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 .
Summary
Claims 1-25 are pending in this office action. All pending claims are under examination in this application.
Priority
The current application was filed on October 19, 2023 is a 371 of PCT/SE2022/050393 filed April 22, 2022. The current application claims foreign priority to SE2150521-9 filed on April 23, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on March 2, 2026 is acknowledged. A signed copy of the document are attached to this office action.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over Ceresa et al. (Molecules, 2019) in view of Silva (Master’s Dissertation, Published January 2021), Pecar et al. (Journal of Microelectronics, 2017), and Persson (US7,166,128B1).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Ceresa et al.
Ceresa et al. is considered the closest prior art as it teaches medical-grade silicone coated with rhamnolipid R89 is effective against Staphylococcus spp. biofilms (see title). Furthermore, Ceresa et al. disclose that Staphylococcus aureus and Staphylococcus epidermidis are considered two of the most important pathogens, and their biofilms frequently cause device-associated infections. Microbial biosurfactants
recently emerged as a new generation of anti-adhesive and anti-biofilm agents for coating implantable devices to preserve biocompatibility. In this study, R89 biosurfactant (R89BS) was evaluated as an anti-biofilm coating on medical-grade silicone. R89BS is composed of homologues of the mono-(75%) and di-rhamnolipid (25%) families, as evidenced by mass spectrometry analysis. The antimicrobial activity against Staphylococcus spp. planktonic and sessile cells was evaluated by microdilution and
metabolic activity assays. R89BS inhibited S. aureus and S. epidermidis growth with minimal inhibitory concentrations (MIC99) of 0.06 and 0.12 mg/mL, respectively and dispersed their pre-formed biofilms up to 93%. Silicone elastomeric discs (SEDs) coated by R89BS simple adsorption significantly counteracted Staphylococcus spp. biofilm formation, in terms of both built-up biomass (up to 60% inhibition at 72 h) and cell metabolic activity (up to 68% inhibition at 72 h). SEM analysis revealed significant
inhibition of the amount of biofilm-covered surface. No cytotoxic effect on eukaryotic cells was detected at concentrations up to 0.2 mg/mL. R89BS-coated SEDs satisfy biocompatibility requirements for leaching products. Results indicate that rhamnolipid coatings are effective anti-biofilm treatments and represent a promising strategy for the prevention of infection associated with implantable devices (see abstract).
2. Silva
Silva teaches antimicrobial glycolipids: evaluation of their antimicrobial activity, antibiofilm activity and mechanisms of action (see title). In addition, Silva discloses that biofilm formation by pathogenic agents on medical devices is a current issue and the available treatment seems ineffective in fighting these infections, therefore new effective molecules are in high demand. Biosurfactants are new promising compounds, that due to their structure can interact with cellular membrane of microorganisms, interfering with the microbial adhesion in the surface of medical devices to prevent these infections.
The aim of this thesis was to evaluate the antimicrobial and antibiofilm activities and antimicrobial mechanism of biosynthesized mixtures of two glycolipids (i.e. rhamnolipids and sophorolipids). These two were immobilized in the surface of silicone by two methods, either by adsorption or covalent bond by plasma activation of the surface, to prevent microbial adhesion.
Initially, antimicrobial activity was evaluated against different planktonic bacteria and S. aureus ATCC 25923, S. aureus ATCC 6538, clinic MRSA and S. epidermidis ATCC 28319 were the most vulnerable to the studied glycolipids mixtures.
The mechanism of action of both glycolipids including membrane integrity (by propidium iodide uptake) and cellular viability (by resazurin reduction), cells’ surface hydrophobicity and cells’ surface charge modifications were studied. Rhamnolipids were the most active on disturbing membrane integrity, while sophorolipids were the most active on disturbing cellular viability. Both glycolipids increased cell surface hydrophobicity more effectively against S. aureus ATCC 25923, S. aureus ATCC 6538, MRSA and P. aeruginosa ATCC 15442, nevertheless rhamnolipids were more active. Furthermore, both compounds caused a decrease in cell surface charge, however only in a significant way against S. aureus ATCC 25923.
