DETAILED ACTION
Notice of 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 the Claims
The amendments filed 7/02/2026 have been entered.
Response to Arguments
Applicant’s arguments, filed 7/02/2026, have been fully considered.
All previous rejections have been either WITHDRAWN or MODIFIED in view of Applicant’s amendments to the claims, which now require “intra-articularly administering” the agent, rendering the majority of Applicant’s arguments moot. To the extent that Applicant’s arguments apply to the instant rejections, the following is provided:
Applicant argues that “the specification provided robust experimental data demonstrating that the IA injection of Formula (I) created a unique pharmacokinetic and pharmacodynamic profile that were fundamentally different from conventional systemic treatments” (Applicant Arguments, Page 7).
First, Applicant points to Example 1 of the Specification. As argued by Applicant:
“Example 1 directly compared IA injection with systemic IP injection, demonstrating that IA injection of TNP-2092 provided statistically significant and superior bactericidal efficacy compared to IP injection at the same doses. The femur colony counts in the 15 mg/kg and 5 mg/kg IA dose groups (QD) of the compound of formula (I) were also determined to be statistically significant (P < 0.0001) compared to the IP administration of the compound of formula (I) at the same doses, and the pin colony counts in the 15 mg/kg IA dose group of the compound of formula (I) were also determined to be statistically significant (P < 0.0001) compared to the 15 mg/kg IP dose group of the compound of formula (I). Moreover, the IA administration had a lower dosing frequency, providing an advantage in improving patient compliance” (Applicant Arguments, Pages 7-8).
While the differences between IP and IA administration are acknowledged, there is nothing unexpected in these differences. As discussed in the basis of the rejection below, Wei et al – recognizing that “[t]he rate of eradication of periprosthetic joint infection (PJI) caused by methicillin-resistant Staphylococcus aureus (MRSA) is still not satisfactory with systemic vancomycin administration” – compared “[t]wo weeks of intraperitoneal (IP) and/or [intra-articular] IA injection of vancomycin... to control the infection after one-stage revision surgery” and report that “the MRSA PJI rats treated with IA injection of vancomycin showed better outcomes in skin temperature, bacterial counts, biofilm on the prosthesis, serum α1-acid glycoprotein levels, residual bone volume, and inflammatory reaction in the joint tissue, compared with those treated with IP vancomycin” (Abstract).
Next, pointing to Example 2 of the Specification, Applicant argues “as disclosed in Example 2 of the present application... the compound of formula (I) had a stronger bactericidal effect compared to vancomycin” and “for the bacteria colonizing the prosthesis, the medium- and high-dose treatment groups of the compound of formula (I) had a stronger ability to inhibit bacterial growth and biofilm formation compared to the vancomycin group” (Applicant Arguments, Page 8).
While again acknowledged, the prior art is similarly directed to the administration of Applicant’s compound of formula (I). As such, the showing that said compound is superior to vancomycin is irrelevant.
Lastly, pointing to Example 3 of the Specification, Applicant argues that
“Example 3 clearly established that IA injection lead to an exceptionally high localized drug concentration in plasma (Cmax of 736±247 ng/mL) and synovial fluid (Cₘₐₓ of 77400±81900 ng/mL), respectively, which were far higher than its MIC90 values against Staphylococcus aureus (15 ng/mL) and Staphylococcus epidermidis (8 ng/mL). The compound of Formula (I) also had relatively high exposure in both plasma and synovial fluid, with AUC0-1ast values of 20800±7150 ng*h/mL and 1000000±1050000 ng*h/mL, respectively, providing strong and direct evidence that this treatment method was broadly effective against a wide spectrum of Gram-positive pathogens causing PJIs. Moreover, the AUC0-1ast ratio of synovial fluid to plasma was 46.1, indicating that the drug can be concentratedly distributed in the synovial fluid, which was expected to reduce the clinical side effects caused by the relatively high systemic exposure” (Applicant Arguments, Page 9).
Again, the findings are acknowledged. However, the data does not compare the IA injection of the compound of Formula (I) with the closest prior art (i.e., IP or IV injections) to even consider whether the results are unexpected.
Accordingly, Applicant’s arguments are NOT found persuasive.
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, 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 1-4 and 9-10 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ma et al (US 2022/0087990; of record) in view of Wei et al (Antimicrob Agents Chemother 65(9):e0030321, 14 pages, published 8/17/2021).
