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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 9, 2026 has been entered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-8, 11, 15, 18-21, 26, and 28-39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “the multilayered container is ready-to-infuse”. The specification recites “[t]he term 'ready-to-infuse' as used herein refers to the intravenous infusion dosage form which can be directly administered from the infusion container to the patients intravenously, without involving any intermediate steps of manipulation, dilution, reconstitution, dispensing, sterilization, transfer, handling or compounding before intravenous administration of the drug solution” [emphasis added] (see instant specification page 9 lines 10-14). The scope of “manipulation” and “handling”, in particular, are unclear. Infusion containers, such as bottles and pouches, require connection to a subject in order to administer their contents. This connection often involves the attachment of tubing and connectors as well as a metering apparatus or at least a stand of some sort to facilitate gravity fed release. In addition, the integration of a cannula/needle to reach a subject’s circulation is also required. All of these connections require handling or manipulation of the packaged solution and none of the ancillary components are recited as part of the instant multilayered container. Thus the scope embraced by “without involving any intermediate steps of manipulation…handling…before intravenous administration” is unclear.
For the sake of application of prior art and compact prosecution, “ready-to-infuse” will be deemed to be met when the prior art product provides the pemetrexed solution in a form that can be dispensed into a subject via a multilayered container that can connect the product to a subject without the addition other ingredients to the solution.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 38 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The claim repeats limitations that appear in its parent claim, thus its scope is no different than that of the parent claim. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 26, 28-29, 31-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateishi et al. (US PGPub No. 2009/0032426 - previously cited) in view of Khattar et al. (previously cited), Yang B (US Patent No. 6,525,123 - previously cited) Ohta et al. (US PGPub No. 2007/0042145) and Beleke (US PGPub No. 2017/0114195) as evidenced by Boutrid (previously cited) and Oobayashi (previously cited).
Tateishi 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 (ready-to-infuse) 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 4 and 6-7). The best performing pouch had no polyamide and a series of seven layers from the outermost to the innermost (fluid contacting) composed of polyethylene (outermost), adherent polyethylene (tie layer; inner/adhesive layer), a polyethylene vinyl alcohol copolymer (intermediate, oxygen scavenging layer), adherent polyethylene (tie layer; inner/adhesive layer), cycloolefin polymer (inner layer), polyethylene, and a blend with polyethylene (innermost) (see example 1, paragraphs 100-108, and figures 6-7; instant claims 1, 3-6, 8, and 16). Their polyethylene is an 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 Tateishi et al. teach the ethylene vinyl alcohol as a gas/oxygen barrier layer (see specification page 13 lines 29-30; Tateishi 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). This bag provides a series of layers from outermost to innermost of polyethylene, adherent polyethylene, EVOH, adherent polyethylene, water absorptive norbornene polymer (cycloolefin polymer), polyethylene, polyethylene-polypropylene blend (see paragraph 100-108; instant claim 3). Tateishi 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). Tateishi 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, Tateishi 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 nor is a ten layer pouch taught.
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).
Ohta et al. teach multilayered plastic formed into various package shapes such as bottles and pouches/bags for holding contents that are easily deteriorated by exposure to oxygen (see paragraphs 82-83 and 89). The contained material is envisioned as food as well as pharmaceuticals (see paragraph 89). The layers are arranged to provide an oxygen barrier layer, followed by an oxygen absorbing layer, that is followed by a thermoplastic polymer layer, when viewed from the outside to the inside of the package (see paragraph 15). They further detail the oxygen barrier as EVOH or its copolymers (see paragraph 20). Ohta et al. also teach that the number of layers can include adhesive layers, and the types of layers may repeat as well as vary in number, where 7 to 10 layers are exemplified (see paragraphs 110, 115, 130, 144, and table 3). They exemplify repetition of the EVOH layer on either side of a central layer as well as the use of an adhesive layer between each pair of active layers (see paragraph 115 and claims 11-12).
