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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/22/26 has been entered.
Response to Amendment
Applicant amended claims 30, 32, and 46. Claims 30-48 are currently pending.
Affidavit/Declaration
The Declaration under 37 CFR 1.132 filed 06/22/26 is insufficient to overcome the rejections of claims 30-34 and 38-48 based upon Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz, of claims 35-36 in further view of Farmer, and of claim 37 in further view of McDorman as set forth in the last Office action because:
The Declaration indicates that the amount of sodium metabisulfite in norepinephrine formulation decreases during storage for up to 15 months at 25°C in Table 1, indicating that the sodium metabisulfite reacts in the formulation, and that the amount of sulfonic acid in the same formulations increased over the storage time in Table 2, demonstrating that sodium metabisulfite reacts with norepinephrine in the formulation. However, even if the sodium metabisulfite reacts with norepinephrine, the evidence provided in Tables 1 and 2 only demonstrates the changes in sodium metabisulfite concentration in the formulation, and does not indicate how the concentration of norepinephrine changed over the storage period. Therefore, the evidence provided in Tables 1 and 2 is not commensurate with the scope of the claimed invention, which recites that there is 90% of the original amount of R-norepinephrine present after storage for at least 120 days (about 4 months) at 25°C.
Furthermore, the Declaration indicates that sodium metabisulfite would be expected to be a less favorable antioxidant in norepinephrine formulations like the claimed formulation due to reacting with norepinephrine. The Declaration further indicates that sodium metabisulfite was unexpectedly found to have superior performance to other tested antioxidants.
However, sodium metabisulfite is known in the art as a suitable antioxidant for stabilizing formulations including catecholamines such as norepinephrine, as evidenced by Baillie (¶0053-0058) and Puri (¶0005-0008 and Tables 1-3), as cited below. In particular, Puri teaches about Levophed®, a commercially available norepinephrine formulation including sodium metabisulfite as an antioxidant. Therefore, the prior art indicates that sodium metabisulfite would be expected to have beneficial stabilizing effects in norepinephrine formulations. Expected beneficial results are evidence of obviousness. Please see MPEP §716.02(c)(II).
The evidence that sodium metabisulfite is a superior antioxidant to other antioxidants as presented in the Declaration does not render it non-obvious to employ sodium metabisulfite as an antioxidant for stabilizing norepinephrine formulations because the prior art has demonstrated that sodium metabisulfite is both known and commercially used, and therefore one of ordinary skill in the art would expect it to have beneficial properties. Please see MPEP §716.02(c)(I).
Response to Arguments
Applicant’s arguments, see pages 7-14 of Applicant’s Remarks, filed 06/22/26, with respect to the rejections of claims 30-34 and 38-48 under 35 U.S.C. 103 as being unpatentable over Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz have been fully considered and are not persuasive.
Applicant argues that one of ordinary skill in the art would not have had an expectation of success that the claimed ready-to-use norepinephrine formulation, which consists essentially of between 0.01 mg/ml to less than 0.04 mg/ml norepinephrine, sodium chloride, water, metabisulfite, a pH between 3.4 and 4.0, and optionally hydrochloric acid and/or sodium hydroxide as pH adjustors, would be stable based on the teachings of the prior art.
Applicant argues, see page 9, the Devouassoux does not describe any norepinephrine formulations in the working examples. However, even if Devouassoux does not disclose a working example comprising norepinephrine, Devouassoux teaches a packaged, sealed container system for stable storage of oxygen sensitive pharmaceutical formulations, such as norepinephrine (¶0008 and 0069-0073), comprising a primary container comprising the pharmaceutical formulation (¶0040-0046), a secondary container enclosing the primary container (¶0047-0054), and an oxygen scavenger enclosed by the secondary container (¶0003, 0017-0018, 0036, and 0055-0056) such that the oxygen scavenger is in fluid communication with the pharmaceutical formulation and may be effective for reducing the dissolved oxygen levels in the pharmaceutical formulation to 0% for an extended period of time (¶0060-0064). Even if the working examples disclosed by Devouassoux are not identical to the claimed packaging system and formulation, the teachings of the whole disclosure of Devouassoux, which include a norepinephrine formulation contained in a primary container, which is further contained in a secondary contained with an oxygen scavenger, are still relevant to the claims.
