DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/26/26 has been entered.
Receipt is acknowledged of Amendments and Remarks filed on 02/26/26. Claims 1, 14 and 26 have been amended, no new claims have been added and claims 13 and 25 have been canceled. Accordingly, claims 1-12, 14-24 and 26 remain pending and under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Applicant’s claims
Claim 1 is drawn to an injectable pharmaceutical formulation comprising: 0.1 mg/mL of one or more of epinephrine or a pharmaceutically-acceptable salt thereof: a tonicity regulating agent including 8.2 mg/mL of sodium chloride; a pH adjusting agent including a mixture of 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate, and, optionally, an as-needed amount of sodium hydroxide to maintain a pH level of the pharmaceutical formulation within a range from 3.6 to 4.0; 0.075 mg/mL of sodium metabisulfite; and 4 ug/mL of ethylene diamine tetra-acetate disodium (EDTA); wherein the pharmaceutical formulation is configured to have an API recovery of 94.5% or more responsive to at 30 months of storage at long-term storage conditions defined as 25°C + 2°C at 1 atmosphere (atm), wherein the formulation is formulated for parenteral administration, wherein the pharmaceutical formulation is free of tartrate and acids, bases, and/or salts thereof.
Claims 1-12, 14-24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Sanghvi et al (US 20190105288) in view of Bruss et al (US 20080269347) and Lowenthal et al (US 20190269781).
Sanghvi et al teach pharmaceutical compositions comprising epinephrine, a pH raising agent, an antioxidant, a transition metal complexing agent, a pH lowering agent, a tonicity regulating agent, optionally a preservative, and optionally a solvent (See abstract).
Regarding claims 1, 14 and 26, it is disclosed that the epinephrine and/or salts thereof is present at a concentration of in the range of about 0.01 to 2 mg/mL, the tonicity regulating agent is present at a concentration of in the range of about 6 to 8 mg/mL, the pH raising agent is present at a concentration of in the range of about 2.8 to 3.8 mg/mL, the transition metal complexing agent is present at a concentration of in the range of about 0.01 to 0.4 mg/mL, the solvent is water, the pH raising agent comprises a buffer system comprising at least two compounds, such as sodium hydroxide, and the transition metal complexing agent comprises EDTA (See [0008]-[0009], [0029], claims 1-12).
Regarding claims 5-6, 8, 10, 18, 20, 22, it is also disclosed that the said composition comprises about 5% or less total impurities after 3 months of storage in accelerated storage conditions, wherein the total impurities comprise D-epinephrine (See claims 13-20).
Sanghvi et al teach that the said compositions contain low levels of D-epinephrine, low levels of epinephrine sulfonic acid (ESA), low levels of oxidative degradants, low levels of total impurities. The said compositions resist significant pH change over shelf life (See [0010]-[0016]).
Regarding pH range and pH adjusting agent, Sanghvi et al teach that the pH raising agent may have a buffer range from a pH of about 2 to 5, preferably from a pH of about 3 to 4.5, and most preferably from a pH of about 3.5 to 4.5. (See [0034]). The pH raising agent may be present at a concentration in the range of about 0.1 and 4 mg/mL (See [0036]). The said pH raising agents comprise the acids or salt forms of one or more of lactate, citrate, acetate, sodium hydroxide, etc, and preferably sodium hydroxide (See [0042]).
Sanghvi et al also teach that, the antioxidant may limit the formation of oxidative degradants in the composition to less than about 1%, preferably less than about 0.5%, and most preferably less than about 0.009%, after a certain period of shelf life (See [0045]). The said antioxidants comprise one or more of an amino acid sulfite, ascorbic acid, ascorbyl, citric acid, sodium metabisulfite, etc, (See [0055]).
Sanghvi et al teach that the said transition metal complexing agent may inhibit the formation of degradants formed from the interaction of epinephrine, bisulfite, and oxygen. These degradants comprise one or more of Impurity A, Impurity B, and Unknown C (See [0062]).
In some embodiments, the concentration of the transition metal complexing agent present in the composition may be such that the concentration of Impurity A, Impurity B, or Unknown C is about 1% or less of the composition after a certain period of shelf life, most preferably about 0.1% or less (See [0063]).
The said transition metal complexing agent may be present at the lowest concentration that reduces and/or inhibits degradation of other components of the composition, such as at a concentration of about 0.1 and 0.5 mg/mL (See [0064]). The transitional metal complexing agent may be disodium edetate dihydrate (EDTA) (See [0065] and claim 12).