Rhamnolipids adsorbed on the surface of silicone caused a decrease of the hydrophobicity of the material. Furthermore, using crystal violet assay and counting of colony forming units’ methods, it was verified that both glycolipids previously adsorbed on silicone caused a reduction in biofilm formation of sessile bacteria, most effectively against S. aureus ATCC 25923, S. aureus ATCC 6538 and MRSA. However, sophorolipids showed higher activity.
Lastly, plasma treatment on silicone specimens functionalized with rhamnolipids provided good results, showing that this can be a good strategy to create a permanent functionalization to these surfaces.
In conclusion, both glycolipids seem an optimistic approach in preventing biofilm formation on the surface of medical grade silicone, decreasing the risk for the development of these infections (see abstract).
3. Pecar et al.
Pecar et al. teach thermoplastic - PDMS polymer covalent bonding for microfluidic applications (see title). In addition, Pecar et al. disclose that two room-temperature bonding processes for thermoplastic - PDMS polymer covalent bonding based on the organic substrate surface functionalization by means of organofunctional silanes APTES and amine-PDMS linker were developed and applied. The efficiency of covalent bonding was evaluated by measuring water contact angles on oxygen plasma pretreated surfaces and by measuring burst pressure on fabricated test devices. Developed amine-PDMS linker bonding process resulted in bond strength of 5 bar and 2 bar on continuous pressure of air and water respectively, while water initiated the hydrolysis of covalent bonds established via the modified APTES bonding process. Both bonding processes were applied on piezoelectric micropumps where glass substrate was replaced by thermoplastic substrate. Micropumps employing amine-PDMS linker exhibit no deterioration in their performance after eight weeks of continuous operation (see abstract).
4. Persson
Persson teaches voice prosthesis (see title). In addition, Persson discloses a voice prosthesis to be mounted in a fistula between trachea and esophagus comprises a spool-shaped element with a through passage and a valve mechanism controlling the connection through said passage and having sealing surfaces which can be pressed against each other, means being provided to produce a magnet force acting between the sealing surfaces to keep said surfaces pressed against each other in the closed position of the valve mechanism (see abstract).
Combination of Ceresa et al., Silva, and Persson
Regarding instant claim 1, Ceresa et al., Silva, and Persson teach a medical device comprising a silicone surface. The necessary citations of Ceresa et al., Silva, and Persson that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Ceresa et al., Silva, and Persson Citations
A medical device comprising a silicone surface,
Ceresa et al. disclose R89 biosurfactant (R89BS) was evaluated as an anti-biofilm coating on medical-grade silicone (see title and abstract within Ceresa et al.).
Silva discloses…glycolipids (rhamnolipids) seem an optimistic approach in preventing biofilm formation on the surface of medical grade silicone, decreasing the risk for the development of these infections (see title and abstract within Silva et al.).
Both Ceresa et al. and Silva disclose the coating of medical-grade silicone and not a medical device. However, as an example of a medical device that would be an excellent candidate for coating the surface with medical-grade silicone, Persson discloses a voice prosthesis device (see abstract and title within Persson).
wherein at least part of the silicone surface is coated with rhamnolipids.
Ceresa et al. disclose R89BS is composed of homologues of the mono-(75%) and di-rhamnolipid (25%) families, as evidenced by mass spectrometry analysis (see title and abstract within Ceresa et al.).
Therefore, a skilled artisan (POSITA; person of ordinary skill in the art) would combine the disclosures of Ceresa et al., Silva, and Persson in order to teach every element of instant claim 1.
Motivation: to move forward with the next logical step of taking rhamnolipid-modified medical-grade silicone disclosed by both Ceresa et al. and Silva and applying it to a medical device (voice prosthesis) taught by Persson.
The remaining instant claims within this 35 U.S.C. § 103 section are directly or indirectly dependent on instant claim 1 and are taught in full by the combination of Ceresa et al., Silva, and Persson.