Applicant further argues, see page 10, that while Baillie discloses compositions comprising adrenergic compounds, which includes catecholamines such as epinephrine and norepinephrine (¶0053-0055), and an antioxidant such as sodium metabisulfite (¶0019 and 0058), the working examples of Baillie are focused on epinephrine formulations and that Baillie does not disclose or suggest a formulation that contains norepinephrine as the only adrenergic compound. However, Baillie teaches liquid pharmaceutical compositions comprising an adrenergic compound (¶0050) and further teaches that “in an embodiment of the present invention, the adrenergic compound is selected from the group consisting of … norepinephrine …” (¶0054). Baillie further teaches that the compositions use water as the solvent, include sodium chloride as an excipient, and may include enough hydrochloric acid and/or sodium hydroxide to achieve a pH in the range of 3.0 to 4.0 in order to stabilize the composition (¶0066-0071). Therefore, Baillie teaches a composition which is within the scope of the claimed formulation containing norepinephrine as the only adrenergic compound.
Applicant further argues, see page 11, that Puri describes norepinephrine formulations that are substantially free of antioxidants and include a chelating agent, and that therefore the teachings of Puri are not relevant to the claimed system containing a metabisulfite antioxidant. However, Puri teaches the concentrations that norepinephrine should be at in order to be ready-to-inject, for both compositions which are free of antioxidants (¶0012-0017 and 0021) and compositions which include a metabisulfite antioxidant (¶0006-0008).
Applicant further argues, see page 11-14, with reference to a submitted declaration, that the high performance of sodium metabisulfite as an antioxidant in low concentration norepinephrine formulations is unexpected, given the submitted evidence that sodium metabisulfite allegedly reacts with norepinephrine in formulation. However, as discussed above, the evidence provided in the declaration only demonstrates the degradation of sodium metabisulfite over the storage time, but not that it changes the concentration of norepinephrine in the formulation over time. Furthermore, as discussed above, sodium metabisulfite is known in the art as a suitable antioxidant for stabilizing formulations including catecholamines such as norepinephrine, as evidenced by Baillie (¶0053-0058) and Puri (¶0005-0008 and Tables 1-3), as cited below. In particular, Puri teaches about Levophed®, a commercially available norepinephrine formulation including sodium metabisulfite as an antioxidant. Therefore, the prior art indicates that sodium metabisulfite would be expected by one of ordinary skill in the art to have beneficial stabilizing effects in norepinephrine formulations. Expected beneficial results are evidence of obviousness. Please see MPEP §716.02(c)(I) and (II).
Furthermore, Puri teaches that prior art low concentration norepinephrine formulations including sodium metabisulfite retain at least 90% of an initial concentration of norepinephrine for at least 3 months (about 90 days) of storage at 25°C (¶0005-0008 and Tables 1-3). Both Puri (¶0029) and Devouassoux (¶0055-0056 and 0060-0064) teach that storing a norepinephrine formulation in a primary container, which is further stored in a secondary container with an oxygen scavenger would be expected to improve the stability of the formulation, with Devouassoux further teaching that such a packaging system can be configured to effectively eliminate dissolved oxygen in the formulation for an extended period of time (¶0063), which would be expected to eliminate some degradation pathways due to the reaction between norepinephrine and oxygen for that extended period of time, thereby improving the stability of the formulation regardless of the presence of an antioxidant in the formulation.
Applicant’s arguments, see pages 14-15, with respect to the rejections of dependent claims 35-36 as obvious over Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, in further view of Babrowicz, and in further view of Farmer, and of dependent claim 37 as obvious in further view of McDorman, have been fully considered and are not persuasive in light of the rejections of the independent claims.
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.
Claims 30-34, 38-48 are rejected under 35 U.S.C. 103 as being unpatentable over Devouassoux et al. (US 2014/0262883 A1) in view of Baillie et al. (US 2012/0129944 A1), in further view of Puri et al. (US 2018/0214394 A1), in further view of Inoue et al. (US 2001/0008686 A1), and in further view of Babrowicz et al. (US 2010/0256590 A1).
