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 .
Status of Claims
Claims 1-4, 7-10, 13-20, 23, 25-27, 29, 33-34, 36, 38, 40, 73 and 146 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-4, 7-20, 13-20, 23, 25-27, 29, 33-34, 36, 38, 73 and 146, in the reply filed on 10 December 2025 is acknowledged. Applicant further elected bacterial infection as the specific infection, Staphylococcus aureus as the pathogen, from an infection spread through the bloodstream or from nearby tissue as the result of the osteomyelitis, and a subject with diabetes as the specific subject. The traversal is on the ground(s) that there is no serious burden to search and examine both groups. This is not found persuasive because of the reasons set forth in restriction requirement mailed on 21 October 2025. The claims of the instant 371 national stage application were found to lack unity of invention (where unity of invention requires a special technical feature) due to the lack of a special technical feature between the different groups. Thus the burden of the search of these different inventions is moot.
The requirement is still deemed proper and is therefore made FINAL.
Claims 3, 14-16, 23, 25, 27, 40 and 146 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, respectively, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10 December 2025.
Claims 1-2, 4, 7-10, 13, 17-20, 26, 29, 33-34, 36, 38 and 73 are examined herein to the extent that the specific infection and specific pathogen is bacterial infection and Staphylococcus aureus, respectively, the result of the osteomyelitis is from an infection spread through the bloodstream or from nearby tissue, and the subject is a subject with diabetes, e.g., applicant's elected species.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 04/01/2024 and 12/17/2025 have been considered by the Examiner. A signed and initialed copy of the IDS is included with the instant Office Action.
Claim Interpretation
Instant claim 8 recites “said microparticles have a D90 of less than 2 µm, a D50 of less than or equal to 0.72 µm to 1.3 µm, and/or a D10 of less than or equal to 0.22 µm to 0.70 µm”, this shall be given its plain meaning and interpreted in the alternative as microparticles with one of the size distributions recited.
Instant claim 34 recites “administered three times per day, two times per day, once daily, every other day, once every three days, three times per week, once every week, once every other week, once every month, or once every other month”, this shall be given its plain meaning and interpreted in the alternative as one of the administration repetitions recited.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 10 recites “about 2% to about 5% methylcellulose” and “amount 0.05% to about 1.0% polysorbate 80”, which renders the claim indefinite because it is unclear if the percentages are by weight, volume or molar.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 4,7-9, 13, 17-20, 26, 29, 33-34, 36, 38 and 73 are rejected under 35 U.S.C. 103 as being unpatentable over BAKER (US 8,389,021 B2; date of patent: 05 March 2013; cited in IDS filed 04/01/2024) in view of LIPSKY (“Treating Diabetic Foot Osteomyelitis Primarily With Surgery or Antibiotics: Have We Answered the Question?”, Diabetes Care, 37, 593-595, 2014).
Baker is primarily directed towards compositions and methods, including homogeneous microparticulate suspensions including bismuth-thiol compounds (abstract).
Regarding claims 1-2, 4, 7-9 and 73, Baker discloses a method of treating including chronic wound or a wound that contains bacterial biofilm (e.g., bacterial infection) in a subject, comprising administering, to a wound site in the subject, a therapeutically effective amount of a topical formulation that comprises at least one BT compound, and a pharmaceutically acceptable excipient or carrier for topical use (column 11, lines 14-21). Baker discloses that BT compound includes BisEDT (column 11, lines 31-32). Baker discloses a BT composition comprising a plurality of microparticles that comprise a bismuth-thiol (BT) compound, substantially all of the microparticles (e.g., at least 70%) having a volumetric mean diameter of from about 0.4 µm to about 5 µm (column 12, lines 6-10). Baker discloses that the wound includes osteomyelitis (bone infection) (column 2, line 40; column 12, lines 43-49). Baker discloses that “substantially” includes at least 90% of the particles have a VMD that is within the recited size range (column 19, lines 33-40). Baker discloses that the composition contains the microparticles in suspension (column 18, lines 48-52). Baker discloses topical administration by direct contact of the BT composition at including bones (column 29, lines 45-58).
