DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Receipt of Remarks/Amendments filed on 02/02/2026 is acknowledged. Claims 1, 7-8, 10-13, 17, and 19 are amended and claims 6, 14, and 18 are canceled. Claims 28-31 are new. Claims 25-27 remain withdrawn as being drawn to a non-elected invention. Claims 1-5, 7-13, 15-17, 19-24, and 28-31 are examined on the merits herein.
Priority
The instant application filed 12/22/2022 claims foreign priority to IN202141061522, filed 12/29/2021.
Withdrawn Rejections
Claims 1-12, 17-18, and 20-24 were rejected under 35 U.S.C. 112(b) as being indefinite. Applicant’s amendments to the claims and remarks have overcome the rejections and the rejections are withdrawn.
Claims 13 and 16 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Augustin. Applicant’s amendments to claim 13 have overcome the rejection and the rejection is withdrawn.
Claims 1-23 were rejected under 35 U.S.C. 103 as being unpatentable over Akasapu. In view of Applicant’s arguments and upon further consideration the rejection is overcome and is withdrawn.
The following rejections are new as necessitated by amendment:
Claim Rejections - 35 USC § 112(a) – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 13, and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite a molar ratio as part of an amendment filed on 02/02/2026. However, the instant specification does not provide support for the full range of the instantly recited molar ratio. In particular, the instant specification recites the broadest range of the molar ratio to be about 0.07 to about 1.2 (paragraph 56). The claims as originally filed only recite a molar ratio in the range of 0.17 to 0.66. Thus, a molar ratio of epinephrine to sodium metabisulfite, measured as sulfite equivalents, above the value of 1.2 represents new matter.
Claims 1, 13, and 19 have been amended to recite that the formulation retains at least about 95% of its initial activity after storage, as part of a preliminary amendment filed on 7/31/03. However, the instant specification does not provide full support for this limitation. In particular, the instant specification and claims as originally filed do not explicitly recite such a limitation and the examples pointed to in tables 1-23 disclose activity for formulations with a narrower scope than the formulation which is instantly claimed. Tables 1-20 disclose the stability of epinephrin premix formulations that do not comprise EDTA. Thus, the results from tables 1-20 cannot be seen as support for the instantly claimed formulations, which all comprise EDTA, having at least 95% activity after storage. Tables 21 to 23 disclose formulations comprising 0.032 mg/mL EDTA and 0.05 mg/mL sodium metabisulfite which would not provide support for the formulations of claims 1 and 13, which comprise any amount of EDTA and sodium metabisulfite (within the molar ratio), having at least 95% activity after storage. Lastly, tables 21 to 23 only disclose examples with pH values around 4, meaning there is no support for a formulation having the full pH range of claim 19 (i.e., 2.2 to 5) having the instantly claimed activity. Thus, the specification does not provide a disclosure of the instantly claimed formulations, in their full scope, having at least about 95% of their initial activity after storage as newly recited in claims 1, 13, and 19.
If Applicant believes these rejections are in error, applicant must disclose where in the specification support for the entire scope of the amendment(s) and/or new claims can be found. As a result, claims 1, 13, and 19 represents new matter.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 9-10, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Leeah, T. A., et al. (US 20210251888 A1, 08/19/2021, on record), hereinafter Leeah.
Leeah teaches ready-to-use liquid, injectable formulations comprising lidocaine and epinephrine (abstract). Sample 1 teaches lidocaine (5.33 mg/mL); epinephrine (10.5 mcg/mL); sodium chloride (7 mcg/mL); sodium metabisulfite (5.45 mcg/mL); EDTA sodium (0.2 mg/mL); sodium citrate; citric acid; and sterile water for injection (table 1a). Sample 1 has an initial and final pH of 5.552 and 5.151, respectively.
