DETAILED OFFICIAL 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 .
Examiner Note
It is noted that all references hereinafter to Applicant’s specification (“spec”) are to the published application US 2023/0310749, unless stated otherwise. Further, any italicized text utilized hereinafter is to be interpreted as emphasis placed thereupon.
Response to Amendment
The Amendment filed 22 August 2025 in response to the Non-Final Rejection dated 22 April 2025 (hereinafter “NFOA”) has been entered. Claims 1-5, 10-12, and 14-16 have been amended; new claims 18-20 have been added. As such, claims 1-20 remain pending and under consideration on the merits.
The amendments to the claims have overcome each and every objection thereto previously set forth in the NFOA [id., ¶4]. As such, the claim objections have been withdrawn, and the Examiner thanks Applicant for correction of the issues.
The amendments to claim 14 have overcome the rejection of claims 14-16 under 35 U.S.C. 103 over Yoshida in view of Masser previously set forth [NFOA, ¶27-28]. As such, the rejection of claims 14-16 under 103 has been withdrawn.
However, it is noted that the rejection of claims 1-7 and 10-13 under 35 U.S.C. 103 over Yoshida in view of Masser [NFOA, ¶9-26], the rejection of claims 8-9 under 35 U.S.C. 103 over Yoshida in view of Masser, further in view of Jinbo [NFOA, ¶29-34], and the rejection of claim 17 under 35 U.S.C. 103 over Yoshida in view of Masser, further in view of Rault and/or Thorne and/or Amarchinta [NFOA, ¶35-42] are maintained herein. Applicant’s corresponding arguments presented in the Remarks filed 22 August 2025 (hereinafter “Remarks”) are addressed hereinafter.
Further, new grounds of rejection are set forth herein, necessitated by the amendments to the claim 14 and the addition of new claims 18-20.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-7 and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Yoshida et al. (US 2017/0014431; “Yoshida”), in view of Masser et al. (US 2023/0014293; “Masser”) (both previously cited).
Regarding claim 1, Yoshida discloses a rocuronium bromide injection solution, and a syringe filled with said injection solution (“prefilled syringe”) [Abstract; Figs. 1-2; 0001, 0006-0007, 0012, 0017]. The syringe includes outer cylinder (21), inclusive of a generally-tubular barrel (30) and a tip (31, 35) which is integral with said barrel (i.e. single element formed from the same material) [Figs. 2-3; 0017, 0019, 0022-0023]. The outer cylinder, and thus barrel and tip, are formed from, inter alia cyclic polyolefins (COP) [0025] (see MPEP 2131.02(II); MPEP 2144.07). The syringe further comprises a plunger (24), of which is suitably plastic [Figs. 1-2; 0020, 0032, 0048]; and a gasket (22), i.e. stopper formed from chlorinated butyl rubber (chlorobutyl rubber) [Figs. 1-2; 0012, 0017, 0027, 0031].
The solution comprises: (a) rocuronium bromide, at a concentration of 5-15 mg/mL [0043]; (b) sodium chloride (tonicity agent) [0043, 0046]; (c) acetic acid or sodium hydroxide (pH adjusting agent) [0043, 0046]; (d) sodium acetate (buffering agent) [0043, 0046]; and (e) water (the solution is aqueous) [0007, 0009, 0046]. The solution exhibits a pH of about 4 [0046].
Yoshida is silent regarding the stopper (22) being formed from bromobutyl rubber.
Masser is directed to aqueous injection solutions of rocuronium bromide, and syringes filled with said injection solution (i.e. prefilled syringes) [Abstract; 0002-0005, 0012, 0049, 0060-0065]. The syringe is preferably formed from cyclic olefin polymer (COP) or cyclic olefin copolymer (COC) [0050, 0053-0054, 0057]. Masser teaches that the stopper for the prefilled syringe is suitably formed from chlorobutyl rubber or bromobutyl rubber [0054]. That is, Masser effectively teaches that bromobutyl rubber is functionally equivalent to chlorobutyl rubber for the purpose/use as rubber stoppers for syringes or other medical/pharmaceutical containers which come into contact with the subject solution, and in particular aqueous solutions comprising rocuronium bromide. See MPEP 2144.06(II) – an express suggestion to substitute one equivalent component for another is not necessary to render such substitution obvious; see MPEP 2144.07 – the selection of a known material based on its suitability for its intended use has been held prima facie obvious by the Courts.
Yoshida and Masser each constitute prior art which is directly analogous to the claimed invention, given the disclosures set forth/cited above.
