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 .
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateshi et al. in view of Khattar et al. (previously cited) and Yang et al. (US Patent No. 6,525,123 – henceforth Yang B) as evidenced by Boutrid and Oobayashi (US PGPub No. 2011/0060075).
Tateshi et al. teach a multilayered drug solution container for oxidation sensitive drugs that is also heat resistant (see abstract and paragraphs 3 and 16). The container is a multilayered infusion pouch system that suppresses the internal oxygen level prior to and during steam sterilization (autoclaving) as well as upon post-sterilization storage (see paragraphs 20 and 126-129 and figures 6-7). The best performing pouch had no polyamide and a series of layers from the outermost to the innermost (fluid contacting) composed of polyethylene (outermost), adherent polyethylene (tie layer), a polyethylene vinyl alcohol copolymer (intermediate, oxygen scavenging layer), adherent polyethylene (tie layer), polyethylene (inner layer), and a blend with polyethylene (innermost) (see examples 1 and 2, paragraphs 100-102, 104, 107-108, and figures 6-7; instant claims 1, 3-6, 8, and 16). Their polyethylene is a ethylene-1-butene copolymer or a mixture of ethylene-1-butene copolymer and polyethylene homopolymer which are varieties of polyethylene (see paragraphs 100-101 and Oobayashi paragraph 107). A polyamide component or layer is not recited or required in the exemplified pouch. Ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer are instantly disclosed as oxygen scavenging polymers and Tateshi et al. teach the ethylene vinyl alcohol as a gas/oxygen barrier layer (see specification page 13 lines 29-30; Tateshi et al. paragraphs 6 and 12-13; instant claims 1 and 16). In addition to polyethylene, the outer layer is also envisioned as polyethylene terephthalate amongst a small set of specifically named options (see paragraph 68; instant claims 12-13). The inner layer polyethylene has a density of 0.94 g/cm3 which makes it high density and the innermost layer has density of 0.92 g/cm3 which makes it low density (see paragraphs 100-101; Boutrid paragraph 38; instant claims 3 and 10). The example 1 bag exhibits an oxygen transmission rate of about 0 cc/m2 • day • atm three days after high pressure stem sterilization (see paragraph 119 and figure 5; instant claim 20). Tateshi et al. further detail the polyethylene vinyl alcohol copolymer layer with a 3 to 20 mm thickness, the innermost layer with a 20 mm thickness, the outermost layer with a 30 mm thickness, and the multilayer film that composes the bag with a 180 to 300 mm thickness (see paragraphs 78 and 81; instant claims 11, 15, and 18-19). Table 1 lists several functional layers where 2 adherent layers are included to attach functional layers to one another while figure 3 illustrates the exclusion of adherent layers and implies dry lamination (see paragraph 78; instant claim 7). They further teach filling the bag with 300 ml of model drug solution (see paragraph 121; instant claims 21 and 23). Tateshi et al. go on to teach autoclaving the packaged liquid and then placing the bagged liquid in a secondary package (see paragraph 123; instant claims 31 and 39). The outer pouch may be aluminum foil (see paragraph 90; instant claim 32). This packaging material does not include an oxygen scavenging or oxygen absorbing material as a constituent (see instant claim 33). Additionally, Tateshi et al. teach that the pouch is filled with a desired solution then sealed, the oxygen content of the headspace is reduced to 10% via nitrogen purging, the pouch is autoclave sterilized, then the pouch is subsequently sealed in a secondary container and a head space oxygen content of no more than 2% via nitrogen purging (see paragraph 123-124; instant claims 34-36). The result is an oxygen level in the contained solution of less than 1 ppm (see figures 6 and 7). The drug solution to employ in the pouch is not particularly limited and the pouch is recommended for drugs that are readily oxidized (see paragraph 84). Pemetrexed is not explicitly taught as the drug in the solution.
Khattar et al. teach ready-to-use parenteral aqueous solutions of pemetrexed that are free of antioxidant (see page 4 lines 37-39, page 6 lines 28-29, and example 1). The pemetrexed is noted to be sensitive to oxidation and is protected from oxygen by the control of the oxygen content in the solution and headspace of its vial via the inclusion of nitrogen throughout the process (see page 2 lines 21-26, page 4 line 31-page 5 lines 6, and page 8 lines 1-11; instant claim 35-36). The concentration of pemetrexed is taught to range from 2.5 to 50 mg/ml and be administered via intravenous infusion (see page 5 lines 20-25; instant claims 22 and 28). They exemplify the composition to contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 6.6 to 7.8 (see table A; instant claims 28-29). In addition, the composition is also free of complexing agents, chelating agents, and amino acids (see table A and page 4 lines 27-29; instant claim 26).
