DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/10/2025 has been entered.
Status of the Claims
The response and amendment filed 09/10/2025 is acknowledged.
Claims 29-33, 42-46, 51-52, and 54-61 are pending.
Claim 33 is objected to.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Rejections not reiterated herein have been withdrawn.
Amendment
Independent claim 29 includes amended subject matter including:
The host polymeric material making up a largest component of the composition;
at least one release-modifying material making up an amount of the composition less than the host polymeric material;
said at least one release-modifying material comprising polyethylene glycol;1 wt% to 20 wt% of rifampin a first drug; and 1 wt% to 20 wt% of minocycline;
wherein the rifampin and the minocycline do not fully melt during the melt processing
The previous rejections have been modified to address Applicant’s amendment.
Withdrawn
Rejections under 35 U.S.C. 103 as being unpatentable over Labib, US 20110300202 in view of Darouiche, US 5624704 have been withdrawn because of Applicant’s amendment. The combined teachings of Labib and Darouiche do not expressly teach the composition comprising 1 wt% to 20 wt% of rifampin and 1 wt% to 20 wt% of minocycline in combination with the other features required by claim 29. However, Buevich teaches polymer compositions like those of Labib which comprise rifampin and minocycline in amounts within the claimed range as effective for imparting antibacterial effects to implantable medical devices.
Response to Argument
Applicant' s arguments with respect to claim(s) 29-32, 42-46, 51-52, and 54-61 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
To the extent that Applicant’s arguments relate to the new grounds of rejection Applicant’s arguments are addressed as follows:
Applicant argues the inventors of the above-identified application discovered that by combining rifampin and minocycline, "wherein at least some of said rifampin is present in the form of discrete first particles within said composition formed by melt processing, and at least some of said minocycline is present in the form of discrete second particles within said composition formed by melt processing" and "wherein said rifampin has a respective cumulative release of said rifampin from said composition formed by melt processing to an aqueous environment that is greater than would occur with an identical composition absent said minocycline, and wherein said minocycline has a respective cumulative release of said minocycline from said composition formed by melt processing to an aqueous environment that is greater than would occur with an identical composition absent said rifampin" in a composition as claimed, it is possible to take advantage of the significant difference in water solubility by the two drugs so that the cumulative release of the two drugs is increased beyond what would be expected by each drug individually. Applicant argues minocycline assists with the release of the rifampin, and the rifampin assists with the release of the minocycline. Applicant argues this is a surprising and synergistic effect and is described in the published application (US 2023/0149603) at, for example, paragraphs [0089]-[0090]. Applicant argues this surprising discovery that the minocycline assists with the release of the rifampin, and that the minocycline assists with the release of the rifampin is shown with data in, for example, Example 8 in the published application (US 2023/0149603) at paragraphs [0180]- [0181], Tables 10 and 11, and Figures 13A and 13B. It is noted that Blends 6, 7, and 8 are also presented in Tables 1 and 8. As explained in the published application, Blend 6 includes 75% ethylene vinyl acetate, 10% polyethylene glycol, 10% polycaprolactone, 5% rifampin, and 0% minocycline; Blend 7 includes 75% ethylene vinyl acetate, 10% polyethylene glycol, 10% polycaprolactone, 0% rifampin, and 5% minocycline; and Blend 8 includes 70% ethylene vinyl acetate, 10% polyethylene glycol, 10% polycaprolactone, 5% rifampin, and 5% minocycline. Comparing Blends 6 and 8, the cumulative release of rifampin in Blend 8 (when minocycline is present) is greater that the cumulative release of rifampin in Blend 6 (when no minocycline is present) by a factor of about 2.5. When comparing Blends 7 and 8, the cumulative release of minocycline in Blend 8 (when rifampin is present) is greater that the cumulative release of minocycline in Blend 7 (when no rifampin is present) by a factor of about 8. See the published application at Example, 8, paragraphs [0180]-[0181], Tables 10 and 11, and Figures 13A and 13B. It is submitted that this is clearly a surprising result and is not suggested by the prior art.
These arguments are unpersuasive.
