DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/21/2026 has been entered.
Election/Restrictions
Applicant’s election of
PNG
media_image1.png
196
296
media_image1.png
Greyscale
as the elected compound species in the reply filed on 01/28/2025 is acknowledged and maintained.
Priority
This application is a continuation of application no. 15/764,174, filed Mar. 28, 2018, which is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US2016/053223, filed September 23, 2016, which published as WO 2017/058645 Al on April 6, 2017, and claims priority from U.S. Patent Application Numbers 62/234,584, filed September 29, 2015, and 62/336,381, filed May 13, 2016.
Claim Status
. Claims 1-6, 9, and 11-12 are pending and are examined in accordance to the elected species. Claims 7-8 and 10 are canceled.
Action Summary
Claims 1-6, 9, and 11 rejected under 35 U.S.C. 103 as being un-patentable over Rayid (European Respiratory Journal, 2013 in view of Broka (US8,008,313; published 30 August 2011), Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014, and Daughton et al. (Science of The Total Environment, Volume 443, 15 January 2013, Pages 324-337, are maintained, but revisited and modified in light of the inclusion of new claim 12.
Claims 1-6, 9, and 11 rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-15 of U.S. Patent 9,724,346 in view of Broka (US8,008,313), Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014, and Daughton et al. (Science of The Total Environment, Volume 443, 15 January 2013, Pages 324-337, are maintained, are maintained, but revisited and modified in light of the inclusion of new claim 12.
Claims 1-6, 9, and 11 rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,206,922 in in view of Broka (US8,008,313), Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014, and Daughton et al. (Science of The Total Environment, Volume 443, 15 January 2013, Pages 324-337, are maintained, are maintained, but revisited and modified in light of the inclusion of new claim 12.
Claims 1-5, 9, and 11 rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,260,056 in in view of Broka (US8,008,313) and Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014, and Daughton et al. (Science of The Total Environment, Volume 443, 15 January 2013, Pages 324-337, are maintained, are maintained, but revisited and modified in light of the inclusion of new claim 12.
Specification
The disclosure is objected to because it includes the term “novel,” in paragraph [0007] which is a relative and subjective term that may be considered promotional in nature.
Appropriate correction is required.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 non-obviousness.
Claims 1-6, 9, 11, and 12 are rejected under 35 U.S.C. 103 as being un-patentable over Rayid (European Respiratory Journal, 2013) in view of Broka (US8,008,313; published 30 August 2011), Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014.
Rayid teaches a method for treating a patient having chronic daytime cough that is refractory comprising administering to the subject over a 2-weeks period, 600 mg twice daily (bd) AF-219, which is a P2X3 antagonist, wherein AF-219 markedly and significantly reduced cough, daytime cough rate by about 75%. (See Body Section.) AF-219 is the same as the elected compound. At least “treatment-resistant” alternative of claim 2 is taught by Rayid. Because claim 2 is written in the alternative (“idiopathic or treatment-resistant”), teaching of one alternative is sufficient.
Rayid et al. do not teach about 15 mg. Moreover, Rayid doe not teach the compound is administered for 16 or more days and the method exhibits a reduced taste disturbance relative to a taste disturbance resulting from administering a dose of about 100 mg or greater of the compound of Formula (I) or the pharmaceutically acceptable salt thereof twice daily to a patient with chronic cough.
Broka teaches methods for treating respiratory and gastrointestinal diseases mediated by P2X2/3 receptor agonist, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I). (See Abstract). Moreover, Broka teaches one of the preferred compounds of the formula (I) includes compound 114, namely 5-(2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. (See column 65-66.) This compound is the same as the compound of Rayid and the claimed elected compound. Broka further teaches in general; the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease. Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insulation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. (See column 131, lines 32-56.)
Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks; however, long-term safety and efficacy need to be established. At a dose of 600 mg twice a day, AF-219 was associated with disturbances in taste. (See page 1203, left column, last paragraph.) Moreover, Abdulqawi teaches AF-219 has much greater potency at P2X3 receptors than heteromeric P2X2/3 receptors, therefore lower doses of AF-219 might maintain efficacy with less frequent changes in taste. (See page 1204, left column, second paragraph.)