Yang B teach of the inclusion of oxygen scavenging additives in poly(ethylene vinyl alcohol) (EVOH), which is commonly known for its gas barrier properties, as a packaging for oxygen sensitive products, such as foods and pharmaceuticals (see abstract column 1 lines 1-14 and 56-64 and column 3 lines 1-5). The material is envisioned in multilayered packaging (see column 2 lines 19-27). Yang B detail the superior oxygen scavenging capabilities of a film composed of EVOH that includes cobalt oleate salt and oxygen scavenging polymer additive (see column 12 lines 29-38 and example 2). Transition metal salts are more generically taught as an included oxygen scavenging additive, where the metal is envisioned as cobalt, copper, nickel, iron, manganese, rhodium, or ruthenium (see claims 1 and 11).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare the infusion pouch of Tateshi et al. following their guidance further in view of Khattar et al. regarding the solution to hold and in view of Yang B, where their oxygen scavenging additives are included in the EVOH layer. This modification to the pouch of Tateshi et al. would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. Since the pemetrexed composition of Khattar et al. was known to be oxygen sensitive and the packaging of Tateshi et al. is specifically designed for such compositions, the selection of the Khattar et al. solution as the product to package would have been obvious. Within the teachings of Tateshi et al., the selection of foil as the secondary package material would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome. Similarly, employing polyethylene terephthalate as the outermost layer constituent material would have been obvious for the same reason, it also would have been obvious to include polyethylene or polyethylene terephthalate in this outermost layer since they are alternatives suggested by Tateshi et al. The inclusion of adherent layers between each pairing of functional layers would also have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The result is a nine layer pouch. The inclusion of more than one of any of the categories of functional layers would have been obvious as the duplication of parts which does not produce an unexpectedly superior outcome and yields a pouch with at least 10 layers (see MPEP 2144.04(VI)(B); instant claim 2). An alternative application of the teachings of Tateshi et al. is the preparation of the layered structure without adherent layers (see instant claim 7). Layer thicknesses are detailed by Tateshi et al. in regard to the total layered structure and one of its layers, it would have been obvious to extend the teachings of the thickness of one layer to the other layers within the bounds of the total thickness that is also taught. This yields a range of 3 to 20 mm which overlaps with those recited for instant claims 11 and 15, thereby rendering them obvious. “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed.Cir. 1990)” (see MPEP 2144.05). The pemetrexed concentration range overlaps with that instantly claimed, thereby rendering the claimed range obvious (see MPEP 2144.05). Provision of the packaged pemetrexed solution after autoclaving follows from the teachings of Tateshi et al. who teach autoclave sterilization. The occurrence of impurities in the pemetrexed solution due to autoclaving is not explicitly discussed (see instant claims 24-25 and 38). According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Here, the pemetrexed solution containing infusion bag that is rendered obvious has all the instantly claimed components in the instantly claimed configurations and at the instantly claimed proportions, therefore the claimed functionality associated with this arrangement, namely the solution impurity level and absence of polyamide 11 particles, would also occur, absent evidence to the contrary. Therefore claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39 are obvious over Tateshi et al. in view of Khattar et al. and Yang B as evidenced by Boutrid and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateshi et al. in view of Khattar et al. and Yang B as evidenced by Boutrid and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39 above, further in view of Busolli et al. (previously cited).
Tateshi et al. in view of Khattar et al. and Yang B as evidenced by Boutrid and Oobayashi render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39. The pemetrexed composition of Khattar et al. is produced as a pemetrexed disodium solution from a pemetrexed diacid starting material, sodium hydroxide, hydrochloride acid for pH adjustment, and water (see example 1). The presence of sodium chloride is not detailed.
Busolli et al. teach the production of a pemetrexed disodium from pemetrexed diacid that is useful for reconstitution into a liquid preparation without purification (see abstract and paragraphs 32-33 and 35). Here a pemetrexed diacid or diacid salt is combined with an agent capable for forming a pharmaceutically acceptable salt of pemetrexed, preferably sodium hydroxide (see paragraphs 13-15). Sodium chloride is a preferred salt that forms and can be generated from pemetrexed diacid hydrochloride as the starting diacid salt and sodium hydroxide (see paragraphs 16-18 and 24-25 and example 5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare the pemetrexed solution of Tateshi et al. in view of Khattar et al. and Yang B as evidenced by Boutrid and Oobayashi from a pemetrexed diacid hydrochloride salt as taught by Busolli et al. This modification would have been obvious because both the pemetrexed diacid and pemetrexed diacid salt starting compounds are known as alternatives to one another for generating the desired pemetrexed disodium via the same fundamental reaction path. The modification is obvious as the simple substitution of one known element for another in order to yield a predictable outcome. The result would be packaging of Tateshi et al. in view of Khattar et al. and Yang B as evidenced by Boutrid and Oobayashi containing an autoclaved pemetrexed solution that includes sodium chloride, an osmotic agent according to the instant specification (see page 25 lines 1-3). Therefore claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39 are obvious over Tateshi et al. in view of Khattar et al., Yang B, and Busolli et al. as evidenced by Boutrid and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, and 31-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateshi et al. in view of Khattar et al. and Yang B as evidenced by Boutrid and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39 above, as further evidenced by the Pressure in Fluid Mechanics Reference (previously cited) and the MetMatters reference (previously cited).
