DEXMEDETOMIDINE-SOLUTION IN A LOW-DENSITY POLYETHYLENE CONTAINER

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 . Priority The instant application, filed on November 3, 2023, is a national stage entry of International Application No. PCT/EP2022/061796, filed May 3, 2022, which claims priority to European Patent Application No. EP21172306.9, filed on May 5, 2021. Receipt was acknowledged of certified copies of papers required by 37 CFR § 1.55. Status of Claims Claims 1-5, 7-10, 12-14, and 16-21 were rejected in the Non-Final Rejection mailed 05/07/2026. Applicant’s amendments received 07/23/2026, are acknowledged and entered. The amendments change the status indicator of the claims to previously presented and remove markup. Accordingly, claims 1-5, 7-10, 12-14, and 16-21 are pending. Claim Rejections - 35 USC § 103 - Maintained The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Previous Grounds of Rejection are Maintained Claims 1-5, 7-10, 12-14, and 16-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’0491 as evidenced by the Ecoflac plus Product Sheet,2 in view of the Ecoflac plus DHCP Letter,3 WO’188,4 Ahmad 2012,5 Sautou-Miranda 1999,6 Waxman 2019,7 EP’631,8 US’736,9 and WO’765.10 The rejections are reiterated following Response to Arguments. In the interests of compact prosecution, the rejection of claim 21 in further view of US’44411 is withdrawn. Returning Applicant’s remarks for not responding to the rejection would delay prosecution. Response to Arguments: Applicant's arguments, see Remarks Received 07/23/2026, at 9-13 of 13, with respect to the rejections of claims 1-5, 7-10, 12-14, and 16-21 under 35 U.S.C. 103 as stated in the 05/07/2026 Non-Final Rejection have been fully considered but they are not persuasive. Applicant’s position is at the time of filing that there was no reasonable expectation of success in selecting an Ecoflac container to store an aqueous solution of dexmedetomidine despite the fact that the drug product patent for PRECEDEX (dexmedetomidine hydrochloride injection) US’049 expressly teaches that premix formulations of dexmedetomidine may be stored in plastic flexible containers. US’049 cited on the face of the patent as an example of a plastic flexible container the Ecoflac plus container which has an inner surface of the compartment that is in contact with the aqueous solution when the container is in an upright position, and at least the inner surface of the compartment is made of a low density polyethylene. The Ecoflac series of plastic flexible containers that was cited by the inventors of the PRECEDEX drug product patent was developed specifically for IV drug products. The Ecoflac series of plastic flexible containers were made of LDPE which is chemically inert and toxicologically safe. The Ecoflac series of plastic flexible containers were DEHP-free which was crucial for IV infusion products because the plasticizer DEHP is known to leach into solutions and potentially cause adverse health effects. Moreover, it was known to specifically avoid DEHP with respect to dexmedetomidine because dexmedetomidine dissolves into DEHP. Applicant selected the Ecoflac series of containers to store its aqueous solution of dexmedetomidine. See Specification at 5, Table 1, at 12 (“Such an embodiment is used for ECOFLAC® PLUS”), and at 17, Example 1 (“A container (ECOFLAC® PLUS)….”). Applicant presently claims what the PRECEDEX drug product patent taught – that an aqueous solution of dexmedetomidine may be stored in a plastic flexible container such as one from the commercially available Ecoflac series. In the Remarks, Applicant designates US’049, i.e., the drug product patent for PRECEDEX, as “Roychowdhury”. Applicant in Remarks at 6 states “Roychowdhury does not even mention LDPE”. Applicant’s position is not persuasive. The PRECEDEX drug product patent cites the Ecoflac plus Product Sheet on the face of the patent. Applicant never addresses this fact. Applicant in Remarks at 6–8 argues that the drug product patent for PRECEDEX “teaches, both expressly and implicitly, a clear preference for glass over plastic when selecting an inner surface material that will come in contact with dexmedetomidine.” Remarks at 8. Applicant concludes that “a person having ordinary skill in the art would not, after following the teachings in Roychowdhury, have any inclination to choose a material other than glass for the inner surface of a container.” Remarks at 8. Applicant’s position is not persuasive because the drug product patent for PRECEDEX taught that premix formulations of dexmedetomidine may be stored in plastic flexible containers and cited as evidence of a plastic flexible container suitable for IV infusion products the Ecoflac series of plastic flexible containers. Applicant never addresses this fact in its Remarks and ignores entirely the citation to the Ecoflac plus Product Sheet on the face of the PRECEDEX drug product patent. Applicant’s Remarks not once address the reference other than to say it was cited in the Non-Final Rejection. See Remarks at 6, first full paragraph. Moreover, Applicants position that “a person having ordinary skill in the art would not, after following the teachings in Roychowdhury, have any inclination to choose a material other than glass for the inner surface of a container” is inconsistent with its Remarks at 10-11 discussing WO’188. WO’188 teaches that other persons of ordinary skill in the art were inclined to select plastic flexible containers substantially free of DEHP that had a material other than glass for the inner surface of a container to contain aqueous solutions of dexmedetomidine. WO’188 cites “U.S. Patent No. 8,242,158” on page 2, first paragraph. The patent cited is the first U.S. Patent that issued from U.S. Patent Application No. 13/343,672, of which US’049 is a continuation. See US’049 at page 1: PNG media_image1.png 205 362 media_image1.png Greyscale