Regarding instant claim 2, Ceresa et al., Silva, and Persson teach wherein the rhamnolipids comprise 70-85% (weight/weight) mono-rhamnolipids and 15-30% (weight/weight) di-rhamnolipids, and wherein the rhamnolipids have a purity of at least 85%. Ceresa et al. disclose R89BS is composed of homologues of the mono-(75%) and di-rhamnolipid (25%) families, as evidenced by mass spectrometry analysis (see title and abstract within Ceresa et al.). Furthermore, a skilled artisan (POSITA) could ensure the rhamnolipids have a purity of at least 85% by using a suitable chromatography technique compatible with the product (silica gel, Sephadex, or reverse-phase high-performance liquid chromatography).
Regarding instant claim 3, Ceresa et al., Silva, and Persson teach wherein the rhamnolipids are covalently attached to silicone. Silva discloses that the aim of this thesis was to evaluate the antimicrobial and antibiofilm activities and antimicrobial mechanism of biosynthesized mixtures of two glycolipids (i.e. rhamnolipids and sophorolipids). These two were immobilized in the surface of silicone by two methods, either by adsorption or covalent bond by plasma activation of the surface, to prevent microbial adhesion (see abstract within Silva).
Regarding instant claim 7, Ceresa et al., Silva, and Persson teach wherein the medical device is one of a voice prosthesis, a tracheostomy speaking valve, and a holder for tracheostomy speaking valve. Persson disclose a voice prosthesis (see title and abstract within Persson) which could be coated with medical-grade silicone covered with rhamnolipids (see Table I).
Regarding instant claim 8, Ceresa et al., Silva, and Persson teach wherein the medical device is a voice prosthesis comprising a voice prosthesis valve, and wherein the silicone surface coated with rhamnolipids comprise at least one of a sealing surface of the voice prosthesis valve and a retaining flange of the voice prothesis. Persson disclose a voice prosthesis (see title and abstract within Persson) which could be coated with medical-grade silicone covered with rhamnolipids (see Table I). A skilled artisan (POSITA) would identify at least one of a sealing surface of the voice prosthesis valve and a retaining flange of the voice prothesis as a site designated for a silicone surface coated with rhamnolipids.
Regarding instant claims 19-23, Ceresa et al., Silva, and Persson teach a voice prosthesis for mounting in a fistula between a trachea and an esophagus, the voice prosthesis comprising:
- a tubular body having a lumen;
- a valve disc and a valve seat, arranged in the lumen of the tubular body, said valve disc and said valve seat controlling the communication through said lumen by interaction between said valve disc and said valve seat; wherein at least a part of the voice prosthesis comprises silicone and at least a part of said silicone being coated with rhamnolipids. Persson disclose a voice prosthesis (see title and abstract within Persson) which could be coated with medical-grade silicone covered with rhamnolipids (see Table I). The voice prosthesis disclosed by Persson is represented within Figure I (see Fig. 8 within Persson):
Figure I
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A direct comparison of the device disclosed within the instant application (see Fig. 7b within the instant drawings) shown in Figure II, reveals a similar design.
Figure II
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Additionally, claim 1 within Persson discloses nearly identical structure compared to the instant specification. Thus, a skilled artisan (POSITA) would identify the claim limitation sites as an area designated for a silicone surface coated with rhamnolipids.
Regarding instant claim 24, Ceresa et al., Silva, and Persson teach wherein the rhamnolipids comprise 75% (weight/weight) mono-rhamnolipids and 25% (weight/weight) di-rhamnolipids, and the rhamnolipids have a purity of at least 90%. Ceresa et al. disclose R89BS is composed of homologues of the mono-(75%) and di-rhamnolipid (25%) families, as evidenced by mass spectrometry analysis (see title and abstract within Ceresa et al.). Furthermore, a skilled artisan (POSITA) could ensure the rhamnolipids have a purity of at least 90% by using a suitable chromatography technique compatible with the product (silica gel, Sephadex, or reverse-phase high-performance liquid chromatography).