This argument has been found persuasive for claim 33. Claim 33 requires a combination of melt processable host polymer, polyethylene glycol, polycaprolactone, minocycline and rifampin in particle form. The current specification, e.g., Table 8, blend 8 compared with blend 11 show results both with PCL (blend 8) and without PCL (blend 11). According to table 8, the blend with PCL releases more minocycline and rifampin than the blend without PCL. The skilled artisan could not have predicted that the inclusion of PCL would result in increased release of minocycline and rifampin present in amounts within the claimed range as shown even if contemplating the modification of compositions suggested by Labib. Polycaprolactone is relatively hydrophobic compared to polyethylene glycol. While Buevich teaches polymer composition may be used to alter release rate of drug from the composition, the skilled artisan would have likely predicted that the addition of caprolactone would result in decreased release of minocycline and/or rifampin since Buevich suggests polymers with limited water uptake, i.e., more hydrophobic, will retard release of agents (Buevich, e.g., 0049). Thus, the subject matter of claim 33 is commensurate in scope with materials having properties which could not have been predicted by the skilled artisan before the effective filing date of the presently claimed invention and this evidence outweighs the evidence of obviousness for the subject matter of claim 33.
However, the remaining claims are not commensurate in scope with the compositions exemplified having unexpected results. The application publication at ¶ 0089-0090 shows no data commensurate in scope with the invention as presently claimed. The dissolution data is presented only in the context of ethylene vinyl acetate host material blended with specific amounts of the release modifying materials PEG and PCL, and specific amounts of rifampin and minocycline (See, e.g., table 4 and example 1). To the extent that the results rely on this known combination of antibiotics, the solubility difference between minocycline and rifampin in water was recognized by the prior art of record (Darouiche, e.g., c5:25-46). Additionally, since the rifampin/minocycline combination was known and used by the prior art of record (Buevich and Darouiche), advantages which stem solely from this combination, e.g., increase of both the first and second drug compared to either drug alone was a latent property of the prior art combination absent evidence to the contrary.
The relative release of each of rifampin and minocycline when present in combination alone is not found persuasive. There was a clear teaching in the prior art that minocycline and rifampin be used in combination (Buevich and Darouiche). Thus, the increased release of each agent based on the combination is a latent property of the prior art of record. Comparison of the release of each agent absent the other with the release of each agent in combination is not a comparison with the prior art since the prior art of record clearly teaches minocycline and rifampin in combination in the same polymer matrix to inhibit infection. Further still increased release of the combination of minocycline and rifampin is only shown by comparing blends containing EVA, PEG and PCL which is not required by claim 29. Thus, claim 29 would not be found commensurate in scope with the proffered data when comparing blends 6, 7, and 8 even if the results were found unexpected.
The claimed invention is directed to a product rather than a method of producing a composition. While the claimed invention includes the product by process limitation wherein said composition is formed by melt processing said host polymeric material, said at least one release-modifying material, said first drug, and said second drug, this limitation is suggested by Labib as set forth in the modified rejection below. Similarly, while the claimed invention includes the limitation of wherein at least some of said first drug is present in the form of discrete first particles within said composition formed by melt processing, and at least some of said second drug is present in the form of discrete second particles within said composition formed by melt processing, this limitation is suggested by Labib.