US’049 at page 1. If, as Applicant purports, no person of ordinary skill in the art reading the same specification as US’049 would have any inclination to choose a material other than glass for the inner surface of a container, then why did the inventors of WO’188 cite the same specification and still proceed to invent plastic flexible containers for dexmedetomidine that have a material other than glass for the inner surface of the container. Applicant does not address this question. Applicant then argues “WO '188 does not say that the innermost layer can be made of polyolefin.” Remarks at 10. Applicant’s position is not persuasive because WO '188 does not say that LDPE cannot be the innermost layer. It therefore does not teach away as Applicant purports. Applicant never acknowledges the wide-spread use of LDPE containers for parenteral/IV drug products cited in the Non-Final Rejection. Nothing teaches away from the instantly claimed and alleged invention. In Remarks at 11 of 13, Applicant concludes that “In summary, neither Roychowdhury nor WO '188 teach, either alone or in combination, a container with an inner surface in contact with dexmedetomidine that is made of LDPE as claimed.” Applicant then alleges at 12 “The deficiencies outlined above are not cured or overcome by any of the other cited references.” No discussion of the remaining references cited in the rejection are presented in Applicant’s remarks. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant has not addressed the combination of references cited in the 05/07/2026 Non-Final Rejection. Applicant’s discussion limited exclusively to the PRECEDEX drug product patent and WO '188 was found not persuasive for the reasons stated above. Therefore, Applicant has not overcome the rejections of record, which are reiterated below. Claims 1-5, 7-10, 12-14, and 16-21 were Obvious over US’049 as evidenced by the Ecoflac plus Product Sheet, in view of the Ecoflac plus DHCP Letter, WO’188, Ahmad 2012, Sautou-Miranda 1999, Waxman 2019, EP’631, US’736, and WO’765 Claims 1-5, 7-10, 12-14, and 16-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’049 as evidenced by the Ecoflac plus Product Sheet, in view of the Ecoflac plus DHCP Letter, WO’188, Ahmad 2012, Sautou-Miranda 1999, Waxman 2019, EP’631, US’736, and WO’765. Hospira, Inc currently markets PRECEDEX (dexmedetomidine hydrochloride injection), and holds several patents directed to its drug products that are listed in the FDA Orange Book. The latest drug product patent from the Orange Book listing is US’049, which is directed to premix formulations of dexmedetomidine. Being a drug product patent, US’049 describes suitable packaging for the premixed dexmedetomidine pharmaceutical compositions. US’049 expressly teaches these include “plastic flexible containers”. See, e.g., US’049 at col. 9: In certain non-limiting embodiments, the container or vessel includes, but is not limited to, glass vials (for example, but not limited to, flint glass vials), ampoules, plastic flexible containers, for example, but not limited to, PVC (polyvinyl chloride) containers, VisIV™ plastic containers (Hospira, Inc., Lake Forest, Ill.), and CR3 elastomer copolyester ether containers (Hospira, Inc., Lake Forest, Ill.), CZ resin containers, poly propylene containers and syringes. US’049 at col. 9 (emphasis added). However, Hospira had difficulties using PVC bags due to the complication of dexmedetomidine dissolving in DEHP. See, e.g., US’049 at col. 15: The cause of potency loss in PVC bags and CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.) during autoclaving was investigated. Related substances testing on autoclaved premixed dexmedetomidine composition filled in PVC and CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.) revealed that potency drop did not occur due to degradation, because the total percent of impurities was much less than 20% (Table 2). Loss of potency may be due to either adsorption (restricted to the surface of the flex bag) and/or absorption (not restricted to the surface) of the drug in to the flex bags. To confirm the absorption/adsorption phenomena, the CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.) and PVC bags that showed 20% potency loss were emptied and rinsed with MeOH. The rinse solvent was tested for dexmedetomidine. Nearly all the drug was recovered from CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.)—indicating adsorption and only 1% of the drug was recovered from PVC bags—indicating absorption, since drug dissolves in DEHP. US’049 at col. 15 (emphasis added). While US’049 does not exemplify storing its premix formulations of dexmedetomidine in a “container comprising a compartment filled with an aqueous solution of dexmedetomidine, wherein at least an inner surface of the compartment is in contact with the aqueous solution of dexmedetomidine when the container is in an upright position, and at least the inner surface of the compartment is made of a low density polyethylene”, one of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in storing a premix formulation of dexmedetomidine in such a container because The Ecoflac plus Product Sheet teaches that such containers were commercially available, suitable for all IV procedures, and DEHP-free, the Ecoflac plus DHCP Letter teaches that the container is indeed made of LDPE, WO’188 teaches that when storing aqueous premix solutions of dexmedetomidine in a flexible plastic container, that the container should avoid DEHP, concurring with the teachings of US’049, Ahmad 2012 teaches that no DEHP was released from the ECOFLAC® containers into aqueous solutions and that the stability of the active pharmaceutical ingredient was comparable to storage in glass, Sautou-Miranda 1999 teaches that ECOFLAC® containers were made by the known blow-fill-seal process and contain no additives to contaminate the drug product, Waxman 2019 explains