claim 1) would anticipate a method for treating hyperuricemia comprising administering said pharmaceutical composition.
Itai does not specify a 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, and does not specify a dose/formulation that achieves the specific results disclosed in instant claim 28 (i.e., 80 mg/day in an amorphous solid dispersion using HPMCAS as the carrier). However, a person of ordinary skill in the art would have a reasonable expectation of success in administering the compound of Itai’s claim 11 within the range of 10-320 mg for a period of at least 7 days, and specifically at an 80 mg/day dose in an amorphous solid dispersion using HPMCAS as the carrier, because the clinically efficacious and safe dosage(s) and regimens of dosing xanthine oxidase inhibitors for treating hyperuricemia are result-effective variables that can be routinely optimized, and the effective formulation of poorly water-soluble drugs is a result-effective variable, and the determination of such result-effective variables was known in the art at the effective time of filing. See, for example, the disclosure of Gunawardhana and the teachings of Nasatto and Friesen, discussed in the rejections above.
Thus, the instant claims are not patentably distinct from the reference claims.
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 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 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.
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/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 Extended release formulation.
5 Immediate release formulation.
6 Indicating moderate renal impairment. Renal impairment is common among patients with hyperuricemia. – see paragraph [0175].
7 Page 1005.
8 Page 1008.
9 See “Solid-State Properties” section on page 1010 and Figure 3 on page 1011.
10 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine
11 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.
12 Extended release formulation.
13 Immediate release formulation.
14 Indicating moderate renal impairment. Renal impairment is common among patients with hyperuricemia. – see paragraph [0175].
15 Page 1005.
16 Page 1008.
17 See “Solid-State Properties” section on page 1010 and Figure 3 on page 1011.
18 Col 23, lines 38-43.
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