Applicant has argued nowhere do Darouiche et al. teach or suggest using minocycline and rifampin in particulate form where it is not dissolved in an organic solvent. Applicant argues Darouiche et al. clearly teach dissolving the antimicrobial agent in an organic solvent. See Darouiche et al. at the abstract, column 3, lines 23-54, and column 7, lines 1-29. The outstanding Office Action points out that "Darouiche teaches minocycline and rifampin as crystalline powders (Darouiche, e.g., c5:25-46)." See the Office Action at page 14. Applicant argues one skilled in the art, however, would understand that a solid would not impregnate an implant when applied to the surface of the medial implant, and that is why Darouiche et al. teach dissolving the minocycline and rifampin in a solvent. Applicant argues Darouiche et al. clearly teach that it necessary to first dissolve the minocycline and rifampin in a solvent. Applicant has argued it is the present inventors who discovered that providing the presence of discrete first particles of the first drug and discrete second particles of the second drug within the melt processed composition allows for the drugs to interact with each other in a way that both drugs provide cumulative release that is improved. Labib et al. and Darouiche et al. fail to suggest the claimed melt-processed and drug-particle-containing composition that provides a desired release profile for the both the first drug and the second drug according to the presently claimed invention. Applicant argues Example 8 of the published application (paragraphs [0180]-[0181]) clearly show in Blends 6, 7, and 8 that the cumulative release of rifampin in Blend 8 (when minocycline is present) is significantly greater that the cumulative release of rifampin in Blend 6 (when no minocycline is present), and that the cumulative release of minocycline in Blend 8 (when rifampin is present) is greater that the cumulative release of minocycline in Blend 7 (when no rifampin is present). This is illustrated by Figures 13A and 13B and is clearly unexpected from Labib et al. and Darouiche et al.
This argument is unpersuasive.
Labib teaches formulating the antimicrobial agent using a melt blending technique so that the antimicrobial agent(s) remain as particles in the processed composition. The configuration of antimicrobial agent as solid solution and dispersed particles, i.e., so that the drug does not fully melt during the melt processing, provides articles which have a combination of desirable features, e.g., release drug through diffusion, low cost and ease of manufacture combined with extended drug release and essentially constant release rate (Labib, e.g., 0022).
In view of Labib’s known melt processing technique, it is clear the skilled artisan was aware that the prior art is not limited to the dissolution techniques of Darouiche before the effective filing date of the presently claimed invention. In view of Labib’s known melt processing technique, it is clear the skilled artisan understood that antimicrobial agents could be effectively incorporated into implantable devices without requiring dissolution of the antimicrobial agents.
Applicant’s argument that the Office Action seems to suggest that one skilled in the art would dissolve the rifampin and minocycline of Darouiche et al. in a solvent and then melt mix it into the polymer of Labib et al., but this would go against the teachings of Labib et al. is not found persuasive. It is agreed modifying Labib using a solution of minocycline and rifampin does not make sense. That is why the Office action explains that the skilled artisan would have used Labib’s technique of melt processing particles to formulate compositions of minocycline/rifampin combination antibiotic known in the prior art, e.g., Buevich.
Applicant argues the Office relies on Labib et al.' 185 for the disclosure of "constructs which elute antibiotics, e.g., a first and second antibiotic (Labib 185, e.g., claim 19), in the form of a sleeve for use with devices which pass through the skin such as pins or catheters (Labib 185, e.g., 0548-0550)." Applicant argues that the Examiner's attention is directed at Labib et al.' 185 at, for example, paragraph [0494], which describes a drug being stored in the lumen of a hollow fiber. It is submitted that this would not have suggested, to one skilled in the art, to modify the combination of Labib et al. and Darouiche et al. to provide a melt processed composition, as claimed.
This argument is unpersuasive. Labib teaches the composition may be formed into a variety of devices and shapes including catheters (hollow tube), or meshes, stents, or sutures (fibers). Thus, the skilled artisan would have had a reasonable expectation of successfully forming compositions suggested by the combined teachings of Labib and Buevich into a wrap or sleeve as suggested by Labib 185. Labib 185 recognizes hollow fibers as an alternative for “structural fibers” for drug delivery (Labib 185, e.g., 0546).
Applicant argues the Office relies upon Melo et al. for the disclosure of Rifampin having some particle sizes. Applicant argues, however, that this disclosure is not relevant to modifying Labib et al. and Darouiche et al. to provide a melt processed composition, as claimed.
Applicant argues the Office relies upon Shoichet et al. for the disclosure of solubility based on particle size. Applicant argues, however, that solubility based on particle size is not relevant to the presently claimed composition. Applicant argues that neither of these disclosures by Melo et al. and Shoichet et al. would have suggested modifying the combination of Labib et al. and Darouiche et al. to provide a melt processed composition, as claimed.