Thus, Leeah teaches a formulation comprising 10 to 70 mcg/ml of epinephrine, sodium chloride, EDTA, and sodium metabisulfite, wherein the formulation is an aqueous premix formulation (i.e., ready-to-use liquid formulation) with a pH of about 2 to about 6 (i.e., ~5.5 and 5.1) as defined in instant claim 1. Regarding the molar ratio of claim 1, epinephrine is present at 10.5 mcg/mL (MW: 183.2 g/mol), which is equivalent to 0.0573 mM, and sodium metabisulfite is present at 5.45 mcg/mL (MW:190.1 g/mol), which is equivalent to 0.0287 mM. There are two sulfite equivalents per mole of sodium metabisulfite meaning the molar ratio of epinephrine to sodium metabisulfite, measured as sulfite equivalents, is equal to (0.0573/(2 x 0.0287)) which is ~1, which falls within the instantly claimed range (i.e., 0.07 to 1.33).
The pH of ~5.5 and 5.14 further reads on the pH range of claim 9. The amount of EDTA is 0.2 mg/mL which falls within the range of claim 10.
A further embodiment of the invention includes a light-sensitive container comprising a syringe containing the ready-to-use liquid formulation. Said light-resistant container may comprise, for example, an amber-colored bag, film, or plastic ([0021]), which reads on a flexible container comprising the formulation of claim 1 as defined in claim 20.
Claims 1, 9-10, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Leeah, T. A., et al. (US 10952962 B1, 03/23/2021, on record), hereinafter Leeah2.
Leeah2 teaches a ready-to-use liquid formulation comprising lidocaine hydrochloride and epinephrine hydrochloride (abstract). A first embodiment is directed to a ready-to-use liquid formulation comprising: lidocaine hydrochloride in an amount of about 10 mg/mL or about 20 mg/mL; epinephrine hydrochloride in an amount of about 10 mcg/mL, based on epinephrine free base; sodium chloride in an amount of about 7 mg/mL; sodium metabisulfite in an amount of about 5.2 mcg/mL; citric acid in an amount of about 0.2 mg/mL; ethylenediaminetetraacetic acid (“EDTA”) sodium in an amount of about 0.2 mg/mL; a sufficient amount of sterile water for injection; and a sufficient amount of a pH adjuster to obtain a pH of about 3.4 (col. 1, lines 57-67; exemplary compositions L1 and L2).
Thus, Leeah2 teaches a formulation comprising 10 mcg/mL of epinephrine, a salt, EDTA, sodium metabisulfite, wherein the formulation is an aqueous premix formulation (i.e., ready-to-use liquid formulation) with a pH of about 2 to about 6 (i.e., 3.4) as defined in instant claim 1. Regarding the molar ratio of claim 1, epinephrine is present at 10 mcg/mL (MW: 183.2 g/mol), which is equivalent to 0.0573 mM, and sodium metabisulfite is present at 5.45 mcg/mL (MW:190.1 g/mol), which is equivalent to 0.0287 mM. There are two sulfite equivalents per mole of sodium metabisulfite meaning the molar ratio of epinephrine to sodium metabisulfite, measured as sulfite equivalents, is equal to (0.0573/(2 x 0.0287)) which is ~1, which falls within the instantly claimed range (i.e., 0.07 to 1.33). Regarding the molar ratio of claim 1, epinephrine is present at 10 mcg/mL (MW: 183.2 g/mol), which is equivalent to 0.0546 mM, and sodium metabisulfite is present at 5.2 mcg/mL (MW:190.1 g/mol), which is equivalent to 0.0274 mM. There are two sulfite equivalents per mole of sodium metabisulfite meaning the molar ratio of epinephrine to sodium metabisulfite, measured as sulfite equivalents, is equal to (0.0546/(2 x 0.0274)) which is ~1, which falls within the instantly claimed range (i.e., 0.07 to 1.33).
The pH of 3.4 further reads on the pH range of claim 9. The amount of EDTA is 0.2 mg/mL which falls within the range of claim 10.