Regarding claim 30, Devouassoux discloses a packaged, sealed container system (Figs. 1 and 2; ¶0003 and 0017-0018) for stable storage of a ready-to-use, stable norepinephrine formulation (¶0008 and 0069-0073), the package, sealed container system comprising: a primary container (Figs. 1a-d and 2, feat. 3; ¶0017-0018 and 0040-0046) comprising a ready-to-use, stable norepinephrine formulation therein (¶0008 and 0069-0073); a secondary container (Figs. 1a-d and 2, feat. 1; ¶0017-0018 and 0047-0054), wherein the primary container is disposed between and enclosed by the secondary container (Figs. 1a-d and 2; ¶0047, lines 1-4); and an oxygen scavenger disposed between and enclosed by the secondary container (Figs. 1a-b and 2, feat. 2; ¶0003, 0017-0018, 0036, and 0055-0056), the oxygen scavenger being in fluid communication with the contents of the primary container (¶0037-0038: the oxygen absorber in the pharmaceutical packaging system leads to the absorbance and removal of oxygen in the drug inside the primary packaging).
Devouassoux is silent with respect to the components of the norepinephrine formulation. Devouassoux discloses that the primary and secondary containers may be bags or pouches (¶0040 and 0047), but does not disclose the construction of the bags or pouches.
Baillie teaches stabilized compositions of adrenergic compounds, which includes catecholamines such as epinephrine and norepinephrine (¶0053-0055), which are advantageously protected against auto-oxidation through the inclusion of an antioxidant, which may be sodium metabisulfite (¶0019 and 0058), so that the composition may be stable in all types of climates and temperatures (¶0052). Baillie teaches that such compositions use water as the solvent, include sodium chloride as an excipient, and may include enough hydrochloric acid and/or sodium hydroxide to achieve a pH in the range of 3.0 to 4.0 in order to stabilize the adrenergic compound composition (¶0066-0071; ¶0070 recites that hydrochloric acid and/or sodium hydroxide are included q.s. pH 3.4 – q.s. is an abbreviation of quantum satis, which means “as much as sufficient”). The claimed pH range of 3.4 to 4.0 lies within the prior art range of 3.0 to 4.0, and therefore, a prima facie case of obviousness exists for the claimed pH range. Please see MPEP §2144.05(I). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system disclosed by Devouassoux so that the ready-to-use, stable norepinephrine formulation consists essentially of norepinephrine; sodium chloride; water; metabisulfite; and optionally, hydrochloric acid and/or sodium hydroxide as pH adjustors, wherein the ready-to-use, stable norepinephrine formulation has a pH between 3.4 and 4.0 in order to provide a stabilized norepinephrine composition that is stable in all types of climates as taught by Baillie.
Baillie is silent with respect to particular concentrations of norepinephrine.
Puri teaches ready-to-inject norepinephrine formulations (Abstract). Puri teaches that the norepinephrine formulations should generally be available at concentrations between 0.01 mg/ml and 0.1 mg/ml, and more specifically at concentrations of 0.016 mg/ml (±10%), 0.032 mg/ml (±10%), and 0.064 mg/ml (±10%), in order to be available at the most commonly required concentrations for emergency restoration of blood pressure (¶0021). Puri further teaches that ready-to-inject formulations of norepinephrine have concentrations in this range regardless of whether the formulation includes an antioxidant, such as sodium metabisulfite, or not (¶0006-0008). The claimed concentration range of 0.01 mg/ml to 0.04 mg/ml lies within the prior art concentration range of 0.01 mg/ml to 0.1 mg/ml, and therefore a prima facie case of obviousness exists for the claimed concentration range. MPEP §2144.05(I). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie so that the concentration of the norepinephrine is between 0.01 mg/ml to less than 0.04 mg/ml in order to provide the norepinephrine at the most commonly required concentrations for emergency restoration of blood pressure as taught by Puri.
