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 .
Priority
This application is a National Stage entry of PCT/US2022/032862, filed 06/09/2022; PCT/US2022/032862 Claims Priority from Provisional Application 63208863, filed 06/09/2021.
Information Disclosure Statement
The IDS filed on 11/25/2024 has been considered. See the attached PTO 1449 form.
Election/Restrictions
Applicant’s election without traverse of Group I and potassium bumetanide salt (Claims 5, 7-9, 11, 13, 15, 17, 19, 21, 22) in the reply filed on 6/12/2026 is acknowledged.
Claims 1, 3, 4 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
Claim Status
Receipt of Remarks filed on 6/12/2026 is acknowledged. Claims 1, 3-4, 5, 7-9, 11, 13, 15, 17, 19, 21, 22 are currently pending. Claims 1, 3, 4 have been withdrawn. Accordingly, claims 5, 7-9, 11, 13, 15, 17, 19, 21, 22 are currently under examination.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 5, 7, 8, 9, 11, 15, 17, 19, 21, 22 are rejected under 35 U.S.C. 103 as being unpatentable over Roy (IN2476/MUM/2011 A; Mar. 15 2013) in view of Ong (CrystEngComm, 2012, 14, 2428-2434).
Roy throughout the reference teaches stable pharmaceutical compositions of bumetanide or salts thereof for parenteral administration. The composition is used in the treatment of congestive heart failure, hepatic and renal disease, including nephrotic syndrome. (e.g. Abstract; Title). Roy teaches the composition comprises one or more parenterally acceptable excipients including buffers, tonicity agents, diluents, co-solvents and stabilizers among others taught by Roy. Roy teaches mannitol (sugar alcohol) as suitable diluent. (pages 2-3 and 5). Roy teaches the composition is in the form of a solution. The composition comprises a solution of bumetanide. Roy also teaches the composition comprises a suitable vehicle including one or more of water and an aqueous solution, thus reading on the composition comprising an aqueous solution. (e.g. pages 3-6). The pH of the composition is from about 5.5 to about 8 (page 6). Roy teaches composition in the form of solution, including a vehicle which can be water (i.e. aqueous solution) and the composition pH is from about 5.5 to about 8, which reads on the claimed aqueous solution having a pH of between about 5 and about 9. The composition comprises bumetanide or salts thereof in an amount in the range of from about 0.1 mg/ml to 5 mg/ml, overlapping the claimed amount of bumetanide. Roy teaches the parenteral administration includes administration through subcutaneous injection (page 4). The instant specification disclose patients with congestive heart failure experience edema and Roy teaches the composition is used in the treatment of congestive heart failure, thus treating edema. (see entire document).
The teachings of Roy have been set forth above.
While Roy teaches the composition comprises bumetanide or salts thereof, Roy does not teach potassium bumetanide salt and wherein the edema is refractory to oral diuretics. However, Ong cures these deficiencies.
Ong teaches bumetanide potassium trihydrate salt was five times more soluble in water relative to sodium trihydrate salt. Utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. APIs intended for parenteral administration require extensive salt screening to ensure that a suitable form is selected. Bumetanide is indicated to manage oedema typically associated with congestive heart failure, hepatic and renal disease. As free acid in solid oral dosage and injectable forms, bumetanide has low aqueous solubility, which limits its utility in low volume injectable delivery. Identification of salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. Ong discloses pH solubility profile of bumetanide in aqueous solution wherein the potassium salt is five times more soluble in water at pH > 7.5. Ong does not teach or require any additional buffer other than potassium hydroxide (KOH). Ong teaches the solubility increase for the potassium salt can be particularly important to low-volume parenteral formulations of bumetanide, as it facilitates the preparation of concentrated drug solutions at the near neutral pH. (Abstract; Introduction; Material and Methods; Results and Discussion; Conclusion; Entire Document).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Roy and Ong and specifically incorporate potassium bumetanide salt in the composition of Roy. One would have been motivated to do so because Roy teaches the composition comprises bumetanide or salts thereof and Ong teaches bumetanide potassium trihydrate salt was five times more soluble in water relative to sodium trihydrate salt. Ong teaches salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. As mentioned above, Ong teaches APIs having low solubility in aqueous systems often result in poor oral bioavailability. Roy also teaches parenteral (e.g. subcutaneous) formulation of bumetanide salt and thus, it would have been obvious to one skilled in the art to incorporate potassium bumetanide salt as it provides higher aqueous solubilities.