In a second aspect of the first embodiment, the ready-to-use liquid formulation may be stored within a light-resistant container such as an amber-colored bag, film, or plastic (col. 2, lines 4-10), which reads on a flexible container comprising the formulation of claim 1 as defined in claim 20.
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 1-5, 7-13, 15-17, 19, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Augustin, S., et al. (WO 2019072723 A1, 04/18/2019, on record), hereinafter Augustin in view of Matre, E.T., et al. (2017). Extended Stability of Epinephrine Hydrochloride Injection in Polyvinyl Chloride Bags Stored in Amber Ultraviolet Light-Blocking Bags. Hosp Pharm. 52(8):570-573. (on record), hereinafter Matre.
Augustin discloses stabilized injectable pharmaceutical compositions of L-epinephrine (title). The pharmaceutical composition comprises epinephrine and an antioxidant selected from the group consisting of sodium metabisulfite, sodium sulfite and sodium bisulfite with a specific molar ratio of epinephrine to sulfite equivalents (E:S). The composition further comprises a tonicity regulating agent (i.e., NaCl), EDTA or Na2EDTA*2H2O, and pH 3-4.5 (claim 1).
A specific embodiment is a pharmaceutical composition comprising epinephrine and an antioxidant selected from the group consisting of sodium metabisulfite, sodium sulfite and sodium bisulfite in a molar ratio of epinephrine to sulfite equivalents (E:S) of 0.6. The composition further comprises 8-9.5 mg/mL of NaCl (i.e., sodium chloride), 0.09-0.16 mg/mL EDTA or 0.12-0.2 mg/mL Na2EDTA*2H2O (i.e., edetate disodium dihydrate), and pH 3.3-4.2. The concentration of epinephrine is 2.5-3.5 or 5.5-6.5 mM (p. 12-13, lines 31-4).
The pharmaceutical compositions of Augustin provide surprisingly- enhanced stability over other formulations. The stability enhancements provide benefits at least in terms of patient safety, enhanced shelf-life, reduced waste, reduced cost, and/or improved convenience for the user. The compositions of the present invention provide formulations that are stable at room temperature and can be stored without the need for refrigeration (p. 20, lines 25-31). Formulations with an E:S ratio = 0.6 are regarded optimal for long term stability (p. 38, lines 1-2).
Augustin further teaches a process of preparation of the pharmaceutical composition wherein the epinephrine, antioxidant, NaCl and EDTA together with water are brought into a suitable dosage form (claim 10). The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (p. 27, lines 12-14). For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration (p. 27-28, lines 29-1).
The teachings of Augustin differ from that of the instant invention in that Augustin does not explicitly teach about 10 mcg/ml to about 70 mcg/ml epinephrine as recited in instant claims 1 and 13 nor does Augustin explicitly teach the limitation of claim 17 and 0.032 mg/ml of edetate disodium dihydrate as recited in claims 19 and 28.
Matre teaches that epinephrine hydrochloride for intravenous infusion is commonly diluted to concentrations ranging from 16 to 64 µg/mL (p. 1, col. 1, para. 1). Epinephrine contains a catechol moiety which is susceptible to oxidative reactions catalyzed by ultraviolet light, oxygen, increases in temperature, and basic conditions. As such, Matre studies the physical and chemical stability of epinephrine hydrochloride at concentrations of 16 and 64 µg/mL in 0.9% sodium chloride when stored at room temperature or refrigerated for 60 days while in amber ultraviolet light–blocking bags (p. 2, col. 1, para. 2; table 1).