Tateshi et al. in view of Khattar et al. and Yang et al. as evidenced by Boutrid and Oobayashi render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39. Tateshi et al. teach the sterilization at 100 to 120C for 10 to 60 minutes at 2000 to 3500 hPa barometric (absolute) pressure (see paragraph 48). Atmospheric pressure on Earth ranges from 950 to 1050 hPa (see MetMatters reference page 1). In gauge pressure, this corresponds to 950 to 2550 hPa, in consideration of the atmospheric range (as calculated by the examiner; absolute pressure = gauge pressure+ atmospheric pressure; Pressure in Fluid Mechanics page 1). The instantly claimed gauge pressure of about 2 to about 3.5 bar G corresponds to about 2000 to about 3500 hPa. This pressure range overlaps with that instantly claimed as do the temperature and time ranges of Tateshi et al., thereby rendering the claimed ranges obvious (see MPEP 2144.05). Therefore claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, and 31-39 are obvious over Tateshi et al. in view of Khattar et al. and Yang et al. as evidenced by Boutrid, Oobayashi, the MetMatters reference, and the Pressure in Fluid Mechanics reference.
Claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateshi et al. in view of Khattar et al. and Yang et al. as evidenced by Boutrid and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39 above, and further in view of Sarbach et al. and Jenke et al.
Tateshi et al. in view of Khattar et al. and Yang et al. render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39. Tateshi et al. do not explicitly discuss the exclusion of polyamide from the layered structure, beyond exemplifying its absence.
Sarbach et al. teach that a cyclic form of the monomer of the polyamide Nylon 6, namely -caprolactam, appears in an infusion solution packaged in a tri-layer infusion bag containing a Nylon 6 intermediate layer (see page 170 first column first full paragraph and page 171 second column –page 172 first column first partial paragraph and second column last paragraph). Sarbach et al. explicitly note that the source of the -caprolactam is the Nylon 6 (see page 172 second column last paragraph). They also detail that packaging for pharmaceuticals should not induce interaction between the packaging and the contents (see page 169 first-second column).
Jenke et al. noted the issue of packaging material compatibility in pharmaceuticals manifesting in the degree of interaction between the product and packaging, where components undesirably leach from or into the product (see page 1262 first column first paragraph). Jenke et al. go a bit further with a more detailed study, specifically looking for various oligomers of the Nylon 6 monomer upon extracting a tri-layer polyolefin film with a Nylon 6 intermediate layer in an ethanol/water mixture and comparing to extracts of Nylon 6 in various solutions at various temperatures (see abstract and tables I-II). Amongst those tested is water at 121⁰C, a temperature within the instantly envisioned range for autoclaving. Here cyclic amide monomers and cyclic polyamide oligomers up to hexamers were detected in the extracts (see table II). This is further indication that the prior art recognized the issue of impurities from polyamide materials employed in infusion bags appearing in the contained solution.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to explicitly exclude polyamide from the infusion bag of Tateshi et al. in view of Khattar et al. and Yang et al. as evidenced by Boutrid and Oobayashi in light of Sarbach et al. and Jenke et al. who discuss the deleterious effects it can have on a contained infusion fluid. Therefore claims 1, 3-8, 11, 15, 18-21, 24-26, 28-29, 31-36, and 38-39 are obvious over Tateshi et al. in view of Khattar et al., Yang et al., Sarbach et al., and Jenke et al. as evidenced by Boutrid and Oobayashi.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,869,867 in view of Khattar et al., Tateshi et al., Yang B, Sarbach et al., and Jenke et al. as evidenced by Boutrid and Oobayashi.
Although the claims at issue are not identical, they are not patentably distinct from each other because both recite a flexible container containing an aqueous solution of pemetrexed. An antioxidant is not a recited component. The patented composition is packaged in a flexible container/bag such that the liquid and container headspace contain an inert gas to reduce the oxygen level. The dosage form is recited to be subjected to autoclaving (called moist heat sterilization). This flexible bag is then included in an additional second container that is recited as aluminum and also includes an inert gas between the two containers. Total impurities total no more than 2 wt%. The concentration of pemetrexed in the solution of the patented claims is 0.7 to 21 mg/ml. An infusion bag as instantly claimed is not taught for the composition.
Khattar et al. teach ready-to-use parenteral aqueous solutions of pemetrexed that are free of antioxidant, chelating agent, complexing agent and amino acid (see page 4 lines 37-39, page 6 lines 28-29, and example 1). The pemetrexed is noted to be sensitive to oxidation and is protected from oxygen by the control of the oxygen content in the solution and headspace of its vial via the inclusion of nitrogen (see page 2 lines 21-26 and page 4 line 31-page 5 lines 6).