Regarding claim 8, as discussed supra, Roy teaches buffering agent can be included in the composition but does not require it (i.e. the use of buffer is optional). Ong also does not require a buffer other than KOH combined with bumetanide free acid.
Regarding claim 19, as discussed supra, Ong teaches Bumetanide is indicated to manage oedema typically associated with congestive heart failure, hepatic and renal disease and that as free acid in solid oral dosage and injectable forms, bumetanide has low aqueous solubility, which limits its utility in low volume injectable delivery. Identification of salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. Thus, it would have been obvious to ones skilled in the art to treat edema, which is not treated well with oral dosage (e.g. due to bumetanide having low aqueous solubility), with potassium bumetanide in low volume parenteral form. Thus, the combination of Roy and Ong render obvious treating edema refractory to oral diuretic.
Regarding claim 15, as discussed supra, Ong teaches the solubility increase for the potassium salt can be particularly important to low-volume parenteral formulations of bumetanide, as it facilitates the preparation of concentrated drug solutions at the near neutral pH. Thus, it would have been obvious to one skilled in the art that use of potassium salt of bumetanide can provide concentrated drug solution which can be administered with low volume. The amount of volume of the dose would depend on the subject size, disease severity, etc., and therefore it would have been obvious to optimize the dose volume based on these parameters. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 17, as discussed supra, Ong teaches utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. This suggests that low solubility results poor bioavailability and Ong teaches potassium salt of bumetanide provides increased aqueous solubility. Thus, it would have been obvious to one skilled in the art to optimize and maximize the bioavailability of the composition by increasing the solubility because a composition having higher bioavailability is desired per the teachings of Ong. Moreover, the combination of the references teach the same composition as recited in the instant claims and therefore, the composition taught by the prior art would necessarily have a similar bioavailability as recited in the claims.
Regarding claim 22, it would have been obvious to one skilled in the art to administer the composition subcutaneously to the subject in an outpatient setting or self-administer depending on the severity of the disease (e.g. edema or congestive hear failure) and whether the subject requires hospitalization or can be treated in an outpatient setting or at home by self-administration.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Claims 5, 7, 9, 11, 13, 15, 17, 19, 21, 22 are rejected under 35 U.S.C. 103 as being unpatentable over Westward (Bumetanide Injection, USP, Safety Data Sheet, 2012) in view of Roy (IN2476/MUM/2011 A; Mar. 15 2013) and Ong (CrystEngComm, 2012, 14, 2428-2434).
Westward disclose bumetanide injection formulation comprising bumetanide, water (excipient), sodium chloride (tonicity agent), benzyl alcohol (preservative), glycine and acetic acid ammonium salt (buffer agent). The composition is in an aqueous solution form having a pH of 6.8 to 7.8. The bumetanide injection is taught as being a diuretic. (see entire document).
Westward does not teach the method of treating edema wherein the subject has edema and/or congestive heart failure and the edema is refractory to oral diuretics, administering the formulation to the subject subcutaneously, potassium bumetanide salt and the amount thereof. Westward also does not teach the composition comprising sugar or sugar alcohol. However, these deficiencies are cure by Roy and Ong.
Roy throughout the reference teaches stable pharmaceutical compositions of bumetanide or salts thereof for parenteral administration. The composition is used in the treatment of congestive heart failure, hepatic and renal disease, including nephrotic syndrome. (e.g. Abstract; Title). Roy teaches the composition comprises one or more parenterally acceptable excipients including buffers, tonicity agents, diluents, co-solvents and stabilizers among others taught by Roy. Roy teaches mannitol (sugar alcohol) as suitable diluent. Roy also teaches sugar alcohol can be added to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral administration. (pages 2-3 and 5-6). Roy teaches the composition is in the form of a solution. The composition comprises a solution of bumetanide. Roy also teaches the composition comprises a suitable vehicle including one or more of water and an aqueous solution. (e.g. pages 3-6). The pH of the composition is from about 5.5 to about 8 (page 6). The composition comprises bumetanide or salts thereof in an amount in the range of from about 0.1 mg/ml to 5 mg/ml, overlapping the claimed amount of bumetanide. Roy teaches the parenteral administration includes administration through subcutaneous injection (page 4). The instant specification disclose patients with congestive heart failure experience edema and Roy teaches the composition is used in the treatment of congestive heart failure, thus treating edema. (see entire document).