Sanghvi et al further teach that the pH lowering agent comprises one or more of acetic acid, ascorbic acid, citric acid, hydrochloric acid, lactic acid, etc (See [0069]). The said tonicity regulating agent comprises one or more of sodium chloride, sodium iodide, sorbitol, etc. Preferably, sodium chloride. The said tonicity regulating agent may be present in the composition at a concentration of in the range of about 4 and 9 mg/mL (See [0071] and [0072]).
Regarding claims 3-11 and 16-23, Sanghvi et al state that “The present invention provides for a composition that may have a low level of impurities. The term “impurity” refers to an undesired substance in a composition. In some embodiments, an amount of impurities may be present in an initial composition and/or may be formed after a certain period of shelf life of a composition. In some embodiments, impurities may be formed via degradation of one or more components of the composition. Sources of degradation include, but are not limited to, oxidation, racemization, sulfite addition, visible light, ultraviolet light, moisture, heat, changes in pH, and composition component interactions. Unless indicated otherwise, the percentages of impurities expressed herein are expressed as % w/w of the active agent” (See [0080]).
It is disclosed that the composition may have no more than about 10% of total impurities after a certain period of shelf life, preferably no more than about 3.7%, more preferably no more than about 2% (See [0082]).
It is stated that the concentration of D-epinephrine in the composition after a certain period of shelf life may be no more than about 9.5%, most preferably no more than about 0.5% (See [0086]-[0087]), and a low level of epinephrine sulfonic acid (ESA), including no more than about 5.5%, and most preferably no more than about 0.025% (See [0091]-[0093]).
It is stated that the said period of shelf life of the composition may be 1 month, preferably 3 months, more preferably 6 months, 12 months, preferably 18 months, more preferably 24 months, more preferably 30 months, and most preferably 36 months (See [0130]).
Sanghvi et al teach that shelf life may be determined by measuring the concentration of impurities in the composition after storage at 25° C. and 60% relative humidity. In some embodiments, shelf life may be determined by measuring the concentration of impurities in the composition after storage at 37° C. and 65% relative humidity. In Tables 9 and 10, Sanghvi et al disclose the amounts of impurities, ESA and D-epinephrine in samples at 40 ˚C after 3 months or more (See [0131]).
Regarding claims 14-15 and 24, it is disclosed that the said composition may have an initial active agent overage of less than about 20%, more preferably less than about 1%, and most preferably about 0% (See [0058]). The said compositions are administered as intravenous, subcutaneous, intramuscular, etc, ([0008], [0025] and [0077]).
The said composition may be contained in vials. The vials may comprise clear glass, amber glass, or plastic. The vials may be in the range of about 0.1 to 500 mL in volume, preferably in the range of about 10 to 50 mL. In some embodiments, the vial is a 1 mL vial which may be a single-dose formulation. In some embodiments, the vial is a 30 mL vial which may be a multi-dose formulation (See [0144]). The said composition may be contained in a pre-filled syringe (See [0146]).
Sanghvi et al lack a specific disclosure on the presence of sodium citrate dihydrate and citric acid monohydrate. These are well known pH adjusting agents as taught by Bruss et al and Lowenthal et al. Bruss et al also teaches the claimed concentration of epinephrine.
Bruss et al teach epinephrine formulations, with enhanced stability, the formulation comprising epinephrine, EDTA, and one or more of antioxidants such as cysteine, citric acid, etc. (See abstract).
Regarding claims 1-2, 14-15 and 26, Bruss et al teach a formulation, epinephrine injection, USP, a sterile, non-pyrogenic solution administered parenterally by the intravenous or intracardiac routes, or via endotracheal tube into the bronchial tree. Each milliliter (mL) of the 1:10,000 solution contains epinephrine 0.1 mg; sodium chloride 8.16 mg; sodium metabisulfite 0.46 mg; citric acid, anhydrous 2 mg and sodium citrate, dihydrate 0.6 mg added as buffers. The formulation may contain additional citric acid and/or sodium citrate for pH adjustment. pH 3.3 (2.2 to 5.0) (See [0009]).
Bruss et al further teach that cysteine formulation containing just EDTA, or EDTA and citric acid, or EDTA, citric acid and thioglycerol all were significantly better than metabisulfite alone (See [0078]). It is disclosed that the hydrochloride, sulphate, and bitartrate salts are known in the art. The bitartrate has the advantage of being less acidic and is used in the eye because its solutions have a pH close to that of lacrimal fluid. Epinephrine is destroyed readily in alkaline solutions by aldehydes, weak oxidizing agents and oxygen of the air (See [0005] and [0012]).