Combination of Ceresa et al., Silva, Pecar et al. and Persson
Regarding instant claims 4-5, Ceresa et al., Silva, Pecar et al. and Persson teach wherein the rhamnolipids are covalently attached to the silicone surface via a linker comprising an amide bond. Pecar et al. disclose treatment of the silicone with plasma to generate hydroxyl groups (see Figure 2 within Pecar et al.). Furthermore, the hydroxyl groups could be further elaborated with 3-aminopropyltriethoxysilane (APTES) to afford the amino variant. This is shown below in Figure III:
Figure III
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In this specific case a thermoplastic (TP) was treated with APTES to afford the amino variant (see Figure 2 within Pecar et al.). Alternatively, a skilled artisan (POSITA) could modify the plasma treated silicone with APTES and yield a similar result. Both the mono- and di-rhamnolipids have a carboxylic acid “handle” for modification (see Figure IV; PTO-892 NPL X; NF):
Figure IV
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Therefore, the anchoring step is a straightforward amine / acid coupling affording an amide linker [-O3-Si-(CH2)3-N(H)-C(=O)-].
Regarding instant claims 9-12, Ceresa et al., Silva, Pecar et al. and Persson teach a method of coating a medical device having irregular and/or curved silicone surfaces silicone surface with rhamnolipids, wherein the method comprises the steps of:
1) creating an activated silicone surface by activating the medical device silicone surfaces surface that are to be coated by introducing with free amino groups; and
2) covalently attaching rhamnolipids to said the activated silicone surfaces surface. Please see the discussion and citations within instant claims 1 and 4. Additionally, Persson discloses final curing at 80 °C for 1 h (see page 149, right column, paragraph 2 within Persson). A skilled artisan (POSITA) could easily modify this temperature and time under routine experimental conditions to optimize the curing process (taking advantage of the Arrhenius Equation).
Regarding instant claim 13, Ceresa et al., Silva, Pecar et al. and Persson teach the method according to instant claim 9 comprising: creating the activated silicone surface by activating the medical device silicone surface with free amino-groups to have a surface density of amino-groups that is more than 6 x 1015 amino-groups per cm2. Although none of the listed prior art disclose a specific surface density of amino groups, the Examiner believes this surface density would be achieved following the APTES protocol. In addition, the molar equivalents of APTES used by a skilled artisan (POSITA) would play a significant role in the overall anchoring reaction. This surface density could be achieved under routine experimental conditions.
Regarding instant claim 14, Ceresa et al., Silva, Pecar et al. and Persson teach The method according to instant claim 9, comprising covalently attaching rhamnolipids to the activated silicone surface wherein step 2) is performed using carbodiimide chemistry. Please see instant claim 4 regarding the anchoring of APTES. Carbodiimide chemistry is the standard way of affording an amide bond in synthetic organic chemistry. This would be within the scope of a skilled artisan (POSITA).
Regarding instant claim 15, Ceresa et al., Silva, Pecar et al. and Persson teach the method according to instant claim 14, wherein step 2 comprises the steps of comprising:
2a) forming a mixture by mixing an aqueous solution of rhamnolipids with an aqueous solution comprising N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide and N- hydroxysuccinimide at pH 4.5 to 6;
2b) increasing the pH to 7.4 by the addition of NaOH; and
2c) subjecting the medical device silicone surface that is to be coated to the mixture for 1 to 24 h at a temperature in a range of 4 to 25°C.
Please see the discussion within instant claim 14. The instant claim 15 limitations fall within the reaction optimization parameters that are all within the scope of a skilled artisan (POSITA).
Regarding instant claim 16, Ceresa et al., Silva, Pecar et al. and Persson teach the method according to instant claim 15, further comprising the step of: 3) rinsing the coated medical device silicone surface obtained after step 2) with distilled water; and 4) drying the coated medical device silicone surface under vacuum at room temperature. The instant claim 16 protocol is standard procedure and would be within the scope of a skilled artisan (POSITA).
Regarding instant claim 17, Ceresa et al., Silva, Pecar et al. and Persson teach the method according to instant claim 9, wherein the rhamnolipids comprise 70-85% (weight/weight) mono-rhamnolipids, and the rhamnolipids have a purity of at least 85%. The specification does not support this instant claim limitation. Please see the discussion and citations within instant claims 2 and 9 for the necessary rejection text.