Ong teaches bumetanide potassium trihydrate salt was five times more soluble in water relative to sodium trihydrate salt. Utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. APIs intended for parenteral administration require extensive salt screening to ensure that a suitable form is selected. Bumetanide is indicated to manage oedema typically associated with congestive heart failure, hepatic and renal disease. As free acid in solid oral dosage and injectable forms, bumetanide has low aqueous solubility, which limits its utility in low volume injectable delivery. Identification of salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. Ong discloses pH solubility profile of bumetanide in aqueous solution wherein the potassium salt is five times more soluble in water at pH > 7.5. Ong does not teach or require any additional buffer other than potassium hydroxide (KOH). Ong teaches the solubility increase for the potassium salt can be particularly important to low-volume parenteral formulations of bumetanide, as it facilitates the preparation of concentrated drug solutions at the near neutral pH. (Abstract; Introduction; Material and Methods; Results and Discussion; Conclusion; Entire Document).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Westward, Roy and Ong and utilize the formulation of Westward for treating edema wherein the subject has edema and/or congestive heart failure and administer the formulation to the subject subcutaneously. As discussed supra, both Roy and Ong teach bumetanide used for treating congestive heart failure and Ong specifically teaches bumetanide is a diuretic used for treating edema in congestive heart failure. Thus, it would have been obvious to one skilled in the art to utilize bumetanide for treating edema wherein the subject has congestive heart failure as bumetanide was known and indicated to treat this disease/condition in a subject. Further, it would have been obvious to administer the formulation comprising bumetanide through subcutaneous route because Roy teaches the injection formulation comprising bumetanide to treat congestive heart failure can be administered subcutaneously. The administration of an injection formulation comprising bumetanide through subcutaneous route was known in the art and therefore, one skilled in the art would have easily envision administering the injection through subcutaneous route.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Westward, Roy and Ong and specifically incorporate potassium bumetanide salt in the composition of Westward. One would have been motivated to do so because Westward teaches the composition comprises bumetanide and Ong teaches that as free acid in solid oral dosage and injectable forms, bumetanide has low aqueous solubility, which limits its utility in low volume injectable delivery. Identification of salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. Ong teaches bumetanide potassium trihydrate salt was five times more soluble in water relative to sodium trihydrate salt. Ong teaches salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. As mentioned above, Ong teaches APIs having low solubility in aqueous systems often result in poor oral bioavailability. Westward also teaches parenteral formulation of bumetanide and thus, it would have been obvious to one skilled in the art to incorporate potassium bumetanide salt as it provides higher aqueous solubilities.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Westward, Roy and Ong and further incorporate sugar alcohol or mannitol in the formulation of Westward. As discussed supra, Roy teaches mannitol (sugar alcohol) as suitable diluent. Roy also teaches sugar alcohol can be added to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral administration. Thus, one skilled in the art would have been motivated to include mannitol in the injection formulation of Westward as a diluent or include sugar alcohol to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral administration.
Regarding claim 19, as discussed supra, Ong teaches Bumetanide is indicated to manage oedema typically associated with congestive heart failure, hepatic and renal disease and that as free acid in solid oral dosage and injectable forms, bumetanide has low aqueous solubility, which limits its utility in low volume injectable delivery. Identification of salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. Thus, it would have been obvious to ones skilled in the art to treat edema, which is not treated well with oral dosage (e.g. due to bumetanide having low aqueous solubility), with potassium bumetanide in low volume parenteral form. Thus, the combination of Westward, Roy and Ong render obvious treating edema refractory to oral diuretic.