Further regarding the dose of epinephrine, Bruss et al teach that the adult intravenous dose for hypersensitivity reactions or to relieve bronchospasm usually ranges from 0.1 to 0.25 mg (1 to 2.5 mL of 1:10,000 solution), injected slowly. Neonates may be given a dose of 0.01 mg per kg of body weight; for the infant 0.05 mg is an adequate initial dose and this may be repeated at 20 to 30 minute intervals in the management of asthma attacks (See [0010] and [0083]-[0086]).
Regarding claims 1, 3-11, 14 and 16-23, Bruss et al teach that in specific cases, the formulation is enhanced to be stable in light, oxygen, and/or heat conditions and/or after an amount of time no less than 12 months, including 24 months. The said epinephrine formulations employ an improved purity over known formulations, such as, for example, by comprising fewer epinephrine degradation products in the formulation as a result of the combination of EDTA and antioxidants (See [0016] and [0052]).
Regarding claims 14-24 in part, Bruss et al teach that epinephrine is commonly administered parenterally by means of an injection device, including a simple manual syringe system or an auto-injector. Such simple syringes may be adapted to accept pre-filled cartridges, be packaged with the drug formulation loaded in the syringe, or used with vials (See [0042]).
Lowenthal et al teach epinephrine formulations. The said formulation comprises between about 0.1 mg and about 2.4 mg of epinephrine, or a salt thereof, in a single dose of the aqueous nasal spray pharmaceutical formulation (See abstract and claim 1). The formulation is administered at a dose of about 100 μL of the nasal spray comprising 1 mg/mL to about 40 mg/mL of epinephrine, or a salt thereof (i.e. 0.1 mg) (See [0016]).
It is disclosed that the said pharmaceutical formulation has a pH between about 3.0 and about 5.0, preferably, the formulation has a pH of about 4.0, which is adjusted by pH adjustment agents. The said pH adjustment agent may be an acid, a base, a buffer, or a combination thereof. The acid may be citric acid, hydrochloric acid, etc; the base may be sodium hydroxide or sodium citrate; and the buffer maybe citrate buffer (See [0028]).
Lowenthal et al teach that formulation may comprise a tonicity agent including dextrose, or sodium chloride. Preferably, sodium chloride (See [0035]), and a stabilizing agent, including ethylenediaminetetraacetic acid (EDTA) or a salt thereof, preferably the EDTA is disodium EDTA. The said formulation comprises from about 0.001% (w/v) to about 1% (w/v) of disodium EDTA (See [0036]).
The said formulation may comprise 0.001% to 1% sodium metabisulfite and 0.001% to 1% citric acid (See [0042]). The said formulation also may comprise about 0.001% to 1% of any antioxidants or a combination thereof. A suitable antioxidant is sodium metabisulfite (See [0039], [0042], [0044] and [0064]).
Lowenthal et al further teach that formulation may comprise a buffering agent. Buffering agents include, citric acid monohydrate, dibasic sodium phosphate, monobasic sodium phosphate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, etc, (See [0045] and [0410]).
Lowenthal et al also state that “The term “storage-stable,” as used herein, refers to a formulation in which at least about 90% to 115% of the active ingredient remains within acceptable regulatory specifications after storage of the formulation at specified temperature and humidity for a specified time, for example, for at least 12 months at 25° C. and 60% relative humidity and about six months at about 40° C. and about 75% relative humidity” (See [0381], [0482] and [0504]).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Bruss et al and Lowenthal et al with that of Sanghvi et al to arrive at the instant invention. It would have been obvious to do so because Sanghvi et al, Bruss et al and Lowenthal et al teach storage stable formulations comprising epinephrin and provide sufficient guidance on the excipients and their concentration ranges that would result in the preparation of a stable formulation for administration to a subject for an effective treatment as needed.
While Sanghvi et al teach adding citrates and citric acid, Bruss et al and Lowenthal et al disclose specific salts of the said compounds and teach adding sodium citrate dihydrate and citric acid monohydrate to prepare stable formulations. As such one of ordinary skill in the art is given adequate teachings to select sodium citrate dihydrate and citric acid monohydrate as a combination of pH adjusting agents with a reasonable expectation of success.
That is, the claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Regarding some ranges, while the prior art’s disclosure may recite similar ranges but not exact ranges, the difference in concentration ranges are not support for patentability as optimization of ranges is obvious to one of ordinary skill in the art. That is “[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); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). Also see MPEP 2144.05.
From the combined teaching of the cited references, 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 at the time the invention was made.
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 1-12, 14-24 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,564,562 in view of Sanghvi et al (US 20190105288). (Previously rejected as provisional over Application No. 17/976,111).