that LDPE is frequently used as the fluid contact layer for aqueous solutions because of its good chemical compatibility profile, EP’631 teaches that such containers were simple to prepare and suitable for parenteral or intravenous administration, US’736 teaches that Braun Ecoflac containers have been used for other IV infusion drug products, and WO’765 teaches when storing a dexmedetomidine solution in flexible plastic containers, that the container should be resilient to the ingress of oxygen. Ecoflac plus Product Sheet The “Ecoflac plus Product Sheet” is cited on the face of the US’049 patent. See US’049 at 4, right column.12 The Ecoflac plus Product Sheet discloses a specific example of a commercially available flexible plastic container that was suitable for the drug products of US’049. For example, the Ecoflac plus Product Sheet at 2 discloses that “Ecoflac® plus is Braun’s IV container solution safe for infusion therapy. With an extensive portfolio of standard solutions, plasma volume replacement, premixed solutions and ready-to-use drugs, Ecoflac® plus stands as the state-of-the-art IV container system that offers safe and convenient application of all IV procedures.” Further, the Ecoflac plus Product Sheet at 2 lists that the container “prevents” “DEHP Exposure”. See the Ecoflac plus Product Sheet at 2: PNG media_image2.png 823 1510 media_image2.png Greyscale The Ecoflac plus Product Sheet at 2. The Ecoflac plus Product Sheet at 5 explains that the container is “virtu-ally unbreakable”. See the Ecoflac plus Product Sheet at 5: PNG media_image3.png 396 675 media_image3.png Greyscale Ecoflac plus Product Sheet at 5. The Ecoflac plus Product Sheet at 9 explains that the “Ecoflac® plus is made of pure medical grade polyethylene (PE) which is chemically inert and toxicologically safe. Polyethylene is a flexible and resistant material which pro-vides an excellent compatibility with a maximum number of pharmaceuticals, reducing the risk of interactions.” See the Ecoflac plus Product Sheet at 9: PNG media_image4.png 441 768 media_image4.png Greyscale The Ecoflac plus Product Sheet at 9. The Ecoflac plus Product Sheet at 9 further explains that the “Ecoflac® plus is free of PVC…”. PNG media_image5.png 471 782 media_image5.png Greyscale The Ecoflac plus Product Sheet at 9. The Ecoflac plus Product Sheet at 15 further explains that the “Ecoflac® plus is free of DEHP as well as other additives and compounds that may poten-tially migrate into the finished preparation.” See the Ecoflac plus Product Sheet at 15: PNG media_image6.png 387 762 media_image6.png Greyscale The Ecoflac plus Product Sheet at 15. Ecoflac plus DHCP Letter The Ecoflac plus DHCP Letter at pages 3-5, excerpted below, discloses properties of the commercially available Ecoflac plus container. On page 4 , it states the container is made of LDPE. PNG media_image7.png 766 719 media_image7.png Greyscale The Ecoflac plus DHCP Letter at page 3/5. PNG media_image8.png 816 710 media_image8.png Greyscale The Ecoflac plus DHCP Letter at page 4/5. PNG media_image9.png 393 671 media_image9.png Greyscale The Ecoflac plus DHCP Letter at page 5/5. WO’188 WO’188 discloses that the issues Hospira had with dexmedetomidine dissolving in DEHP can be resolved by using a “flexible plastic container” that is “substantially free of DEHP”, including those where “[t]he primary polymeric materials … include … LDPE”. See, e.g., WO’188 at 11-12, excerpted below: If the dexmedetomidine formulation is aseptically sterilized in addition to the bags having at least the inner most layer comprising a styrene-ethylene-butylene-styrene (SEBS) and an ethylene- propylene copolymer, bags made of CR3 elastomer copolyester ether bags, or bags made of a polyolefin (Hospira VISIV bags) may be used. PVC may be successfully used for the aseptically sterilized dexmedetomidine formulation provided specific bag does not absorb the dexmedetomidine. Dexmedetomidine has been reported in U.S.P. 8,242,158 as being soluble in DEHP used as a plasticizer in many PVC bags. Accordingly the bag should be substantially free of DEHP. Substantially free of DEHP means that the amount of DEHP present is insufficient to appreciably impact the amount of dexmedetomidine retained in the solution upon storage stability testing. That is, the amount of dexmedetomidine remains at or above 90% of the initial level. In an embodiment of the present invention, provided are a flexible plastic container with modified ports and closure system suitable for storing dexmedetomidine formulations of the present invention which is subjected to typically product sterilization by steam sterilization (e.g., autoclaving, 121°C for a about 15 minutes) without altering the thermal properties of the film layers, ports and closure system as well as maintaining the integrity container. The primary polymeric materials which may be used include: polysulfone, polycarbonate, polypropylene, polyethylene (LDPE or HDPE), ethylene/propylene copolymers, polyolefins, acrylic-imide copolymers, polyester (e.g. PET, PEN and the like), Teflon, Nylon, acetal (Delrin), polymethylpentene, PVDC, ethylvinylacetate, AN-copolymer etc. In addition to plastic bags, CZ resin containers, polypropylene and similar resins can be used as rigid containers and syringes. WO’188 at 11-12 (emphases added). Ahmad 2012 Ahmad 2012 examines and reviews the biocompatibility of LDPE containers for various parenteral/IV products. Amhad 2012 explains that “LDPE-based products do far better than DEHA products when tested for leaching”, and references studies of paclitaxel in LDPE containers wherein researchers found that “[n]o DEHP is released from the ECOFLAC® containers into the Paclitaxel solutions.” Ahmad 2012 at 84. It remarks that the stability of the API Paclitaxel was comparable to that obtained in glass containers. Id. See, e.g., Ahmad 2012 at 84, reproduced below: PNG media_image10.png 315 