It would have been obvious to combine the teachings of Augustin and Matre before the effective filing date of the claimed invention by providing the pharmaceutical composition of Augustin in water as an aqueous dosage form as suggested by Augustin wherein the epinephrine dosage is 16 to 64 µg/mL as taught by Matre, thereby yielding the instantly claimed invention. First, one of ordinary skill in the art would have been motivated to provide the pharmaceutical composition of Augustin as an aqueous solution as motivated by ease of administration via injection. Additionally, Augustin teaches that aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Regarding the amount of epinephrin in the aqueous solution for administration, it would have been obvious to dilute the composition of Augustin to reach the epinephrine concentration of 16 to 64 µg/mL as taught by Augustin since such a concentration is most commonly used for intravenous infusion as taught by Matre. Combining prior art elements according to known methods to yield predictable results is considered prima facie obvious. Within the aqueous solution for administration, that comprises 16 to 64 µg/mL of epinephrine, it would have also been obvious to maintain the E:S ratio, concentration of NaCl, concentration of EDTA, and pH taught by Augustin. One of ordinary skill in the art would have been motivated to maintain these parameters in the final aqueous solution for administration since they are responsible for increased formulation stability as taught by Augustin. Such a formulation would therefore have the advantage of being stable during storage, and capable of being readily administered immediately following storage. One of ordinary skill in the art would have had a reasonable expectation of success in making these modifications since Augustin and Matre both teach epinephrine compositions that are suitable for administration via injection. Furthermore, one of ordinary skill in the art would have been more than capable of adding water and adjusting concentrations, as is known and routine in the art.
It would have also been obvious to select edetate disodium dihydrate (i.e., Na2EDTA*2H2O) as the form of EDTA and sodium metabisulfite as the form of sulfite since Augustin teaches a finite number of options and it would have been “obvious to try”. It is considered prima facie obvious to choose from a finite number of identified, predictable solutions, with a reasonable expectation of success.
As such, the combined composition of Augustin and Matre comprises 16 to 64 µg/mL of epinephrine as taught by Matre and 8-9.5 mg/mL of NaCl, 0.12-0.2 mg/mL Na2EDTA*2H2O, and pH 3.3-4.2 as taught by Augustin. The composition further comprises sodium metabisulfite at a molar ratio of epinephrine to sulfite equivalents (E:S) of 0.6 as taught by Augustin. The combined composition is in the form of an aqueous solution ready for administration as made obvious above. Regarding the recitation of “for intravenous administration”, this is simply a recitation of intended use. Composition claims are analyzed based on their structural limitations. Since the composition made obvious by the prior art meets all of the structural limitations of the claim it would necessarily be capable of carrying out the recited function. Furthermore, the combined composition of Augustin and Matre is suitable for injection, specifically intravenous injection, as taught by both Augustin and Matre. This is further evidence that the combined composition would be capable of performing the recited function. Thus, the combined composition of Augustin and Matre reads on claims 1 and 13.
Regarding the epinephrine activity of the formulations of claims 1 and 13, since the composition made obvious by the prior art is identical to the composition claimed, the composition must necessarily have the characteristics claimed as an inherent property. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter, which there is reason to believe inherently includes functions that are newly cited, or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter to be shown in the prior art does not possess the characteristic relied on” (205 USPQ 594). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference.
The combined composition of Augustin and Matre reads on claim 2 since it comprises 16-64 µg/mL of epinephrine.
Regarding claims 3-5, the claimed amounts of epinephrine fall within the range of 16 to 64 µg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05.
Regarding claims 7 and 15, the combined composition of Augustin and Matre comprises NaCl (i.e., sodium chloride) at a concentration of 8-9.5 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05.
Regarding claim 8, a formulation comprising 0.9% w/v of NaCl is the same as one comprising 9 mg/ml of NaCl. Since the combined composition of Augustin and Matre comprises NaCl at a concentration of 8-9.5 mg/mL, 0.9% w/v would have been obvious. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05. Furthermore, Matre teaches using 0.9% sodium chloride in the epinephrine solution. Thus, it would have been obvious to also use 0.9% sodium chloride in the combined composition of Augustin and Matre since combining prior art elements according to known methods to yield predictable results is prima facie obvious. One of ordinary skill in the art would have had a reasonable expectation of success providing a composition with 0.9% w/v since this is a known and effective concentration of NaCl to be used in an injectable composition.