As amended, claim 1 is drawn to a method for treating or preventing prosthetic joint infections (PJI) or alleviating PJI-related symptoms, comprising intra-articularly administering a therapeutic agent to a joint cavity of a patient in need thereof, wherein the therapeutic agent is a compound of Formula (I) (aka TNP-2092, CBR-2092):
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Ma et al teach “a rifamycin-quinolizidone conjugate molecule shown in formula I” – which is the instantly claimed compound of Formula (I) (aka TNP-2092, CBR-2092) – “for treating or preventing diseases caused by multiple-resistant Staphylococcus aureus infections” (Paragraph 0005) wherein “the infections caused by multiple-resistant Staphylococcus aureus includes acute bacterial infections and/or biofilm-associated infections” (Paragraph 0007), wherein “the acute bacterial infections include skin and skin tissue infections, respiratory infections or bacteremia” (Paragraph 0008) and “the biofilm-associated infections include one or a combination of cardiac valve infections, prosthetic joint infections and catheter related bloodstream infections” (Paragraph 0009). In particular, Ma et al – utilizing “a mouse biofilm implantation model using isogenic multiple-resistant Staphylococcus aureus strains” (Paragraph 0041) – teach that administration of 30 mg/kg TNP-2092, CBR-2092 (Paragraph 0042) “by intraperitoneal injections (IP)” (Paragraph 0046) “can effectively treat or prevent bacterial infections and diseases caused by methicillin-resistant, quinolone-resistant, and methicillin and quinolone multidrug resistant Staphylococcus aureus” (Paragraph 0069).
As such, the method of Ma et al differs from the instantly claimed method as follows:
Ma et al do not disclose any embodiments specifically demonstrating the treatment or prevention of prosthetic joint infections (PJI); and
Ma et al teach intraperitoneal administration as opposed to intra-articular administration.
Yet, as to (A): although Ma et al do not specifically disclose treating or preventing prosthetic joint infections (PJI) comprising administering TNP-2092/CBR-2092, as recognized by In re Schaumann, 572 F.2d 312 (CCPA 1978), claims to a species are anticipated where the prior art teaches a genus embracing a limited number of members closely related to each other such that one of ordinary skill in the art could immediately envisage each member. Notably, in In re Petering, 301 F.2d 676 (CCPA 1962) the court determined that a prior art genus containing only 20 members anticipated a claimed species within the genus because “one skilled in [the] art would... envisage each member” of the genus (emphasis in original)).
In the instant case, considering that the genus of conditions to be treated with TNP-2092/CBR-2092 disclosed by Ma et al comprises only six members, the skilled artisan would have immediately envisaged selecting any one of those conditions for treatment, including prosthetic joint infections.
And, as to (B): Wei et al – recognizing that “[t]he rate of eradication of periprosthetic joint infection (PJI) caused by methicillin-resistant Staphylococcus aureus (MRSA) is still not satisfactory with systemic vancomycin administration” – compared “[t]wo weeks of intraperitoneal (IP) and/or [intra-articular] IA injection of vancomycin... to control the infection after one-stage revision surgery” and report that “the MRSA PJI rats treated with IA injection of vancomycin showed better outcomes in skin temperature, bacterial counts, biofilm on the prosthesis, serum α1-acid glycoprotein levels, residual bone volume, and inflammatory reaction in the joint tissue, compared with those treated with IP vancomycin” (Abstract).
Accordingly, based further on Wei et al, it would have been prima facie obvious to modify the method of Ma et al so as to administer TNP-2092, CBR-2092 intra-articularly as opposed to intraperitoneally. It would have been obvious to do so to avoid the known drawbacks of treating PJI via systemic administration and to provide a better outcome than intraperitoneal administration with a reasonable expectation of success.
In view of all of the foregoing, claim 1 is rejected as prima facie obvious.
Claims 2-4 are drawn to the method of claim 1, comprising administering the therapeutic agent “at a dosing frequency optionally selected from: once daily, once every 2 days...” and so on (claim 2), for a duration of 1 day to about 6 months, during which the dosing frequency remains the same or is changed (claim 3), comprising about 10 mg to about 300 mg of the compound of formula (I) in a single administration (claim 4).
As discussed above, Ma et al in view of Wei et al teach the method of claim 1. However, Ma et al do not teach the instantly claimed dosing frequency, duration and amount in the treatment of PJI.
At the outset, as drafted, claim 2 merely requires the administration of the therapeutic agent “at a dosing frequency” but does not require that dosing frequence to be “once daily, once every 2 days...” and so on, each of which is defined by the claim to be optional.
Moreover, as stated by MPEP 2144.05, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” As further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
In the instant case, the dosing regimen including concentration of active ingredient in a pharmaceutical formulation is clearly a result-effective variable. Indeed, as indicated by the court in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 809 F.3d 1282, 1293 (Fed. Cir. 2015), every ordinary artisan in medicine performs “merely routine optimization of drug dosage to maximize therapeutic effect.” Accordingly, it would have been customary for an artisan of ordinary skill in the art to determine the optimal dosing frequency, duration and amount of agent to administer in order to best achieve the desired results.