In view of the combined teachings of the foregoing prior art, and in light of the aforecited MPEP sections, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the prefilled syringe of Yoshida by substituting bromobutyl rubber for chlorobutyl rubber as the rubber material which forms the stopper (22).
Per the aforesaid modification, the prefilled syringe of Yoshida (hereinafter interchangeably “modified Yoshida”) would have comprised all of the elements indicated hereinabove, wherein the stopper (22) would have been formed from bromobutyl rubber.
Given that the prefilled syringe of modified Yoshida is substantially identical to the syringe which is claimed and disclosed, specifically in terms of the barrel and tip being formed from COP and as a single piece, and the stopper being formed from bromobutyl rubber; and given that the aqueous solution of rocuronium bromide disposed therein is identical to that which is claimed and disclosed in terms of the concentration of rocuronium bromide, the species of tonicity agent, pH adjuster, and buffering agent, and in terms of the pH, there is a strong and reasonable expectation that the solution in the syringe would have necessarily contained at least 90% of the initial amount of rocuronium bromide after storage at 2-8° C for up to 12 months (determined by HPLC), absent factually supported objective evidence to the contrary. Applicant is respectfully directed to MPEP 2112(V); MPEP 2112.01(I) and (II); MPEP 2111; MPEP 2111.01(II); MPEP 2145; and MPEP 2145(I).
In view of the totality of the foregoing, the prefilled syringe of modified Yoshida reads on the prefilled syringe defined by each and every limitation of claim 1.
Regarding claims 2-3, the grounds of rejection of claim 1 above read on each prefilled syringe defined by claims 2-3 – that is, there is a strong and reasonable expectation that the aqueous solution of rocuronium bromide in the prefilled syringe of modified Yoshida would have necessarily contained at least 95% of the initial amount of rocuronium bromide, and necessarily contained not more than 3.5 wt.% total impurities, after storage at 2-8° C for up to 12 months (determined by HPLC), absent factually supported objective evidence to the contrary.
Regarding claim 4, in view of the grounds of rejection of claim 1 above, Yoshida discloses that the (a) rocuronium bromide is present in the solution in a preferred concentration of from 8-12 mg/mL [0043], such as 10 mg/mL [0046]. The broad range identified above, and the aforesaid preferred range encompass, and thereby render prima facie obvious the claimed concentration of about 10 mg/mL (see MPEP 2144.05(I)). Alternatively, the disclosed exemplary concentration of 10 mg/mL reads on the claimed concentration.
Regarding claim 5, in view of the grounds of rejection of claim 1 above, Yoshida discloses that the solution filled in the syringe exhibits a volume of from 2-10 mL [0042], such as 5 mL [0049]. The disclosed range encompasses, and thereby renders prima facie obvious the claimed range of about 5 mL to about 10 mL of the solution (see MPEP 2144.05(I)). The disclosed exemplary amount of 5 mL is within the claimed range.
Regarding claim 6, the grounds of rejection of claim 1 above read on the prefilled syringe defined by claim 6 – the pH of the solution is about 4, of which is within the claimed pH range of about 3.8 to about 4.2.
Regarding claim 7, in view of the grounds of rejection of claim 1 above, it is noted that the Yoshida [0023-0024; Fig. 3] discloses that the tip (31), i.e. “needle mounting portion” of the outer cylinder (21) of the syringe includes (integrally formed with the cylinder barrel) nozzle portion (35) and collar portion (36), of which define a space therebetween inclusive of a spiral groove (37), i.e. screw threads disposed on the inner circumferential surface of the collar portion (36) for receiving a seal cap or needle [0023-0024; Fig. 3]. The tip (31) of the syringe of modified Yoshida, inclusive of the foregoing elements, reads on the luer adapter defined by claim 7, in accordance with the spec [Fig. 1 – 106; Fig. 2 – 206; Fig. 3 – 306; 0024-0025, 0030].
Regarding claims 10-11, in view of the grounds of rejection of claim 1 above, Yoshida discloses that the exemplary solution was formulated with 500 mg rocuronium bromide, resulting in a concentration of 10 mg/mL [0046]. Through simple calculation, it stands that the total solution volume (prior to filling the syringe) was 50 mL. Yoshida discloses that 160 mg of sodium chloride was utilized in formulating the solution. Through simple calculation based on 50 mL solution, Yoshida teaches use of about 3.2 mg/mL of sodium chloride. The aforesaid concentration of sodium chloride is within the range of about 3 mg/mL to about 4 mg/mL (claim 10), and is substantially identical to the range of about 3.3 mg/mL (claim 11), thereby rendering prima facie obvious the claimed range (see MPEP 2144.05(I)).
