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 .
Priority
This application is a U.S. national stage patent application under 35 U.S.C. § 371 of
International Application No. PCT/US2021/044723, filed on August 5, 2021, which claims the benefit of, and priority to, U.S. Provisional Application No. 63/061,518, filed on August 5, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/09/2025 has been considered by the examiner.
Claims status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on October 17, 2025. Claims 1, 10-11, 16-18, 20-24, 26-29, and 31-32 are pending and under examination. Claims 2-9, 12-15, 19, 25, and 30 are cancelled.
Action Summary
Claims 1, 10-11, 16-18, 24, 26, 29, and 31 rejected under 35 U.S.C. 103 as being unpatentable over Sica et al (Jacc Basic to Translational Science Vol. 3, No. 1, February 2018, pages 25-34) in view of Frederick Furness (ONdrugDelivery Issue No 97, May 13th, 2019) and Madhu (Differencebetween.com, February 23, 2018), are withdrawn.
Claims 20-23 and 32 rejected under 35 U.S.C. 103 as being unpatentable over Sica et al (Jacc: Basic to Translational Science Vol. 3, No. 1, February 2018, pages 25-34) in view of Frederick Furness (ONdrugDelivery Issue No 97, May 13th, 2019) and Madhu (Differencebetween.com, February 23, 2018) as applied to claims 1, 10-11, 16-18, 24, 26, 29, and 31, in further view of American Reagent Inc (Furosemide injection, USP, 10 mg/ml label, published online on February 16, 2017 by Wayback machine), are withdrawn.
Claims 27 and 28 rejected under 35 U.S.C. 103 as being unpatentable over Sica et al (Jacc: Basic to Translational Science Vol. 3, No. 1, February 2018, pages 25-34) in view of Frederick Furness (ONdrugDelivery Issue No 97, May 13th, 2019) and Madhu (Differencebetween.com, Februrary 23, 2018) as applied to claims 1, 10-11, 16-18, 24, 26, 29, and 31, in further view of Goulding et al (Can J Crit Care Nurs. 2015 Winter;26(4):23-7), are withdrawn.
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.
Claims 1, 10-11, 16-18, 24, 26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Sica et al (Jacc Basic to Translational Science Vol. 3, No. 1, February 2018, pages 25-34) in view of Frederick Furness (ONdrugDelivery Issue No 97, May 13th, 2019) and Michaels et al (US9,884,039 B2).
Sica discloses a method of treating fluid overload in congestive heart failure comprising a buffered subcutaneously infusion liquid formulation comprising 30 mg furosemide in hour 1 followed by 12.5 mg/h for 4 h at a pH 7.4 using a wearable patch pump. (See the Highlights Section of page 26). Sica teaches parenteral diuretics form the cornerstone of decongestion in heart failure. (See Summary Section.) Moreover, Sica teaches the subcutaneous furosemide formulation consists of furosemide reconstituted in a buffered solution containing tromethamine at a physiological pH of approximately 7.4 (range 7.2 to 7.6). Following SC administration, therapeutic levels of furosemide were reached within 30 min and maintained for up to 6 h. This resulted in complete bioavailability and equivalent diuresis when compared with 80 mg of intravenous furosemide. (See last paragraph of the right column of page 27) The buffer solution taught by Sica contemplates water. Sica further teaches the subject is an adult. (See Table 1.) Lastly Sica teaches the adult patient has a NYHA class II. However, due to some overlap between class II and class III, the patient taught by Sica can reasonably encompasses both classes II and III heart failure.
Sica does not teach a prefilled polymeric cartridge. Moreover, Sica does not teach tromethamine hydrochloride in the amount of 89 mg.