370 media_image10.png Greyscale PNG media_image11.png 935 375 media_image11.png Greyscale Ahmad 2012 at 84 (left column and right). Sautou-Miranda 1999 The paclitaxel/TAXOL studies Ahmad 2012 referenced are those reported in Sautou-Miranda 1999. Sautou-Miranda 1999 explains that paclitaxel, which is also an IV drug, was formulated with CHREMOPHOR, which in turn “produces an incompatibility of the drug solution with PVC bags, which release di-(2-ethylhexyl) phthalate (DEHP).” Sautou-Miranda 1999 at 77-78. Sautou-Miranda 1999 at 78 explains that ECOFLAC® containers were used in their experiments because “they are flexible, and will collapse like a bag when the contents are drawn off, while being sufficiently stiff to stand up like a bottle.” Sautou-Miranda 1999 at 78 further explains that these “low-density polyethylene” containers “contain[] no additives that liable to migrate into the drug solutions.…” and that “[n]o additive is used during the manufacture of ECOFLAC® containers, which are hot-formed by the blow-fill-seal process.” Id. See, e.g., Sautou-Miranda 1999 at 78, reproduced below: PNG media_image12.png 532 485 media_image12.png Greyscale Sautou-Miranda 1999 at 78. Waxman 2019 Waxman 2019 provides textbook examples of plastics used in IV drug products at the time of filing. It teaches that in disposable systems/drug products such as large-volume parenteral (LVP) or small-volume parenteral (SVP) products, “LDPE is frequently used as the fluid contact layer because of its good chemical compatibility profile.” Waxman 2019 at 503 (emphasis added). See, e.g., Waxman 2019 at 503, excerpted below: PNG media_image13.png 384 335 media_image13.png Greyscale PNG media_image14.png 375 334 media_image14.png Greyscale Waxman 2019 at 503 (left and right columns). Waxman 2019 at 504 further explains that LDPE has an “acceptable compatibility profile” for “most aqueous formulations”. See Waxman 2019 at 504, excerpted below: PNG media_image15.png 109 343 media_image15.png Greyscale Waxman 2019 at 504. EP’631 EP’631 teaches that means of making various LDPE containers for parenteral or intravenous administration were known in the art at the time of filing. In particular EP’631 discloses LDPE containers free of DEHP “with a density between 915 and 935 k/m3 (LDPE)”. See, e.g., EP’631 at Abstract: The invention relates to a container made from a polyethylene composition comprising a mixture of two types of polyethylene, the polyethylene composition comprising 50-80% of a predominantly linear homo- or copolymer of ethylene with one or more α-olefins with 3-12 C-atoms and optionally one or more non-conjugated dienes with a density between 920 and 965 kg/m³ (LLDPE) and 20-50% of a branched polyethylene, prepared according to a radical high-pressure polymerization process, with a density between 915 and 935 kg/m³ (LDPE). EP’631 at Abstract. The containers of EP’631 are suitable for medicinal/pharmaceutical use, sterilization, and for containing liquids for parenteral or intravenous administration. See, e.g., EP’631 at 3: Afterwards, the filled containers can, for the sake of safety, be resterilized by means of steam sterilization. This depends on the country where the containers are going to be used. Each country has its own requirements as regards medical/pharmaceutical containers. To meet these requirements, the containers must be able to withstand high sterilization temperatures for a certain period of time. The containers can be filled with liquids for parenteral or intravenous administration, such as liquid feed, isotonic salt solutions and the like. Solutions with medicines also can be administered by means of dosing systems using the container. EP’631 at 3. EP’631 at 3 further teaches that such containers may be made using blow-form-fill-seal or fill-seal processes. See, e.g., EP’631 at 3: It has been found that the polyethylene composition as described here is eminently suitable for the so-called blow-form-fill-seal process. According to this process, the polymer composition is first melted, and from the melt a tube is blown. Sterile air is then used to force this tube against a mould, upon which the container, for example a bottle, is formed. The container is subsequently filled with a predetermined amount of liquid using a dosing unit. Following this, the container is vacuum sealed. This is effected, for instance, in the Bottelpack® machines of Rommelag®. The entire process takes place under sterile conditions. The cycle time of this process is about 10-15 seconds. Besides the blow-form-fill-seal principle there is also the fill-seal principle, according to which finished containers are filled up and sealed by producers of intravenous or parenteral liquids. EP’631 at 3. US’736 IV infusion drug products commonly used LDPE containers including specific Braun Ecoflac containers. For example, US’736 at Abstract discloses: A pharmaceutical product comprises a container containing a bisphosphonate solution, in which at least the internal surface of the container comprises a plastic material and in which the container is heat sterilisable, and which is in the form of a ready to use infusion solution, for administration of the bisphosphonate to a patient in need of bisphosphonate treatment. US’736 at Abstract. The containers of US’736 comprised LDPE. See, e.g., US’736 at 2, paragraph [0025]: [0025] The container for the product of the invention may comprise a glass container having a transparent plastic inner lining. Preferably, however, the container is made of plastic material and does not comprise a glass outer shell. Examples of plastic materials which may be used include: polysulfone, polycarbonate, polypropylene, polyethylene (LDPE or HDPE), ethylene/propylene copolymers, polyolefines, acrylic-imide copolymers, PVC, polyester (e.g. PET, PEN and the like), Teflon, Nylon, acetal (Delrin), polymethylpentene, PVDC, ethylvinylacetate, AN-copolymer