The Obviousness Double Patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims and would have been obvious over the reference claims in view of Sanghvi et al.
Examined claim 1 is drawn to an injectable pharmaceutical formulation comprising: 0.1 mg/mL of one or more of epinephrine or a pharmaceutically-acceptable salt thereof: a tonicity regulating agent including 8.2 mg/mL of sodium chloride; a pH adjusting agent including a mixture of 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate, and, optionally, an as-needed amount of sodium hydroxide to maintain a pH level of the pharmaceutical formulation within a range from 3.6 to 4.0; 0.075 mg/mL of sodium metabisulfite; and 4 ug/mL of ethylene diamine tetra-acetate disodium (EDTA); wherein the pharmaceutical formulation is configured to have an API recovery of 94.5% or more responsive to at 30 months of storage at long-term storage conditions defined as 25°C ± 2°C at 1 atmosphere (atm), wherein the formulation is formulated for parenteral administration, wherein the pharmaceutical formulation is free of tartrate and acids, bases, and/or salts thereof.
Reference claim 1 is directed to a pharmaceutical formulation comprising: 1 mg/mL of an active pharmaceutical ingredient (API) comprising epinephrine or a pharmaceutically acceptable salt thereof; between 0.04 mg/mL and 0.08 mg/mL of an antioxidant comprising sodium metabisulfite; between 5 mg/mL and 7 mg/mL of a tonicity regulating agent, the tonicity regulating agent configured to regulate an osmolality of the pharmaceutical formulation between 210 milliosmoles per kilogram (mOsmol/kg) and 300 mOsmol/kg; a pH-stabilizing buffer system including 2 mg/mL of citric acid and 2 mg/mL of sodium citrate configured to maintain a pH level of the pharmaceutical formulation at 3.8; and a preservative comprising chlorobutanol; wherein the pharmaceutical formulation is configured to have an API recovery of greater than about 96% after responsive to storage at a storage temperature of 25°C + 2°C for a duration of at least 24 consecutive months, and wherein the pharmaceutical formulation is formulated for parenteral administration.
The examined claims differ from reference claims in that 1- examined claimed formulation comprises EDTA, while reference claimed formulation comprises chlorobutanol; 2- the concentration ranges of components differ. However, the differences would have been obvious to one of ordinary skill in the art especially in view of the teachings of Sanghvi et al.
Regarding the presence of EDTA in examined formulation and chlorobutanol in the reference formulation, it is noted that both claims recite the open transitional phrase of “comprising” which allows for inclusion of unrecited components. Additionally, Sanghvi et al teach a formulation comprising epinephrine and teach that the said formulation may comprise a preservative such as chlorobutanol. It would have been obvious to one of ordinary skill in the art to add a suitable preservative to a formulation that is disclosed as sensitive to stability.
Regarding the concentration ranges, one of ordinary skill in the art is more than capable of optimizing the concentration ranges to achieve the desired formulation. Where 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, 105 USPQ 233 (CCPA 1955). Additionally, as taught by Sanghvi et al, one of ordinary skill in the art is given guidance on selecting suitable concentration ranges. For example, examined formulation comprises 0.1 mg/mL of one or more epinephrine, while reference formulation comprises 1 mg/mL of an API, comprising epinephrine. Sanghvi et al teach the formulations may comprise epinephrine at a concentration of about 0.01 to 2 mg/mL, preferably about 0.01 to 1 mg/mL. The tonicity agent, sodium chloride is present in the examined formulation at 8.2 mg/mL and from 5 to 7 mg/mL in the reference formulation. Sanghvi et al teach that the sodium chloride may be present from the range of about 4 and 9 mg/mL, preferably in the range of about 5 and 8 mg/mL. Thus, one of ordinary skill in the art would have achieved the same osmolality rage as claimed.
As such it is obvious to one of ordinary skill in the art to adjust the concentration ranges and especially in view of the teachings of the prior art to achieve the desired formulation with a reasonable expectation of success.
Furthermore, the courts have held that “Where 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, 105 USPQ 233 (CCPA 1955).
Claims 1-12, 14-24 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-47 of copending Application No. 17/975,998 (US 20230137790) in view of Bruss et al (US 20080269347) and Lowenthal et al (US 20190269781).
The Obviousness Double Patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims and would have been obvious over the reference claims in view of Sanghvi et al.