Regarding claim 12, the grounds of rejection of claim 1 above read on the prefilled syringe defined by claim 12 – that is, there is a strong and reasonable expectation that the prefilled syringe of modified Yoshida would have necessarily exhibited a glide force of less than 30 N and a break force of less than 10 N after storage at 2-8° C for up to 12 months, absent factually supported objective evidence to the contrary. See MPEP 2112(V); MPEP 2112.01(I) and (II); MPEP 2111; MPEP 2111.01(II); MPEP 2145; and MPEP 2145(I).
Regarding claim 13, in view of the grounds of rejection of claim 1 above, Yoshida does not require or suggest the use of preservatives as an additive to the injection solution, of which is reasonably interpreted as reading on the solution being free of added preservatives.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Yoshida in view of Masser as applied to claim 1 above, further in view of Jinbo et al. (US 2016/0143919; “Jinbo”) (previously cited).
Regarding claims 8-9, in view of the grounds of rejection of claim 1 above, Yoshida, as modified, is silent regarding the osmolality of the solution being from about 240 to about 340 mOsm/kg.
Jinbo is directed to aqueous solutions of rocuronium bromide inclusive of acetate buffer and having a pH of 6 or less, suitable for injections; Jinbo seeks to reduce injection pain experienced by patients receiving the aqueous solution [Abstract; 0002-0003, 0011, 0014, 0016, 0018, 0026-0029, 0034]. Jinbo teaches that it is preferable to formulate the solution to have an osmolality of from 250-1,000 mOsmol/kg (i.e. mOsm/kg), such as 260-600 mOsmol/kg, to not contribute to (i.e. not detrimentally increase) vascular pain [0036].
Jinbo constitutes prior art which is directly analogous to the claimed invention.
In view of the combined teachings of the foregoing prior art, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the aqueous solution of modified Yoshida by formulating said solution to exhibit an osmolality of from 260-600 mOsm/kg, as taught by Jinbo in order to not increase, or to lessen the pain experienced by a patient during injection of the solution from the prefilled syringe.
Per the aforesaid modification, the aqueous injection solution of rocuronium bromide filled in the syringe of Yoshida would have exhibited an osmolality of 260-600 mOsm/kg, of which overlaps with, and thereby renders prima facie obvious the range of about 240 to about 340 mOsm/kg (claim 8); and which encompasses and thereby renders prima facie obvious the range of about 270 to about 320 mOsm/kg (claim 9). See MPEP 2144.05(I).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Yoshida in view of Masser as applied to claim 1 above, further in view of Rault et al. (US 2020/0016323; “Rault”) and/or Thorne, Jr. et al. (US 2009/0194453; “Thorne”) and/or Amarchinta et al. (US 2015/0209503; “Amarchinta”) (all previously cited).
Regarding claim 17, in view of the grounds of rejection of claim 1 above, Yoshida discloses that the prefilled syringe, along with an oxygen scavenger, is sealed within a laminated packaging material (film), in particular an aluminum-metallized polyethylene terephthalate (PET) [0049-0050], thereby defining a kit, wherein the metallized-PET film reads on the claimed plastic packaging which is flexible, given that the requisite degree of flexibility is not defined in the claim or spec such that any degree reads thereon under the broadest reasonable interpretation. It logically flows that the packaging of Yoshida is tamper evident to at least some degree, given that the seal would have to be broken to access the pre-filled syringe.
However, Yoshida does not explicitly disclose the packaging film being tamper evident or including a tamper evident element/feature.
Rault teaches tamper-evident pharmaceutical packaging, in particular for pre-filled syringes [Abstract; Figs. 1, 3; 0001-0005, 0007, 0009]. Rault teaches that it is desirable for the packaging to be tamper-evident to ensure/protect the integrity of the content of the syringe [0005, 0009-0012]. Rault teaches that the tamper-evident feature may include sealing of the packaging, such as heat-sealing, which requires puncture or requisite force resulting in damage upon opening such that tampering is readily evident [0017-0020]; PET is recognized as suitable for the material forming said tamper-evident feature(s) [0020, 0024, 0039-0040, 0044].