etc. The plastic material used for either type of container is preferably a transparent plastic material, i.e. it is translucent and permits visual inspection of the contents. US’736 at 2, paragraph [0025]. The inventors of US’736 had success with Braun Ecoflac containers, see claim 22 of US’736. WO’765 WO’765 discloses examples of various oxidation-related degradation products that result from the storage of dexmedetomidine solutions in flexible plastic containers. See, e.g., WO’765 at 18. Claim 1 was Obvious at the Time of Filing Therefore, while US’049 does not exemplify storing its premix formulations of dexmedetomidine in a: “container comprising a compartment filled with an aqueous solution of dexmedetomidine, wherein at least an inner surface of the compartment is in contact with the aqueous solution of dexmedetomidine when the container is in an upright position, and at least the inner surface of the compartment is made of a low density polyethylene”, such as Applicant’s exemplified Ecoflac plus container, one of ordinary skill in the art would have had a reasonable expectation of success in storing a premix formulation of dexmedetomidine in a such a container because the Ecoflac plus container was a commercially available container suitable for all IV procedures that was DEHP-free and eliminated the issue of dexmedetomidine dissolving into DEHP. Numerous other IV drug products were stored in the same container. It was obvious to the person of ordinary skill in the art at the time of filing to select the same container successfully utilized in related drug products that itself was cited on the face of the drug product patent for PRECEDEX, US’049. Accordingly, claim 1 was obvious at the time of filing. Claim 2 was Obvious at the Time of Filing Claim 2 recites the container of claim 1, wherein the LDPE has a density range of 0.910 g/cm3 to 0.937 g/cm3, as indicated below: PNG media_image16.png 99 1064 media_image16.png Greyscale Instant claim 2. EP’631 discloses LDPE containers free of DEHP “with a density between 915 and 935 k/m3 (LDPE)”. See, e.g., EP’631 at 2: PNG media_image17.png 135 1046 media_image17.png Greyscale EP’631 at 2. The containers of EP’631 are suitable for medicinal/pharmaceutical use, sterilization, and for containing liquids for parenteral or intravenous administration. See, e.g., EP’631 at 3: PNG media_image18.png 145 823 media_image18.png Greyscale EP’631 at 3. Therefore, one of ordinary skill in the art at the time of filing had a reasonable expectation of success in preparing LDPE with a density in the recited range and utilizing it for containing liquids for parenteral or intravenous administration. Accordingly, claim 2 was obvious at the time of filing for the reasons stated above, and for the reasons stated regarding why claim 1 was obvious at the time of filing. Claim 3 was Obvious at the Time of Filing Regarding claim 3, it requires some type of sealing of the compartment. See, e.g., instant claim 3: PNG media_image19.png 86 1023 media_image19.png Greyscale Instant claim 3. See, e.g., the Ecoflac plus DHCP Letter at 4 of 5 (indicating that the container is sealed): PNG media_image20.png 447 595 media_image20.png Greyscale The Ecoflac plus DHCP Letter at 4 of 5. Accordingly, claim 3 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claim 1 was obvious at the time of filing. Claim 4 was Obvious at the Time of Filing Regarding claim 4, it recites the following limitations of the container. See, e.g., instant claim 4: PNG media_image21.png 230 1039 media_image21.png Greyscale Instant claim 4. See, e.g., the Ecoflac plus DHCP Letter at 4 of 5 (there is a separate sealing member attached for closure): PNG media_image20.png 447 595 media_image20.png Greyscale The Ecoflac plus DHCP Letter at 4 of 5. Further, as previously stated, these containers were made of “pure medical grade polyethylene”, see the Ecoflac plus Product Sheet at 9. The Ecoflac plus DHCP Letter explains that this material was LDPE. The Ecoflac plus DHCP Letter at 4 of 5. Accordingly, claim 4 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 3 and 1 were obvious at the time of filing. Claim 5 was Obvious at the Time of Filing Regarding claim 5, it recites the following limitations of the container. See, e.g., instant claim 5: PNG media_image22.png 84 1062 media_image22.png Greyscale Instant claim 5. See the Ecoflac plus Product Sheet at 15: PNG media_image6.png 387 762 media_image6.png Greyscale The Ecoflac plus Product Sheet at 15. Accordingly, claim 5 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claim 1 was obvious at the time of filing. Claim 7 was Obvious at the Time of Filing Regarding claim 7, it recites the following limitations of the container. See, e.g., instant claim 7: PNG media_image23.png 219 1108 media_image23.png Greyscale Instant claim 7. See, e.g., US’049 at col. 10 (explaining these were standard sizes for premixed dexmedetomidine drug products): In certain non-limiting embodiments, the premixed dexmedetomidine composition of the present invention can be stored as a liquid in an aliquot having a total volume of about 5 mL, or about 10 mL, or about 15 mL, or about 20 mL, or about 25 mL, or about 30 mL, or about 35 mL, or about 40 mL, or about 45 mL, or about 50 mL, or about 55 mL, or about 60 mL, or about 65 mL, or about 70 mL, or about 75 mL, or about 80 mL, or about 85 mL, or about 90 mL, or about 95 mL, or about 100 mL, or about 105 mL, or about 110 mL, or about 115 mL, or about 120 mL, or about 125 mL, or about 130 mL, or about 135 mL, or about 140 mL, or about 145 mL, or about 150 mL, or about 200 mL, or about 250 mL, or about 500 mL. US’049 at col. 10. See also, the Ecoflac plus Product Sheet at 20 (and depicting a 500 mL flexible plastic container made of LDPE): PNG media_image24.png 707 478 media_image24.png Greyscale The Ecoflac plus Product Sheet at 20. Accordingly, claim 7 