Inoue teaches a medical container packaging bag (Fig. 4, feat. b; ¶0060) comprising a first flexible sheet layer, a second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second flexible sheet layers (Fig. 4; ¶0057 and 0060) for enclosing a medical container containing a medicinal (Fig. 4, feat. a1). Inoue further teaches that the base film (Fig. 4, feat. B1) of the packaging bag (b) has high gas barrier properties in order to prevent the degradation of the medicinal (¶0061-0062). As discussed above, Devouassoux in view of Baillie and in further view of Puri discloses many of the elements of claim 1, except for those pertaining to the structure of the secondary container, and Inoue teaches the structure of the secondary container. Therefore, the prior art includes each element claimed, with respect to the secondary container, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. One of ordinary skill in the art could have been combined the elements as claimed because Inoue teaches a secondary container with the claimed structure enclosing a medical container between its first and second flexible sheet layer (Fig. 4) and would have recognized that enclosing the primary container of Devouassoux in view of Baillie and in further view of Puri in a secondary container with the structure taught by Inoue would have the predictable results of preventing the degradation of the norepinephrine formulation because Devouassoux discloses that the secondary container should prevent oxygen ingress, i.e. the secondary container should have oxygen barrier properties (Devouassoux: ¶0047-0050) and Inoue teaches a secondary container with the claimed structure (Inoue: Fig.4, feat. B) which has high gas barrier properties for preventing degradation (¶0061-0062). Therefore, it would have been prima facie obvious to one ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie and in further view of Puri so that the secondary container comprises a first flexible sheet layer, an opposing second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second sheet layer as taught by Inoue. Please see MPEP §2143(I)(A).
Babrowicz teaches a multilayer film and medical solution pouches formed therefrom (Abstract). Babrowicz teaches a coextruded multilayer film (¶0055) comprising an inner polypropylene heat seal layer (Fig. 1, feat. 14; ¶0033-0034) and an outer polyamide composite layer (Fig. 1, feat. 16; ¶0024-0029) which can be formed into a pouch by mating two films such that the heat seal layers are brought into contact and providing heat to the peripheral edges of the films (¶0033, 0057, and 0058). Babrowicz teaches that pouches made of such a film may be sterilized via autoclaving without the formation of foam in the solution held in the pouch (¶0018). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie, in further view of Puri, and in further view of Inoue so that the primary container is a plastic bag comprising a third flexible sheet layer, an opposing fourth flexible sheet layer, and a primary container seal disposed along a common peripheral edge of the third and fourth flexible sheet layers as taught by Babrowicz so that the primary container may be sterilized via autoclaving without the formation of foam in the norepinephrine solution.
Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz does not explicitly disclose or suggest that the ready-to-use, stable norepinephrine formulation retains at least about 90% of an initial activity as measured by an initial and a final amount of R-norepinephrine present in the formulation after storage for at least 120 days at 25°C as claimed. However, as discussed in more detail above, the combination of Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests a container system which is substantially identical to the claimed container system, and a norepinephrine composition held within the container system which is substantially identical to the claimed composition. Because the container system and norepinephrine composition suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz is structurally and compositionally the same as the claimed container system and norepinephrine composition, the claimed properties are presumed to be inherent in the prior art container system and norepinephrine composition. Please see MPEP §2112.01(I) and (II). Therefore, the ready-to-use, stable norepinephrine formulation in the packaged, sealed container system suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz inherently retains at least about 90% of an initial activity as measured by an initial and a final amount of R-norepinephrine present in the formulation after storage for at least 120 days at 25°C.
Regarding claim 31, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system of claim 30. Devouassoux discloses that the primary container may be a bag or pouch used for infusion therapy (¶0042) and Babrowicz further teaches that the pouch comprises a discharge outlet for releasing medicine (Fig. 2, feat. 60; ¶0059). Therefore, Devouassoux in view of Puri, in further view of Inoue, and in further view of Babrowicz further suggests that the primary container has a single port, the single port comprising an administration port for delivering the ready-to-use, stable norepinephrine formulation to a patient.