Regarding claim 15, as discussed supra, Ong teaches the solubility increase for the potassium salt can be particularly important to low-volume parenteral formulations of bumetanide, as it facilitates the preparation of concentrated drug solutions at the near neutral pH. Thus, it would have been obvious to one skilled in the art that use of potassium salt of bumetanide can provide concentrated drug solution which can be administered with low volume. The amount of volume of the dose would depend on the subject size, disease severity, etc., and therefore it would have been obvious to optimize the dose volume and amount of bumetanide based on these parameters. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 17, as discussed supra, Ong teaches utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. This suggests that low solubility results poor bioavailability and Ong teaches potassium salt of bumetanide provides increased aqueous solubility. Thus, it would have been obvious to one skilled in the art to optimize and maximize the bioavailability of the composition by increasing the solubility because a composition having higher bioavailability is desired per the teachings of Ong. Moreover, the combination of the references teach the same composition as recited in the instant claims and therefore, the composition taught by the prior art would necessarily have a similar bioavailability as recited in the claims.
Regarding claim 22, it would have been obvious to one skilled in the art to administer the composition subcutaneously to the subject in an outpatient setting or self-administer depending on the severity of the disease (e.g. edema or congestive heart failure) and whether the subject requires hospitalization or can be treated in an outpatient setting or at home by self-administration.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 5, 7-9, 11, 13, 15, 17, 19, 21, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11123319B2 in view of Roy (IN2476/MUM/2011 A; Mar. 15 2013) and Ong (CrystEngComm, 2012, 14, 2428-2434).
‘319 claims a stable pharmaceutical composition comprising (i) an aqueous solution having a pH of between about 5 and about 9, (ii) between about 4 mg/mL and about 20 mg/mL potassium bumetanide salt, and (iii) one or more pharmaceutically acceptable excipients, wherein the aqueous solution is free of a buffering agent other than the buffer formed by bumetanide free acid combined with potassium hydroxide, wherein the pharmaceutical composition is formulated for intranasal or sublingual administration. The one or more pharmaceutically acceptable excipients comprises a preservative, a viscosity enhancer, or a tonicity agent.
‘319 does not teach the composition for treating edema, wherein the subject has congestive heart failure, and administering the composition subcutaneously. ‘319 also does not teach the composition further comprising buffering agent, sugar or sugar alcohol, the dose volume, bioavailability of the composition, wherein the edema is refractory to oral diuretics and the composition administered in outpatient setting. However, Roy and Ong cure these deficiencies.
The teachings of Roy and Ong discussed supra are incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘319, Roy and Ong and utilize the formulation of ‘319 for treating edema wherein the subject has edema and/or congestive heart failure and administer the formulation to the subject subcutaneously. As discussed supra, both Roy and Ong teach bumetanide used for treating congestive heart failure and Ong specifically teaches bumetanide is a diuretic used for treating edema in congestive heart failure. Thus, it would have been obvious to one skilled in the art to utilize bumetanide for treating edema wherein the subject has congestive heart failure as bumetanide was known and indicated to treat this disease/condition in a subject. Further, it would have been obvious to administer the formulation comprising bumetanide through subcutaneous route because Roy teaches the formulation comprising bumetanide in the form of aqueous solution to treat congestive heart failure can be administered subcutaneously. The administration of a formulation comprising an aqueous solution of bumetanide through subcutaneous route was known in the art and therefore, one skilled in the art would have easily envisioned administering the composition comprising an aqueous solution through subcutaneous route.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘319, Roy and Ong and further incorporate sugar alcohol or mannitol in the formulation of ‘319. As discussed supra, Roy teaches mannitol (sugar alcohol) as suitable diluent. Roy also teaches sugar alcohol can be added to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral administration. Thus, one skilled in the art would have been motivated to include mannitol in the formulation of ‘319 as a diluent or include sugar alcohol to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral (e.g. subcutaneous) administration.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘319, Roy and Ong and further incorporate a buffering agent as taught in Roy because addition of a buffer to maintain the pH of the composition was commonly known in the art.