Tateshi et al. teach a multilayered drug solution container for oxidation sensitive drugs that is also heat resistant (see abstract and paragraphs 3 and 16). The container is a multilayered infusion pouch system that suppresses the internal oxygen level prior to and during steam sterilization (autoclaving) as well as upon post-sterilization storage (see paragraphs 20 and 126-129 and figures 6-7). The best performing pouch had no polyamide and a series of layers from the outermost to the innermost (fluid contacting) composed of polyethylene (outermost), adherent polyethylene (tie layer), a polyethylene vinyl alcohol copolymer (intermediate, oxygen scavenging layer), adherent polyethylene (tie layer), polyethylene (inner layer), and a blend with polyethylene (innermost) (see examples 1 and 2, paragraphs 100-102, 104, 107-108, and figures 6-7; instant claims 1, 3-6, 8, and 16). Their polyethylene is a ethylene-1-butene copolymer or a mixture of ethylene-1-butene copolymer and polyethylene homopolymer which are varieties of polyethylene (see paragraphs 100-101 and Oobayashi paragraph 107). A polyamide component or layer is not recited or required in the exemplified pouch. Ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer are instantly disclosed as oxygen scavenging polymers and Tateshi et al. teach the ethylene vinyl alcohol as a gas/oxygen barrier layer (see specification page 13 lines 29-30; Tateshi et al. paragraphs 6 and 12-13; instant claims 1 and 16). In addition to polyethylene, the outer layer is also envisioned as polyethylene terephthalate amongst a small set of specifically named options (see paragraph 68; instant claims 12-13). The inner layer polyethylene has a density of 0.94 g/cm3 which makes it high density and the innermost layer has density of 0.92 g/cm3 which makes it low density (see paragraphs 100-101; Boutrid paragraph 38; instant claims 3 and 10). The example 1 bag exhibits an oxygen transmission rate of about 0 cc/m2 • day • atm three days after high pressure stem sterilization (see paragraph 119 and figure 5; instant claim 20). Tateshi et al. further detail the polyethylene vinyl alcohol copolymer layer with a 3 to 20 mm thickness, the innermost layer with a 20 mm thickness, the outermost layer with a 30 mm thickness, and the multilayer film that composes the bag with a 180 to 300 mm thickness (see paragraphs 78 and 81; instant claims 11, 15, and 18-19). Table 1 lists several functional layers where 2 adherent layers are included to attach functional layers to one another while figure 3 illustrates the exclusion of adherent layers and implies dry lamination (see paragraph 78; instant claim 7). They further teach filling the bag with 300 ml of model drug solution (see paragraph 121; instant claims 21 and 23). Tateshi et al. go on to teach autoclaving the packaged liquid and then placing the bagged liquid in a secondary package (see paragraph 123; instant claims 31 and 39). The outer pouch may be aluminum foil (see paragraph 90; instant claim 32). This packaging material does not include an oxygen scavenging or oxygen absorbing material as a constituent (see instant claim 33). Additionally, Tateshi et al. teach that the pouch is filled with a desired solution then sealed, the oxygen content of the headspace is reduced to 10% via nitrogen purging, the pouch is autoclave sterilized, then the pouch is subsequently sealed in a secondary container and a head space oxygen content of no more than 2% via nitrogen purging (see paragraph 123-124; instant claims 34-36). The result is an oxygen level in the contained solution of less than 1 ppm (see figures 6 and 7). The drug solution to employ in the pouch is not particularly limited and the pouch is recommended for drugs that are readily oxidized (see paragraph 84).
Yang B teach of the inclusion of oxygen scavenging additives in poly(ethylene vinyl alcohol) (EVOH), which is commonly known for its gas barrier properties, as a packaging for oxygen sensitive products, such as foods and pharmaceuticals (see abstract column 1 lines 1-14 and 56-64 and column 3 lines 1-5). The material is envisioned in multilayered packaging (see column 2 lines 19-27). Yang B detail the superior oxygen scavenging capabilities of a film composed of EVOH that includes cobalt oleate salt and oxygen scavenging polymer additive (see column 12 lines 29-38 and example 2). Transition metal salts are more generically taught as an included oxygen scavenging additive, where the metal is envisioned as cobalt, copper, nickel, iron, manganese, rhodium, or ruthenium (see claims 1 and 11).
Sarbach et al. teach that a cyclic form of the monomer of the polyamide Nylon 6, namely e-caprolactam, appears in an infusion solution packaged in a tri-layer infusion bag containing a Nylon 6 intermediate layer (see page 170 first column first full paragraph and page 171 second column –page 172 first column first partial paragraph and second column last paragraph). Sarbach et al. explicitly note that the source of the e-caprolactam is the Nylon 6 (see page 172 second column last paragraph). They also detail that packaging for pharmaceuticals should not induce interaction between the packaging and the contents (see page 169 first-second column).