Thorne is directed to tamper-evident kits comprising resealable packaging and medical devices, e.g. pre-filled syringes packaged therein, and generally teaches that it is known/recognized to make the package of said kits tamper evident through inclusion of one or more indicators so the relevant persons know the contents within the packaging have been accessed/utilized and/or tampered with [Abstract; Figs. 1, 11A-11C, 13-15, 21-25; 0051, 0092, 0105, 0133, 0147-0148].
Amarchinta teaches that it was known/recognized to provide sealed packaging for pre-filled syringes with tamper-evident features, such as tear strips which are required to be broken by a user to access the pre-filled syringe and thereby are indicative of tampering if the strip or other feature has been broken prior to the intended use of the syringe [Abstract; Figures; 0096, 0147-0148].
Rault, Thorne, and Amarchinta each constitute prior art which is directly analogous to the claimed invention – kits comprising pre-filled syringes or other medical devices, and packaging for said syringes which include tamper-evident features/elements.
In view of the combined teachings of the foregoing prior art – that is, modified Yoshida taken in view of the teachings of one or more of Rault, Thorne, and Amarchinta – it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the packaging of Yoshida would have necessarily been tamper-evident given that the pre-filled syringe is sealed therein, and/or obvious to have modified said packaging of Yoshida to include one or more tamper-evident features in order to ensure/protect the integrity of the content of the syringe packaged therein and indicate to a user whether or not the package/syringe has been previously accessed and/or tampered with.
Claims 14-16 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Taha et al. (US 2023/0263957; “Taha”) (newly cited), in view of the FDA Label for Teva Rocuronium Bromide Injection (https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/078717s000lbl.pdf, November 2008, accessed online 03 December 2025) (hereinafter “Teva”; newly cited; copy provided herewith).
Regarding claim 14, Taha discloses a pre-filled syringe suitable for cold chain storage (e.g. refrigerated at 2° C to 8° C) and administration by injection of, inter alia rocuronium bromide (injection solution), as well as other drug product solutions inclusive of pharmacologically active substance(s) and excipients including buffering agents such as acetates and tonicity modifiers such as sodium chloride [Abstract; Figs. 3, 52-53, 55-57, 64; 0012, 0023, 0033, 0059, 0121, 0159, 0164, 0211, 0217, 0331-0333, 0544, 0560, 0593, 0692, 0695, 0699, 0749].
The syringe includes a cylindrical barrel, front dispensing opening (tip), and luer adapter, integrally (single element) formed from COP or COC [prev. cited Figs.; 0022, 0057-0059, 0121-0122, 0156, 0312, 0346, 0560-0562, 0567, 0695, 0804]. The syringe also includes a plastic plunger rod (510) [Figs. 52-53, 64; 0165-0187, 0312, 0618, 0632, 0647-0681], and a plunger gasket (509) (plunger rod stopper) [Figs. 52-53, 55-57, 64; 0596-0597, 0602-0603, 0618-0619, 0633]; the plunger gasket is formed from rubber, in particular brominated butyl rubber (bromobutyl rubber) [0596, 0613-0614, 0619-0620, 0633]. None of the syringe barrel, tip, luer adapter, plunger rod, and plunger gasket are formed from or otherwise required to include calcined clay, and thereby read on “wherein the syringe does not comprise calcined clay”, as claimed.
With respect to the difference(s) relative to the claimed invention, Taha does not explicitly disclose the components and initial relative concentrations of the rocuronium bromide solution which is pre-filled into the syringe, and is silent regarding the initial pH of the solution.
Teva teaches that the (FDA approved) rocuronium bromide injection (aqueous) solution contains, per mL solution, 10 mg of rocuronium bromide, 2 mg sodium acetate, 3.3 mg sodium chloride, and acetic acid and/or sodium hydroxide to adjust the solution to a pH of 4 [Description, 11]. Teva also teaches/recognizes that the rocuronium bromide solution should be stored in a refrigerator at a temperature of 2° C to 8° C [How Supplied/Storage and Handling, 16], in accordance with the disclosure/teachings of Taha set forth/cited above. As disclosed/taught by Taha above, Teva also recognizes that rocuronium bromide solution is suitably stored in/compatible for use with glass bottles/vials or plastic syringes [Preparation for Administration of Rocuronium Bromide, 2.6; Incompatibility with Alkaline Solutions, 5.1; How Supplied/Storage and Handling, 16].
Taha and Teva each constitute prior art which is directly analogous to the claimed invention, given the aforecited disclosures/teachings.