Regarding claim 19, as discussed supra, Ong teaches Bumetanide is indicated to manage oedema typically associated with congestive heart failure, hepatic and renal disease and that as free acid in solid oral dosage and injectable forms, bumetanide has low aqueous solubility, which limits its utility in low volume injectable delivery. Identification of salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. Thus, it would have been obvious to ones skilled in the art to treat edema, which is not treated well with oral dosage (e.g. due to bumetanide having low aqueous solubility), with potassium bumetanide in low volume parenteral form. Thus, the combination of ‘319, Roy and Ong render obvious treating edema refractory to oral diuretic.
Regarding claim 15, as discussed supra, Ong teaches the solubility increase for the potassium salt can be particularly important to low-volume parenteral formulations of bumetanide, as it facilitates the preparation of concentrated drug solutions at the near neutral pH. Thus, it would have been obvious to one skilled in the art that use of potassium salt of bumetanide can provide concentrated drug solution which can be administered with low volume. The amount of volume of the dose would depend on the subject size, disease severity, etc., and therefore it would have been obvious to optimize the dose volume and amount of bumetanide based on these parameters. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 17, as discussed supra, Ong teaches utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. This suggests that low solubility results poor bioavailability and Ong teaches potassium salt of bumetanide provides increased aqueous solubility. Thus, it would have been obvious to one skilled in the art to optimize and maximize the bioavailability of the composition by increasing the solubility because a composition having higher bioavailability is desired per the teachings of Ong. Moreover, the combination of the references teach the same composition as recited in the instant claims and therefore, the composition taught by the prior art would necessarily have a similar bioavailability as recited in the claims.
Regarding claim 22, it would have been obvious to one skilled in the art to administer the composition subcutaneously to the subject in an outpatient setting or self-administer depending on the severity of the disease (e.g. edema or congestive heart failure) and whether the subject requires hospitalization or can be treated in an outpatient setting or at home by self-administration.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Claims 5, 7-9, 11, 13, 15, 17, 19, 21, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11260038B1 in view of Roy (IN2476/MUM/2011 A; Mar. 15 2013), Ong (CrystEngComm, 2012, 14, 2428-2434) and Westward (Bumetanide Injection, USP, Safety Data Sheet, 2012).
‘038 claims a method of treating edema in a subject in need thereof, said method comprising sublingually or intranasally administering to the subject an effective amount of a solution comprising between about 4 mg/mL and about 20 mg/mL potassium bumetanide salt; wherein the subject has congestive heart failure or renal insufficiency; wherein the subject is suffering from edema in the lung; wherein the potassium bumetanide salt is administered intranasally to the subject in an outpatient setting or the potassium bumetanide salt is self-administered; wherein the subject has failed to achieve diuresis with oral diuretic therapy prior to the administering, wherein the subject is experiencing swelling of the legs, shortness of breath, difficulty breathing, or chest pain unresolved with oral diuretic therapy prior to the administering; the administering comprises delivering a dose of from 25 μl to 250 μl of the solution; wherein the subject has edema refractory to oral diuretics. ‘038 does not claim or require a buffering agent in the solution.
‘038 does not teach administering the formulation subcutaneously, the formulation comprising an aqueous solution having a pH of 5 to 9, and further comprising buffering agent and other excipients which include tonicity agent, sugar or sugar alcohol, and preservative, and the bioavailability of the composition. However, Roy, Ong and Westward cure these deficiencies.