Jenke et al. noted the issue of packaging material compatibility in pharmaceuticals manifesting in the degree of interaction between the product and packaging, where components undesirably leach from or into the product (see page 1262 first column first paragraph). Jenke et al. go a bit further with a more detailed study, specifically looking for various oligomers of the Nylon 6 monomer upon extracting a tri-layer polyolefin film with a Nylon 6 intermediate layer in an ethanol/water mixture and comparing to extracts of Nylon 6 in various solutions at various temperatures (see abstract and tables I-II). Amongst those tested is water at 121⁰C, a temperature within the instantly envisioned range for autoclaving. Here cyclic amide monomers and cyclic polyamide oligomers up to hexamers were detected in the extracts (see table II). This is further indication that the prior art recognized the issue of impurities from polyamide materials employed in infusion bags appearing in the contained solution.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select a modified version of the bag of Tateshi et al. as the flexible container of the patented claims, where the oxygen scavenging additives of Yang B are included in the EVOH layer. Since Khattar et al. detail that pemetrexed is oxidation sensitive, the gas barrier oxygen scavenging layer containing modified bag of Tateshi et al. would have been desirable to employ. Within the teachings of Tateshi et al., the selection of foil as the secondary package material would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome. Similarly, employing polyethylene terephthalate as the outermost layer constituent material would have been obvious for the same reason, it also would have been obvious to include polyethylene or polyethylene terephthalate in this outermost layer since they are alternatives suggested by Tateshi et al. The inclusion of adherent layers between each pairing of functional layers would also have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The result is a nine layer pouch. The inclusion of more than one of any of the categories of functional layers would have been obvious as the duplication of parts which does not produce an unexpectedly superior outcome and yields a pouch with at least 10 layers (see MPEP 2144.04(VI)(B); instant claim 2). An alternative application of the teachings of Tateshi et al. is the preparation of the layered structure without adherent layers (see instant claim 7). Layer thicknesses are detailed by Tateshi et al. in regard to the total layered structure and one of its layers, it would have been obvious to extend the teachings of the thickness of one layer to the other layers within the bounds of the total thickness that is also taught. This yields a range of 3 to 20 mm which overlaps with those recited for instant claims 11 and 15, thereby rendering them obvious (see MPEP 2144.05). The pemetrexed concentration range overlaps with that instantly claimed, thereby rendering the claimed range obvious (see MPEP 2144.05). Moist heat (autoclaving) sterilization as envisioned by the patented claims would then follow. Avoidance of polyamides would have been obvious in light of Sarbach et al. and Jenke et al. who point to the recognized deleterious effect it can have when in a layered infusion bag that is subjected to heat sterilization.
The cited references are silent in regard to polyamide particles in the pemetrexed solution upon autoclaving. According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Here, the pemetrexed solution containing infusion bag that is rendered obvious has all the instantly claimed components in the instantly claimed configurations and at the instantly claimed proportions, therefore the claimed functionality associated with this arrangement, namely the solution impurity level and absence of polyamide 11 particles, would also occur, absent evidence to the contrary. Therefore claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39 are obvious over claims 1-7 of U.S. Patent No. 10,869,867 in view of Tateshi et al., Khattar et al., Yang B, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 24-26, and 28-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,869,867 in view of Tateshi et al., Khattar et al., Yang B, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39 above, as further evidenced by the Pressure in Fluid Mechanics Reference and the MetMatters reference.
Claims 1-7 of U.S. Patent No. 10,869,867 in view of Tateshi et al., Khattar et al., Yang B, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39. Tateshi et al. teach the sterilization at 100 to 120C for 10 to 60 minutes at 2000 to 3500 hPa barometric (absolute) pressure (see paragraph 48). Atmospheric pressure on Earth ranges from 950 to 1050 hPa (see MetMatters reference page 1). In gauge pressure, this corresponds to 950 to 2550 hPa, in consideration of the atmospheric range (as calculated by the examiner; absolute pressure = gauge pressure+ atmospheric pressure; Pressure in Fluid Mechanics page 1). The instantly claimed gauge pressure of about 2 to about 3.5 bar G corresponds to about 2000 to about 3500 hPa. This pressure range overlaps with that instantly claimed as do the temperature and time ranges of Tateshi et al., thereby rendering the claimed ranges obvious (see MPEP 2144.05). Therefore claims 1, 3-8, 11, 15, 18-21, 24-26, and 28-39 are obvious claims 1-7 of U.S. Patent No. 10,869,867 in view of Tateshi et al., Khattar et al., Yang B, Sarbach et al., and Jenke et al. as Boutrid et al., Oobayashi, the MetMatters reference, and the Pressure in Fluid Mechanics reference.
Claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,403,070 in view of Khattar et al., Tateshi et al., Yang B, Sarbach et al., and Jenke et al. as evidenced by Boutrid and Oobayashi.