Regarding claim 18, Baker discloses that treating the wound comprises at least one of including reducing the bacterial biofilm, impairing growth of the bacterial biofilm (column 12, lines 54-57).
Regarding claims 19-20, Baker discloses that the bacterial pathogen causing the biofilm includes Staphylococcus aureus (S. aureus) (column 9, lines 8-10).
Regarding claim 29, Baker discloses about 0.001 to about 50 mg of the active ingredient per cc (e.g., about 1 µg/cm2 to about 50 mg/ cm2) (column 44, lines 1-3).
Regarding claims 34 and 36, Baker discloses applying the formulation including once weekly (column 41, 32-35). Baker discloses that one of ordinary skill may readily determine the optimum including repetition rates using factors including severity of the wound and its responsiveness to initial treatment (column 41, lines25-32).
Regarding claim 38, Baker discloses BT compound(s) and antibiotic(s) provide synergy in the antibacterial effects of such formulations (column 7, lines 42-48). Baker disclose the BT compound in synergizing combination with one or more antibiotic (column 51, lines 14-25; lines 32-36).
Baker does not specifically teach that the osteomyelitis results from an infection spread through the bloodstream or from nearby tissue and that the subject has diabetes (e.g., elected species). The deficiencies are made up for by the teachings of Lipsky.
Lipsky is primarily directed towards treating diabetic foot osteomyelitis with surgery or antibiotics (see entire publication of Lipsky).
Regarding claims 1, 13, 17, 26 and 73, Lipsky teaches that foot infections are among the most frequent diabetes-related causes for hospitalization. Lipsky teaches that infection usually starts in ulcerated soft tissues, but can spread contiguously to underlying bone. Lipsky teaches that about 20% of patients with a diabetic foot infection and over 60% of those with severe infections have underlying osteomyelitis (first column on page 593). Lipsky teaches reports appeared of patients with diabetic foot osteomyelitis cured by antibiotic therapy with little or no surgical resection (paragraph bridging the first and second column on page 593).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat osteomyelitis including diabetic foot osteomyelitis by administering to including the infected bone a composition comprising suspended microparticles comprising BT compound including BisEDT, wherein the amount of the BT compound including BisEDT is about 0.001 to about 50 mg of the active ingredient per cc (e.g., about 1 µg/cm2 to about 50 mg/ cm2). The person of ordinary skill in the art would have been motivated to make those modifications because Baker discloses a method that can be used to treat including osteomyelitis, therefore, one of ordinary skill in the art would expect that the method of Baker can be used for specific osteomyelitis including diabetic foot osteomyelitis that is taught by Lipsky, and reasonably would have expected success because Baker discloses a method of treating including chronic wound or a wound that contains bacterial biofilm (e.g., bacterial infection) in a subject, comprising administering, to a wound site in the subject, a therapeutically effective amount of a topical formulation that comprises at least one BT compound, and a pharmaceutically acceptable excipient or carrier for topical use (column 11, lines 14-21). Baker discloses that BT compound includes BisEDT (column 11, lines 31-32). Baker discloses a BT composition comprising a plurality of microparticles that comprise a bismuth-thiol (BT) compound, substantially all of the microparticles (e.g., at least 70%) having a volumetric mean diameter of from about 0.4 µm to about 5 µm (column 12, lines 6-10). Baker discloses that the wound includes osteomyelitis (bone infection) (column 2, line 40; column 12, lines 43-49). Baker discloses that “substantially” includes at least 90% of the particles have a VMD that is within the recited size range (column 19, lines 33-40). Baker discloses that the composition contains the microparticles in suspension (column 18, lines 48-52). Baker discloses topical administration by direct contact of the BT composition at including bones (column 29, lines 53-58). Lipsky teaches that foot infections are among the most frequent diabetes-related causes for hospitalization. Lipsky teaches that infection usually starts in ulcerated soft tissues, but can spread contiguously to underlying bone. Lipsky teaches that about 20% of patients with a diabetic foot infection and over 60% of those with severe infections have underlying osteomyelitis (first column on page 593). Lipsky teaches reports appeared of patients with diabetic foot osteomyelitis cured by antibiotic therapy with little or no surgical resection (paragraph bridging the first and second column on page 593).