While Rayid does not explicitly teach a dose of about 15 mg. Broka discloses that compounds of the same class, including the same compound, may be administered at preferred dosage range of 1-30 mg. In view of Abdulqawi’s teaching that high dose (600 mg twice daily) are associated with taste disturbance and that lower doses may maintain efficacy with reduced side effects, a person of ordinary skill in the art would have been motivated to reduce the dose of Rayid. Moreover, Rayid demonstrates that AF-219 (claimed compound) is effective for treating chronic cough, and Broka teaches that therapeutically effective dose for compounds at the same class fall within a lower dosage range. In addition, Abdulqawi teaches that AF-219 exhibits greater potency at P2X3 receptors, supporting the expectation that lowers doses would retain therapeutic efficacy. Accordingly, a person of ordinary skill in the art would have had a reasonable expectation of success in reducing the dose while maintaining efficacy and reducing taste disturbance.
The selection of a specific dose within the disclosed range, including about 15 mg (e.g., twice daily, corresponding to a total daily dose within the preferred range taught by Broka), would have been a matter of routine optimization of a result-effective variable. A person of ordinary skill in the art would have reasonably expected that, upon reducing the total daily dose, administration could likewise be divided into multiple doses (e.g. twice daily) to maintain therapeutic drug levels and efficacy because Rayid teaches administration of AF-219 (claimed compound) at a dosage of 600 mg twice daily, thereby demonstrating that divided dosing regimens are suitable for this compound in treating chronic cough. Such dose optimization involves a finite number of predictable solutions and would have been achieved through routine optimization.
Additionally, with respect to the compound is administered for 16 or more days as recited in claim 12. Rayid teaches administration over a two-week period, and Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks, establishing that multi-day continuous treatment regimens are effective. It would have been within the routine skill of the art to adjust the duration of treatment, including extending demonstration beyond 14 days (e.g., to 16 days or more), based on patient response and clinical considerations.
With respect to the “exhibits a reduced taste disturbance relative to a taste disturbance resulting from administering a dose of about 100 mg (claims 1, 5 9) or about 600 mg (claim 11) or greater of the compound of Formula (I) or a pharmaceutically acceptable salt thereof twice daily” limitation. This limitation does not impart patentable weight as a separate limitation, but rather reflects an expected result of practicing the otherwise obvious method. Abdulqavi teaches administration of AF-219 at 600 mg twice daily is associated with taste disturbance and further suggests that lower doses may maintain efficacy with less frequent taste-related side effects, thereby establishing a dose-dependent relationship between dose and taste disturbance. In view of this teaching, a person of ordinary skill in the art would have reasonably expected that reducing the dose as suggested by the combined references would result in a corresponding reduction in taste disturbance. Accordingly, the claimed reduction in taste disturbance resulting from a dose of about 100 mg or greater twice daily is an inherent and predictable result of the obvious method steps, rather than a patentable distinction.
Applicant’s argument
Applicant argues that Rayid does not disclose the claimed dose of about 15 mg twice daily.
Examiner’s response
In response, Applicant’s argument is not persuasive. The rejection does not rely on Rayid alone to teach the claimed dose. Rather, Rayid is relied upon for teaching the same compound (AF-129) and its use in treating chronic cough. Broka teaches that compounds of the same class, including the same compound, may be administered at a preferred dosage range of 1-30 mg daily. The selection of a specific dose within a disclosed range, including about 15 mg twice daily (corresponding to a total daily dose within the preferred range), constitutes routine optimization or a result-effective variable and would have been within the ordinary skill in the art.
Applicant’s argument
Applicant argues that Broka relates to different diseases such as asthma and COPD, which have different etiologies from chronic cough, and therefore would not have been relevant.
Examiner’s response
In response, Applicant’s argument is not persuasive. The rejection does not rely on Broka to teach treatment of chronic cough. Rather, Broka relied upon for its teaching of dosage range from compounds of the same class, including the same claimed compound. A person of ordinary skill in the art would have reasonably considered such dosage teachings relevant to the same compound regardless of the specific indication, particularly, where, as here Rayid already establishes that the compound is effective for treating chronic cough. Accordingly, the modification involves optimization of the dose of a known effective compound for the same disease, not substitution of treatments across unrelated diseases.