Regarding claim 9, the combined composition of Augustin and Matre has a pH of 3.3-4.2 which falls within the instantly claimed range.
Regarding claims 10 and 16, the combined composition of Augustin and Matre comprises 0.12-0.2 mg/mL of edetate disodium dihydrate which falls within the instantly claimed range.
Regarding claim 11, the combined composition of Augustin and Matre comprises a molar ratio of epinephrine to sulfite equivalents (E:S) of 0.6 which falls within the instantly claimed range.
Regarding claims 12, 16, and 29, the combined composition of Augustin and Matre comprises a E:S ratio of 0.6 and 16-64 µg/mL epinephrine. The E:S ratio of 0.6 is optimal for long term stability as taught by Augustin. As such, one of ordinary skill in the art would be motivated to maintain this ratio in the combined composition by adjusting the equivalences of sulfite. By examiners calculations, 16 µg/mL of epinephrine (MW: 183.2 g/mol) is equivalent to 0.0873 mM and at the desired E:S molar ratio of 0.6, 0.1455 mM of sodium metabisulfite (MW:190.1 g/mol) would be necessary, which is equivalent to 0.028 mg/mL of sodium metabisulfite. By the same calculations, 64 µg/mL of epinephrine is equivalent to 0.349 mM and at an E:S molar ratio of 0.6, 0.582 mM of sodium metabisulfite would be necessary which is equivalent to 0.111 mg/mL of sodium metabisulfite. Thus, the combined composition of Augustin and Matre must comprise from 0.028 mg/mL to 0.111 mg/mL of sodium metabisulfite in order to maintain the desired E:S ratio of 0.6 when the epinephrine concentration is 16-64 µg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05. Regarding claim 17, because the composition made obvious by the prior art is identical to the composition of claim 13, the composition must necessarily have the characteristics claimed as an inherent property. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter, which there is reason to believe inherently includes functions that are newly cited, or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter to be shown in the prior art does not possess the characteristic relied on” (205 USPQ 594). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference.
Regarding claim 19, the combined composition of Augustin and Matre comprises 16 to 64 µg/mL of epinephrine which encompasses the claimed amounts of epinephrine. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05. The combined composition may further comprise 0.9% sodium chloride as made obvious above in regards to claim 8. Also discussed above, in regards to claim 12 and 16, the combined composition of Augustin and Matre must comprise from 0.028 mg/mL to 0.111 mg/mL of sodium metabisulfite in order to maintain the stability effects of Augustin. The claimed amount of 0.05 mg/ml falls within that range, and in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05. The combined composition of Augustin and Matre is an aqueous premix formulation with a pH of 3.3-4.2, which falls within the instantly claimed pH range.
Regarding the concentration of edetate disodium dihydrate recited in claims 19 and 28, Augustin discloses an amount of 0.12-0.2 mg/mL. While such a concentration does not overlap or fall within the instantly claimed concentration (i.e., 0.032 mg/ml), it is well within the abilities of an ordinary artisan to optimize the amount of edetate disodium dihydrate in the composition depending on the desired stability of the final product. As such, one of ordinary skill in the art would have arrived at the instantly claimed amount of 0.032 mg/ml edetate disodium dihydrate through no more than routine experimentation. 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 the epinephrine activity of the formulation of claim 19, since the composition made obvious by the prior art is identical to the composition claimed, the composition must necessarily have the characteristics claimed as an inherent property. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter, which there is reason to believe inherently includes functions that are newly cited, or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter to be shown in the prior art does not possess the characteristic relied on” (205 USPQ 594). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference.
Claims 1-5, 7-13, 15-17, 19-22, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Augustin and Matre as applied to claims 1-5, 7-13, 15-17, 19, and 28-29 above, and further in view of Baxter Healthcare Corporation. Sodium Chloride Injection, USP in VIAFLO Plastic Container. Rev. June 2018, accessed July 25, 2025, (on record), hereinafter Baxter.
The combined teachings of Augustin and Matre are discussed above.