Regarding claim 33, although the combination of Baker and Lipsky do not specifically teach that the composition maintains activity on the site of direct application after one week, one month, or two months, the claimed method of treating osteomyelitis, the method comprising administering t a subject in need thereof a therapeutically effective amount of a bismuth-thiol (BT) composition that comprises BisEDT suspended therein, wherein the composition is topically applied to an infected bone of said patient (Baker: column 11, lines 14-21; column 11, lines 31-32; column 12, lines 6-10, lines 43-49; column 18, lines 48-52; column 19, lines 33-40; column 29, lines 53-58; Lipsky: page 593) appears to be the same as the prior art, absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition is different from that taught by the prior art and to establish patentable differences. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Claims 10 is rejected under 35 U.S.C. 103 as being unpatentable over Baker in view of Lipsky as applied to claims 1-2, 4,7-9, 13, 17-20, 26, 29, 33-34, 36, 38 and 73 above, and further in view of BATHURST (US 2008/0095806 A1, publication date of 24 April 2008) and LEUNG (US 6,329,343 B1; date of patent: 11 December 2001).
Regarding claim 10, the method of claim 1 is described above in section 10.
Regarding claim 10, Baker discloses that the topical composition can be in the form of including a gel (column 30, lines 8-10; column 31, lines 27-29). Baker discloses skin permeation enhancer in the composition which includes Tween® 80 (column 33, lines 39-46). Baker discloses that the composition includes emollients including polysorbate 80 (paragraph bridging columns 37-39). Baker discloses that the composition includes thickening agents including methylcellulose (column 40, lines 38-45). Baker discloses that the formulation is effective at pH values of including preferably about pH 7 to about pH 8 (column 41, lines 4-11). Baker discloses that the topical composition includes agents for the adjustment of tonicity including sodium chloride (column 41, lines 66). Baker discloses that the topical composition includes buffers including phosphates (column 41, line 65). Baker discloses about 0.001 to about 50 mg of the active ingredient per cc (e.g., about 1 µg/cm2 to about 50 mg/ cm2) (column 44, lines 1-3).
Baker and Lipsky do not specifically teach about 1% to about 5% methylcellulose, about 0.05% to about 1.0% polysorbate 80, about 1 to 40 mM sodium chloride, and about 2 to 20 mM sodium phosphate. The deficiencies are made up for by the teachings of Bathurst and Leung.
Bathurst is primarily directed towards a gel formulation for including coating a wound (paragraph [0069]).
Regarding claim 10, Bathurst teaches that uniform pH in a gel formulation is required for safety in topical products (paragraph [0013]). Bathurst teaches physiological buffer in a composition includes buffers including salts that are preferably NaCl or phosphate salts. Bathurst teaches that physiological buffer preferably contains 0-250 mM phosphate, 0-250 mM NaCl, or 0-250 mM KCl and the pH range of the physiological buffer used in the composition is preferably including about 7 to about 7.5 (paragraph [0018]). Bathurst teaches that the composition with the suitable pH conditions within the gel provides including gel consistency and stability (paragraph [0023] and [0027]). Bathurst teaches topical composition with a gelling agent and a physiological buffer (paragraph [0047]). Bathurst teaches that gelling agent including methylcellulose and that the gel contains from about 1% to about 5% w/w of the methylcellulose (paragraph [0052]). Bathurst teaches the composition comprises including buffers that render the formulation isotonic (paragraph [0071]).
Salamone is primarily directed towards antimicrobial coating formulations (abstract).