Examined claim 1 is drawn to an injectable pharmaceutical formulation comprising: 0.1 mg/mL of one or more of epinephrine or a pharmaceutically-acceptable salt thereof: a tonicity regulating agent including 8.2 mg/mL of sodium chloride; a pH adjusting agent including a mixture of 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate, and, optionally, an as-needed amount of sodium hydroxide to maintain a pH level of the pharmaceutical formulation within a range from 3.6 to 4.0; 0.075 mg/mL of sodium metabisulfite; and 4 ug/mL of ethylene diamine tetra-acetate disodium (EDTA); wherein the pharmaceutical formulation is configured to have an API recovery of 94.5% or more responsive to at 30 months of storage at long-term storage conditions defined as 25°C ± 2°C at 1 atmosphere (atm), wherein the formulation is formulated for parenteral administration, wherein the pharmaceutical formulation is free of tartrate and acids, bases, and/or salts thereof.
Reference claim 1 is directed to a pharmaceutical formulation configured to be administered to a human patient, the pharmaceutical formulation comprising: 0.1 mg/mL of an active pharmaceutical ingredient (API), the API comprising epinephrine or a pharmaceutically acceptable salt thereof; one or more tonicity regulating agents; one or more pH adjusting agents configured to maintain a pH level of the pharmaceutical formulation within a range from 3.6 to 4.0; 0.01 mg/mL to 0.08 mg/mL of sodium metabisulfite; and 1µg/mL to 8 µg/mL of ethylene diamine tetra-acetate disodium (EDTA);wherein the pharmaceutical formulation is configured to yield an EDTA-zinc binding level from about 0.19 µg/mL to about 1.6 µg/mL in the human patient, wherein the pharmaceutical formulation is formulated for parenteral administration.
The differences between the examined claims and reference claims are minor differences in scope which would have been obvious to one of ordinary skill in the art.
For example, the examined claims recite a tonicity agent including 8.2 mg/mL of sodium chloride, while the reference claims recite one or more tonicity agents. However, sodium chloride is a tonicity agent and well within the scope of one or more tonicity agent of reference claims. Examined claims recite a pH adjusting agent including a mixture of sodium citrate dihydrate, citric acid monohydrate and optionally sodium hydroxide to maintain the pH at a range of from 3.6 to 4.0. Reference claims recite one or more pH adjusting agents to maintain the pH at a range of from 3.6 to 4.0. While the said pH adjusting agents of examined claims are well within the scope of reference claims, Bruss et al and Lowenthal et al also teach the specific pH adjusting agents of examined claims. Thus, one of ordinary skill in the art would have been motivated to have incorporated beneficial agents taught by the prior art into the examined claims with a reasonable expectation of success.
Additionally, the 4 µg/mL of EDTA in examined claims is well within the claimed renage of 1 to 8 µg/mL of EDTA in reference claims.
Regarding the reference claim’s proviso that the formulation yields an EDTA-zinc binding level of from 0.19 to about 1.6 µg/mL in a human patient, it is noted that 1-this is an effect achieved after administration, which does not materially affect the claimed formulation, and 2- that the same level of EDTA is added to the formulation which would have had the same outcome.
As such the examined claims are rendered obvious over the reference claims in view of Bruss et al and Lowenthal et al.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 02/26/26 have been fully considered but they are not persuasive.
Applicant argues that the rejection of claims 1-26 over Sanghvi et al and Lowenthal should be withdrawn because Lowenthal teaches nasal formulations and Sanghvi et al does not. Applicant argues that one of ordinary skill in the art would not have looked into Lowenthal et al’s teachings to combine with that of Sanghvi et al because the formulations are for different uses (Lowenthal et al teachings nasal formulations, while Sanghvi et al teaching injectable, oral topical, but not nasal) (See Remarks, pages 8-9).
The argument is not found persuasive. Both references teach a solution formulation comprising epinephrin and additive that formulate a stable epinephrin formulation for administration. Sanghvi et al teach that the said formulations comprise pH adjusting agents including citrates and citric acid. However, they do not expressly disclose sodium citrate dihydrate. Lowenthal was relied upon for disclosing citric acid and sodium citrate dihydrate as the pH adjusting compounds. In other words, Lowenthal et al teach solution formulations comprising epinephrine and excipients that are both compatible with epinephrine and suitable including pH adjusting agents. That is, one of ordinary skill in the art would be motivated to follow guidance from the prior art to select specific agents that can make a formulation more stable without being bound to its route of delivery.
Applicant then compares the concentration ranges of epinephrine and antioxidant between Sanghvi et al and Lowenthal et al and argues that “the divergence in antioxidant-to-drug ratios demonstrates that the references are aimed at incompatible formulation objectives” (See Remarks, pages 9-10).