Regarding claim 32, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system according to claim 30. As discussed above, Babrowicz teaches that the inner layers of the laminate may comprise polypropylene (Fig. 1, feat. 14; ¶0033-0034) and that the laminate may be made via coextrusion (¶0055). Therefore, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz further suggests that the third or the fourth flexible sheets are coextruded film laminates comprising a polypropylene layer.
Regarding claim 33, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system according to claim 33. As discussed above, Babrowicz teaches that the outer layers of the laminate may comprise polyamide (Fig. 1, feat. 16; ¶0024-0029) and that the laminate may be made via coextrusion (¶0055). Therefore, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz further suggests that the coextruded film laminates further comprise a polyamide layer.
Regarding claim 34, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system of claim 30, and Devouassoux further teaches that the secondary packaging may be made from coextruded films incorporating a metal foil to reduce the oxygen permeability (¶0048-0050). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the system suggested by Devouassoux in view of Ballie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz so that the first flexible sheet layer comprises a coextruded film including a metal foil in order to reduce the oxygen permeability as taught by Devouassoux.
Regarding claim 38, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system of claim 30, and Devouassoux further discloses that the oxygen scavenger comprises iron powder, iron oxide powder, or a mixture thereof (¶0056).
Regarding claims 39-41, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system of claim 30.
As discussed above, Puri teaches antioxidant free, ready-to-inject norepinephrine formulations (Abstract). Puri further teaches that the norepinephrine formulations should generally be available at concentrations between 0.01 mg/ml and 0.1 mg/ml, and more specifically at concentrations of 0.016 mg/ml (±10%), 0.032 mg/ml (±10%), and 0.064 mg/ml (±10%), in order to be available at the most commonly required concentrations for emergency restoration of blood pressure (¶0021). The specific example concentrations of 0.016 mg/ml (±10%) and 0.032 mg/ml (±10%) lie inside of the claimed ranges of 0.015 mg/ml to 0.035 mg/ml, with respect to claim 39, 0.015 mg/ml to 0.020 mg/ml, with respect to claim 40, and 0.030 mg/ml to 0.035 mg/ml, with respect to claim 41. Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz so that the concentration of norepinephrine is between about 0.015 mg/ml and about 0.035 mg/ml, with respect to claim 39, so that the concentration of norepinephrine is between about 0.015 mg/ml and about 0.020 mg/ml, with respect to claim 40, or so that the concentration of norepinephrine is between about 0.030 mg/ml and about 0.035 mg/ml, with respect to claim 41, in order to provide the norepinephrine at the most commonly required concentrations for emergency restoration of blood pressure as taught by Puri.
Regarding claim 42, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system of claim 30. Puri further teaches that the formulation should include a pharmaceutically acceptable salt such as sodium chloride at a concentration of between 0.6 wt % and 1.2 wt %, and more specifically 0.9 wt %, in order to achieve a desired osmolality (¶0025). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz so that the norepinephrine formulation comprises 0.9% sodium chloride in order to achieve a desired osmolality as taught by Puri.
Regarding claim 43, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system of claim 30.
As discussed above, Baillie teaches that the pH should be in the range of 3.0 to 4.0 in order to stabilize the formulation (¶0066-0068). The claimed pH range of 3.5 to 3.9 lies within the prior art range of 3.0 to 4.0, and therefore, a prima facie case of obviousness exists for the claimed pH range. Please see MPEP §2144.05(I). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz so that the pH is between about 3.5 and about 3.9 in order to stabilize the formulation as taught by Baillie.
Regarding claims 44 and 45, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system according to claim 30. Devouassoux further discloses that liquids degassed by nitrogen bubbling may have a residual oxygen level of up to approximately 400 ppb (¶0060), and that the oxygen absorber may remove up to about 400 ppb of oxygen per month from the liquid drug (¶0061) in order to establish and maintain a substantially oxygen free environment for at least 12 months (Fig. 9; ¶0063) such that the liquid drug is stable at 25°C for at least 12 months (¶0072), or about 365 days. Therefore, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz further suggests that the ready-to-use, stable norepinephrine formulation (¶0008 and 0069-0073) has a dissolved oxygen level of less than 0.5 ppm after storage for at least 150 days at 25°C (¶0060-0063 and 0072), with respect to claim 44, and that the ready-to-use, stable norepinephrine formulation (¶0008 and 0069-0073) has a dissolved oxygen level of less than 0.5 ppm after storage for at least 180 days at 25°C (¶0060-0063 and 0072), with respect to claim 45.