Applicant’s argument
Applicant asserts that there would have no reasonable expectation of success because efficacy in one disorder does not predict efficacy in another.
Examiner’s response
In response, Applicant’s argument is not persuasive, because it is based on the incorrect characterization of the rejection. Again, the rejection relies on Rayid and Abdulqawi for demonstrating that AF-219 is effective for treating chronic cough. Thus, efficacy in the claimed indication is already established in the prior art. Broka is relied upon only for its teaching of the dosage ranges for compounds of the same class, and Abdulquwi further teaches that AF-219 exhibits high potency and that lower doses may maintain efficacy while reducing taste disturbance. In view of these teachings, a person of ordinary skill in the art would have ha reasonable expectation of success in reducing the dose while maintaining therapeutic efficacy.
Applicant’s argument
Applicant argues Abdulqavi does not disclose the claimed dose.
Examiner’s response
In response, Applicant’s argument is not persuasive. Specifically, Abdulqavi is not relied upon to teach the specific dose claimed, but rather to provide motivation to reduce the dose due to the known association of high dose with taste disturbance and the suggestion that lower doses may maintain efficacy with fewer side effects.
Lastly, Applicant’s argument with respect to the limitation requiring reduced taste disturbance, Abdulqawi teaches that administration of AF-219 at 600 mg twice daily is associated with taste disturbance and suggests that lower doses may reduce such side effects. This establishes a dose-dependent relationship between dose and taste disturbance. Accordingly, reducing the dose as suggested by the combined teachings would have been expected to result in reduced taste disturbance. The claimed limitation therefore represents an expected result of the obvious modification, rather than a patentable distinction.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-6, 9, 11, and 12 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,284,279 in view of Broka (US8,008,313), Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014.
The U.S. patent claims teach a method for treating idiopathic or treatment resistant chronic cough in a patient in need thereof, the method comprising administering to said patient 600 mg twice daily of a compound of Formula (I):
PNG
media_image2.png
355
742
media_image2.png
Greyscale
or a pharmaceutically acceptable salt thereof for about two weeks, wherein the chronic cough is reduced by about 75%. (See claims 1-7.) Moreover, the U.S. patent claims teach the compounds of the formula include the elected compound. (See claim 20.)
The U.S. patent claims do not teach about 15 mg. Moreover, the U.S. patent claims do not teach the compound is administered for 16 or more days
Broka teaches methods for treating respiratory and gastrointestinal diseases mediated by P2X2/3 receptor agonist, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I). (See Abstract). Moreover, Broka teaches one of the preferred compounds of the formula (I) includes compound 114, namely 5-(2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. (See column 65-66.) This compound is the same as the compound of Rayid and the claimed elected compound. Broka further teaches in general; the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease. Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insulation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. (See column 131, lines 32-56.)
Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks; however, long-term safety and efficacy need to be established. At a dose of 600 mg twice a day, AF-219 was associated with disturbances in taste. (See page 1203, left column, last paragraph.) Moreover, Abdulqawi teaches AF-219 has much greater potency at P2X3 receptors than heteromeric P2X2/3 receptors, therefore lower doses of AF-219 might maintain efficacy with less frequent changes in taste. (See page 1204, left column, second paragraph.)
Daughton teaches medication dose can often be reduced while still achieving therapeutic targets; reduced dose translates into lower environmental loadings of excreted drug residues; reduced dose can help prevent adverse side effects, drug diversion, and poisonings; and reduced dose can lessen cost of health care and reduce need for waste treatment. (See Highlights Section.)
While the U.S. patent claims do not explicitly teach a dose of about 15 mg. Broka discloses that compounds of the same class, including the same compound, may be administered at preferred dosage range of 1-30 mg. In view of Abdulqawi’s teaching that high dose (600 mg twice daily) are associated with taste disturbance and that lower doses may maintain efficacy with reduced side effects, a person of ordinary skill in the art would have been motivated to reduce the dose of the U.S. patent claims. Moreover, the U.S. patent claims demonstrate that AF-219 (claimed compound) is effective for treating chronic cough, and Broka teaches that therapeutically effective dose for compounds at the same class fall within a lower dosage range. In addition, Abdulqawi teaches that AF-219 exhibits greater potency at P2X3 receptors, supporting the expectation that lowers doses would retain therapeutic efficacy. Accordingly, a person of ordinary skill in the art would have had a reasonable expectation of success in reducing the dose while maintaining efficacy and reducing taste disturbance.