This argument is also not found persuasive. Firstly, the rejection clearly states that the missing teaching in Sanghvi et al is the lack of express disclosure of sodium citrate dihydrate and citric acid as the pH adjusting agent, which is taught by Lowenthal. That is, the rejection was not based on combining the formulations of Sanghvi et al and Lowenthal et al, rather incorporating the missing limitation from the secondary reference into the primary reference to optimize the formulations. As the courts have held, "The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference.... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA 1981). See also In re Sneed, 710 F.2d 1544, 1550, 218 USPQ 385, 389 (Fed. Cir. 1983) ("[I]t is not necessary that the inventions of the references be physically combinable to render obvious the invention under review."); and In re Nievelt, 482 F.2d 965, 179 USPQ 224, 226 (CCPA 1973) ("Combining the teachings of references does not involve an ability to combine their specific structures.").
Secondly, the modified rejection now relies on the teachings of Bruss et al which teach the same excipients at different concentration ranges. One of ordinary skill in the art having possession of all three references would have been motivated to test epinephrine with different concentrations of each additive and determine the optimal range.
Next argument is that “Additional objective evidence supports the absence of a motivation to combine. Although Sanghvi predates Lowenthal by a year or more, Sanghvi was not cited during prosecution of Lowenthal. In fact, a review of the CCD FiveIPOffices database reveals that Sanghvi was not cited, i.e., not deemed relevant, anywhere globally. If Sanghvi was not relevant to Lowenthal during examination by multiple patent offices, then a skilled artisan likewise would have no reason to consider Lowenthal relevant, much less combine its teachings with those of Sanghvi. Accordingly, because the formulations disclosed in Lowenthal and Sanghvi are directed to distinct routes of administration, optimized for different concentration regimes, and constrained by different physiological requirements, the skilled artisan would lack any motivation and lack any reasonable expectation of success to combine Lowenthal and Sanghvi” (See Remarks, pages 10-11).
The above argument is neither convincing nor relevant. Firstly, the prosecution of Applications is not proper grounds for rebuttal of a rejection. Secondly, the prosecution history of Applications depends on multiple factors, including the claims and the search. The prosecution usually involves the search of claimed invention and discovery of one or more references that are relevant to the claims. That is, not all prior art references are used to reject a claim. In the case of Lowenthal et al’s Application, the examiner discovered and applied other references (than Sanghvi et al) that were adequate and suitable for the prosecution of the claims. It is also noted that the claims of Lowenthal Application were to a method of treating a type-1 hypersensitivity reaction in a mammal by intranasal administration of a formulation. Sanghvi et al would not have been the best and most relevant reference because it does not teach a method of treating a type-1 hypersensitivity reaction in a mammal by intranasal administration. However, Sanghvi et al and Lowenthal et al are combinable in the manner disclosed in the rejection for rendering a solution formulation comprising epinephrine and additives obvious.
Applicant further argues that “Even if Sanghvi and Lowenthal were to be combined, their combination would still not lead to the claimed invention.
In making the rejection, the Office asserts that Sanghvi in view of Lowenthal discloses all the elements of the claimed invention. In particular, the Office asserts that Sanghvi discloses all the elements of the claimed invention but for the presence of sodium citrate dihydrate. However, to do so, the skilled artisan would have to pick and choose among the disparate disclosures in Sanghvi and Lowenthal” (See remarks, pages 10-12).
This argument is also not found persuasive. Firstly, the argument is in a way moot since the current rejection also relies on the teachings of Bruss et al which teach a very similar formulation, for parenteral administration.
Secondly, it is noted that Sanghvi et al teach that preferred antioxidants include sodium metabisulfite which is listed in exemplified formulations (See e.g. [0055] and Examples 3-4) and Lowenthal teaches that preferred antioxidants include sodium metabisulfite (See e.g. [0039]). In fact, Lowenthal teaches that sodium metabisulfite is also a suitable preservative and is listed in exemplified formulations (See [0401] and Table 4). As for the argument of tartaric acid, Sanghvi et al teach that the pH lowering agent may be selected from a number of acids including citric acid and tartaric acid (See [0069]) and Lowenthal et al teach the same (See [0028]). Additionally, Bruss et al teach a solution formulation that does not contain tartaric acid and state that bitartrate salt of epinephrine is suitable for administration to the eye. Furthermore, Sanghvi et al further disclose that the said formulations preferably have an overage of 0%.
As for the concentration ranges of the components, one of ordinary skill in the art is more than capable of optimization of ranges to achieve the desired formulation. That is, “Where 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, 105 USPQ 233 (CCPA 1955).