Regarding claim 46, Devouassoux discloses a packaged, sealed container system (Figs. 1 and 2; ¶0003 and 0017-0018) for stable storage of a ready-to-use, stable norepinephrine formulation (¶0008 and 0069-0073), the package, sealed container system comprising: a primary container (Figs. 1a-d and 2, feat. 3; ¶0017-0018 and 0040-0046) comprising a ready-to-use, stable norepinephrine formulation therein (¶0008 and 0069-0073); a secondary container (Figs. 1a-d and 2, feat. 1; ¶0017-0018 and 0047-0054), wherein the primary container is disposed between and enclosed by the secondary container (Figs. 1a-d and 2; ¶0047, lines 1-4); and an oxygen scavenger disposed between and enclosed by the secondary container (Figs. 1a-b and 2, feat. 2; ¶0003, 0017-0018, 0036, and 0055-0056), the oxygen scavenger being in fluid communication with the contents of the primary container (¶0037-0038: the oxygen absorber in the pharmaceutical packaging system leads to the absorbance and removal of oxygen in the drug inside the primary packaging).
Devouassoux is silent with respect to the components of the norepinephrine formulation. Devouassoux discloses that the primary and secondary containers may be bags or pouches (¶0040 and 0047), but does not disclose the construction of the bags or pouches.
Baillie teaches stabilized compositions of adrenergic compounds, which includes catecholamines such as epinephrine and norepinephrine (¶0053-0055), which are advantageously protected against auto-oxidation through the inclusion of an antioxidant, which may be sodium metabisulfite (¶0019 and 0058), so that the composition may be stable in all types of climates and temperatures (¶0052). Baillie teaches that such compositions use water as the solvent, include sodium chloride as an excipient, and may include enough hydrochloric acid and/or sodium hydroxide to achieve a pH in the range of 3.0 to 4.0 in order to stabilize the adrenergic compound composition (¶0066-0071; ¶0070 recites that hydrochloric acid and/or sodium hydroxide are included q.s. pH 3.4 – q.s. is an abbreviation of quantum satis, which means “as much as sufficient”). The claimed pH range of 3.4 to 4.0 lies within the prior art range of 3.0 to 4.0, and therefore, a prima facie case of obviousness exists for the claimed pH range. Please see MPEP §2144.05(I). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system disclosed by Devouassoux so that the ready-to-use, stable norepinephrine formulation consists essentially of norepinephrine; sodium chloride; water; metabisulfite; and optionally, hydrochloric acid and/or sodium hydroxide as pH adjustors, wherein the ready-to-use, stable norepinephrine formulation has a pH between 3.4 and 4.0 in order to provide a stabilized norepinephrine composition that is stable in all types of climates as taught by Baillie.
Baillie is silent with respect to particular concentrations of norepinephrine.
Puri teaches ready-to-inject norepinephrine formulations (Abstract). Puri teaches that the norepinephrine formulations should generally be available at concentrations between 0.01 mg/ml and 0.1 mg/ml, and more specifically at concentrations of 0.016 mg/ml (±10%), 0.032 mg/ml (±10%), and 0.064 mg/ml (±10%), in order to be available at the most commonly required concentrations for emergency restoration of blood pressure (¶0021). Puri further teaches that ready-to-inject formulations of norepinephrine have concentrations in this range regardless of whether the formulation includes an antioxidant, such as sodium metabisulfite, or not (¶0006-0008). The claimed concentration range of 0.01 mg/ml to 0.04 mg/ml lies within the prior art concentration range of 0.01 mg/ml to 0.1 mg/ml, and therefore a prima facie case of obviousness exists for the claimed concentration range. MPEP §2144.05(I). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie so that the concentration of norepinephrine is between 0.01 mg/ml to less than 0.04 mg/ml in order to provide the norepinephrine at the most commonly required concentrations for emergency restoration of blood pressure as taught by Puri.