Regarding instant claim 18, Ceresa et al., Silva, Pecar et al. and Persson teach the method according to instant claim 9, comprising creating an activated silicone surface on one of a voice prosthesis medical device, a tracheostomy speaking valve medical device, and a holder for a tracheostomy speaking valve medical device. Please see the citations and discussion within instant claims 9 and 19 for the necessary rejection text.
Regarding instant claims 6 and 25, Ceresa et al., Silva, Pecar et al. and Persson teach wherein a surface density of rhamnolipids is in a range from 4.5 x 1015 rhamnolipids per cm2 to 8 x 1015 rhamnolipids per cm2. Please see the discussion within instant claim 13 regarding the anchoring step to install amino functional groups on the silicone. Reaction of the rhamnolipids under acid / amine coupling conditions is standard protocol within synthetic organic chemistry. Moreover, the molar equivalents of rhamnolipids would play a significant role to afford the instant claim limitation appropriate surface area.
Analogous Art
The Ceresa et al., Silva, Pecar et al. and Persson references are directed to the same field of endeavor as the instant claims, that is, a medical device comprising a silicone surface, wherein at least part of the silicone surface is coated with rhamnolipids.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the rhamnolipid coating of medical-grade silicone disclosed by Ceresa et al., using the teachings of Silva, Pecar et al. and Persson to promote a rhamnolipid covering of a medical device.
One would have been motivated to do so to obtain improved rhamnolipid coating of medical-grade silicone that is applied to a variety of medical devices, as suggested by the combination of Silva, Pecar et al. and Persson.
Starting with Ceresa et al., the skilled person only had to try the necessary claim limitations disclosed by Silva, Pecar et al. and Persson. The combination of Ceresa et al., Silva, Pecar et al. and Persson would allow one to arrive at the present application without employing inventive skill. This combination of the rhamnolipid coating of medical-grade silicone taught by Ceresa et al. along with the use of the necessary claim limitations taught by Silva, Pecar et al. and Persson would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
It would have only required routine experimentation to modify the rhamnolipid coating of medical-grade silicone disclosed by Ceresa et al. with the use of the necessary claim limitations taught by Silva, Pecar et al. and Persson. This combined modification would have led to an enhanced rhamnolipid coating of medical-grade silicone that would be beneficial for patients in need of an implantable medical device.
In the context of instant method claims 9-18 the desired purpose defines an effect that arises from and is implicit in the method step(s). Thus, where the purpose is limited to stating a technical effect that inevitably occurs during the performance of the claimed method step(s), and is therefore inherent in that/those step(s), that technical effect is not limiting to the subject-matter of the claim. Thus, the present method claim, defining the application/use of the composition according to the prior art, and defining its purpose as "use", is anticipated by any document of the state of the art describing a method of application/use although not mentioning this specific use.
Response to Arguments
Applicant's arguments filed March 2, 2026 have been fully considered but they are not persuasive.
The instant claim amendments were sufficient to address the 35 U.S.C. 112(b) rejections and the claim objections. Therefore, they are both withdrawn from the Non-Final office action dated October 28, 2025.
The amendments did not necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that the since the references of record do not support the use of rhamnolipids to resist candida fungus, there would be no motivation to use a rhamnolipid coated silicone to coat a medical device.
Examiner’s Rebuttal: The Examiner respectfully disagrees. As currently amended, the instant claims make no mention of candida bioactivity. Thus, this is not a limitation that has an impact on patentability. A skilled artisan (POSITA) would take the next logical step of taking rhamnolipid-modified medical-grade silicone disclosed by both Ceresa et al. and Silva and applying it to a medical device (voice prosthesis) as taught by Persson.
Applicant Argument: The Applicant argues that the synthetic modification of the silicone is not disclosed by the prior art of record.
Examiner’s Rebuttal: Pecar et al. disclose the same synthetic technology needed for the rhamnolipids. The only difference being that Pecar et al. uses a thermoplastic. A skilled artisan (POSITA) would not need to make a significant inventive conclusion to apply this method to the medical-grade silicone. In a similar manner, a skilled artisan (POSITA) would coat the desired portion of the medical device, generating the best response within the patient.
Therefore, the 35 U.S.C. §103 rejection for instant claims 1-25 is maintained.
Conclusion
No claims are 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.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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