Bekele explicitly teach multilayered films for forming pouches for medical solutions and detail layers ranging in number from 1 to 20 (see abstract and paragraph 31).
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 Tateishi et al. following their guidance further in view of 1) Khattar et al. regarding the solution to hold, 2) Yang B, where their oxygen scavenging additives are included in the EVOH layer, and 3) Ohta et al., where their repetition of the EVOH layer and configuration of adhesive layers is considered/incorporated. Since the pemetrexed composition of Khattar et al. was known to be oxygen sensitive and the packaging of Tateishi 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. The pemetrexed concentration range overlaps with that instantly claimed, thereby rendering the claimed range 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). Provision of the packaged pemetrexed solution after autoclaving follows from the teachings of Tateishi et al. who teach autoclave sterilization. The modifications to the pouch of Tateishi et al. would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The placement of the already contemplated oxygen scavenging component within pouch layers would further support the exclusion of oxygen from the package contents in a manner demonstrated to be better than EVOH alone, in light of Kang B. Similarly, the configuration of the pouch, in light of Ohta et al., where this EVOH layer is duplicated and adhesive layers are included between more sets of active layers would have been obvious to improve upon the connectivity in the multilayered structure as well as the oxygen exclusion from the contained liquid. Further, the mere duplication of parts has no patentable significance unless a new and unexpected result is produced (see MPEP 22144.04(VI)(B)). The result, when an adherent layer is employed between each set of functional layers, is a modified version of the pouch of Tateishi with layers, from outermost to innermost, of 1) polyethylene, 2) adhesive polyethylene, 3) EVOH with oxygen scavenging additive, 4) adhesive polyethylene, 5) water absorptive norbornene polymer, 6) adhesive polyethylene 7) EVOH with oxygen scavenging additive, 8) adhesive polyethylene, 9) polyethylene, 10) adhesive polyethylene, and 11) polyethylene-polypropylene blend. This number of layers is within the range contemplated in the art for the polymer film employed to compose pouches for medical solutions, as shown by Bekele. Similarly, the use of dry lamination for one or more of the pairings of functional layers also would have been obvious in light of Tateishi et al. , whoemploys such a combination of adhesive mechanisms in their layered structure. The resulting layered structures include an embodiment where the outermost layer is dry laminated to the next functional layer which is the EVOH layer (see instant claims 7-8). Employing polyethylene terephthalate as the outermost layer constituent material would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome. It also would have been obvious to include polyethylene or polyethylene terephthalate in this outermost layer since they are alternatives suggested by Tateishi et al. Layer thicknesses are detailed by Tateishi et al. in regard to the total layered structure and several of its layers. These teachings meet or overlap with those instantly claimed, thereby rendering the claimed ranges obvious (see MPEP 2144.05; instant claims 11, 15, and 18-19). Within the teachings of Tateishi 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.
The occurrence of impurities in the pemetrexed solution due to autoclaving is not explicitly discussed by Tateishi et al. (see instant claim 1). 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. Further, the instantly claimed duration of autoclaving is not stated; thus a few seconds or minutes of autoclave exposure would fulfill the instant test condition. In light of the low level of impurities in the pemetrexed solution of Khattar et al. with its low dissolved oxygen and inert gas purged headspace, a packaged version in the modified pouch of Tateishi et al. would likely fulfill the performance criteria instantly recited over a sufficiently short autoclave duration. Therefore claims 1, 3-8, 11, 15, 18-21, 26, 28-29, 31-36, and 38-39 are obvious over Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 26, 28-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 26, 28-29, 31-36, and 38-39 above, further in view of Busolli et al. (previously cited).
Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 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; instant claim 30).
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 Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke 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 Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke 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, 26, 28-36, and 38-39 are obvious over Tateishi et al. in view of Khattar et al., Khattar et al., Yang B, Ohta et al., Beleke, and Busolli et al. as evidenced by Boutrid and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 26, 28-29, and 31-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 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).
Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 26, 28-29, 31-36, and 38-39. Tateishi et al. teach sterilization at 100 to 120⁰C 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 Tateishi et al., thereby rendering the claimed ranges obvious (see MPEP 2144.05). Therefore claims 1, 3-8, 11, 15, 18-21, 26, 28-29, and 31-39 are obvious over Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid, Oobayashi, the MetMatters reference, and the Pressure in Fluid Mechanics reference.
Claims 1, 3-8, 11, 15, 18-21, 26, 28-29, 31-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateishi et al. Khattar et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 26, 28-29, 31-36, and 38-39 above, and further in view of Sarbach et al. (previously cited) and Jenke et al. (previously cited).
Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 26, 28-29, 31-36, and 38-39. Tateishi 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 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 explicitly exclude polyamide from the infusion bag of Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., and Beleke 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, 26, 28-29, 31-36, and 38-39 are obvious over Tateishi et al. in view of Khattar et al., Yang B, Ohta et al., Beleke, Sarbach et al., and Jenke et al. as evidenced by Boutrid and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 28-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateishi et al. in view of Mandal et al. (US PGPub No. 2017/0340639), Yang B, Ohta et al. and Beleke as evidenced by Boutrid and Oobayashi.
Tateishi 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 seven 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 an 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 Tateishi et al. teach the ethylene vinyl alcohol as a gas/oxygen barrier layer (see specification page 13 lines 29-30; Tateishi 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). This bag provides a series of layers from outermost to innermost of polyethylene, adherent polyethylene, EVOH, adherent polyethylene, water absorptive norbornene polymer (cycloolefin polymer), polyethylene, polyethylene-polypropylene blend (see paragraph 100-108; instant claim 3). Tateishi 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). Tateishi 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, Tateishi 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 nor is a ten layer pouch taught.
Mandal et al. teach ready-to-use parenteral aqueous solutions of pemetrexed (see abstract). 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 paragraphs 6-7 and 34; instant claim 35-36). They exemplify the composition to have a pH of 6 to 8 via a pH adjusting agent , if needed, where the best performing composition with lowest amount of impurities included sodium chloride (osmotic agent), mannitol (osmotic agent), an antioxidant, and pemetrexed at 10 mg/ml (see table after/in paragraph 36, example 5 in table after paragraph 42; instant specification page 25 lines 1-3; instant claims 28-30).
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).
Ohta et al. teach multilayered plastic formed into various package shapes such as bottles and pouches/bags for holding contents that are easily deteriorated by exposure to oxygen (see paragraphs 82-83 and 89). The contained material is envisioned as food as well as pharmaceuticals (see paragraph 89). The layers are arranged to provide an oxygen barrier layer, followed by an oxygen absorbing layer, that is followed by a thermoplastic polymer layer, when viewed from the outside to the inside of the package (see paragraph 15). They further detail the oxygen barrier as EVOH or its copolymers (see paragraph 20). Ohta et al. also teach that the number of layers can include adhesive layers, and the types of layers may repeat as well as vary in number, where 7 to 10 layers are exemplified (see paragraphs 110, 115, 130, 144, and table 3). They exemplify repetition of the EVOH layer on either side of a central layer as well as the use of an adhesive layer between each pair of active layers (see paragraph 115 and claims 11-12).
Bekele explicitly teach multilayered films for forming pouches for medical solutions and detail layers ranging in number from 1 to 20 (see abstract and paragraph 31).