Frederick Furness teaches traditional methods of SC drug delivery include autoinjectors and infusion pumps. These delivery regimens have traditionally been limited by the volume which can be delivered. (See third paragraph of the middle column of page 41.) Moreover, Frederick Furness teaches in the drive to formulate biologics for patient adherence, higher volumes and higher viscosities are typical product profiles of many SC drugs. However, higher viscosities may not allow for conventional delivery due to the need for longer injection times to reduce patient discomfort. West recognized this trend and responded by developing its SmartDose® drug delivery platform, which includes a first-generation device that allows up to 3.5 mL of liquid drug to be administered over a longer period. (See last paragraph of the right column of page 35.) Frederick Furness also teaches the second generation SmartDose® 10 mL device had a well-received on-body size and was intuitive, easy to use and desirable. The second-generation SmartDose® 10 mL device was voted the most preferable treatment that allows for monthly dosing, compared with the other treatment options, which included weekly autoinjectors, monthly dosing via multiple autoinjectors, visiting a clinic or via infusion. Patients don’t like taking frequent injections and a second generation SmartDose® 10 mL device monthly injection helped them with less frequent injections (See last paragraph of the right column of page 36.) Monthly dosing is considered a single dose. The smartdose device as wearable device contains preloaded options and large volume and a (See page first paragraph of the left column of page 36 bridging last paragraph of the left column of page 37.) Preloaded meets the limitation of prefilled. Lastly, Frederick Furness teaches the SmartDose® drug as a delivery system for delivery of FUROSCIX® (furosemide) for the treatment of oedema in patients with heart failure. (See first paragraph of the left column of page 37.)
Michaels teaches a method of treating a patient with or exhibiting the symptoms of edema, hypertension or heart failure, the method comprising: administering to a patient a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation comprises: furosemide, or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein furosemide is the sole therapeutically active agent in the liquid pharmaceutical formulation and the amount of furosemide in the liquid pharmaceutical formulation is between about 2 mg/mL to about 15 mg/mL; and a pharmaceutically acceptable buffer comprising tris(hydroxymethyl)aminomethane, wherein the concentration of tris(hydroxymethyl)aminomethane in the liquid pharmaceutical formulation is in a range of about 50 mM to about 250 mM; wherein the liquid pharmaceutical formulation is isosmotic and has a pH between about 7.2 to about 8, and the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is greater than or equal to two. (See claim 1.) tris(hydroxymethyl)aminomethane is the same as tromethamine. Moreover, Michaels teaches the administering comprises administering subcutaneously the pharmaceutical formulation. (See claim 2.) A particular preference was given on a liquid pharmaceutical composition consisting of 8 mg/ml furosemide and 50 nM tris buffer at pH 7.0 to 8.0. (See Example 5.) Converting mM to mg/ml: mg/ml = mM x Molecular weight (g/mol)/1000; 50 mM X 157.60 (MW of tromethamine hydrochloride)/1000 = 7.9 mg/ml. Therefore, the 50nM amounts to 7.9 g/ml. Furthermore, Michaels teaches water was used to prepare the Tris buffer. (See lines 50-65 of column 14.)
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method taught by Sica by including congestion due to fluid overload and by substituting the wearable patch pump with the smartdose® taught by Frederick Furness that comprises a preloaded (prefilled) polymeric cartridge (Daikyo Crystal Zenith® polymer cartridge) and by substituting the tromethamine taught by Sica with trometamine hydrochloride taught by Madhu and Michaels to give Applicant’s claimed invention. One would have been motivated to do so, because Sica teaches parenteral diuretics form the cornerstone of decongestion in heart failure and fluid overload in heart failure and because Frederick Furness teaches pumps and other devices are limited by their small volume where said limitation can be overcome by the use of a smartdoce® device containing a preloaded polymeric cartridge comprising furosemide and that can utilize a large volume of 10 ml and because Michaels teaches trometamine hydrochloride can be used as a buffer in the amount of 7.9 mg/ml to prepare 8 mg/ml furosemide. The 7.9 mg/ml Tris and 8 mg/ml furesemide for the total volume of 10 mg of the smartdoce® device result in 79 mg Tris Hcl and 80 mg furosemide. One would reasonably expect the method to minimize frequent administration and easy to use and desirable and to treat congestion due to fluid overload with success.
With respect to the plasma concentration, the total urine output, and the maximum/total urine sodium excretion limitations of claim 18. These limitations simply express the intended outcome of the method step positively recited. These limitations would naturally flow from the fact the claimed method step claimed is obvious over the prior references in combination.