In view of the combined teachings of the foregoing prior art, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the pre-filled syringe of Taha by utilizing the Teva rocuronium bromide injection solution as the rocuronium injection solution which is [pre]filled into the syringe for storage therein and subsequent administration via injection to a patient – Taha explicitly names rocuronium bromide injections as a drug solution capable of being pre-filled therein, and thus the rocuronium bromide solution of Teva would have been readily recognized as suitable for use as said injection solution. Additionally/alternatively, the syringe of Taha would have been readily recognized as suitable for refrigerated storage (2° C to 8° C) of rocuronium bromide solutions, as explicitly specified/required by Teva. See MPEP 2144.07.
In accordance with the aforesaid modifications, the rocuronium bromide injection solution of the pre-filled syringe of Taha (hereinafter interchangeably “modified Taha”) would have been the Teva rocuronium bromide solution, thereby necessarily exhibiting an initial pH of 4, and including the aforesaid solution components and relative concentrations thereof, specifically: (per mL solution) 10 mg of rocuronium bromide, 2 mg sodium acetate (buffering agent), 3.3 mg sodium chloride (tonicity agent), acetic acid and/or sodium hydroxide (pH adjuster), and water (solution is aqueous).
The initial pH of 4 is within the claimed range of about 3.8 to 4.2. The concentrations (weight per volume) of rocuronium bromide (10 mg/mL), sodium chloride (3.3 mg/mL), and sodium acetate (2 mg/mL) are identical to the respective claimed amounts, i.e. about 10 mg/mL, about 3.3 mg/mL, and about 2 mg/mL.
The pre-filled syringe of modified Taha set forth above is identical or substantially identical to the claimed and disclosed prefilled syringe in terms of (1) the rocuronium bromide solution (aqueous, identical component species, identical component concentrations, pH within claimed range) and (2) the syringe elements and materials thereof (barrel, tip, luer adapter integrally formed from COC or COP; plastic plunger rod and stopper (gasket); stopper formed from bromobutyl rubber and does not include calcined clay). Further, (3) the solution has a pH of 4, of which does not contribute to erosion of the barrier/tie/protective layer(s) provided on the inner surface of the syringe barrel of Taha [Taha, 0391, 0407-0408], and (4) the syringe has low and/or readily-tailorable oxygen and water-vapor transmission rates (COC or COP; selection of coating layer(s) and materials thereof) which contribute to, i.e. prevent degradation/dissolution of the contents, e.g. aqueous components of the solution or the material of the syringe barrel/coatings over the shelf life thereof, thereby extending the shelf life, such as by, e.g. at least a year [Taha, Full Disclosure, including 0008-0009, 0033-0044, 0048-0055, 0057-0059, 0069, 0408, 0410, 0421, 0475, 0481].
Furthermore, as set forth/cited above, (5) Taha explicitly discloses that the pre-filled syringe is suitable for storage/administration of rocuronium bromide solutions, and in particular (6) storage at 2° C to 8° C (refrigerated). Additionally, Taha discloses that (7) the pre-filled syringe exhibits high closure integrity, thereby resulting in a shelf-life of over a year, such as at least 3 years [0089, 0340, 0344-0348, 0475]; Taha discloses (8) that the aforesaid coating layers (as applied to inner surface of COP syringe barrel) prevent degradation of drug solutions exhibiting a pH of 4 over the intended shelf life [0344, 0346-0347, 0349].
Given that the pre-filled syringe of modified Taha is identical or substantially identical to the invention claimed and disclosed in terms of at least elements (1) and (2) above, and further in view of elements (3)-(8) above, there is a strong and reasonable expectation – and it stands to reason – that the pre-filled syringe of modified Taha having the rocuronium bromide injection solution contained therein would have necessarily contained at least 90% of the initial amount of rocuronium bromide (i.e. contained at least 9 mg/mL) after storage at 2° C to 8° C for up to 12 months determined by HPLC, absent a showing of factually supported objective evidence to the contrary. See MPEP 2112(V); MPEP 2112.01(I) and (II); MPEP 2145; and MPEP 2145(I).
The pre-filled syringe of modified Taha reads on the prefilled syringe defined by each and every limitation of claim 14.
Regarding claims 15-16, the grounds of rejection of claim 14 above read on each prefilled syringe defined by claims 15-16 – that is, there is a strong and reasonable expectation, and it stands to reason, that the (aqueous) rocuronium bromide injection solution of the pre-filled syringe of modified Taha would have necessarily contained at least 95% of the initial amount of rocuronium bromide, and necessarily contained not more than 3.5 wt.% total impurities, after storage at 2° C to 8° C for up to 12 months (determined by HPLC), absent a showing of factually supported objective evidence to the contrary. See MPEP 2112(V); MPEP 2112.01(I) and (II); MPEP 2145; and MPEP 2145(I).