These arguments are unpersuasive. Melo, e.g., Abstract, recognizes that optimizing particle size was a known technique for addressing rifampin pharmacokinetic variability due to the known poor water solubility of rifampin (Darouiche, e.g., c5:40-41 rifampin crystalline powder is very slightly soluble in water). To the extent that claim 52 recites wherein said first particles of rifampin are smaller than said second particles of said second drug, Shoichet teaches the technique of formulating drugs with different particles sizes to achieve highly tunable release rates from polymeric materials, e.g., biphasic profiles having the release profile desired by Labib, rapid release followed by slow, dissolution limited release (Shoichet, e.g., c7:23-35). Based on the known correlation between particle size and drug solubility recognized in Melo and Shoichet, it would have been obvious before the effective filing date of the presently claimed invention to apply Shoichet’s known technique of combining different particle sizes for optimized release to address the pharmacokinetic variability of rifampin based on solubility recognized in Melo for the antimicrobial combination of rifampin and minocycline suggested by Buevich with a reasonable expectation of success.
Modified Rejections Necessitated by Applicant’s Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 32 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 32 does not further limit the subject matter of claim 29 since claim 29 includes the limitation that the at least one release modifying material comprises polyethylene glycol.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
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 29, 30-32, 42-46, 54-57, and 60-61 are rejected under 35 U.S.C. 103 as being unpatentable over Labib, US 20110300202 in view of Buevich, US 20140046350.
Labib teaches a composition comprising a thermoplastic polymeric composite matrix (Labib, e.g., 0022). The matrix comprises a host polymer, e g., polyurethane, polysilicone, polyethylene glycol, ethylene-vinyl acetate copolymers, and blends or mixtures thereof (Labib, e.g., 0085 and claim 11). Labib exemplifies compositions comprising a blend of ethylene vinyl acetate copolymer with polyethylene glycol and at least one active agent (Labib, e.g., example 3, 0134-0143 and example 11, 0165-0168). Active agent includes antibiotic such that the articles have a long-term antibacterial effect (Labib, e.g., claims 6-8, and 22-23, and 0022 and 0109-0110). Bioactive agent may be present in an amount ranging from 2 to about 30 wt% (Labib, e.g., 0090). Labib exemplifies materials comprising a melt blended combination of antimicrobial agent with EVA in a major proportion and polyethylene glycol in a minor proportion (Labib, e.g., examples 3 and 11).
The claimed host polymeric material making up a major portion of said composition reads on ethylene vinyl acetate copolymer which is present as the largest amount of the composition, e.g., Labib, e.g., examples 3 and 11.
The claimed at least one release-modifying material, said at least one release-modifying material being mixed, together with said host polymeric material and making up a minor portion of the composition reads on polyethylene glycol, e.g., Labib, e.g., examples 3 and 11.
Applicable to claim 29: 1 wt% to 20 wt% of rifampin and 1 wt% to 20 wt% of minocycline Applicable to claim 29: wherein the rifampin and the minocycline do not fully melt during the melt processing:
Labib teaches melt processing to prepare the material so that the bioactive agent, e.g., antimicrobial agent is present in the composition in two phases, e.g., a solid solution phase and discrete particles (Labib, e.g., example 3, 0143: presence of a dispersed phase of un-dissolved ciprofloxacin particles). Further explanation of the melt processing result is found at Labib, e.g., 0034, 0042, 0075, 0083, 0119, 0129, and 0137. The configuration of antimicrobial agent as solid solution and dispersed particles, i.e., so that the drug does not fully melt during the melt processing, provides articles which have a combination of desirable features, e.g., release drug through diffusion, low cost and ease of manufacture combined with extended drug release and essentially constant release rate (Labib, e.g., 0022).