Applicant then argues that Sanghvi et al preferred a thiol containing antioxidant and “Sanghvi discloses that the antioxidant is: "present at the lowest concentration that will inhibit and/or prevent the composition from undergoing unacceptable physical changes;" …. Sanghvi further discloses that 0.1 to 3.0 mg/mL and "most preferably about 0.4 to 0.5 mg/mL" of antioxidant are used. Thus, Sanghvi teaches that the lowest concentration to inhibit or prevent these undesirable changes is greater than 0.1 mg/mL with a preferred amount of about 0.4 to 0.5 mg/mL. …. In contrast, the claimed invention requires using less than 0.1 mg/mL of sodium metabisulfite” (See Remarks, pages 12-14).
The above arguments are similarly not found convincing. Sanghvi et al disclose that thiol-containing antioxidants are preferred, however, Sanghvi et al also teach that the antioxidant can be selected from other suitable antioxidants including sodium metabisulfite. Sanghvi et al incorporate sodium metabisulfite in most of their formulation examples (See Examples 3-4, 7-9, 12-14, 17-18).
Regarding the concentration of sodium metabisulfite, Bruss et al teach that in one instance, the formulation has no metabisulfite and was stable, and also teach that the formulation containing EDTA and citric acid, or EDTA, citric acid and thioglycerol all were significantly better than metabisulfite alone. Thus, based on the combination of references, one of ordinary skill in the art would have been motivated to reduce the amount of sodium metabisulfite and add other antioxidants including citric acid and EDTA to improve the stability of the formulation while reducing the possibility of reaction.
Regarding the incorporation of EDTA into the formulation, Applicant argues that “Sanghvi provides various choices of preferable metal complexing agents with EDTA mentioned as a preferred metal complexing agent. Lowenthal also includes EDTA in its formulations. Lowenthal at [0036]. Thus, to the extent the skilled artisan were to pick EDTA from the list of preferable complexing agents in Sanghvi, the skilled artisan would be motivated to use at least 0.1 mg/mL of EDTA to achieve the lowest concentration that reduces and/or inhibits degradation” (See Remarks, pages 14-15).
This argument is also not found persuasive because Sanghvi et al teach a formulation wherein the transition metal complexing agent is present at a concentration of in the range of about 0.01 to 0.4 mg/mL. Lowenthal et al also teach a formulation that comprises from about 0.001% (w/v) to about 1% (w/v) of disodium EDTA. Additionally, Bruss et al teach a sterile aqueous solution comprising EDTA in the exemplary range from 0.01% to 0.048%. Thus, from the references, one of ordinary skill in the art would be motivated to incorporate the least amount of EDTA in a formulation that would provide the required stability and shelf life, as taught by the prior art. That is, the references provide guidance on the suitable range of antioxidants and EDTA and one of ordinary skill in the art is more than capable of optimizing the concentration of components.
The following argument is regarding the formulation overage. Applicant argues that the combined references would lead the skilled artisan to formulations containing an overage of epinephrine. Applicant states that “Sanghvi discusses epinephrine-containing compositions that may include an initial overage of the active agent. Specifically, Sanghvi notes that “traditional epinephrine-containing compositions may have an overage of up to 25% of the amount indicated on the label,” citing the USP 39 monograph which allows for such a variance. Sanghvi at [0057]. While stating that most preferably the initial agent overage is about 0% (id. at [0058]), Sanghvi provides no teaching or guidance on how to achieve an overage-free formulation. Lowenthal does not mention overage at all, nor does Lowenthal provide any teaching that would motivate the skilled artisan to formulate epinephrine compositions without an overage. Sanghvi in view of Lowenthal would lead the skilled artisan to follow the prevailing practice and include an overage of up to 25% to ensure label compliance and product stability. As such, Sanghvi in view of Lowenthal would lead the skilled artisan to epinephrine formulations containing more than 0.1 mg/mL, as claimed” (See Remarks, page 15).
The above argument is not found convincing. The courts have held that “It is impermissible within the framework of section 103 to pick and choose from any one reference only so much of it as will support a given position, to the exclusion of the other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art." In re Wesslau, 353 F.2d 238, 241 (C.C.P.A. 1965); see also Bausch & Lomb, Inc. v. Barnes-Hind/Hydrocurve, Inc., 796 F.2d 443,448-49 (Fed. Cir. 1986). Sanghvi et al appears to be critical of the “traditional formulations” that have up to 25% overage and discloses that the formulations according to the disclosure have less overage and preferably 0% overage. Contrary to Applicant’s recitation, Sanghvi et al teach formulations that preferably contain 0% overage and discloses ways to achieve that including use of antioxidants. Additionally, the formulations of Sanghvi et al contain 0.1 mg/mL epinephrine as claimed.