Although the claims at issue are not identical, they are not patentably distinct from each other because both recite a flexible container containing an aqueous solution of pemetrexed. An antioxidant is not a recited component. The patented composition is packaged in a flexible container/bag such that the liquid and container headspace contain an inert gas to reduce the oxygen level. The dosage form is recited to be subjected to autoclaving (called moist heat sterilization). This flexible bag is then included in an additional second container that is recited as aluminum and also includes an inert gas between the two containers. Total impurities total no more than 2 wt%. The concentration of pemetrexed in the solution of the patented claims is 0.7 to 21 mg/ml. An infusion bag as instantly claimed is not taught for the composition.
Khattar et al. teach ready-to-use parenteral aqueous solutions of pemetrexed that are free of antioxidant, chelating agent, complexing agent and amino acid (see page 4 lines 37-39, page 6 lines 28-29, and example 1). The pemetrexed is noted to be sensitive to oxidation and is protected from oxygen by the control of the oxygen content in the solution and headspace of its vial via the inclusion of nitrogen (see page 2 lines 21-26 and page 4 line 31-page 5 lines 6).
Tateshi et al. teach a multilayered drug solution container for oxidation sensitive drugs that is also heat resistant (see abstract and paragraphs 3 and 16). The container is a multilayered infusion pouch system that suppresses the internal oxygen level prior to and during steam sterilization (autoclaving) as well as upon post-sterilization storage (see paragraphs 20 and 126-129 and figures 6-7). The best performing pouch had no polyamide and a series of layers from the outermost to the innermost (fluid contacting) composed of polyethylene (outermost), adherent polyethylene (tie layer), a polyethylene vinyl alcohol copolymer (intermediate, oxygen scavenging layer), adherent polyethylene (tie layer), polyethylene (inner layer), and a blend with polyethylene (innermost) (see examples 1 and 2, paragraphs 100-102, 104, 107-108, and figures 6-7; instant claims 1, 3-6, 8, and 16). Their polyethylene is a ethylene-1-butene copolymer or a mixture of ethylene-1-butene copolymer and polyethylene homopolymer which are varieties of polyethylene (see paragraphs 100-101 and Oobayashi paragraph 107). A polyamide component or layer is not recited or required in the exemplified pouch. Ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer are instantly disclosed as oxygen scavenging polymers and Tateshi et al. teach the ethylene vinyl alcohol as a gas/oxygen barrier layer (see specification page 13 lines 29-30; Tateshi et al. paragraphs 6 and 12-13; instant claims 1 and 16). In addition to polyethylene, the outer layer is also envisioned as polyethylene terephthalate amongst a small set of specifically named options (see paragraph 68; instant claims 12-13). The inner layer polyethylene has a density of 0.94 g/cm3 which makes it high density and the innermost layer has density of 0.92 g/cm3 which makes it low density (see paragraphs 100-101; Boutrid paragraph 38; instant claims 3 and 10). The example 1 bag exhibits an oxygen transmission rate of about 0 cc/m2 • day • atm three days after high pressure stem sterilization (see paragraph 119 and figure 5; instant claim 20). Tateshi et al. further detail the polyethylene vinyl alcohol copolymer layer with a 3 to 20 mm thickness, the innermost layer with a 20 mm thickness, the outermost layer with a 30 mm thickness, and the multilayer film that composes the bag with a 180 to 300 mm thickness (see paragraphs 78 and 81; instant claims 11, 15, and 18-19). Table 1 lists several functional layers where 2 adherent layers are included to attach functional layers to one another while figure 3 illustrates the exclusion of adherent layers and implies dry lamination (see paragraph 78; instant claim 7). They further teach filling the bag with 300 ml of model drug solution (see paragraph 121; instant claims 21 and 23). Tateshi et al. go on to teach autoclaving the packaged liquid and then placing the bagged liquid in a secondary package (see paragraph 123; instant claims 31 and 39). The outer pouch may be aluminum foil (see paragraph 90; instant claim 32). This packaging material does not include an oxygen scavenging or oxygen absorbing material as a constituent (see instant claim 33). Additionally, Tateshi et al. teach that the pouch is filled with a desired solution then sealed, the oxygen content of the headspace is reduced to 10% via nitrogen purging, the pouch is autoclave sterilized, then the pouch is subsequently sealed in a secondary container and a head space oxygen content of no more than 2% via nitrogen purging (see paragraph 123-124; instant claims 34-36). The result is an oxygen level in the contained solution of less than 1 ppm (see figures 6 and 7). The drug solution to employ in the pouch is not particularly limited and the pouch is recommended for drugs that are readily oxidized (see paragraph 84).
Yang B teach of the inclusion of oxygen scavenging additives in poly(ethylene vinyl alcohol) (EVOH), which is commonly known for its gas barrier properties, as a packaging for oxygen sensitive products, such as foods and pharmaceuticals (see abstract column 1 lines 1-14 and 56-64 and column 3 lines 1-5). The material is envisioned in multilayered packaging (see column 2 lines 19-27). Yang B detail the superior oxygen scavenging capabilities of a film composed of EVOH that includes cobalt oleate salt and oxygen scavenging polymer additive (see column 12 lines 29-38 and example 2). Transition metal salts are more generically taught as an included oxygen scavenging additive, where the metal is envisioned as cobalt, copper, nickel, iron, manganese, rhodium, or ruthenium (see claims 1 and 11).