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claim 1 was obvious at the time of filing. Claim 8 was Obvious at the Time of Filing Regarding claim 8, it recites the following limitations of the container. See, e.g., instant claim 8: PNG media_image25.png 97 1103 media_image25.png Greyscale Instant claim 8. See the Ecoflac plus Product Sheet at 20 (depicting a cap): PNG media_image24.png 707 478 media_image24.png Greyscale The Ecoflac plus Product Sheet at 20. Accordingly, claim 8 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claim 1 was obvious at the time of filing. Claim 9 was Obvious at the Time of Filing Regarding claim 9, it recites the following limitations of the container. See, e.g., instant claim 9: PNG media_image26.png 80 1117 media_image26.png Greyscale Instant claim 9. The premix compositions of US’049 contain 0.9% NaCl. See, e.g., US’049 at col. 9 (“In one non-limiting example, the 0.9% NaCl solution is formulated by mixing 9.0 g NaCl/1000 mL of water. In certain embodiments, the premix compositions of the present invention are formulated by adding 0.118 g dexmedetomidine HCl plus 9.0 g NaCl into the same 1000 mL of water. The solution can then be mixed with addition 0.9% NaCl solution to achieve a desired concentration of dexmedetomidine, for example, 4 g/mL.”). Accordingly, claim 9 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claim 1 was obvious at the time of filing. Claim 10 was Obvious at the Time of Filing Regarding claim 10, it recites the following limitations of the container. See, e.g., instant claim 10: PNG media_image27.png 137 1104 media_image27.png Greyscale Instant claim 10. See, e.g., US’049 at col. 8 (explaining these were standard API concentrations for premixed dexmedetomidine drug products). In certain non-limiting embodiments, the premixed dexmedetomidine composition comprises dexmedetomidine at a concentration of … about 2 μg/mL, or about 2.5 μg/mL, or about 3 μg/mL, or about 3.5 μg/mL, or about 4 μg/mL, or about 4.5 μg/mL, or about 5 μg/mL, or about 5.5 μg/mL, or about 6 μg/mL, or about 6.5 μg/mL, or about 7 μg/mL, or about 7.5 μg/mL, or about 8 μg/mL, or about 8.5 μg/mL, or about 9 μg/mL, or about 9.5 μg/mL, or about 10 μg/mL, or about 10.5 μg/mL, or about 11 μg/mL, or about 11.5 μg/mL, or about 12 μg/mL…. US’049 at col. 8. Accordingly, claim 10 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claim 1 was obvious at the time of filing. Claim 16 was Obvious at the Time of Filing Regarding claim 16, it recites the following limitations of the container. See, e.g., instant claim 16: PNG media_image28.png 216 1116 media_image28.png Greyscale Instant claim 16. See, e.g., the Ecoflac plus DHCP Letter at 4 of 5 (They had a “Twin cap with peel tab cover” that is separate from the compartment): PNG media_image20.png 447 595 media_image20.png Greyscale The Ecoflac plus DHCP Letter at 4 of 5. Further, as previously stated, these containers were made of “pure medical grade polyethylene”, see the Ecoflac plus Product Sheet at 9. The Ecoflac plus DHCP Letter explains that this material was LDPE. The Ecoflac plus DHCP Letter at 4 of 5. As shown in the above figure, the “Twin Port with peel tab cover and two interchangeable access ports” has a “thermoplastic elastomeric septum”. The Ecoflac plus Product Sheet at 13 states that this septum is free of latex. PNG media_image29.png 263 518 media_image29.png Greyscale The Ecoflac plus Product Sheet at 13. Therefore, claim 16 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 4 and 1 were obvious at the time of filing. Claim 17 was Obvious at the Time of Filing Regarding claim 17, it recites the following limitations of the container. See, e.g., instant claim 17: PNG media_image30.png 102 1047 media_image30.png Greyscale Instant claim 17. As previously stated, these containers were made of “pure medical grade polyethylene”, see the Ecoflac plus Product Sheet at 9. The Ecoflac plus DHCP Letter explains that this material was LDPE. The Ecoflac plus DHCP Letter at 4 of 5. See also, the Ecoflac plus Product Sheet at 15: PNG media_image6.png 387 762 media_image6.png Greyscale The Ecoflac plus Product Sheet at 15. Therefore, claim 17 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 5 and 1 were obvious at the time of filing. Claim 18 was Obvious at the Time of Filing Regarding claim 18, it recites the following limitations of the container. See, e.g., instant claim 18: PNG media_image31.png 93 998 media_image31.png Greyscale Instant claim 18. Applicant states this was the wall thickness of the commercial Ecoflac plus container in specification at 18: PNG media_image32.png 620 924 media_image32.png Greyscale Further, the wall thickness is a result effective variable as thicker walls limit the rate of which oxygen penetrates the aqueous solution. Around 0.3 mm was standard thickness to limit oxygen ingress: Waxman 2019 at 492 explains that the rate of oxygen transmission and water vapor permeability of plastics is a function of the thickness of the plastic using the example of the resulting oxidation of biopharmaceuticals. See Waxman 2019 at 492, and at Figure 23.5: PNG media_image33.png 306 474 media_image33.png Greyscale PNG media_image34.png 116 489 media_image34.png Greyscale PNG media_image35.png 472 983 media_image35.png Greyscale Waxman 2019 at 492 , and at Figure 23.5. Further, dexmedetomidine was known to be liable to oxidation. See, e.g., WO’765 at 18 (depicting various impurities developed from the storage of dexmedetomidine in flexible plastic containers): PNG media_image36.png 768 600 media_image36.png Greyscale WO’765 at 18. The inventors of WO’765 utilized various antioxidants to prevent the formation of the above impurities in their dexmedetomidine compositions that were contained in flexible plastic containers. See, e.g., WO’765 at 29, claims 8 and 1: PNG media_image37.png 51 565 media_image37.png Greyscale PNG media_image38.png 138 