Buevich teaches articles comprising a polymer matrix containing antimicrobial agents (Buevich, e.g., Abstract, examples, and claims) which articles contain antimicrobial agent in amounts effective to reduce post-surgical implant infection (Buevich, e.g., 0003-0004). Like Labib, Buevich teaches antimicrobial agents incorporated in articles in polymers for controlled release (Beuvich, e.g., 0047-0055). Buevich exemplifies the combination of rifampin and minocycline wherein each antibiotic is present in an amount within the claimed range, e.g., 10wt% minocycline and 10wt% rifampin (Buevich, e.g., Examples, e.g., 0080-0085). Buevich teaches implantable devices improved by the antibiotic combination of minocycline and rifampin (Buevich, e.g., 0084, catheter and claims 46-47). The combination of minocycline and rifampin was a known antibiotic alternative for ciprofloxacin (Buevich, e.g., 0069-0070). The combination of minocycline and rifampin is shown to be effective to inhibit S. epidermidis and S. aureus (Buevich, e.g., 0084, Tables 2-3).
Labib teaches minocycline and/or rifampicin may be used as bioactive agent (Labib, e.g., 0094). Labib does not exemplify an embodiment containing 1 wt% to 20 wt% of rifampin and 1 wt% to 20 wt% of minocycline. However, Buevich teaches minocycline and rifampin used in combination is effective when present in polymer materials in an amount within the claimed range.
Regarding the limitation of wherein at least some of the drug is present in the form of discrete first particles within said composition and at least some of said second drug is present in the form of discrete second particles within said composition formed by melt processing; and
Regarding the limitation of wherein said composition is formed by melt processing said host polymeric material, said at least one release modifying material, said rifampin, and minocycline as found in claim 29:
Labib teaches articles comprising composite prepared by uniformly dispersing bioactive agent in a polymer melt (Labib, e.g., 0022). Labib teaches one or more melt processable polymeric materials which polymer materials are suitable for implantation in a living mammal (Labib, e.g., 0111-0117). Melt processing of polymer melt material and bioactive agent is exemplified in Labib, e.g., example 1, 0122-0129 and examples 2-5. This includes melt processing host polymer EVA with at least one release modifying material (PEG) and bioactive agent to form a bioactive agent polymer dispersion (Labib, e.g., 0134-0136). Labib teaches the melt processing method including at least one bioactive agent in the melt processing step with melt processable polymer materials enables the formation of two solid solution phases in the formed polymer matrix (Labib, e.g., 0119 and 0129). The technique of melt processing enables production with lower cost and ease of fabrication combined with extended drug release and essentially constant drug release after an initial induction period, which allows long term antimicrobial effect thereby satisfying needs in the art (Labib, e.g., 0022). Labib attributes the observed extended, essentially constant, drug release profile to the bioactive agent being in the form of particles and the unique phase structure of the composite enabled by melt processing (Labib, e.g., 0154).
Thus, Labib clearly teaches wherein the composition is formed by melt processing said host polymeric material, the release modifying materials, and the bioactive agents, wherein the bioactive agents are in the form of discrete particles (not fully melted) and solid solution phases of the bioactive agent(s) obtained by melt processing which enables extended, essentially constant, drug release profiles at a low cost with increased ease of fabrication.
It would have been obvious before the effective filing date of the presently claimed invention to modify a polymeric matrix material formed by melt processing a host polymer, at least one release modifying material, and bioactive agents taught by Labib by incorporating a known antimicrobial combination of first and second drug, e.g., minocycline and rifampin, in effective amounts suggested by Buevich to improve the composition in the same way with a reasonable expectation of success. The skilled artisan would have been motivated to select a combination of minocycline and rifampin to inhibit bacteria known to present complications for implantable devices, e.g., S. aureus, thereby reducing colonization of bacteria and reducing infectious complications in the same way reported by Buevich with a reasonable expectation of success. The skilled artisan would have had a reasonable expectation of success because Labib suggests the antimicrobial agent may be selected from minocycline, rifampin and combinations thereof.
It would have been obvious before the effective filing date of the presently claimed invention to incorporate minocycline and rifampin so that they are present in the composition as discrete first and second particles with a reasonable expectation of success. The skilled artisan would have been motivated to incorporate minocycline and rifampin so that they are present in the composition as discrete particles because Labib teaches this technique for formulating antimicrobial agents so that the composition may be formed into useful articles effective to elute drug by diffusion with extended and constant drug release for long term antibacterial effect.