Regarding claim 18, the grounds of rejection of claim 14 above read on the prefilled syringe defined by claim 18 – the plunger gasket (stopper) of the pre-filled syringe of modified Taha does not comprise chlorobutyl rubber. Rather, said gasket is formed from bromobutyl rubber.
Regarding claim 19, the grounds of rejection of claim 14 above are incorporated herein by reference (not repeated for sake of brevity) and read on the prefilled syringe defined by each and every limitation of claim 19.
Regarding claim 20, in view of the grounds of rejection of claim 19 above, the grounds of rejection of claim 18 above are incorporated herein and read on the prefilled syringe defined by claim 20. The plunger gasket (stopper) of the pre-filled syringe of modified Taha is formed from bromobutyl rubber and does not comprise chlorobutyl rubber.
Response to Arguments
Applicant’s arguments presented on pp. 8-11 of the Remarks – applicable to the grounds of rejection of claims 1-7 and 10-13 under 103 over Yoshida in view of Masser, which are maintained hereinabove – have been fully considered but not found persuasive.
On p. 8–p. 9 of the Remarks, Applicant first asserts (A) that the grounds of rejection fail to establish a prima facie case of obviousness, in particular because the formulations of Yoshida and Masser are different, e.g. different solution pH values, and thus no reason has been provided which suggests that the “syringe options” provided for the solution of Masser are interchangeable with the syringe/solution of Yoshida. As such, one of ordinary skill in the art would not have had a reasonable expectation of success in modifying the stopper of Yoshida by utilizing the bromobutyl rubber stopper taught by Masser.
Thereafter, Applicant also asserts (A) that Yoshida explicitly requires the inclusion of calcined clay in the rubber which forms the stopper, and subsequently asserts that the stopper is required to be formed from chlorinated butyl rubber and said clay in accordance with the disclosure of Yoshida and criticality of the stopper material formulation discussed therein.
However, while the Examiner agrees that the rubber stopper of Yoshida does require the presence of calcined clay [Yoshida, 0027-0028], it is the Examiner’s position that Yoshida does not require the rubber to be chlorinated butyl rubber when taken in view of (i.e. combined with) the teachings of Masser, wherein the grounds of rejection previously set forth and maintained herein are based on said combination of teachings rather than the disclosure of Yoshida alone (see MPEP 2145(IV)). It is the Examiner’s position that Applicant may have misconstrued the grounds of rejection and/or is not considering the grounds of rejection as a whole based on the combined teachings of the references, as explained below.
First, while Yoshida does disclose – and prefers – the use of chlorinated butyl rubber [Yoshida, 0012, 0017-0018, 0027, 0064], Yoshida also explicitly states “The material for forming the gasket is not specifically limited except that the material does not contain inorganic fillers classified as the inorganic reinforcing agent and the inorganic filling agent…” [Yoshida, 0028]. Further, prior to the aforecited statement, Yoshida recognizes that butyl rubbers (genus) may generally be utilized, wherein the chlorinated butyl rubber is selected in particular for cost, vulcanization speed, moldability, inter alia [Yoshida, 0027] – the context of the chlorinated butyl rubber being “selected” is reasonably interpreted/recognized by one of ordinary skill in the art as preferential language. Furthermore, after the aforecited statement, Yoshida explicitly states that the chlorinated butyl rubber constitutes a preference within the genus of halogenated butyl rubbers [Yoshida, 0039]. Applicant is respectfully directed to MPEP 2123(I), which states that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Additionally, see MPEP 2123(II) – discloses examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. As such, it is the Examiner’s position that Yoshida, when considered as a whole, reasonably teaches or recognizes that halogenated butyl rubbers are suitable for use in forming the stopper, but chlorobutyl rubber is preferred over other species due to the one or more factors cited above.
Second, as stated above the grounds of rejection are based on the combined teachings of the prior art (MPEP 2145(IV)), i.e. the disclosure of Yoshida taken in view of the teachings of Masser, and not solely the disclosure of Yoshida. As previously set forth [NFOA, ¶13], Masser teaches that the rubber forming the stopper may suitably be formed from chlorobutyl rubber or bromobutyl rubber, thereby establishing – through explicit naming of both halogenated butyl rubber species as suitable for the intended use as halogenated butyl rubber stoppers for pre-filled syringes including pharmaceutical formulations – the functional equivalence thereof within the art directly analogous to the claimed invention, in accordance with the cited MPEP sections 2144.06(II) and 2144.07.