Claims 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over Sica et al (Jacc Basic to Translational Science Vol. 3, No. 1, February 2018, pages 25-34) in view of Frederick Furness (ONdrugDelivery Issue No 97, May 13th, 2019) and Michaels et al (US9,884,039 B2) as applied to claims 1, 10-11, 16-18, 24, 26, 29, in further view of American Reagent Inc (Furosemide injection, USP, 10 mg/ml label, published online on February 16, 2017 by Wayback machine).
The teachings of Sica, Frederick Furness, and Michaels have been discussed in the rejection set forth above.
Sica, Frederick Furness, and Michaels collectively do not teach one or more pharmaceutically acceptable excipient in this case sodium chloride.
American Reagent Inc. teaches furosemide is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Furosemide Injection 10 mg/mL is a sterile, non-pyrogenic solution in vials for intravenous and intramuscular injection. Each mL contains: Furosemide 10 mg, Water for Injection q.s., Sodium Chloride for isotonicity, Sodium Hydroxide. (See first few paragraphs of the left column.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to include sodium chloride as a pharmaceutically acceptable excipient as taught by American Reagent Inc into the method taught by Sica, Frederick Furness, and Michaels to give Applicant’s claimed invention. One would have been motivated to do so, because American Reagent Inc. teaches furosemide Injection 10 mg/mL is a sterile, non-pyrogenic solution in vials for intravenous and intramuscular injection and each mL contains furosemide 10 mg, Water for Injection q.s., Sodium Chloride for isotonicity, Sodium Hydroxide. One would reasonably expect the inclusion of sodium chloride as an isotonic agent to match the osmotic pressure of body fluids, preventing cell damage and ensuring patient comfort.
Claims 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Sica et al (Jacc Basic to Translational Science Vol. 3, No. 1, February 2018, pages 25-34) in view of Frederick Furness (ONdrugDelivery Issue No 97, May 13th, 2019) and Michaels et al (US9,884,039 B2) as applied to claims 1, 10-11, 16-18, 24, 26, and 29, in further view of Goulding et al (Can J Crit Care Nurs. 2015 Winter;26(4):23-7).
The teachings of Sica, Frederick Furness, and Michaels have been discussed in the rejection set forth above.
Sica, Frederick Furness, and Michaels collectively do not teach alerting and visualizing not all of the total volume of 10 ml; of the liquid formulation was delivered from the prefilled polymeric cartridge.
Goulding teaches most intravenous medication errors occur during administration. Smart pumps can reduce the incidence of dose or rate errors using soft and hard limits. However, industry standard dose error reduction software misses errors that occur during titration. The dose change alert was developed to detect errors during titration. (See Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the smartdose® delivery system by including into the program an alert that allows the user or the patient to visualize not all of the total volume of 10 ml; of the liquid formulation was delivered from the prefilled polymeric cartridge to give Applicant’s claimed invention. The motivation to do so is taught by Goulding. One would reasonably expect the smartdose® delivery system to reduce the incidence of the dose or rate errors and improve patient compliance.
Claims 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Michaels et al (US9,884,039 B2) in view of Sica et al (Jacc Basic to Translational Science Vol. 3, No. 1, February 2018, pages 25-34) in view of Frederick Furness (ONdrugDelivery Issue No 97, May 13th, 2019).