Applicable to claim 31: Labib teaches and exemplifies compositions comprising poly ethylene vinyl acetate copolymer as the major component of the thermoplastic matrix material.
Applicable to claim 32: Labib teaches and exemplifies compositions comprising polyethylene glycol in a host polymer matrix as a minor component.
Applicable to claim 46: Labib suggests minocycline and rifampin are suitable to form a solid solution to at least some extent in the material (Labib, e.g., 0094, 0072-0075, 0119, and example 3).
Applicable to claim 54: Labib teaches the composition effective for at least 30 days (Labib, e.g., claim 28). Labib, e.g., Figs. 6-8 show release which would extend to at least 40 days. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05. The skilled artisan would have been motivated to formulate the composition for release of antibiotic, e.g., minocycline and rifampin, over the time frames desired by Labib with a reasonable expectation of success. Buevich teaches drug release may be modified by changing polymer composition, e.g., polymer water affinity (Buevich, e.g., 0049) and amount of drug present in the polymer composition (Buevich, e.g., 0089).
Applicable to claim 55: Labib teaches wherein at least one said bioactive agent has less than about 5 percent weight loss at a temperature of 200° C (Labib, e.g., claim 1 and 0096). Thus, there exists a temperature according to claim 22 in the prior art.
Applicable to claims 56-57: Labib teaches the composition formed into a part of a medical device such as a catheter (Labib, e.g., 0050, 0110, and claim 7).
Applicable to claims 60-61: Labib teaches wherein the thermoplastic material is polyurethane or polysilicone or ethylene-vinylacetate copolymer (Labib, e.g., claim 11). Thus, the skilled artisan would have found it obvious to substitute polyurethane or polysilicone for ethylene vinyl acetate copolymer in the exemplified compositions.
Applicable to claims 30 and 42-43: Labib teaches the composition further comprising plasticizers, colorant, antioxidants, stabilizers, inert fillers, and combinations thereof (Labib, e.g., claim 12 and 0091). Any of these additional materials meet the limitation of a second release-modifying material so long as they are in a minor proportion. Labib teaches the composition containing less than about 25 percent of plasticizers, colorant, antioxidants, stabilizers, inert fillers, and combinations thereof (Labib, e.g., 0091).
Applicable to claim 44: polyethylene glycol is more hydrophilic than ethylene vinyl acetate copolymer.
Applicable to claim 45: Labib teaches the composition comprising less than about 25 percent of plasticizers, colorant, antioxidants, stabilizers, inert fillers, and combinations thereof (Labib, e.g., 0091). Labib teaches the composition having a similar amount of polyethylene glycol, e.g., about 12-20% of the composition. Labib, e.g., example 3 teaches a composition having about 12.99% PEG by mass (5.53/42.55x100). Labib, e.g., example 11, teaches a composition having about 20% by mass PEG. Consider, e.g., that 50% of 12% is 6 percent and 200 percent of 12 percent is 24%. Both 6 percent and 24 percent are within the range of less than about 25%. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05.
Accordingly, the subject matter of claims 29, 30-32, 42-46, 54-57, and 60-61 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Claims 29, 30-32, 42-46, 51, 54-57, and 60-61 are rejected under 35 U.S.C. 103 as being unpatentable over Labib, US 20110300202 in view of Buevich, US 20140046350 as applied to claims 29, 30-32, 42-46, 54-57, and 60-61 above, and further in view of Darouiche, US 5624704.
The combined teachings of Labib and Buevich teach a composition according to claim 29 as enumerated above. The combined teachings of Labib and Buevich teach a composition comprising a base polymer (host polymer), e.g., ethylene vinyl acetate (EVA), polyethylene glycol (at least one release modifying material) mixed together with the base polymer and making up a minor proportion of the composition, and further comprising a combination antibiotic containing rifampin and minocycline. The combined teachings of Labib and Buevich teach minocycline present as particles in the composition but do not expressly teach wherein minocycline is in crystalline form.