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 Tateishi et al. following their guidance further in view of 1) Mandal et al. regarding the solution to hold, 2) Yang B, where their oxygen scavenging additives are included in the EVOH layer, and 3) Ohta et al., where their repetition of the EVOH layer and configuration of adhesive layers is considered/incorporated. Since the best performing pemetrexed composition of Mandal et al. was known to be oxygen sensitive and the packaging of Tateishi et al. is specifically designed for such compositions, the selection of this solution of Mandal et al. as the product to package would have been obvious. Provision of the packaged pemetrexed solution after autoclaving follows from the teachings of Tateishi et al. who teach autoclave sterilization. The modifications to the pouch of Tateishi et al. would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The placement of the already contemplated oxygen scavenging component within pouch layers would further support the exclusion of oxygen from the package contents in a manner demonstrated to be better than EVOH alone, in light of Kang B. Similarly, the configuration of the pouch, in light of Ohta et al., where this EVOH layer is duplicated and adhesive layers are included between more sets of active layers would have been obvious to improve upon the connectivity in the multilayered structure as well as the oxygen exclusion from the contained liquid. Further, the mere duplication of parts has no patentable significance unless a new and unexpected result is produced (see MPEP 22144.04(VI)(B)). The result, when an adherent layer is employed between each set of functional layers, is a modified version of the pouch of Tateishi with layers, from outermost to innermost, of 1) polyethylene, 2) adhesive polyethylene, 3) EVOH with oxygen scavenging additive, 4) adhesive polyethylene, 5) water absorptive norbornene polymer, 6) adhesive polyethylene 7) EVOH with oxygen scavenging additive, 8) adhesive polyethylene, 9) polyethylene, 10) adhesive polyethylene, and 11) polyethylene-polypropylene blend. This number of layers is within the range contemplated in the art for the polymer film employed to compose pouches for medical solutions, as shown by Bekele. Similarly, the use of dry lamination for one or more of the pairings of functional layers also would have been obvious in light of Tateishi et al., who employs such a combination of adhesive mechanisms in their layered structure. The resulting layered structures include an embodiment where the outermost layer is dry laminated to the next functional layer which is the EVOH layer (see instant claims 7-8). Employing polyethylene terephthalate as the outermost layer constituent material would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome. It also would have been obvious to include polyethylene or polyethylene terephthalate in this outermost layer since they are alternatives suggested by Tateishi et al. Layer thicknesses are detailed by Tateishi et al. in regard to the total layered structure and several of its layers. These teachings meet or overlap with those instantly claimed, thereby rendering the claimed ranges obvious (see MPEP 2144.05; instant claims 11, 15, and 18-19). Within the teachings of Tateishi 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.
The occurrence of impurities in the pemetrexed solution due to autoclaving is not explicitly discussed by Tateishi et al. (see instant claim 1). 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. Further, the instantly claimed duration of autoclaving is not stated; thus a few seconds or minutes of autoclave exposure would fulfill the instant test condition. In light of the low level of impurities in the pemetrexed solution of Khattar et al. with its low dissolved oxygen and inert gas purged headspace, a packaged version in the modified pouch of Tateishi et al. would likely fulfill the performance criteria instantly recited over a sufficiently short autoclave duration. Therefore claims 1, 3-8, 11, 15, 18-21, 28-36, and 38-39 are obvious over Tateishi et al. in view of Mandal et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, and 28-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateishi et al. in view of Mandal et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 26, 28-29, 31-36, and 38-39 above, as further evidenced by the Pressure in Fluid Mechanics Reference and the MetMatters reference.
Tateishi et al. in view of Mandal et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 28-36, and 38-39. Tateishi et al. teach sterilization at 100 to 120⁰C 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 Tateishi et al., thereby rendering the claimed ranges obvious (see MPEP 2144.05). Therefore claims 1, 3-8, 11, 15, 18-21, and 28-39 are obvious over Tateishi et al. in view of Mandal et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid, Oobayashi, the MetMatters reference, and the Pressure in Fluid Mechanics reference.
Claims 1, 3-8, 11, 15, 18-21, 28-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Tateishi et al. Mandal et al., Yang B, Ohta et al., and Beleke as evidenced by Boutrid and Oobayashi as applied to 1, 3-8, 11, 15, 18-21, 28-36, and 38-39 above, and further in view of Sarbach et al. and Jenke et al.