Inoue teaches a medical container packaging bag (Fig. 4, feat. b; ¶0060) comprising a first flexible sheet layer, a second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second flexible sheet layers (Fig. 4; ¶0057 and 0060) for enclosing a medical container containing a medicinal (Fig. 4, feat. a1). Inoue further teaches that the base film (Fig. 4, feat. B1) of the packaging bag (b) has high gas barrier properties in order to prevent the degradation of the medicinal (¶0061-0062). As discussed above, Devouassoux in view of Baillie and in further view of Puri discloses many of the elements of claim 46, except for those pertaining to the structure of the secondary container, and Inoue teaches the structure of the secondary container. Therefore, the prior art includes each element claimed, with respect to the secondary container, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. One of ordinary skill in the art could have been combined the elements as claimed because Inoue teaches a secondary container with the claimed structure enclosing a medical container between its first and second flexible sheet layer (Fig. 4) and would have recognized that enclosing the primary container of Devouassoux in view of Baillie and in further view of Puri in a secondary container with the structure taught by Inoue would have the predictable results of preventing the degradation of the norepinephrine formulation because Devouassoux discloses that the secondary container should prevent oxygen ingress, i.e. the secondary container should have oxygen barrier properties (Devouassoux: ¶0047-0050) and Inoue teaches a secondary container with the claimed structure (Inoue: Fig. 4, feat. B) which has high gas barrier properties for preventing degradation (¶0061-0062). Therefore, it would have been prima facie obvious to one ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie and in further view of Puri so that the secondary container comprises a first flexible sheet layer, an opposing second flexible sheet layer, and a seal disposed along a common peripheral edge of the first and second sheet layer as taught by Inoue. Please see MPEP §2143(I)(A).
Babrowicz teaches a multilayer film and medical solution pouches formed therefrom (Abstract). Babrowicz teaches a coextruded multilayer film (¶0055) comprising an inner polypropylene heat seal layer (Fig. 1, feat. 14; ¶0033-0034) and an outer polyamide composite layer (Fig. 1, feat. 16; ¶0024-0029) which can be formed into a pouch by mating two films such that the heat seal layers are brought into contact and providing heat to the peripheral edges of the films (¶0033, 0057, and 0058). Babrowicz teaches that pouches made of such a film may be sterilized via autoclaving without the formation of foam in the solution held in the pouch (¶0018). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie, in further view of Puri, and in further view of Inoue so that the primary container is a plastic bag comprising a third flexible sheet layer, an opposing fourth flexible sheet layer, and a primary container seal disposed along a common peripheral edge of the third and fourth flexible sheet layers as taught by Babrowicz so that the primary container may be sterilized via autoclaving without the formation of foam in the norepinephrine solution.
As discussed above, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz does not explicitly disclose or suggest that the ready-to-use, stable norepinephrine formulation retains at least about 90% of an initial activity as measured by an initial and a final amount of R-norepinephrine present in the formulation after storage for at least 120 days at 25°C as claimed. However, as discussed in more detail above, the combination of Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests a container system which is substantially identical to the claimed container system, and a norepinephrine composition held within the container system which is substantially identical to the claimed composition. Because the container system and norepinephrine composition suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz is structurally and compositionally the same as the container system and norepinephrine composition used in the claimed method, the claimed properties are presumed to be inherent in the prior art container system and norepinephrine composition. Please see MPEP §2112.01(I) and (II). Therefore, the ready-to-use, stable norepinephrine formulation in the packaged, sealed container system suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz inherently retains at least about 90% of an initial activity as measured by an initial and a final amount of R-norepinephrine present in the formulation after storage for at least 120 days at 25°C.