The teachings of Roy, Ong and Westward discussed supra are incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘038, Roy, Ong and Westward and formulate the solution comprising bumetanide of ‘038 into an aqueous solution with a pH of 5 to 9 and administer it through subcutaneous route because Roy, Ong and Westward all teach aqueous solutions having a pH within 5 to 9 and the aqueous solution compositions are taught to be used to treat edema and congestive heart failure wherein Roy specifically teaches the formulation comprising bumetanide in the form of aqueous solution to treat congestive heart failure can be administered subcutaneously. The administration of a formulation comprising an aqueous solution of bumetanide through subcutaneous route was known in the art and therefore, one skilled in the art would have easily envisioned administering the composition in the form of an aqueous solution through subcutaneous route and having a pH which is suitable for subcutaneous administration, such as the pH taught by the cited prior art references.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘038, Roy, Ong and Westward and further incorporate sugar alcohol/mannitol, tonicity agent, and preservative in the formulation of ‘038. As discussed supra, Roy teaches mannitol (sugar alcohol) as suitable diluent. Roy also teaches sugar alcohol, sodium chloride and other tonicity adjusting agent can be added to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral administration. Thus, one skilled in the art would have been motivated to include mannitol in the formulation of ‘038 as a diluent and include other sugar alcohol and tonicity adjusting agent to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral (e.g. subcutaneous) administration.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘038, Roy, Ong and Westward and further incorporate a buffering agent as taught in Roy because addition of a buffer to maintain the pH of the composition was commonly known in the art. It would have also been obvious to include a preservative such as benzyl alcohol, as taught in Westward, to prevent microbial growth in the formulation.
Regarding claim 17, as discussed supra, Ong teaches utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. This suggests that low solubility results poor bioavailability and Ong teaches potassium salt of bumetanide provides increased aqueous solubility. Thus, it would have been obvious to one skilled in the art to optimize and maximize the bioavailability of the composition by increasing the solubility because a composition having higher bioavailability is desired per the teachings of Ong. Moreover, the combination of the references teach the same composition as recited in the instant claims and therefore, the composition taught by the prior art would necessarily have a similar bioavailability as recited in the claims.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Claims 5, 7-9, 11, 13, 15, 17, 19, 21, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12329731B2 in view of Roy (IN2476/MUM/2011 A; Mar. 15 2013), Ong (CrystEngComm, 2012, 14, 2428-2434).
‘731 claims a stable pharmaceutical composition for intranasal administration, comprising an aqueous solution having a pH of between about 6 and about 8, between about 5 mg/mL and about 10 mg/mL potassium bumetanide salt. The composition comprises a preservative, a viscosity enhancer, and a tonicity agent (mannitol). ‘731 does not claim or require a buffering agent in the solution. ‘731 claims a method of treating edema in a subject comprising intranasally administering to the subject a dose of from 25 μL to 250 μL of the pharmaceutical composition, wherein the subject has congestive heart failure or renal insufficiency, wherein the subject is experiencing impaired gastrointestinal absorption of oral diuretic therapy or reduced intestinal motility prior to the administering (i.e. edema is refractory to oral diuretics).
‘731 does not teach administering the composition subcutaneously. ‘731 also does not teach the composition further comprising buffering agent, sugar or sugar alcohol, bioavailability of the composition, and wherein the composition administered in outpatient setting. However, Roy and Ong cure these deficiencies.
The teachings of Roy and Ong discussed supra are incorporated herein.
It would have been obvious to administer the formulation comprising bumetanide through subcutaneous route because Roy teaches the formulation comprising bumetanide in the form of aqueous solution to treat congestive heart failure can be administered subcutaneously. The administration of a formulation comprising an aqueous solution of bumetanide through subcutaneous route was known in the art and therefore, one skilled in the art would have easily envisioned administering the composition comprising an aqueous solution through subcutaneous route.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘731, Roy and Ong and further incorporate sugar alcohol or mannitol in the formulation of ‘731. As discussed supra, Roy teaches mannitol (sugar alcohol) as suitable diluent. Roy also teaches sugar alcohol can be added to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral administration. Thus, one skilled in the art would have been motivated to include mannitol in the formulation of ‘731 as a diluent or include sugar alcohol to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral (e.g. subcutaneous) administration.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘731, Roy and Ong and further incorporate a buffering agent as taught in Roy because addition of a buffer to maintain the pH of the composition was commonly known in the art.
Regarding claim 17, as discussed supra, Ong teaches utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. This suggests that low solubility results poor bioavailability and Ong teaches potassium salt of bumetanide provides increased aqueous solubility. Thus, it would have been obvious to one skilled in the art to optimize and maximize the bioavailability of the composition by increasing the solubility because a composition having higher bioavailability is desired per the teachings of Ong. Moreover, the combination of the references teach the same composition as recited in the instant claims and therefore, the composition taught by the prior art would necessarily have a similar bioavailability as recited in the claims.