Tateishi et al. in view of Mandal et al., Yang B, Ohta et al., and Beleke render obvious the limitations of instant claims 1, 3-8, 11, 15, 18-21, 28-36, and 38-39. Tateishi 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 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 explicitly exclude polyamide from the infusion bag of Tateishi et al. in view of Mandal et al., Yang B, Ohta et al., and Beleke 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, 28-36, and 38-39 are obvious over Tateishi et al. in view of Mandal et al., Yang B, Ohta et al., Beleke, 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, 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., Tateishi et al., Yang B, Ohta et al., Bekele, 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).
Tateishi 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 an 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 Tateishi et al. teach the ethylene vinyl alcohol as a gas/oxygen barrier layer (see specification page 13 lines 29-30; Tateishi 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). Tateishi 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). Tateishi 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, Tateishi 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).
Ohta et al. teach multilayered plastic formed into various package shapes such as bottles and pouches/bags for holding contents that are easily deteriorated by exposure to oxygen (see paragraphs 82-83 and 89). The contained material is envisioned as food as well as pharmaceuticals (see paragraph 89). The layers are arranged to provide an oxygen barrier layer, followed by an oxygen absorbing layer, that is followed by a thermoplastic polymer layer, when viewed from the outside to the inside of the package (see paragraph 15). They further detail the oxygen barrier as EVOH or its copolymers (see paragraph 20). Ohta et al. also teach that the number of layers can include adhesive layers, and the types of layers may repeat as well as vary in number, where 7 to 10 layers are exemplified (see paragraphs 110, 115, 130, 144, and table 3). They exemplify repetition of the EVOH layer on either side of a central layer as well as the use of an adhesive layer between each pair of active layers (see paragraph 115 and claims 11-12).
Bekele explicitly teach multilayered films for forming pouches for medical solutions and detail layers ranging in number from 1 to 20 (see abstract and paragraph 31).
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 Tateishi et al. as the flexible container of the patented claims, where the oxygen scavenging additives of Yang B are included in the EVOH layer and the repetition of the EVOH layer and configuration of adhesive layers of Ohta et al. is considered/incorporated. Since Khattar et al. detail that pemetrexed is oxidation sensitive, the gas barrier oxygen scavenging layer containing modified bag of Tateishi et al. would have been desirable to employ. The modifications to the pouch of Tateishi et al. would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The placement of the already contemplated oxygen scavenging component within pouch layers would further support the exclusion of oxygen from the package contents in a manner demonstrated to be better than EVOH alone, in light of Kang B. Similarly, the configuration of the pouch, in light of Ohta et al., where this EVOH layer is duplicated and adhesive layers are included between more sets of active layers would have been obvious to improve upon the connectivity in the multilayered structure as well as the oxygen exclusion from the contained liquid. Further, the mere duplication of parts has no patentable significance unless a new and unexpected result is produced (see MPEP 22144.04(VI)(B)). The result, when an adherent layer is employed between each set of functional layers, is a modified version of the pouch of Tateishi with layers, from outermost to innermost, of 1) polyethylene, 2) adhesive polyethylene, 3) EVOH with oxygen scavenging additive, 4) adhesive polyethylene, 5) water absorptive norbornene polymer, 6) adhesive polyethylene 7) EVOH with oxygen scavenging additive, 8) adhesive polyethylene, 9) polyethylene, 10) adhesive polyethylene, and 11) polyethylene-polypropylene blend. This number of layers is within the range contemplated in the art for the polymer film employed to compose pouches for medical solutions, as shown by Bekele. Similarly, the use of dry lamination for one or more of the pairings of functional layers also would have been obvious in light of Tateishi et al., who employs such a combination of adhesive mechanisms in their layered structure. The resulting layered structures include an embodiment where the outermost layer is dry laminated to the next functional layer which is the EVOH layer (see instant claims 7-8). Employing polyethylene terephthalate as the outermost layer constituent material would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome. It also would have been obvious to include polyethylene or polyethylene terephthalate in this outermost layer since they are alternatives suggested by Tateishi et al. Layer thicknesses are detailed by Tateishi et al. in regard to the total layered structure and several of its layers. These teachings meet or overlap with those instantly claimed, thereby rendering the claimed ranges obvious (see MPEP 2144.05; instant claims 11, 15, and 18-19). Within the teachings of Tateishi 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. 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, 26, 28-36, and 38-39 are obvious over claims 1-7 of U.S. Patent No. 10,869,867 in view of Tateishi et al., Khattar et al., Yang B, Ohta et al., Bekele, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 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 Tateishi et al., Khattar et al., Yang B, Ohta et al., Bekele, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 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 Tateishi et al., Khattar et al., Yang B, Ohta et al., Bekele, 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, 26, 28-36, and 38-39. Tateishi 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 Tateishi 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 Tateishi et al., Khattar et al., Yang B, Ohta et al., Bekele, 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, 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., Tateishi et al., Yang B, Ohta et al., Bekele, 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).