Sarbach et al. teach that a cyclic form of the monomer of the polyamide Nylon 6, namely e-caprolactam, appears in an infusion solution packaged in a tri-layer infusion bag containing a Nylon 6 intermediate layer (see page 170 first column first full paragraph and page 171 second column –page 172 first column first partial paragraph and second column last paragraph). Sarbach et al. explicitly note that the source of the e-caprolactam is the Nylon 6 (see page 172 second column last paragraph). They also detail that packaging for pharmaceuticals should not induce interaction between the packaging and the contents (see page 169 first-second column).
Jenke et al. noted the issue of packaging material compatibility in pharmaceuticals manifesting in the degree of interaction between the product and packaging, where components undesirably leach from or into the product (see page 1262 first column first paragraph). Jenke et al. go a bit further with a more detailed study, specifically looking for various oligomers of the Nylon 6 monomer upon extracting a tri-layer polyolefin film with a Nylon 6 intermediate layer in an ethanol/water mixture and comparing to extracts of Nylon 6 in various solutions at various temperatures (see abstract and tables I-II). Amongst those tested is water at 121⁰C, a temperature within the instantly envisioned range for autoclaving. Here cyclic amide monomers and cyclic polyamide oligomers up to hexamers were detected in the extracts (see table II). This is further indication that the prior art recognized the issue of impurities from polyamide materials employed in infusion bags appearing in the contained solution.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select a modified version of the bag of Tateshi et al. as the flexible container of the patented claims, where the oxygen scavenging additives of Yang B are included in the EVOH layer. Since Khattar et al. detail that pemetrexed is oxidation sensitive, the gas barrier oxygen scavenging layer containing modified bag of Tateshi et al. would have been desirable to employ. Within the teachings of Tateshi et al., the selection of foil as the secondary package material would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome. Similarly, employing polyethylene terephthalate as the outermost layer constituent material would have been obvious for the same reason, it also would have been obvious to include polyethylene or polyethylene terephthalate in this outermost layer since they are alternatives suggested by Tateshi et al. The inclusion of adherent layers between each pairing of functional layers would also have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The result is a nine layer pouch. The inclusion of more than one of any of the categories of functional layers would have been obvious as the duplication of parts which does not produce an unexpectedly superior outcome and yields a pouch with at least 10 layers (see MPEP 2144.04(VI)(B); instant claim 2). An alternative application of the teachings of Tateshi et al. is the preparation of the layered structure without adherent layers (see instant claim 7). Layer thicknesses are detailed by Tateshi et al. in regard to the total layered structure and one of its layers, it would have been obvious to extend the teachings of the thickness of one layer to the other layers within the bounds of the total thickness that is also taught. This yields a range of 3 to 20 mm which overlaps with those recited for instant claims 11 and 15, thereby rendering them obvious (see MPEP 2144.05). The pemetrexed concentration range overlaps with that instantly claimed, thereby rendering the claimed range obvious (see MPEP 2144.05). Moist heat (autoclaving) sterilization as envisioned by the patented claims would then follow. Avoidance of polyamides would have been obvious in light of Sarbach et al. and Jenke et al. who point to the recognized deleterious effect it can have when in a layered infusion bag that is subjected to heat sterilization.
The cited references are silent in regard to polyamide particles in the pemetrexed solution upon autoclaving. According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Here, the pemetrexed solution containing infusion bag that is rendered obvious has all the instantly claimed components in the instantly claimed configurations and at the instantly claimed proportions, therefore the claimed functionality associated with this arrangement, namely the solution impurity level and absence of polyamide 11 particles, would also occur, absent evidence to the contrary. Therefore claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39 are obvious over claims 1-11 of U.S. Patent No. 12,403,070 in view of Tateshi et al., Khattar et al., Yang B, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 24-26, and 28-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,403,070 in view of Tateshi et al., Khattar et al., Yang B, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39 above, as further evidenced by the Pressure in Fluid Mechanics Reference and the MetMatters reference.
Claims 1-11 of U.S. Patent No. 12,403,070 in view of Tateshi et al., Khattar et al., Yang B, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 24-26, 28-36, and 38-39. Tateshi et al. teach the sterilization at 100 to 120C for 10 to 60 minutes at 2000 to 3500 hPa barometric (absolute) pressure (see paragraph 48). Atmospheric pressure on Earth ranges from 950 to 1050 hPa (see MetMatters reference page 1). In gauge pressure, this corresponds to 950 to 2550 hPa, in consideration of the atmospheric range (as calculated by the examiner; absolute pressure = gauge pressure+ atmospheric pressure; Pressure in Fluid Mechanics page 1). The instantly claimed gauge pressure of about 2 to about 3.5 bar G corresponds to about 2000 to about 3500 hPa. This pressure range overlaps with that instantly claimed as do the temperature and time ranges of Tateshi et al., thereby rendering the claimed ranges obvious (see MPEP 2144.05). Therefore claims 1, 3-8, 11, 15, 18-21, 24-26, and 28-39 are obvious claims 1-11 of U.S. Patent No. 12,403,070 in view of Tateshi et al., Khattar et al., Yang B, Sarbach et al., and Jenke et al. as Boutrid et al., Oobayashi, the MetMatters reference, and the Pressure in Fluid Mechanics reference.