582 media_image38.png Greyscale WO’765 at 29, claims 8 and 1. Therefore, it was obvious to select a container of around 0.3 mm thickness to limit oxygen ingress. One of ordinary skill in the art had a reasonable expectation of success in selecting this feature of the container. Therefore, claim 18 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 7 and 1 were obvious at the time of filing. Claim 19 was Obvious at the Time of Filing Regarding claim 19, it recites the following limitations of the container. See, e.g., instant claim 19: PNG media_image39.png 91 1094 media_image39.png Greyscale Instant claim 19. The examiner finds no difference between the above discussion of claim 1 and the instant claim 19. If there is some difference, “premixed, ready-to-use” formulations are just simple embodiments of the “premix formulations”. See, e.g., US’049 at col. 4: In certain embodiments, the compositions of the present invention can be formulated as “ready to use” compositions which refer to premixed compositions that are suitable for administration to a patient without dilution. For example, in certain embodiments, the compositions of the present invention are “ready to use” upon removing the compositions from a sealed container or vessel. US’049 at col. 4. As such, claim 19 was obvious at the time of filing for the reasons stated above, and for the same reasons claim 1 was obvious at the time of filing. Claim 12 was Obvious at the time of Filing Regarding claims 12-14 and 20-21, these claims are directed to a method for manufacturing a container. For example, claim 12 recites the following method. See, e.g., instant claim 12: PNG media_image40.png 346 1112 media_image40.png Greyscale Instant claim 12. Applicant thus claims a method for making a container, wherein the container is the container of claim 3. The container of claim 3 was obvious. The claim add no feature of merit because it simply recites filling an Ecoflac plus container with dexmedetomidine using standard procedures known in the art. As explained previously, the Ecoflac plus DHCP Letter at page 4/5 states that the Ecoflac plus container was a “Blow/Fill/Seal (BFS)” container. Similarly, the Ecoflac containers used by Sautou-Miranda 1999 were “hot-formed by the blow-fill-seal process.” See Sautou-Miranda 1999 at 78. Waxman 2019 explains that the BFS process was common for SVP and LVP drugs.13 See Waxman 2019 at 483: PNG media_image41.png 290 483 media_image41.png Greyscale Waxman 2019 at 483. Waxman 2019 at 488 explains the BFS process in the following way: PNG media_image42.png 257 487 media_image42.png Greyscale PNG media_image43.png 643 494 media_image43.png Greyscale Waxman 2019 at 488 (left and right columns). Further, EP’631 teaches that an alternative to the BFS method is the fill-seal method. See, e.g., EP’631 at 3: It has been found that the polyethylene composition as described here is eminently suitable for the so-called blow-form-fill-seal process. According to this process, the polymer composition is first melted, and from the melt a tube is blown. Sterile air is then used to force this tube against a mould, upon which the container, for example a bottle, is formed. The container is subsequently filled with a predetermined amount of liquid using a dosing unit. Following this, the container is vacuum sealed. This is effected, for instance, in the Bottelpack® machines of Rommelag®. The entire process takes place under sterile conditions. The cycle time of this process is about 10-15 seconds. Besides the blow-form-fill-seal principle there is also the fill-seal principle, according to which finished containers are filled up and sealed by producers of intravenous or parenteral liquids. EP’631 at 3. As explained by EP’631 at 3, the fill-seal process omits the blowing process, and the “finished containers” are simply “filed up and sealed by producers of intravenous or parenteral liquids.”14 Applicant’s claimed method recited in the instant claim 12 similarly omits the blowing process, and simply requires providing the container with the compartment, filling it with the solution, and then sealing it. Such a process was known in the art at the time of filing and was used for the preparation of LDPE containers for intravenous or parenteral liquids, as disclosed in EP’631. Therefore, one of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in preparing the obvious container of claim 3 utilizing standard procedures known in the art. Accordingly, claim 12 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 3 and 1 were obvious at the time of filing. Claim 13 was Obvious at the Time of Filing Claim 13 recites the following method. See, e.g., instant claim 13: PNG media_image44.png 113 1096 media_image44.png Greyscale Instant claim 13. Applicant thus claims a method for making a container, wherein the container is the container of claim 3, wherein the container is sterilized. As shown in the excerpts from Waxman 2019 at 483 and 488, and EP’631 at 3, BFS technologies were available to ordinary IV/parenteral drug product manufactures at the time of filing. Such technologies were used to develop sterilized IV/parenteral drug products. Further means of sterilization of the container after it had been filled and sealed were well within the ordinary skills of an ordinary IV/parenteral drug product manufacture at the time of filing. See, e.g., EP’631 at 4: Afterwards, the filled containers can, for the sake of safety, be resterilized by means of steam sterilization. This depends on the country where the containers are going to be used. Each country has its own requirements as regards medical/pharmaceutical containers. To meet these requirements, the containers must be able to withstand high sterilization temperatures for a certain period of time. EP’631 at 4. Accordingly, one having ordinary skill in the art at the time of filing would have had a reasonable expectation