Regarding claim 22, it would have been obvious to one skilled in the art to administer the composition subcutaneously to the subject in an outpatient setting or self-administer depending on the severity of the disease (e.g. edema or congestive heart failure) and whether the subject requires hospitalization or can be treated in an outpatient setting or at home by self-administration.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Claims 5, 7-9, 11, 13, 15, 17, 19, 21, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12558330B2 in view of Roy (IN2476/MUM/2011 A; Mar. 15 2013), Ong (CrystEngComm, 2012, 14, 2428-2434).
‘330 claims a stable pharmaceutical composition comprising an aqueous solution comprising (a) about 0.5 to 2 percent bumetanide (i.e. 5mg/ml to 20 mg/ml), (b) about 0.1 percent low viscosity sodium carboxymethyl cellulose, (c) about 0.5 percent benzyl alcohol (preservative), (c) about 0.078 to 0.31 percent potassium ion, and (d) about 2 to 4 percent mannitol (which reads on sugar alcohol and tonicity agent), and wherein the aqueous solution has a pH between about 6 and about 8. The aqueous solution comprising bumetanide and potassium ion would result in potassium bumetanide as recited in the instant claims and also disclosed in Ong. Moreover, addition of potassium bumetanide would have been obvious in view of the teachings of Ong. ‘330 also teaches the method of treating edema comprising administing to the subject a dose of from 25 μL to 250 μL of the pharmaceutical composition, wherein the subject has congestive heart failure or renal insufficiency, wherein the subject is experiencing impaired gastrointestinal absorption of oral diuretic therapy or reduced intestinal motility prior to the administering (i.e. edema is refractory to oral diuretics). ‘731 does not claim or require any additional buffering agent in the solution.
‘330 does not teach administering the composition subcutaneously. ‘330 also does not teach the composition further comprising buffering agent, bioavailability of the composition, and wherein the composition administered in outpatient setting. However, Roy and Ong cure these deficiencies.
The teachings of Roy and Ong discussed supra are incorporated herein.
It would have been obvious to administer the formulation comprising bumetanide through subcutaneous route because Roy teaches the formulation comprising bumetanide in the form of aqueous solution to treat congestive heart failure can be administered subcutaneously. The administration of a formulation comprising an aqueous solution of bumetanide through subcutaneous route was known in the art and therefore, one skilled in the art would have easily envisioned administering the composition comprising an aqueous solution through subcutaneous route.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘330, Roy and Ong and further incorporate a buffering agent as taught in Roy because addition of a buffer to maintain the pH of the composition was commonly known in the art.
Regarding claim 17, as discussed supra, Ong teaches utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. This suggests that low solubility results poor bioavailability and Ong teaches potassium salt of bumetanide provides increased aqueous solubility. Thus, it would have been obvious to one skilled in the art to optimize and maximize the bioavailability of the composition by increasing the solubility because a composition having higher bioavailability is desired per the teachings of Ong. Moreover, the combination of the references teach the same composition as recited in the instant claims and therefore, the composition taught by the prior art would necessarily have a similar bioavailability as recited in the claims.
Regarding claim 22, it would have been obvious to one skilled in the art to administer the composition subcutaneously to the subject in an outpatient setting or self-administer depending on the severity of the disease (e.g. edema or congestive heart failure) and whether the subject requires hospitalization or can be treated in an outpatient setting or at home by self-administration.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Claims 5, 7-9, 11, 13, 15, 17, 19, 21, 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19457923 in view of Roy (IN2476/MUM/2011 A; Mar. 15 2013) and Ong (CrystEngComm, 2012, 14, 2428-2434).
‘923 claims a pharmaceutical composition comprising (i) an aqueous solution of between about 5 mg/mL and about 10 mg/mL potassium bumetanide salt, (ii) a tonicity agent, and (iii) a preservative, wherein the pharmaceutical composition has a pH of between about 5 and about 9.
‘923 does not teach the composition for treating edema, wherein the subject has congestive heart failure, and administering the composition subcutaneously. ‘319 also does not teach the composition further comprising buffering agent, sugar or sugar alcohol, the dose volume, bioavailability of the composition, wherein the edema is refractory to oral diuretics and the composition administered in outpatient setting. However, Roy and Ong cure these deficiencies.