Matre further teaches that the samples were prepared in 250 mL polyvinyl chloride bags. The prepared solutions were then placed in amber ultraviolet light clocking bags and refrigerated or stored at room temperature (p. 2, col. 1, para. 3).
The combined teachings of Augustin and Matre differ from that of instantly claimed invention in that they do not explicitly teach a flexible container comprising the formulation of claim 1 as defined in claims 20-22.
Baxter teaches a sodium chloride injection which is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration (p. 1, para. 1). It is specifically a 0.9% sodium chloride injection (p. 1, para. 2). The solution is comprised in a VIAFLO container which is a flexible plastic container fabricated from a multilayer sheeting composed of polypropylene (PP), polyamide (PA) and polyethylene (PE) (p. 1, para. 3). The available sizes include 250 mL, 500 mL, and 1000 mL (p. 6, para. 4).
It would have been obvious to modify the combined teachings of Augustin and Matre with those of Baxter before the effective filing date of the claimed invention by placing the combined composition of Augustin and Matre in the VIAFLO container of Baxter to yield the instantly claimed invention. First, it would have been obvious to store the combined composition of Augustin and Matre in a bag of some sort since the storage of ready-to-administer epinephrine solutions for injection in bags is taught by Matre. The combining of prior art elements according to known methods to yield predictable results is considered prima facie obvious. Second, it would have been obvious to replace the PVA bags of Matre with the VIAFLO bags of Baxter since the simple substitution of one known element (i.e., a storage bag for an injectable solution) for another to obtain predictable results is also considered prima facie obvious. It would have been further obvious to use a bag with a volume of 250 mL since this volume is taught by both Matre and Baxter and would have been “obvious to try”. One of ordinary skill in the art would have had a reasonable expectation of success since Augustin, Matre, and Baxter all relate to injectable solutions.
Thus, the combined product of Augustin, Matre, and Baxter comprises the formulation of claim 1 within a VIAFLO container. The VIAFLO container is flexible, made of PP, PA, and PE, and has a volume of 250 mL which reads on claims 20-22.
Claims 1-5, 7-13, 15-17, 19-24 and 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over Augustin, Matre, and Baxter as applied to claims 1-5, 7-13, 15-17, 19-22, and 28-29 above, and further in view of Hekal, I. M. (WO 2005087365 A1, 09//22/2005, on record), hereinafter Hekal.
The combined teachings of Augustin, Matre, and Baxter are discussed above.
Augustin further teaches that epinephrine is destroyed readily in alkaline solutions by aldehydes, weak oxidizing agents, oxygen of the air and by auto-oxidation involving the formation of adrenaline-o-quinone (p. 6, lines 14-16).
Matre further teaches that epinephrine contains a catechol moiety which is susceptible to oxidative reactions catalyzed by ultraviolet light, oxygen, increases in temperature, and basic conditions (p. 2, col. 1, para. 2).
The combined teachings of Augustin, Matre, and Baxter differ from that of the instantly claimed invention in that they do not teach a system comprising an oxygen scavenger as recited in claims 23-24 and 30-31.
Hekal teaches an oxygen absorber including an iron powder and a first layer coated on a surface of the iron powder to form iron chloride (abstract; claim 1). The particle size of the powder may be classified to different mesh sizes by passing the iron powder through a series of screens. It is preferred to use the finest iron powder of 325 mesh (about 50 micrometers in diameter) since the finer the powder is, the larger the surface area becomes, resulting in a higher rate of the reaction (i.e., oxygen absorption). For some specific application, it is possible to use micronized iron powder (about 10 micrometers in diameter) (p. 6, lines 7-14). Further, the oxygen absorber includes a matrix material filled with the iron powder covered with the first layer of iron chloride (abstract; claim 2). The matrix material is a thermoplastic such as polyethylene, polypropylene, etc.. (p. 4, lines 13-15). Example 2 of Hekal teaches mixing the oxygen absorber (i.e., iron powder) with polypropylene and high-density polyethylene and extruding the mixture into films (example 2).