The next argument is that of unexpected results. The argument is that the Applicants have surprisingly discovered that a small amount of the antioxidant sodium metabisulfite is enough to protect epinephrine from oxidation. Applicant also argues that a small amount of EDTA and a small amount of antioxidant provided desired formulation efficacy (See Remarks, pages 15-17).
The arguments have been given full consideration and found unconvincing. While Applicant may have discovered that smaller amounts of antioxidant and EDTA would result in a stable and efficient epinephrine formulation, the references also teach storage stable and efficient formulations comprising epinephrine. Sanghvi et al teach that the antioxidant may limit the amount of oxidative degradation in the composition to less than about 1%. That is, while Sanghvi et al teach higher amount of an antioxidant or EDTA, they teach the same formulations and wherein the degree of oxidation is very low and make efficient formulations. Furthermore, Bruss et al teach that by adding more antioxidants such as citric acid and sodium citrate, the formulation an be more stable and contain less sodium metabisulfite.
Regarding the argument of unexpected results, it has been held that "even though applicant's modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art, unless the claimed ranges produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art." In re Huang, 100 F.3d 135, 139, 40 USPQ2d 1685, 1688 (Fed. Cir. 1996) (quoting In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (1955), and citing In re Woodruff, 919 F.2d 1575, 1578, 16 USPQ2d 1934, 1936-37 (Fed. Cir. 1990)).
Regarding the provisional statutory double patenting rejections over copending Applications 17/976,111 (now Patent No. 12,564,562) and 17/975,998, Applicant argues that the claims are not drawn to the “same invention”. Applicant points to different concentration ranges or additives, and argues that the claims would not have been obvious over each other (See Remarks, pages 18-19).
The arguments are not persuasive. As clearly stated above, the differences between examined claims and reference claims are obvious because the examined claims are obvious variations of the reference claims in each rejection.
For example, Applicant argues that “the claims in the instant application differ from those of the '998 application. For example, the instant claims require "a pH adjusting agent including a mixture of 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate" and "0.075 mg/mL of sodium metabisulfite." In contrast, the claims of the '998 application require "one or more pH adjusting agents" and "0.01 mg/mL to 0.08 mg/mL of sodium metabisulfite." The same invention is not being claimed. Since the claims are directed to distinct subject matter, provisional statutory double patenting does not apply” (See Remarks, page 18).
The arguments are not persuasive because, 1-the rejection is based on obviousness type double patenting, not anticipatory. Therefore, the rejection is not based on “same invention”. 2- the differences between examined claims and reference claims is under obvious to modify based on the teachings of the prior art, namely Bruss et al and Lowenthal et al which teach the specific pH adjusting agents and additives.
Regarding the rejection of claims over ‘562 Patent (previous ‘111 Application), Applicant argues that “Whereas the claimed invention requires an epinephrine formulation containing 0.1 mg/mL of epinephrine, the disclosure of the claims in the co-pending '111 application pertains to the epinephrine formulations containing 1 mg/mL. There is no teaching or suggestion in the disclosure of the claims of the '111 application even when in view of Sanghvi to reduce the amount of epinephrine by a factor of ten. Sanghvi generally teaches that its formulations can contain "about 0.01 to 2 mg/mL" of epinephrine. Sanghvi at [0029]. Thus, while Sanghvi discloses in its epinephrine formulations the amount of epinephrine can vary, Sanghvi provides no motivation to reduce the amount of epinephrine in the formulations disclosed in the claims of the '111 application” (See Remarks, page 19).
This argument is also not persuasive because Sanghvi et al teach the formulations may comprise epinephrine at a concentration of about 0.01 to 2 mg/mL, preferably about 0.01 to 1 mg/mL. while Applicant argues that one of ordinary skill in the art would have no motivation to reduce the amount of epinephrine in the formulations of reference claims, they provide no evidence. A reference is relied upon for all that it teaches, not just the preferred embodiments. Sanghvi et al clearly teach that the formulation may comprise as low as 0.01 mg/mL of epinephrine.
Also as disclosed by Bruss et a (See above), the dosage of epinephrine for children younger than 12 years old is much lower than the dose for adults. Therefore, one of ordinary skill in the art clearly has motivation to lower the dosage for a specific population of patients.
Furthermore, as the courts have held, “Where 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, 105 USPQ 233 (CCPA 1955).
Claims 1-12, 14-24 and 26 are rejected.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
Prosecution Insights