Puri further teaches that norepinephrine is used for the treatment of cardiac arrest, profound hypotension, poliomyelitis, pheochromocytomectomy, spinal anesthesia, myocardial infarction, septicemia, and blood transfusion (¶0005), and further teaches that norepinephrine formulations are typically administered by intravenous infusion (¶0006). Furthermore, Puri teaches that ready-to-inject formulations advantageously avoid the inconvenience associated with diluting small volume formulations prior to infusion and therefore reduce contamination risks and calculation errors (¶0021). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the system suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz in a method of treating hypotension in a subject, the method comprising: obtaining a packaged, sealed container system for stable storage of a ready-to-use, stable norepinephrine formulation; administering to a subject by intravenous infusion a therapeutically effective amount of the ready-to-use stable norepinephrine formulation, wherein the ready-to-use, stable norepinephrine formulation is not diluted prior to infusion, and wherein the subject is in need of treatment for hypotension in order to treat hypotension while avoiding the inconvenience associated with diluting small volume formulations prior to infusion and therefore reduce contamination risks and calculation errors as taught by Puri.
Regarding claim 47, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the method of claim 46. As discussed above, Puri further teaches that conditions such as cardiac arrest, profound hypotension, poliomyelitis, pheochromocytomectomy, spinal anesthesia, myocardial infarction, septicemia, and blood transfusion may be treated using norepinephrine formulations (¶0005). Therefore, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz further suggests that the subject has a condition selected from one or more pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion, and drug reactions.
Regarding claim 48, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the method of claim 46. As discussed above, Puri further teaches that conditions such as cardiac arrest and profound hypotension may be treated using norepinephrine formulations (¶0005). Therefore, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz further suggests that the subject has a condition selected from one or more of cardiac arrest and profound hypotension.
Claims 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, in further view of Babrowicz, and in further view of Farmer et al. (US 6,613,036 B1).
Regarding claims 35 and 36, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system of claim 30, but does not disclose that the opposing second flexible sheet layer comprises a transparent coextruded film configure to allow visual inspection into the secondary container, with respect to claim 35, or that the opposing second flexible sheet layer is colored to protect the ready-to-use, stable norepinephrine formulation from light, with respect to claim 36.
Farmer teaches a light protective container for a light-sensitive fluid including a container for the fluid (Fig. 1, feat. 12) and a colored sleeve (Fig. 1, feat. 14; Abstract). Farmer teaches that the sleeve substantially covers the container (Col. 5, line 62 – Col. 6, line 5) and is made of a colored translucent material in order to allow for visual inspection of the container while protecting the contents from harmful light (Col. 7, lines 7-42). Farmer teaches visual inspection can be used to ensure that the fluid is clean and free of particulates and precipitates (Col. 1, lines 54-65). Farmer further teaches light exposure may cause undesirable photochemical degradation of the fluid (Col. 1, lines 15-32). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz so that the opposing second flexible sheet layer comprises a transparent coextruded film configure to allow visual inspection into the secondary container, with respect to claim 35, and so that the opposing second flexible sheet layer is colored to protect the ready-to-use, stable norepinephrine formulation from light, with respect to claim 36, as taught by Farmer so that the norepinephrine formulation can be inspected for cleanliness and a lack of particulates while protecting it from undesirable photochemical degradation.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, in further view of Babrowicz, and in further view of McDorman (US 2013/0327677 A1).
Regarding claim 37, Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz suggests the system of claim 30, but is silent with respect to the water transmission rate of any component of the secondary container.
McDorman teaches a packaging system for preserving a nonoxygenated hemoglobin based therapeutic agent (Abstract). McDorman teaches that protecting therapeutic agents against oxygen and moisture is important for preserving their therapeutic properties (¶0004 and 0005). McDorman teaches that the packaging system comprises a secondary overwrap for protecting the primary package (¶0009), and that the secondary overwrap has a water vapor transmission rate of 0.0007 g/100 in2/day (approximately 0.0124 g/m2/day). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invnetion to modify the system suggested by Devouassoux in view of Baillie, in further view of Puri, in further view of Inoue, and in further view of Babrowicz so that the second flexible sheet layer has a water transmission rate less than 3.0 g/m2/day as taught by McDorman in order to maintain the therapeutic properties of the norepinephrine formulation.
Conclusion
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/ARJUNA P CHATRATHI/Examiner, Art Unit 3781
/CATHARINE L ANDERSON/Primary Examiner, Art Unit 3781
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