Tateishi 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 an 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 Tateishi et al. teach the ethylene vinyl alcohol as a gas/oxygen barrier layer (see specification page 13 lines 29-30; Tateishi 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). Tateishi 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). Tateishi 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, Tateishi 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).
Ohta et al. teach multilayered plastic formed into various package shapes such as bottles and pouches/bags for holding contents that are easily deteriorated by exposure to oxygen (see paragraphs 82-83 and 89). The contained material is envisioned as food as well as pharmaceuticals (see paragraph 89). The layers are arranged to provide an oxygen barrier layer, followed by an oxygen absorbing layer, that is followed by a thermoplastic polymer layer, when viewed from the outside to the inside of the package (see paragraph 15). They further detail the oxygen barrier as EVOH or its copolymers (see paragraph 20). Ohta et al. also teach that the number of layers can include adhesive layers, and the types of layers may repeat as well as vary in number, where 7 to 10 layers are exemplified (see paragraphs 110, 115, 130, 144, and table 3). They exemplify repetition of the EVOH layer on either side of a central layer as well as the use of an adhesive layer between each pair of active layers (see paragraph 115 and claims 11-12).
Bekele explicitly teach multilayered films for forming pouches for medical solutions and detail layers ranging in number from 1 to 20 (see abstract and paragraph 31).
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 Tateishi et al. as the flexible container of the patented claims, where the oxygen scavenging additives of Yang B are included in the EVOH layer and the repetition of the EVOH layer and configuration of adhesive layers of Ohta et al. is considered/incorporated. Since Khattar et al. detail that pemetrexed is oxidation sensitive, the gas barrier oxygen scavenging layer containing modified bag of Tateishi et al. would have been desirable to employ. The modifications to the pouch of Tateishi et al. would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The placement of the already contemplated oxygen scavenging component within pouch layers would further support the exclusion of oxygen from the package contents in a manner demonstrated to be better than EVOH alone, in light of Kang B. Similarly, the configuration of the pouch, in light of Ohta et al., where this EVOH layer is duplicated and adhesive layers are included between more sets of active layers would have been obvious to improve upon the connectivity in the multilayered structure as well as the oxygen exclusion from the contained liquid. Further, the mere duplication of parts has no patentable significance unless a new and unexpected result is produced (see MPEP 22144.04(VI)(B)). The result, when an adherent layer is employed between each set of functional layers, is a modified version of the pouch of Tateishi with layers, from outermost to innermost, of 1) polyethylene, 2) adhesive polyethylene, 3) EVOH with oxygen scavenging additive, 4) adhesive polyethylene, 5) water absorptive norbornene polymer, 6) adhesive polyethylene 7) EVOH with oxygen scavenging additive, 8) adhesive polyethylene, 9) polyethylene, 10) adhesive polyethylene, and 11) polyethylene-polypropylene blend. This number of layers is within the range contemplated in the art for the polymer film employed to compose pouches for medical solutions, as shown by Bekele. Similarly, the use of dry lamination for one or more of the pairings of functional layers also would have been obvious in light of Tateishi et al., who employs such a combination of adhesive mechanisms in their layered structure. The resulting layered structures include an embodiment where the outermost layer is dry laminated to the next functional layer which is the EVOH layer (see instant claims 7-8). Employing polyethylene terephthalate as the outermost layer constituent material would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome. It also would have been obvious to include polyethylene or polyethylene terephthalate in this outermost layer since they are alternatives suggested by Tateishi et al. Layer thicknesses are detailed by Tateishi et al. in regard to the total layered structure and several of its layers. These teachings meet or overlap with those instantly claimed, thereby rendering the claimed ranges obvious (see MPEP 2144.05; instant claims 11, 15, and 18-19). Within the teachings of Tateishi 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. 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, 26, 28-36, and 38-39 are obvious over claims 1-11 of U.S. Patent No. 12,403,070 in view of Tateishi et al., Khattar et al., Yang B, Ohta et al., Bekele, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi.