Regarding claim 10, Salamone teaches including one or more surfactants to effect lowering of the surface tension of the composition in order to facilitate flow of the composition into skin folds and crevices. Salamone teaches that surfactants include Tween 80 (paragraph [0157]). Salamone teaches that the surfactant is present at a concentration of from 0.01wt-% to 1.0 wt-% (paragraph [0171]). Salamone teaches amount of emollients is from 0.1 to 5 wt-% (paragraph [0163]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat osteomyelitis including diabetic foot osteomyelitis by administering to including the infected bone a composition comprising suspended microparticles comprising BT compound including BisEDT, wherein the amount of the BT compound including BisEDT is about 0.001 to about 50 mg of the active ingredient per cc (e.g., about 1 µg/cm2 to about 50 mg/ cm2); and wherein the composition further comprises from about 1% to about 5% w/w of methylcellulose, 0.1 to 5 wt-% of Tween 80 (e.g., polysorbate 80), and a physiological buffer containing including 0-250 mM phosphate including sodium phosphate and 0-250 mM NaCl so that the pH range is preferably including about pH 7 to about pH 8. The person of ordinary skill in the art would have been motivated to make those modifications because Baker discloses that the composition includes gelling agent including methylcellulose, skin permeation enhancer including surfactants that further include polysorbate 80, buffering agents including phosphates to buffer the composition to pH of including about pH 7 to about pH 8 and sodium chloride to adjust tonicity of the composition, while Bathurst teaches ranges of methylcellulose of from about 1% to about 5% w/w as a gelling agent, ranges of buffering agent including sodium phosphate at 0-250 mM and NaCl at 0-250 mM to provide the composition at a pH of including about 7 to about 7.5, and Salamone teaches a range of 0.01wt-% to 1.0 wt-% of surfactants including polysorbate 80 to facilitate flow of the composition into skin. Therefore, one of ordinary skill in the art would use the ranges taught by Bathurst and Salamone in topical compositions to optimize to determine an optimal amount methylcellulose for gelling, optimal amount of amount of buffer including sodium phosphate and NaCl for buffering the composition to a pH of about 7 to about 8, and optimal amount of surfactant including polysorbate 80 to provide skin permeation enhancement. The person of ordinary skill in the art would have reasonably expected success because Baker discloses that the topical composition can be in the form of including a gel (column 30, lines 8-10; column 31, lines 27-29). Baker discloses skin permeation enhancer in the composition which includes Tween® 80 (column 33, lines 39-46). Baker discloses that the composition includes emollients including polysorbate 80 (paragraph bridging columns 37-39). Baker discloses that the composition includes thickening agents including methylcellulose (column 40, lines 38-45). Baker discloses that the formulation is effective at pH values of including preferably about pH 7 to about pH 8 (column 41, lines 4-11). Baker discloses that the topical composition includes agents for the adjustment of tonicity including sodium chloride (column 41, lines 66). Baker discloses that the topical composition includes buffers including phosphates (column 41, line 65). Baker discloses about 0.001 to about 50 mg of the active ingredient per cc (e.g., about 1 µg/cm2 to about 50 mg/ cm2) (column 44, lines 1-3). Bathurst teaches that uniform pH in a gel formulation is required for safety in topical products (paragraph [0013]). Bathurst teaches physiological buffer in a composition includes buffers including salts that are preferably NaCl or phosphate salts. Bathurst teaches that physiological buffer preferably contains 0-250 mM phosphate, 0-250 mM NaCl, or 0-250 mM KCl and the pH range of the physiological buffer used in the composition is preferably including about 7 to about 7.5 (paragraph [0018]). Bathurst teaches that the composition with the suitable pH conditions within the gel provides including gel consistency and stability (paragraph [0023] and [0027]). Bathurst teaches topical composition with a gelling agent and a physiological buffer (paragraph [0047]). Bathurst teaches that gelling agent including methylcellulose and that the gel contains from about 1% to about 5% w/w of the methylcellulose (paragraph [0052]). Salamone teaches including one or more surfactants to effect lowering of the surface tension of the composition in order to facilitate flow of the composition into skin folds and crevices. Salamone teaches that surfactants include Tween 80 (paragraph [0157]). Salamone teaches that the surfactant is present at a concentration of from 0.01wt-% to 1.0 wt-% (paragraph [0171]).
Thus, the claimed invention as a whole is clearly prima facie obvious over the teachings of the prior art.
Conclusion and Correspondence
No claims are found allowable.
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/John P Nguyen/
Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600