of success in sterilizing the obvious container of claim 3 after it had been sealed because such means of sterilization of the container after it had been filled and sealed were well within the ordinary skills of an ordinary IV/parenteral drug product manufacture at the time of filing. Therefore, claim 13 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 12, 3 and 1 were obvious at the time of filing. Claim 14 was Obvious at the Time of Filing Claim 14 recites the following method. See, e.g., instant claim 14: PNG media_image45.png 132 1099 media_image45.png Greyscale Instant claim 14. The examiner finds no difference between the above discussion of claim 12 and the instant claim 14. Accordingly, claim 14 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 12, 3 and 1 were obvious at the time of filing. Claim 20 was Obvious at the Time of Filing Claim 20 recites the following method. See, e.g., instant claim 20: PNG media_image46.png 94 1109 media_image46.png Greyscale Instant claim 20. The examiner finds no difference between the above discussion of claim 12 and the instant claim 20. To the extent that adding a cap on top of the container makes claim 12 somehow different from claim 20, manufacturers understood how to place a cap on top of Ecoflac plus containers. The claim appears to just recite what was known: See the Ecoflac plus Product Sheet at 20 (depicting a cap): PNG media_image24.png 707 478 media_image24.png Greyscale The Ecoflac plus Product Sheet at 20. Accordingly, claim 20 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 12, 4, 3 and 1 were obvious at the time of filing. Claim 21 was Obvious at the Time of Filing Claim 21 recites the following method. See, e.g., instant claim 21: PNG media_image47.png 95 1096 media_image47.png Greyscale Instant claim 21. The examiner finds no difference between the above discussion of claim 13 and the instant claim 21. To the extent that affixing a label to the container makes claim 13 somehow different from claim 21, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in adding a further step of affixing a label to the container because such labels were known in the art and affixed to IV/parenteral drug products made in the same manner. See The Ecoflac plus Product Sheet at 20 (depicting a label affixed to an LDPE container). PNG media_image24.png 707 478 media_image24.png Greyscale The Ecoflac plus Product Sheet at 20. Labels were known to be important particularly for IV drug products. See the Ecoflac plus Product Sheet at 7, reproduced below: PNG media_image48.png 528 290 media_image48.png Greyscale The Ecoflac plus Product Sheet at 7. Accordingly, claim 21 was obvious at the time of filing for the reasons stated above, and for the same reasons stated regarding why claims 13, 12, 3 and 1 were obvious at the time of filing. Conclusion No claims allowed. THIS ACTION IS MADE FINAL. 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christopher Evan Redwood whose telephone number is (571) 272-8882. The examiner can normally be reached Monday - Friday 6:15 AM - 4:45 PM. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /C.E.R./ Examiner, Art Unit 1629 /JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629 1 Priyanka Roychowdhury, “Dexmedetomidine Premix Formulation”, U.S. Patent No. US 9616049 B2, published April 11, 2017, Assigned to Hospira, Inc, hereinafter “US’049”. 2 “Product Sheet, Ecoflac plus, www.bbraun.com. 24 pages.”, hereinafter the “Ecoflac plus Product Sheet”, cited in US’049 at 4, right column. 3 Dear Health Care Provider (DHCP) letter from B. Braun Medical Inc. dated October 20, 2017, to Health Care Provider[s], hereinafter the “Ecoflac plus DHCP Letter”. Available on FDA website, using the search term “ecoflac”, under the result for “Drug Shortages: Dear Health Care Provider Letter for Ecoflac Plus”. 4 Joseph M. Pizza, “HEAT STERILIZEABLE, PREMIXED, READY TO USE DEXMEDETOMIDINE SOLUTION PACKAGED IN A FLEXIBLE PLASTIC CONTAINER”, International Publication No. WO 2017184188 A1, published October 26, 2017, hereinafter “WO’188”. 5 Mansoor Ahmad and Nudrat Adil “Biocompatibility testing of plastic material (LDPE) of plasma substitutes (Polygeline)”, Int. J. of Pharm. Res. & All. Sci., vol. 1, no. 3, pp. 79-87 (2012), hereinafter “Ahmad 2012”. 6 Sautou-Miranda, V., et al. "Compatibility of paclitaxel in 5% glucose solution with ECOFLAC® low-density polyethylene containers–stability under different storage conditions." International journal of pharmaceutics, vol. 178, no. 1, pp. 77-82 (1999), hereinafter “Sautou-Miranda 1999”. 7 Lloyd Waxman et al., “Plastic Packaging for Parenteral Drug Delivery”, in Parenteral Medications 479-510 (Sandeep Nema and John D. Ludwig eds., 4th ed. 2019), hereinafter “Waxman 2019”. 8 Lucas Evaristus J.M. van de Walle, “Container Made From A Polyethylene Composition”, European Patent Application Publication No. EP 0 601 631 A1, published June 15, 1994, hereinafter “EP’631”. 9 Alexandra Glausch, et al., “Pharmaceutical Products Comprising Bisphosphonates”, U.S. Patent Application Publication No. US 20070015736 A1, published Jan. 18, 2007, hereinafter “US’736”. 10 Ashish Anil Dubewar, et al., “READY-TO-USE DEXMEDETOMIDINE COMPOSITIONS”, International Application No. WO 2019164765 A1, published August 29, 2019, hereinafter “WO’765”. 11 Kimberly A. McClain, et al. “PACKAGING SYSTEM AND METHOD OF ALERTING A PRACTITIONER”, U.S. Patent Application Publication No. US 20080308444 A1, published December 18, 2008, hereinafter “US’444”. 12 See also, IDS entry no. 127 marked considered 11/26/2016 in the annexed IDS from the U.S. Patent Application No. 15/058,602 file history. 13 For clarity, the US’049 premixed dexmedetomidine compositions in flexible plastic containers are either SVPs or LVPs depending upon their volume. 14 Aseptic filling procedures were known in the art at the time of filing – see, e.g., supra passage from Waxman 2019.