Claims 1, 3-8, 11, 15, 18-21, 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 Tateishi et al., Khattar et al., Yang B, Ohta et al., Bekele, Sarbach et al., and Jenke et al. as Boutrid et la. and Oobayashi as applied to claims 1, 3-8, 11, 15, 18-21, 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 Tateishi et al., Khattar et al., Yang B, Ohta et al., Bekele, 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, 26, 28-36, and 38-39. Tateishi 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 Tateishi et al., thereby rendering the claimed ranges obvious (see MPEP 2144.05). Therefore claims 1, 3-8, 11, 15, 18-21, 26, and 28-39 are obvious claims 1-11 of U.S. Patent No. 12,403,070 in view of Tateishi et al., Khattar et al., Yang B, Ohta et al., Bekele, 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 July 9, 2026 have been fully considered. In light of the amendment, the previous grounds of rejection are modified to further highlight the presence of the claimed features in the prior art. The arguments are not persuasive.
Regard the rejection under 35 USC 103 over Tateishi et al. Khattar et al. and Yang B as evidenced by Boutrid and Oobayashi as well as further in view of Busolli or further evidenced by the MetMatters reference and the Pressure in Fluid Mechanics reference:
The applicant argues that Tateishi et al. detail a need for polyamide in their packaging. The text discussing polyamide improving heat resistance highlighted by the applicant is not a requirement for the inclusion of polyamide. In fact, its presence is discussed on an “if needed” and optional basis (see paragraph 58). None of their examples include a polyamide layer and it is not recited in their claimed embodiments. The teachings of other references to justify the absence of polyamide materials in the packaging of Tateishi et al. are useful, but not absolutely necessary, because Tateishi et al. exemplify the absence of polyamide materials and teach that their presence is optional. As an optional added component, the packaging is clearly envisioned without polyamide.
Contrary to the applicant’s argument, the artisan would have a motivation to apply the packaging of Tateishi et al. to pemetrexed because this drug is oxidation sensitive and the purpose of the packaging of Tateishi et al. is to protect and permit parenteral delivery of this category of drug solution.
The applicant argues that the solution of Khattar et al. is not ready to infuse. However this functionality is not a property of the solution alone, but is instead a property of a solution in combination with its packaging (see instant specification page 9 lines 10-14). The rejection renders obvious the instantly claimed packaging and its pairing with a claimed pemetrexed solution. Thus the combination is ready to infuse since the pemetrexed solution could be administered from the container via connection to a subject without adding ingredients to the solution.