Michaels teaches a method of treating a patient with or exhibiting the symptoms of edema, hypertension or heart failure, the method comprising: administering to a patient a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation comprises: furosemide, or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein furosemide is the sole therapeutically active agent in the liquid pharmaceutical formulation and the amount of furosemide in the liquid pharmaceutical formulation is between about 2 mg/mL to about 15 mg/mL; and a pharmaceutically acceptable buffer comprising tris(hydroxymethyl)aminomethane, wherein the concentration of tris(hydroxymethyl)aminomethane in the liquid pharmaceutical formulation is in a range of about 50 mM to about 250 mM; wherein the liquid pharmaceutical formulation is isosmotic and has a pH between about 7.2 to about 8, and the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is greater than or equal to two. (See claim 1.) tris(hydroxymethyl)aminomethane is the same as tromethamine. Moreover, Michaels teaches the administering comprises administering subcutaneously the pharmaceutical formulation. (See claim 2.) A particular preference was given on a liquid pharmaceutical composition consisting of 8 mg/ml furosemide and 50 nM tris buffer at pH 7.0 to 8.0. (See Example 5.) Converting mM to mg/ml: mg/ml = mM x Molecular weight (g/mol)/1000; 50 mM X 157.60 (MW of tromethamine hydrochloride)/1000 = 7.9 mg/ml. Therefore, the 50nM amounts to 7.9 g/ml. Additionally, Michaels teaches a number of devices have been proposed to facilitate self - administration of a pharmaceutical formulation. The device typically includes a reservoir containing for example pre-loaded with the pharmaceutical formulation to be administered. (See lines 32-36 of column 12.) Pre-loaded reads on pre-filled. The medical device can be for a single use. (See lines 4-6 of column 13.) Furthermore, Michaels teaches water and sodium hydroxide/sodium hydrochloride were used to prepare the Tris buffer. (See lines 50-65 of column 14.)
Michaels does not teach a volume of 10 ml.
Frederick Furness teaches traditional methods of SC drug delivery include autoinjectors and infusion pumps. These delivery regimens have traditionally been limited by the volume which can be delivered. (See third paragraph of the middle column of page 41.) Moreover, Frederick Furness teaches in the drive to formulate biologics for patient adherence, higher volumes and higher viscosities are typical product profiles of many SC drugs. However, higher viscosities may not allow for conventional delivery due to the need for longer injection times to reduce patient discomfort. West recognized this trend and responded by developing its SmartDose® drug delivery platform, which includes a first-generation device that allows up to 3.5 mL of liquid drug to be administered over a longer period. (See last paragraph of the right column of page 35.) Frederick Furness also teaches the second generation SmartDose® 10 mL device had a well-received on-body size and was intuitive, easy to use and desirable. The second-generation SmartDose® 10 mL device was voted the most preferable treatment that allows for monthly dosing, compared with the other treatment options, which included weekly autoinjectors, monthly dosing via multiple autoinjectors, visiting a clinic or via infusion. Patients don’t like taking frequent injections and a second generation SmartDose® 10 mL device monthly injection helped them with less frequent injections (See last paragraph of the right column of page 36.) Monthly dosing is considered a single dose. The smartdose device a preloaded (prefilled) polymeric cartridge (Daikyo Crystal Zenith® polymer cartridge) as wearable device contains preloaded options and large volume. (See page first paragraph of the left column of page 36 bridging last paragraph of the left column of page 37.) Preloaded meets the limitation of prefilled. Lastly, Frederick Furness teaches the SmartDose® drug as a delivery system for delivery of FUROSCIX® (furosemide) for the treatment of oedema in patients with heart failure. (See first paragraph of the left column of page 37.)
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method taught by Michaels by substituting the medical reservoir taught by Michaels with the smartdose® taught by Frederick Furness that comprises a preloaded (prefilled) polymeric cartridge (Daikyo Crystal Zenith® polymer cartridge) comprising furosemide and that can utilize a large volume of 10 ml to give Applicant’s claimed invention. One would have been motivated to do so, because Frederick Furness teaches pumps and other devices are limited by their small volume where said limitation can be overcome by the use of a smartdoce® device containing a preloaded polymeric cartridge comprising furosemide and that can utilize a large volume of 10 ml. One would reasonably expect the substitution to successfully give a single-use polymeric prefilled cartridge that can be associated with an on- body wearable delivery device using a five-hour bi-phasic delivery profile (Smartdose®) for administering subcutaneously a liquid pharmaceutical formulation to an adult human.
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on October 17, 2025
Applicant’s argument
Applicant argues that Sica does not teach or suggest a furosemide formulation that is isosmotic and contains 79 mg of Tris. Rather, Sica describes pharmacokinetic studies of subcutaneous administration of a furosemide formulation. Nowhere in Sica do the authors make any mention of a cartridge, let alone the instantly claimed single-use polymeric cartridge that can be associated with an on- body wearable delivery device. Sica only refers to a wearable patch pump without any explanation of how the formulation is loaded into the wearable patch pump. This is because it is only the Applicant who has discovered that the optimized furosemide formulation recited in claim 1 can be loaded in an on-body wearable delivery device using a prefilled cartridge, in part, due to the stability of the formulation, which is neither taught nor suggested in Sica.