The selection of a specific dose within the disclosed range, including about 15 mg (e.g., twice daily, corresponding to a total daily dose within the preferred range taught by Broka), would have been a matter of routine optimization of a result-effective variable. A person of ordinary skill in the art would have reasonably expected that, upon reducing the total daily dose, administration could likewise be divided into multiple doses (e.g. twice daily) to maintain therapeutic drug levels and efficacy because the U.S. patent claims teach administration of AF-219 (claimed compound) at a dosage of 600 mg twice daily, thereby demonstrating that divided dosing regimens are suitable for this compound in treating chronic cough. Such dose optimization involves a finite number of predictable solutions and would have been achieved through routine optimization.
Additionally, with respect to the compound is administered for 16 or more days as recited in claim 12. The U.S. patent claims teach administration over a two-week period, and Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks, establishing that multi-day continuous treatment regimens are effective. It would have been within the routine skill of the art to adjust the duration of treatment, including extending demonstration beyond 14 days (e.g., to 16 days or more), based on patient response and clinical considerations.
With respect to the “exhibits a reduced taste disturbance relative to a taste disturbance resulting from administering a dose of about 100 mg (claims 1, 5 9) or about 600 mg (claim 11) or greater of the compound of Formula (I) or a pharmaceutically acceptable salt thereof twice daily” limitation. This limitation does not impart patentable weight as a separate limitation, but rather reflects an expected result of practicing the otherwise obvious method. Abdulqavi teaches administration of AF-219 at 600 mg twice daily is associated with taste disturbance and further suggests that lower doses may maintain efficacy with less frequent taste-related side effects, thereby establishing a dose-dependent relationship between dose and taste disturbance. In view of this teaching, a person of ordinary skill in the art would have reasonably expected that reducing the dose as suggested by the combined references would result in a corresponding reduction in taste disturbance. Accordingly, the claimed reduction in taste disturbance resulting from a dose of about 100 mg or greater twice daily is an inherent and predictable result of the obvious method steps, rather than a patentable distinction.
Claims 1-6, 9, 11, and 12 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-15 of U.S. Patent 9,724,346 in view of Broka (US8,008,313), Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014.
The U.S. patent claims teach a method for treating chronic cough in a patient, wherein the cough is selected from the group consisting of chronic pathological cough, sub-acute pathological cough, acute pathological cough, neuronal hypersensitivity underlying chronic cough, neuronal hypersensitivity underlying sub-acute cough and neuronal hypersensitivity underlying acute cough, the method comprising administering to the patient in need thereof an effective amount of a compound of Formula (I), wherein about 50 mg of the compound of Formula (I) is administered multiple times daily, wherein about 100 mg of the compound of Formula (I) is administered multiple times daily, and wherein the cough is reduced by about 75%. (See claims 1-8.). The compounds of the formula (I) include the claimed compound. (See claims 11, 12, and 13.) While the U.S. patent claims do not teach twice daily, the multiple times daily encompasses twice daily.
The U.S. patent claims do not teach about 15 mg. Moreover, The U.S. patent claims do not teach about 15 mg. Moreover, the U.S. patent claims do not teach the compound is administered for 16 or more days
Broka teaches methods for treating respiratory and gastrointestinal diseases mediated by P2X2/3 receptor agonist, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I). (See Abstract). Moreover, Broka teaches one of the preferred compounds of the formula (I) includes compound 114, namely 5-(2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. (See column 65-66.) This compound is the same as the compound of Rayid and the claimed elected compound. Broka further teaches in general; the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease. Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insulation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. (See column 131, lines 32-56.)
Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks; however, long-term safety and efficacy need to be established. At a dose of 600 mg twice a day, AF-219 was associated with disturbances in taste. (See page 1203, left column, last paragraph.) Moreover, Abdulqawi teaches AF-219 has much greater potency at P2X3 receptors than heteromeric P2X2/3 receptors, therefore lower doses of AF-219 might maintain efficacy with less frequent changes in taste. (See page 1204, left column, second paragraph.)