The applicant cites post-filing art as basis for arguing that the artisan of ordinary skill would have expected the instantly claimed concentration of pemetrexed to be more unstable than higher concentrations within the range taught by Khattar et al. There is no evidence of record that this nuance was appreciated at the time of filing of the instant application. Thus the artisan of ordinary skill would have expected the range of concentrations of pemetrexed in Khattar et al. to have the same propensity for degradation. The applicant has the potential opportunity to provide evidence to illustrate unexpectedly superior results in a variety of ways such as 1) the pairing of the instantly claimed container could flatten the occurrence of pemetrexed degradation products such that concentration dependent degradation seen in other oxygen absorbing packaging does not occur, 2) the degree of stability attained with the placement of oxygen scavenging material in the wall of a primary package of pemetrexed solution could be significantly better than when outside the primary package, or 3) the choice of a particular outermost or innermost layer material polymer could yield stability not seen with other choices known in the same role in an unexpected manner, depending on data available to the applicant. Nevertheless, the current record still supports the obviousness of the claimed product
The applicant argues against reliance on the teachings of Yang B in support of the obviousness of the instantly claimed product. However, their argument is not based upon the modification that Yang B is cited to support. The teaching of a polyamide layer or compatibilizing component in the polymer pouch of Yang B is not a requirement that polyamide be included in their pouches. Furthermore, Yang b is relied upon as one of combination of references. As such, their teaching are not required to be inserted in whole into the that of the primary reference, as the applicant’s arguments appear to suggest. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
The applicants also argue against the reliance upon Boutrid and Oobayashi, but these two references are only cited as evidence of the meaning of terms that occur in other prior art teachings or in the instant claims. The fact that they include teachings of polyamide polymers is not a teaching away from the instant invention, contrary to the applicant’s argument.
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. Thus a pemetrexed solution devoid of excipients, such as antioxidants and chelating agents. was already known in the art.
Further, the applicant argues that data in the specification indicates that the claimed layered film is “surprisingly” more stable than their comparative container. It is not unexpected that the inclusion of an oxygen scavenger yields a package that increases product stability by reducing degradation induced by the ingress of oxygen. It also is not surprising that a package without polyamide yields fewer polyamide degradation products in its contained product.
In contrast to the applicant’s description, providing pemetrexed solution in a ready-to-use form is detailed by Khattar et al. and Mandal et al. and was not a new idea, in spite of commercial versions of the drug needing reconstitution. Khattar et al. teach the composition and explicitly exclude antioxidants, chelating agents, and amino acids, just like some of the compositions instantly claimed. Thus the existence of a ready to use formulation with minimal additives was not an unmet need.
The applicant argues that Busolli does not teach the instantly claimed ten layer pouch. This limitation is met by the teachings of Tateishi et al. and is further supported by in combination with Ohta et al. and Bekele.
The applicant argues that the MetMatters reference and the Pressure in Fluid Mechanics reference do not teach various claim features. However, they were not cited in order to address these features and the features were addressed by cited primary and/or secondary references.
Regard the rejection under 35 USC 103 over Tateishi et al., Khattar et al., Yang B, Sarbach et al. and Jenke et al. as evidenced by Boutrid and Oobayashi:
The applicant further argues that teachings of Jenke et al. and Sarbach et al. do not discuss several claim limitations, including pemetrexed solutions. While true, Sarbach et al. acknowledge the possibility that polyamide in packaging materials can impact contained drug composition in undesired ways and the limitations noted by the applicant are addressed via citations from other references. The applicant argues that Sarbach et al. is concerned with the contents of a package degrading constituent polyamide in the package and entering the contents, while the applicant is concerned with the polyamide containing packaging interfering with the content’s stability. The relevant aspect of Sarbach et al. is their teaching that interaction between the packaging and the contents is undesirable, particularly for pharmaceutical solutions. According to MPEP 2144 IV, “[t]he reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).” Thus the reason for avoidance of polyamide in pharmaceutical solution packaging in the prior art does not have to be the same as the applicant’s in order to make its explicit exclusion obvious.
The applicant argues that Jenke et al. do not detail that polyamide in a storage pouch degrades contained pemetrexed. 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. Degradation issues for pemetrexed are addressed by Khattar et al. and newly cited Mandal et al. 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 Tateishi et al. who already exemplify their absence, based on the evidence of record.
Regarding the double patenting rejections:
The applicant reiterates the argument against the rejections under 35 USC 103 that rely upon the same prior art references. The response detailed above is similarly reiterated.
Conclusion
No claim is allowed.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
Prosecution Insights