The teachings of Roy and Ong discussed supra are incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘923, Roy and Ong and utilize the formulation of ‘923 for treating edema wherein the subject has edema and/or congestive heart failure and administer the formulation to the subject subcutaneously. As discussed supra, both Roy and Ong teach bumetanide used for treating congestive heart failure and Ong specifically teaches bumetanide is a diuretic used for treating edema in congestive heart failure. Thus, it would have been obvious to one skilled in the art to utilize bumetanide for treating edema wherein the subject has congestive heart failure as bumetanide was known and indicated to treat this disease/condition in a subject. Further, it would have been obvious to administer the formulation comprising bumetanide through subcutaneous route because Roy teaches the formulation comprising bumetanide in the form of aqueous solution to treat congestive heart failure can be administered subcutaneously. The administration of a formulation comprising an aqueous solution of bumetanide through subcutaneous route was known in the art and therefore, one skilled in the art would have easily envisioned administering the composition comprising an aqueous solution through subcutaneous route.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘923, Roy and Ong and further incorporate sugar alcohol or mannitol in the formulation of ‘923. As discussed supra, Roy teaches mannitol (sugar alcohol) as suitable diluent. Roy also teaches sugar alcohol can be added to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral administration. Thus, one skilled in the art would have been motivated to include mannitol in the formulation of ‘923 as a diluent or include sugar alcohol to formulate an isotonic composition to improve the ability of the composition to be tolerated on parenteral (e.g. subcutaneous) administration.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of ‘923, Roy and Ong and further incorporate a buffering agent as taught in Roy because addition of a buffer to maintain the pH of the composition was commonly known in the art.
Regarding claim 19, as discussed supra, Ong teaches Bumetanide is indicated to manage oedema typically associated with congestive heart failure, hepatic and renal disease and that as free acid in solid oral dosage and injectable forms, bumetanide has low aqueous solubility, which limits its utility in low volume injectable delivery. Identification of salts with higher aqueous solubilities could facilitate the development of low volume, parenteral formulations of bumetanide. Thus, it would have been obvious to ones skilled in the art to treat edema, which is not treated well with oral dosage (e.g. due to bumetanide having low aqueous solubility), with potassium bumetanide in low volume parenteral form. Thus, the combination of ‘923, Roy and Ong render obvious treating edema refractory to oral diuretic.
Regarding claim 15, as discussed supra, Ong teaches the solubility increase for the potassium salt can be particularly important to low-volume parenteral formulations of bumetanide, as it facilitates the preparation of concentrated drug solutions at the near neutral pH. Thus, it would have been obvious to one skilled in the art that use of potassium salt of bumetanide can provide concentrated drug solution which can be administered with low volume. The amount of volume of the dose would depend on the subject size, disease severity, etc., and therefore it would have been obvious to optimize the dose volume and amount of bumetanide based on these parameters. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 17, as discussed supra, Ong teaches utilization of salts is a common strategy to enhance solubility of low molecular wight active pharmaceutical ingredients (API). In their neutral forms, ionizable APIs may suffer from sub-optimal pharmaceutical properties, such as slow dissolution rate and low solubility in aqueous systems, often resulting in poor oral bioavailability. This suggests that low solubility results poor bioavailability and Ong teaches potassium salt of bumetanide provides increased aqueous solubility. Thus, it would have been obvious to one skilled in the art to optimize and maximize the bioavailability of the composition by increasing the solubility because a composition having higher bioavailability is desired per the teachings of Ong. Moreover, the combination of the references teach the same composition as recited in the instant claims and therefore, the composition taught by the prior art would necessarily have a similar bioavailability as recited in the claims.
Regarding claim 22, it would have been obvious to one skilled in the art to administer the composition subcutaneously to the subject in an outpatient setting or self-administer depending on the severity of the disease (e.g. edema or congestive heart failure) and whether the subject requires hospitalization or can be treated in an outpatient setting or at home by self-administration.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Conclusion
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/ALI S SAEED/ Examiner, Art Unit 1616
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