The prima facie case of obviousness established in the grounds of rejection [NFOA, ¶13-15] is based on the prior art having established the functional equivalence of the bromobutyl and chlorobutyl rubbers for use (as intended) as rubber stoppers in pre-filled syringes in contact with rocuronium bromide solutions. The proposed modification set forth is based on the substitution of the chlorobutyl rubber with bromobutyl rubber as the rubber which is utilized to form the stopper of Yoshida [NFOA, ¶15]. The proposed modification does not suggest that the calcined clay would or should be excluded from the stopper formed from bromobutyl rubber (“modified Yoshida”), and the Examiner notes that it would necessarily have to include said calcined clay, given that it is agreed (as stated above) that Yoshida requires the presence of the clay, thereby necessitating the withdrawal of the grounds of rejection as previously applied to claim 14 and those dependent thereupon (claim 14 now recites “the syringe does not comprise calcined clay”).
In view of the foregoing, it is noted that Applicant’s assertions on p. 8–p. 9 of the Remarks and identified hereinabove do not address the teachings of Masser or the legal precedence relied upon (aforecited MPEP sections) in formulating the grounds of rejection which establish the prima facie case of obviousness (MPEP 2144.06(II) and MPEP 2144.07). Simply put, Applicant does not address or acknowledge, to any extent, the fact that Masser teaches both bromobutyl and chlorobutyl rubber as suitable for forming the stopper, and has not provided any technical reasoning or objective evidence suggesting that the aforesaid halogenated butyl rubber species would not be functionally equivalent to one another for the intended use as the rubber which forms the stopper. That is, Applicant has not asserted that the bromobutyl rubber and chlorobutyl rubber are not functionally equivalent, and has not provided any evidence that the aforesaid butyl rubbers are not functionally equivalent.
Therefore, it is the Examiner’s position that Applicant has merely argued against or attacked the Yoshida and Masser references individually, has not considered and/or has misconstrued the prima facie case of obviousness established based on the combined teachings of the foregoing prior art, and has not provided the requisite objective evidence to sufficiently rebut the prima facie case. Applicant is respectfully directed to MPEP 2145(IV) – one cannot show nonobviousness by attacking references individually where the rejection is based on combinations of references. The “test for obviousness is what the combined teachings of the references would have suggested to a person having ordinary skill in the art”. Further, see MPEP 2145(I) – arguments presented by Applicant cannot take the place of evidence in the record.
For these reasons above, Applicant’s assertions (A) on p. 8–p. 9 of the Remarks have not been found persuasive.
Applicant’s arguments/assertions (B) presented on p. 9–p. 10 of the Remarks have been found persuasive with respect to claims 14-16 and 18-20, of which [now] explicitly require that “the syringe does not comprise calcined clay” (claim 14, claim 19).
As stated above, the Examiner agrees that the stopper of modified Yoshida, while being formed from bromobutyl rubber in accordance with the modification set forth in the grounds of rejection, still requires the presence of calcined clay in the rubber which forms the stopper. As such, Yoshida does not disclose, and teaches away from “wherein the syringe does not comprise calcined clay” as claimed. Thus, the rejection of claims 14-16 under 103 over Yoshida in view of Masser previously set forth in the NFOA has been withdrawn.
However, Applicant’s arguments/assertions (B) presented on p. 9–p. 10 of the Remarks have not been found persuasive with respect to claims 1-7 and 10-13, as said claims do not exclude the presence of calcined clay from the stopper or any other element of the syringe (i.e. barrel, tip, luer, plunger rod). As such, the pre-filled syringe of “modified Yoshida” set forth in the grounds of rejection under 103 [still] reads on said claims and is maintained hereinabove. Applicant is respectfully directed to MPEP 2145(VI).
Applicant’s remaining arguments presented on p. 10–p. 11 of the Remarks have not been found persuasive.
On p. 10, Applicant asserts (C) that the claimed invention exhibits unexpected results – specifically, the combination of (1) the syringe barrel, tip, and luer adapter formed as a single element from COC or COP, with (2) the plunger rod stopper of the syringe being formed from bromobutyl rubber, unexpectedly and surprisingly resulted in high stability of the rocuronium bromide solution (pre-filled therein) after storage of the pre-filled syringe at 2° C to 8° C for up to 12 months (at least 90% of initial amount of rocuronium bromide present in the pre-filled syringe at said duration), directing the Examiner to the data presented in Table 3 of the spec. Thereafter, Applicant additionally asserts that “the Office has not provided any evidence to question Applicant’s data presented in the spec or its assertion that the demonstrated results were surprising or unexpected”.