Response to Arguments
Applicant's arguments filed September 22, 2025 have been fully considered. In light of the amendment the previous grounds of rejection are hereby withdrawn. New grounds of rejection are detailed in their place to address the new claim limitations and combination of claim limitations. Arguments relevant to the new grounds of rejection are detailed below.
The applicant notes a reduction in the oxygen barrier properties of EVOH due to exposure to humidity and their remedy to this occurrence via the inclusion of claimed oxygen scavenging additives. Yang B teach of the improvement in the oxygen barrier capabilities of EVOH due to the inclusion of such compounds, in the form of transition metal salts, and an oxygen scavenging polymer. While the applicant may have recognized a different condition under which the oxygen barrier capabilities of EVOH would warrant improvement than Yang B (long duration storage vs. thermal/humidity exposure), the addition of claimed oxygen scavenging additives to improve upon the function for which EVOH is used was already recognized. Further, Jansen et al. enumerate several oxidative degradation products of pemetrexed were already known that the instant disclosure also highlights (Journal of Pharmaceutical Sciences 2016 105:3256-3268). Thus the need for protection against the generation of particular oxidative degradation products of pemetrexed was also known.
In contrast to the applicant’s description, providing pemetrexed solution in a ready-to-use form is detailed by Khattar et al. and was not a new idea, in spite of commercial versions of the drug needing reconstitution. Thus the existence of a ready to use formulation has not an unmet need.
The applicant notes some prior art approaches employed to provide ready-to-use pemetrexed preparations included excipients, yet Khattar et al. recognized and acted on the desire to exclude excess additives in ready-to-use pemetrexed formulations.
The applicant also notes their recognition that packaging their pemetrexed solution in infusion plastic with polyamide to yield a stabile preparation resulted in particles forming upon terminal sterilization which the applicant identified as originating from the polyamide layer. Polyamide is known for its utility as an oxygen absorber/barrier and is also recognized as potentially having a deleterious interaction with contained pharmaceutical actives (see Tateshi et al. paragraph 58 and Nakamura et al. – previously cited - paragraph 74). The prior art infusion bag exemplified by Tateshi et al. provides an EVOH layer between an innermost and outermost layer, where the innermost layer is high density polyethylene and polyamide is not a component. The instant specification details a preferred oxygen scavenging layer composed of EVOH (see page 13 lines 1-2). Thus the arrangement of an oxygen scavenging layer as an interior layer of a multilayer container is not new. The instant rejections are currently framed as applying a modified version of an exemplified infusion bag for oxygen sensitive drug solutions to package a pemetrexed solution, as a particular known oxygen sensitive drug solution. The obviousness of this combination is controlled by the predictability of the outcome. If pemetrexed is more susceptible to particle formation when steam sterilized within a polyamide containing bag than other oxygen sensitive drugs, it could indicate the non-obviousness of its pairing with a polyamide free package. Similarly, if the choice of particular outermost or innermost layer materials of Tateshi et al. yield stability not seen with other choices they suggest for the same role in an unexpected manner, it could indicate the non-obviousness of selecting the claimed polymer components for the innermost or outermost layer. Additionally, the applicant notes that the presence of an oxygen scavenging intermediate layer makes a secondary package that encloses an oxygen scavenger outside the primary package unnecessary for maintaining stability through autoclave treatment. If the degree of stability attained with the placement of oxygen scavenging material in the wall of a primary package of pemetrexed solution instead of outside the primary package is unexpectedly superior, it could indicate the non-obviousness of the claimed pairing.
The applicant further argues that teachings of Jenke et al. and Sarbach et al. do not discuss pemetrexed solutions specifically. While true, Tateshi et al. acknowledge the possibility that polyamide in packaging materials can impact contained drug composition in undesired ways. The applicant argues that Jenke et al. do not detail the polyamide degrading a contained active. This argument is not relevant to the rejection which notes the possibility of polyamide sourced contamination of a contained product, not that the polyamide degrades the active that is packaged. When considered in concert, the prior art suggests that polyamide packaging of drug solutions can negatively impact the contained solution and that treatment by heat sterilization conditions can exacerbate their occurrence. These suggestions lend support to the avoidance of polyamide materials beyond the example of Tateshi et al. who already exemplify their absence, based on the evidence of record.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CARALYNNE E HELM/ Examiner, Art Unit 1615
/MELISSA S MERCIER/ Primary Examiner, Art Unit 1615