It would have been obvious to modify the combined teachings of Augustin, Matre, and Baxter with the teachings of Hekal before the effective filing date of the claimed invention by including the oxygen absorber of Hekal in the combined product of Augustin, Matre, and Baxter to yield the instantly claimed invention. One of ordinary skill in the art would have been motivated to include the iron powder of Hekal in the combined product of Augustin, Matre, and Baxter since both Augustin and Matre teach that epinephrine is sensitive to oxygen and Hekal teaches an oxygen absorber that would provide increased stability in the context of epinephrine storage. It would have been further obvious to use micronized iron since Hekal teaches that the finer the powder is, the more effective it is at oxygen absorption. Hekal further teaches that use of a finer powder is made possible by simply passing the iron powder through a series of screens. One of ordinary skill in the art would have had a reasonable expectation of success in including the iron powder of Hekal in the combined product of Augustin, Matre, and Baxter since Hekal teaches that it can be incorporated into matrix materials such as polyethylene and polypropylene and the combined product of Augustin, Matre, and Baxter is stored in a bag comprising these same materials.
Thus, the combined system of Augustin, Matre, Baxter, and Hekal reads on the system of claims 23-24 and 30-31.
Response to Arguments
Applicant's arguments filed 02/02/2026 have been fully considered but they are not persuasive:
(1) Applicant argues against the 102 rejections over Leeah and Leeah2, stating that neither disclose the newly added limitation of the epinephrine and sodium metabisulfite molar ratio.
Based on the examiner’s calculations above it appears that Leeah and Leeah2 do in fact disclose the instantly claimed molar ratio of epinephrine to sodium metabisulfite, which is calculated to be approximately 1. The specific calculations can be seen in the prior art rejections above.
(2) Applicant argues against the 103 rejections over Augustin in view of Van Matre. Applicant argues that Augustin, which only discloses concentrated epinephrine formulations, provides no guidance for providing a stable ready-to-use premix containing the claimed 10-70 mcg/ml of epinephrine without dilution. Applicant argues that the formulations of Van Matre had less than 95% of epinephrine remaining in the formulation with no long-term stability demonstrated. In contrast, the instantly claimed composition have surprising stability that could not be predicted based on Augustin and Matre.
As discussed above, Augustin teaches preparing a pharmaceutical composition wherein the epinephrine, antioxidant, NaCl and EDTA together with water are brought into a suitable dosage form suitable for injection. Matre teaches that epinephrine hydrochloride for intravenous infusion is commonly diluted to concentrations ranging from 16 to 64 µg/mL. Thus, one of ordinary skill could have reasonably prepared a pharmaceutical formulation according to Augustin which has the concentration of epinephrine taught by Matre to give a ready-to-use composition. Applicants’ argument that Augustin provides no guidance for providing a stable ready to use formulation is not found convincing since the entirety of Augustin centers around providing a stable epinephrine formulation. One of ordinary skill in the art could have easily adjusted the concentration of epinephrine to be at a ready to administer dose, while also maintaining the stability-inducing parameters taught by Augustin (i.e., pH, sodium metabisulfite, EDTA, molar ratio etc.). Regarding the fact that the formulations of Van Matre had less than 95% epinephrine and no long term stability, the above rejections are based on the combination of Augustin and Van Matre. The inability of the Matre formulations to achieve the instantly claimed properties is not evidence that the combined composition or the composition of the closest prior art (i.e., Augustin) would not achieve said properties. Regarding applicant’s assertion of surprising or unexpected results, an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). In this case, applicant has not provided a comparison to the closest prior art to sufficiently show unexpected results. Additionally, Augustin explicitly discloses surprisingly- enhanced stability over other formulations, as achieved by the specific formulation parameters (i.e., pH, EDTA, sodium metabisulfite, molar ratio etc.).
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SUSANNAH S ARMSTRONG/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616
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