Darouiche teaches minocycline and rifampin are commercially available as crystalline powders (Darouiche, e.g., c5:25-46). Applicable to claim 51: Darouiche teaches crystalline antibiotics (Darouiche, e.g., c5:25-46).
It would have been obvious before the effective filing date of the presently claimed invention to modify a composition suggested by the combined teachings of Labib and Buevich by incorporating minocycline in the form of crystals with a reasonable expectation of success. The skilled artisan would have been motivated to incorporate minocycline in crystalline form for convenience since minocycline is commercially available in crystalline form. The skilled would have had a reasonable expectation of success because Labib teaches preparing the material so that the drug is present in particulate form without fully melting.
Accordingly, the subject matter of claims 29, 30-32, 42-46, 51, 54-57, and 60-61 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Claims 29 and 56-59 are rejected under 35 U.S.C. 103 as being unpatentable over Labib, US 20110300202 in view of Buevich, US 20140046350 as applied to claims 29, 30-32, 42-46, 54-57, and 60-61 above, and further in view of Labib, US 20180200185 (Labib 185).
The combined teachings of Labib and Buevich teach a composition according to claim 29 as enumerated above. The combined teachings of Labib and Buevich teach a composition comprising a base polymer (host polymer), e.g., ethylene vinyl acetate (EVA), polyethylene glycol (at least one release modifying material), and further comprising a combination antibiotic containing rifampin and minocycline in the form of discrete particles, and wherein the composition is formed by melt processing.
Labib further teaches the composition may be formed into useful articles by standard methods, e.g., extrusion, compression, or injection molding (Labib, e.g., 0022), and useful in articles such as catheters, shunts, drains, implants, sutures, meshes, stents (Labib, e.g., 0110 and claim 16).
The combined teachings of Labib and Darouiche do not expressly teach the composition formed into a sleeve.
Labib 185 teaches constructs which elute antibiotics, e.g., a first and second antibiotic (Labib 185, e.g., claim 19), in the form of a sleeve for use with devices which pass through the skin such as pins or catheters (Labib 185, e.g., 0548-0550).
It would have been obvious before the effective filing date of the presently claimed invention to modify a composition useful for eluting antibiotics suggested by Labib and Buevich by forming the polymeric composition into a sleeve configured for use with a fixation pin or catheter as suggested by Labib 185 with a reasonable expectation of success. Since Labib and Buevich teach an antibiotic eluting composition which may be formed into useful articles by standard polymer processing methods, the skilled artisan would have found it obvious to form the antibiotic eluting composition into a sleeve known from Labib 185 with a reasonable expectation of success. The skilled artisan would have seen this modification as a selection of a known material based on its suitability for its intended use. See MPEP 2144.07. The skilled artisan would have been motivated to make this modification to enable compositions known from Labib and Buevich to reduce infection complications related to the use of fixation pins and catheters as taught by Labib 185. The skilled artisan would have had a reasonable expectation of success because Labib teaches the compositions may be formed into articles using known processing techniques and because Labib teaches the compositions may be used with implants and catheters.
Accordingly, the subject matter of claims 29 and 56-59 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Claims 29 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Labib, US 20110300202 in view of Buevich, US 20140046350 as applied to claims 29, 30-32, 42-46, 54-57, and 60-61 above, and further in view of Melo, Materials Science and Engineering C, 112, 2020 and Shoichet, US 9205047.
The combined teachings of Labib and Buevich teach a composition according to claim 29, wherein the first and second drug are present in the composition in the form of particles. Labib teaches the particles having a particle size distribution, wherein the particles of bioactive agent are prepared by grinding or milling or prepared by agglomeration (Labib, e.g., 0107).
The combined teachings of Labib and Buevich do not expressly teach wherein said first particles of said first drug are smaller than said second particles of said second drug.
Melo teaches Rifampin has high pharmacokinetic variability, mainly due to highly variable absorption caused by poor solubility (Melo, e.g., Abstract). Selection of appropriate rifampin particle size allows for increasing the dissolution rate and improving bioavailability of rifampin (Melo, e.g., Abstract).