Daughton teaches medication dose can often be reduced while still achieving therapeutic targets; reduced dose translates into lower environmental loadings of excreted drug residues; reduced dose can help prevent adverse side effects, drug diversion, and poisonings; and reduced dose can lessen cost of health care and reduce need for waste treatment. (See Highlights Section.)
While the U.S. patent claims do not explicitly teach a dose of about 15 mg. Broka discloses that compounds of the same class, including the same compound, may be administered at preferred dosage range of 1-30 mg. In view of Abdulqawi’s teaching that high dose (600 mg twice daily) are associated with taste disturbance and that lower doses may maintain efficacy with reduced side effects, a person of ordinary skill in the art would have been motivated to reduce the dose of the U.S. patent claims. Moreover, the U.S. patent claims demonstrate that AF-219 (claimed compound) is effective for treating chronic cough, and Broka teaches that therapeutically effective dose for compounds at the same class fall within a lower dosage range. In addition, Abdulqawi teaches that AF-219 exhibits greater potency at P2X3 receptors, supporting the expectation that lowers doses would retain therapeutic efficacy. Accordingly, a person of ordinary skill in the art would have had a reasonable expectation of success in reducing the dose while maintaining efficacy and reducing taste disturbance.
The selection of a specific dose within the disclosed range, including about 15 mg (e.g., twice daily, corresponding to a total daily dose within the preferred range taught by Broka), would have been a matter of routine optimization of a result-effective variable. A person of ordinary skill in the art would have reasonably expected that, upon reducing the total daily dose, administration could likewise be divided into multiple doses (e.g. twice daily) to maintain therapeutic drug levels and efficacy because the U.S. patent claims teach administration of AF-219 (claimed compound) at a dosage of 600 mg twice daily, thereby demonstrating that divided dosing regimens are suitable for this compound in treating chronic cough. Such dose optimization involves a finite number of predictable solutions and would have been achieved through routine optimization.
Additionally, with respect to the compound is administered for 16 or more days as recited in claim 12. The U.S. patent claims teach administration over a two-week period, and Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks, establishing that multi-day continuous treatment regimens are effective. It would have been within the routine skill of the art to adjust the duration of treatment, including extending demonstration beyond 14 days (e.g., to 16 days or more), based on patient response and clinical considerations.
With respect to the “exhibits a reduced taste disturbance relative to a taste disturbance resulting from administering a dose of about 100 mg (claims 1, 5 9) or about 600 mg (claim 11) or greater of the compound of Formula (I) or a pharmaceutically acceptable salt thereof twice daily” limitation. This limitation does not impart patentable weight as a separate limitation, but rather reflects an expected result of practicing the otherwise obvious method. Abdulqavi teaches administration of AF-219 at 600 mg twice daily is associated with taste disturbance and further suggests that lower doses may maintain efficacy with less frequent taste-related side effects, thereby establishing a dose-dependent relationship between dose and taste disturbance. In view of this teaching, a person of ordinary skill in the art would have reasonably expected that reducing the dose as suggested by the combined references would result in a corresponding reduction in taste disturbance. Accordingly, the claimed reduction in taste disturbance resulting from a dose of about 100 mg or greater twice daily is an inherent and predictable result of the obvious method steps, rather than a patentable distinction.
Claims 1-6, 9, 11, and 12 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,206,922 in in view of Broka (US8,008,313), Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014.
The U.S. patent claims teach a method for treating idiopathic or treatment resistant chronic cough in a patient in need thereof, the method comprising administering to said patient an effective amount of compound of Formula (I):
PNG
media_image2.png
355
742
media_image2.png
Greyscale
or a pharmaceutically acceptable salt thereof for about two weeks, wherein the chronic cough is reduced by about 75%. (See claims 1-7.) Moreover, the U.S. patent claims teach the compounds of the formula include the elected compound. (See claim 20.)
The U.S. patent claims do not teach about 15 mg and the compound administered for 16 or more days. However, the U.S. patent describe effective amount to include preferably 500-700 mg twice daily and 1-1000 mg twice daily. (See column 28, lines 51-57.)