First, regarding the latter, it is noted that contrary to Applicant’s assertion, the Office does not bear the burden of, and is not required to, furnish evidence to “question” Applicant’s data presented in the spec and relied upon in support of the asserted unexpected result. Rather, in accordance with MPEP 716.02(b), including 716.02(b)(II), Applicant bears the burden of explaining the data relied upon in support of the asserted unexpected result to rebut the prima facie case of obviousness.
Moreover, regarding the former assertion and the data relied upon in Table 3, Applicant is first respectfully directed to MPEP 716.02(b)(I), which indicates that the evidence relied upon (in support of the unexpected result to rebut the prima facie case of obviousness) should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance”. In order to accomplish the foregoing, i.e. to establish that the unexpected results are factually and statistically unexpected, Applicant bears the burden of comparing the results achieved by the claimed invention, directly or indirectly, to the closest prior art which is commensurate in scope with the claims (see MPEP 716.02(b)(III)). That is, to be effective to rebut a prima facie case of obviousness, the claimed subject matter must be compared with the closest prior art (MPEP 716.02(e)). In making said comparison, Applicant may compare the claimed invention with prior art cited or relied upon by the Examiner, or prior art which is more closely related to the claimed invention than the prior art relied upon by the Examiner (MPEP 716.02(e)(I), MPEP 716.02(e)(III)).
In the instant case, the data presented in Table 3, and the additional data presented in Applicant’s spec in support of the asserted unexpected result, does not include a single comparative example. In other words, the data presented in the spec representative of the claimed invention is not compared to any other example(s) or embodiments – explicitly, no comparisons are made. As such, the data relied upon in support of the asserted unexpected result merely provides evidence that the claimed stability level after 12 months is exhibited/achievable. Thus, differences in results achieved by the claimed invention relative to those of the prior art cannot be assessed by the Examiner, and therefore the data provided in the spec cannot be relied upon to rebut the prima facie case of obviousness based on Applicant’s assertion.
To facilitate compact/expedient prosecution, it is respectfully noted that provision of additional data representative of the closest prior art and comparison thereof to the claimed invention (e.g. data presented in the spec) is required to be of probative value in rebutting the prima facie case of obviousness, i.e. to establish that the difference(s) in results achieved by the claimed invention relative to the prior art are in fact unexpected and statistically significant, in accordance with the aforecited MPEP sections. Additionally, see MPEP 716 and MPEP 716.01.
For these reasons above, Applicant’s assertions (C) presented on p. 10–p. 11 of the Remarks have not been found persuasive.
Pertinent Prior Art
The following constitutes a list of prior art which are not relied upon herein, but are considered pertinent to the claimed invention and/or written description thereof. The prior art are purposely made of record hereinafter to facilitate compact/expedient prosecution, and consideration thereof is respectfully suggested.
US 2023/0060079 to Lee et al. – discloses pre-filled thermoplastic syringes filled with a medicament/drug solution comprising rocuronium bromide, wherein the pre-filled syringe includes a plunger (stopper) and corresponding plunger rod, said plunger formed from bromobutyl rubber; said plunger is suitably bromobutyl rubber FM457/0 from Datwyler [Abstract; Figs. 1-2; 0001, 0018, 0023, 0029, 0035, 0052, 0082, 0117-0119, 0150, 0163, 0166, 0180]
College Ter Beoordeling Van Geneesmiddelen, Public Assessment Report of Rocuronium bromide Noridem 10 mg/mL solution for injection/infusion, 20 February 2020, accessed online 02 December 2025, https://www.geneesmiddeleninformatiebank.nl/pars/h123915.pdf (copy provided herewith) – teaches that the excipients for the rocuronium bromide (10 mg/mL) aqueous injection solution include sodium acetate (trihydrate), sodium chloride, acetic acid, and water, and the pH of the solution is 3.8-4.2 [p. 3, II.1]; teaches that the shelf-life of the solution stored in glass ampoules and vials, respectively, at 2° C to 8° C is 30 months and 24 months, respectively [p. 5, II.3]
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office Action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Michael C. Romanowski whose telephone number is (571)270-1387. The Examiner can normally be reached M-F, 09:30-17:30.
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, Aaron Austin can be reached at (571) 272-8935. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL C. ROMANOWSKI/Primary Examiner, Art Unit 1782