Shoichet teaches the technique of optimizing particle sizes in a formulation to achieve desired release profiles (Shoichet, e.g., c7:23-36)
Shoichet teaches formulating actives with a first particle size and a second particle size, wherein the particle sizes are different (Shoichet, e.g., claims 4-7). The size of the solid particles of active agent determines the release profile of the active (Shoichet, e.g., Fig. 1, c11:35-57, and claims 1 and 4). For a given drug, smaller particles are expected to provide greater solubility (Shoichet, e.g., Fig. 1). The mixed particle size technique offers highly tunable release rates, e.g., Shoichet teaches mixed particle sizes offer biphasic release profiles which results in more rapid release of drug from smaller particle sizes followed by slower, dissolution limited release from larger particles (Shoichet, e.g., c7:23-36). Shoichet teaches particles formulated as larger microparticles, e.g., spherical particles, and/or smaller nanoparticles (Shoichet, e.g., c7:51-65 and claim 9).
Melo, e.g., Abstract, recognizes that optimizing particle size was a known technique for addressing rifampin pharmacokinetic variability due to the known poor water solubility of rifampin (Darouiche, e.g., c5:40-41 rifampin crystalline powder is very slightly soluble in water). To the extent that claim 52 recites wherein said first particles of said first drug are smaller than said second particles of said second drug, Shoichet teaches the technique of formulating drugs with different particles sizes to achieve highly tunable release rates from polymeric materials, e.g., biphasic profiles having the release profile desired by Labib, rapid release followed by slow, dissolution limited release (Shoichet, e.g., c7:23-35).
It would have been obvious before the effective filing date of the presently claimed invention to optimize particle sizes of each of the drugs present in compositions suggested by the combined teachings of Labib and Buevich using techniques known from Melo and Shoichet for greater control over drug solubility and release, thereby tuning desired release profiles and reducing variability of drug effectiveness caused by poor solubility with a reasonable expectation of success. The skilled artisan would have been motivated to formulate at least one of the drugs with a smaller particle size for a biphasic release profile which results in more rapid release of drug from smaller particle sizes followed by slower, dissolution limited release from larger particles as reported in Shoichet. The skilled artisan would have been motivated to apply this technique to compositions comprising solid drug particulates suggested by the combined teachings of Labib and Buevich for desired dissolution of rifampin, and optimized initial release rates of antibiotics rifampin and minocycline from the composition for an initial antimicrobial induction period during use followed by a constant release as desired by Labib. The skilled artisan would have had a reasonable expectation of success because Melo suggests optimizing particle sizes will reduce variability in the effectiveness of drugs such as rifampin.
Accordingly, the subject matter of claims 29 and 52 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Conclusion
No claim is allowed.
Claim 33 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Neither Labib reference of record teaches where said second release modifying material comprises polycaprolactone. On the current record Natu was cited for teaching polycaprolactone as a release modifying material for ethylene vinyl acetate host polymer. However, claim 33 requires a combination of melt processable host polymer, polyethylene glycol, polycaprolactone, minocycline and rifampin in particle form. The current specification, e.g., Table 8, blend 8 compared with blend 11 show results both with PCL (blend 8) and without PCL (blend 11). According to table 8, the blend with PCL releases more minocycline and rifampin than the blend without PCL. The skilled artisan could not have predicted that the inclusion of PCL would result in increased release of minocycline and rifampin present in amounts within the claimed range as shown even if contemplating the modification of compositions suggested by Labib. Polycaprolactone is relatively hydrophobic compared to polyethylene glycol. While Buevich teaches polymer composition may be used to alter release rate of drug from the composition, the skilled artisan would have likely predicted that the addition of caprolactone would result in decreased release of minocycline and/or rifampin since Buevich suggests polymers with limited water uptake, i.e., more hydrophobic, will retard release of agents (Buevich, e.g., 0049). Thus, the subject matter of claim 33 is commensurate in scope with materials having properties which could not have been predicted by the skilled artisan before the effective filing date of the presently claimed invention and this evidence outweighs the evidence of obviousness for the subject matter of claim 33.
Correspondence
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/WILLIAM CRAIGO/Examiner, Art Unit 1615