Broka teaches methods for treating respiratory and gastrointestinal diseases mediated by P2X2/3 receptor agonist, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I). (See Abstract). Moreover, Broka teaches one of the preferred compounds of the formula (I) includes compound 114, namely 5-(2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. (See column 65-66.) This compound is the same as the compound of Rayid and the claimed elected compound. Broka further teaches in general; the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease. Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insulation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. (See column 131, lines 32-56.)
Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks; however, long-term safety and efficacy need to be established. At a dose of 600 mg twice a day, AF-219 was associated with disturbances in taste. (See page 1203, left column, last paragraph.) Moreover, Abdulqawi teaches AF-219 has much greater potency at P2X3 receptors than heteromeric P2X2/3 receptors, therefore lower doses of AF-219 might maintain efficacy with less frequent changes in taste. (See page 1204, left column, second paragraph.)
Daughton teaches medication dose can often be reduced while still achieving therapeutic targets; reduced dose translates into lower environmental loadings of excreted drug residues; reduced dose can help prevent adverse side effects, drug diversion, and poisonings; and reduced dose can lessen cost of health care and reduce need for waste treatment. (See Highlights Section.)
It would have been prima facie obvious to one ordinary skill in the art at the time of filing of the invention to have administered the method of treatment of Rayid for chronic refractory cough to patients at a dosage of about 15 mg twice daily. One would have been motivated to do so because the compound of Rayid, AF-219 is a P2X3 antagonist being used in treatment of the respiratory disease of chronic refractory cough, because Broka teaches that P2X3 antagonists of the same class are effective in treatment of respiratory disease at a preferred dosage of 1-30 mg daily and also because Abdulqawi teaches the 600 mg twice daily is associated with disturbance in taste which can be resolved by administering lower dose of AF-219, and lastly because Daughton teaches dose reduction of medical drugs can reduce side effects, drug diversion and poisoning, and dost of health care. Therefore, one of ordinary skill in the art knowing the taste disturbance effect of the 600 mg AF-219, would look into reducing the dose of the U.S. patent to less than 600 mg that include the 50 mg because the lower dose, the lower the taste disturbance. Doses such as 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 5 mg would be expected to have lower taste disturbance effect than doses higher than 50 mg at the same time providing an effective treatment of chronic cough.
With respect to the comparison effect claimed in claims 1, 21, 22, 27, and 29; this limitation simply expresses the intended result of the process step positively recited. This intended result positively recited would flow naturally from the combined teaching of cited references.
Claims 1-6, 9, 11, and 12 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,260,056 in in view of Broka (US8,008,313) and Abdulqawi, Lancet 2015; 385: 1198–205 Published Online November 25, 2014, and Daughton et al. (Science of The Total Environment, Volume 443, 15 January 2013, Pages 324-337.
The U.S. patent claims teach a method for treating chronic cough, comprising administering to a patient with chronic cough from about 30 mg to about 50 mg twice daily of a compound of Formula (I):
PNG
media_image3.png
355
726
media_image3.png
Greyscale
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen or C1-C6 alkyl; and
R2 is: alkyl; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; carboxyalkyl; cyano or alkylcarbonyl; and wherein the method exhibits a reduced taste disturbance relative to a taste disturbance resulting from administering a dose of about 100 mg or greater of the compound of formula (I), or the pharmaceutically acceptable salt thereof, twice daily to a patient with chronic cough, wherein the chronic cough is idiopathic or treatment resistant cough, wherein the compound of Formula (I), or the pharmaceutically acceptable salt thereof, is administered twice daily for days, weeks, months or years, and wherein the chronic cough is refractory chronic cough. (See claims 1-4.)
The U.S. patent claims do not teach about 15 mg. Moreover, the U.S. patent claims do not teach the compound is administered for 16 or more days.
Broka teaches methods for treating respiratory and gastrointestinal diseases mediated by P2X2/3 receptor agonist, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I). (See Abstract). Moreover, Broka teaches one of the preferred compounds of the formula (I) includes compound 114, namely 5-(2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. (See column 65-66.) This compound is the same as the compound of Rayid and the claimed elected compound. Broka further teaches in general; the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease. Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insulation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. (See column 131, lines 32-56.)
Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks; however, long-term safety and efficacy need to be established. At a dose of 600 mg twice a day, AF-219 was associated with disturbances in taste. (See page 1203, left column, last paragraph.) Moreover, Abdulqawi teaches AF-219 has much greater potency at P2X3 receptors than heteromeric P2X2/3 receptors, therefore lower doses of AF-219 might maintain efficacy with less frequent changes in taste. (See page 1204, left column, second paragraph.)
Daughton teaches medication dose can often be reduced while still achieving therapeutic targets; reduced dose translates into lower environmental loadings of excreted drug residues; reduced dose can help prevent adverse side effects, drug diversion, and poisonings; and reduced dose can lessen cost of health care and reduce need for waste treatment. (See Highlights Section.)
While the U.S. patent claims do not explicitly teach a dose of about 15 mg. Broka discloses that compounds of the same class, including the same compound, may be administered at preferred dosage range of 1-30 mg. In view of Abdulqawi’s teaching that high dose (600 mg twice daily) are associated with taste disturbance and that lower doses may maintain efficacy with reduced side effects, a person of ordinary skill in the art would have been motivated to reduce the dose of the U.S. patent claims. Moreover, the U.S. patent claims demonstrate that AF-219 (claimed compound) is effective for treating chronic cough, and Broka teaches that therapeutically effective dose for compounds at the same class fall within a lower dosage range. In addition, Abdulqawi teaches that AF-219 exhibits greater potency at P2X3 receptors, supporting the expectation that lowers doses would retain therapeutic efficacy. Accordingly, a person of ordinary skill in the art would have had a reasonable expectation of success in reducing the dose while maintaining efficacy and reducing taste disturbance.
The selection of a specific dose within the disclosed range, including about 15 mg (e.g., twice daily, corresponding to a total daily dose within the preferred range taught by Broka), would have been a matter of routine optimization of a result-effective variable. A person of ordinary skill in the art would have reasonably expected that, upon reducing the total daily dose, administration could likewise be divided into multiple doses (e.g. twice daily) to maintain therapeutic drug levels and efficacy because the U.S. patent claims teach administration of AF-219 (claimed compound) at a dosage of 600 mg twice daily, thereby demonstrating that divided dosing regimens are suitable for this compound in treating chronic cough. Such dose optimization involves a finite number of predictable solutions and would have been achieved through routine optimization.
Additionally, with respect to the compound is administered for 16 or more days as recited in claim 12. The U.S. patent claims teach administration over a two-week period, and Abdulqawi teaches our single-center, proof-of-concept study did not identify any safety issues with AF-219 given over 2 weeks, establishing that multi-day continuous treatment regimens are effective. It would have been within the routine skill of the art to adjust the duration of treatment, including extending demonstration beyond 14 days (e.g., to 16 days or more), based on patient response and clinical considerations.
With respect to the “exhibits a reduced taste disturbance relative to a taste disturbance resulting from administering a dose of about 100 mg (claims 1, 5 9) or about 600 mg (claim 11) or greater of the compound of Formula (I) or a pharmaceutically acceptable salt thereof twice daily” limitation. This limitation does not impart patentable weight as a separate limitation, but rather reflects an expected result of practicing the otherwise obvious method. Abdulqavi teaches administration of AF-219 at 600 mg twice daily is associated with taste disturbance and further suggests that lower doses may maintain efficacy with less frequent taste-related side effects, thereby establishing a dose-dependent relationship between dose and taste disturbance. In view of this teaching, a person of ordinary skill in the art would have reasonably expected that reducing the dose as suggested by the combined references would result in a corresponding reduction in taste disturbance. Accordingly, the claimed reduction in taste disturbance resulting from a dose of about 100 mg or greater twice daily is an inherent and predictable result of the obvious method steps, rather than a patentable distinction
Applicant states that the double patenting rejection should be withdrawn for the same reasons presented with respect to the 103 rejections. This argument is not persuasive because it does not specifically address the grounds of the nonstatutory double patenting rejections, which are based on claims of a commonly owned patent. Accordingly, the rejection is maintained.
Conclusion
Claims 1-6, 9, 11, and 12 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEAN P CORNET/Primary Examiner, Art Unit 1628
Prosecution Insights