Examiner’s response
In response, Applicant’s argument is not persuasive. Sica may well not teach or suggest a furosemide formulation that contains 79 mg of Tris and a polymeric cartridge. However, Sica clearly teaches a subcutaneous formulation consists of furosemide reconstituted in a buffered solution containing tromethamine at a physiological pH of approximately 7.4 (range 7.2 to 7.6) using a wearable patch pump. Frederick Furness also teaches a second generation SmartDose® 10 mL device which is a preloaded (prefilled) polymeric cartridge (Daikyo Crystal Zenith® polymer cartridge) that is well-received on-body size and was intuitive, easy to use and desirable that was voted the most preferable treatment that allows for monthly dosing, compared with the other treatment options, which included weekly autoinjectors, monthly dosing via multiple autoinjectors, visiting a clinic or via infusion. Patients don’t like taking frequent injections and a second generation SmartDose® 10 mL device monthly injection helped them with less frequent injections. Michaels teaches pharmaceutical composition for subcutaneous administration consisting of 8 mg/ml furosemide and 50 nM tris buffer at pH 7.0 to 8.0. (See Example 5.) Converting mM to mg/ml: mg/ml = mM x Molecular weight (g/mol)/1000; 50 mM X 157.60 (MW of tromethamine hydrochloride)/1000 = 7.9 mg/ml. Therefore, the 50nM amounts to 7.9 g/ml. Furthermore, Michaels teaches water was used to prepare the Tris buffer. (See lines 50-65 of column 14.) Therefore, a person of ordinary skill in the art can reasonably expect furosemide formulation consisting of furosemide in the amount of 80 mg and Trishydrochlroide in the amount of 7.9 mg/ml can be loaded in an on-body wearable delivery device using a prefilled 10 ml cartridge for the purpose of Sica.
Applicant’s argument
Applicant argues that the claimed treatment regimen of subcutaneously administering the furosemide formulation over about 5 hours results in favorable pharmacokinetic results compared to intravenous administration. See, e.g., Tables 1 and 2, Figures 1 and 2, and page 45, lines 4-7 of the application as filed: "[f]urther analysis of the individual efficacy response data for [subcutaneous administration of] furosemide demonstrated that, surprisingly, both maximum hourly urine output and hourly sodium excretion were achieved in patients with a furosemide blood plasma concentration of about 1000 ng/mL." One of skill in the art could not predict these favorable results based on the teachings of Sica.
Examiner’s response
In response, Applicant’s argument is not persuasive. It may well be true that claimed treatment regimen of subcutaneously administering the furosemide formulation over about 5 hours results in favorable pharmacokinetic results compared to intravenous administration. However, the Examiner contends that said comparison would be expected by the fact that Sica teaches a buffered subcutaneously infusion liquid formulation comprising 30 mg furosemide in hour 1 followed by 12.5 mg/h for 4 h at a pH 7.4 using a wearable patch pump for treating fluid overload in congestive heart failure and by the fact that Michaels teaches pharmaceutical composition for subcutaneous administration consisting of 8 mg/ml furosemide and 50 nM tris buffer at pH 7.0 to 8.0. (See Example 5.) Converting mM to mg/ml: mg/ml = mM x Molecular weight (g/mol)/1000; 50 mM X 157.60 (MW of tromethamine hydrochloride)/1000 = 7.9 mg/ml. Therefore, the 50nM amounts to 7.9 g/ml. A person of ordinary skill in the art can reasonably expect the modified subcutaneous composition taught by Sica and Michaels to result in favorable pharmacokinetic results compared to intravenous administration.
Lastly, Applicant’s argument with respect to Madhu is not persuasive as Madhu is no longer cited in the new rejections set forth above.
Conclusion
Claims 1, 10-11, 16-18, 20-24, 26-29, and 31-32 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628