As such, claims 2-4 are rejected as prima facie obvious.
Claims 9-10 are drawn to the method of claim 1, wherein the PJI are caused by Gram-positive bacteria (claim 9), more specifically Staphylococcus aureus and/or coagulase-negative staphylococcal (claim 10).
As discussed above, Ma et al teach the treatment of prosthetic joint infections caused by multiple-resistant Staphylococcus aureus (Paragraphs 005 and 007-009), which is a gram-positive bacterium.
Accordingly, claims 9-10 are also rejected as prima facie obvious.
Claims 11-12 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ma et al (US 2022/0087990; of record) in view of Wei et al (Antimicrob Agents Chemother 65(9):e0030321, 14 pages, published 8/17/2021) as applied to claims 1-4 and 9-10 above, in further view of Triantafyllopoulos et al (World Journal Orthopedics 7:546-552, 2016; of record).
Claims 11-12 are drawn to the method of claim 1, wherein the prosthetic joint infections (PJI) comprise early PJI, acute hematogenous PJI, and chronic PJI (claim 11) and, more specifically, early PJI occurring within about 3 months after the patient in need undergoes a prosthetic joint replacement surgery, or acute hematogenous PJI occurring within about 4 weeks after the surgery (claim 12).
As discussed above, Ma et al in view of Wei et al teach the method of claim 1. However, Ma et al in view of Wei et al do not teach the treatment of early, acute hematogenous, or chronic PJI, in particular early PJI occurring within about 3 months after the patient in need undergoes a prosthetic joint replacement surgery, or acute hematogenous PJI occurring within about 4 weeks after the surgery.
Yet, as evidenced by Triantafyllopoulos et al, “[p]eriprosthetic joint infections (PJI) of the hip and knee are grossly classified as early post-operative, acute hematogenous and late chronic infections” (Abstract) with “early infections developing within one month post-operatively” and “acute hematogenous deep infections with an onset of more than 4 wk postoperatively” (Page 547, Column 2).
As such, it is evident that any treatment of PJI necessarily encompasses one of early, acute hematogenous, or chronic PJI. Furthermore, it would have been obvious to treat any of the PJI stages with a reasonable expectation of success. Indeed, as indicated by Applicant, “treatments of different PJI stages... do not constitute mutually exclusive or patentably distinct inventions” (Applicant Arguments, Page 4).
As such, claims 11-12 are rejected as prima facie obvious.
Claims 13-15 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ma et al (US 2022/0087990; of record) in view of Wei et al (Antimicrob Agents Chemother 65(9):e0030321, 14 pages, published 8/17/2021) as applied to claims 1-4 and 9-10 above, in further view of Chao et al (Chinese Journal of Tissue Engineering Research 18(48):7714-7718, 2014 – Abstract only).
Claim 13 is drawn to the method of claim 1, wherein the patient in need is a patient who has not yet developed the PJI but is at risk thereof.
As discussed above, Ma et al in view of Wei et al teach the method of claim 1. However, Ma et al in view of Wei et al do not teach the treatment of a patient who has not yet developed the PJI but is at risk thereof.
Yet, as taught by Chao et al – exploring “the efficacy and safety of rifampicin compbined with levofloxacin for preventing periprosthetic joint infection after total hip arthroplasty” – only four out of 150 “patients, who accepted primary total hip arthroplasty” and “[a]fter discharge... were treated orally with rifampicin (0.15 g, three times/d) and levofloxacin (0.1 g, three times/d) for six weeks... suffered from periprosthetic joint infection at the last followed-up” compared to 13 out of 150 patients that “accepted the same surgical procedure” but were not treated with rifampicin or levofloxacin.
Considering that rifampicin and pefloxacin are related to the rifamycin and quinolone components that make up the conjugate TNP-2092, CBR-2092, it would have been prima facie obvious to a person of ordinary skill in the art that the method of Ma et al in view of Wei et al could be applied to a patient who has not yet developed the PJI but is at risk thereof. It would have been obvious to do so in an effort to reduce the likelihood of said patient developing a PJI with a reasonable expectation of success thereof.
As such, claim 13 is also rejected as prima facie obvious.
Claims 14-15 are directed to the method of claim 13, wherein the therapeutic agent is administered for a duration of 1 day to 14 days (claim 14), wherein first administration is the day on which the subject undergoes the prosthetic joint replacement surgery (claim 15).
For the same reasons as discussed above, it would have been prima facie obvious to determine the optimal dosing regimen in administering TNP-2092, CBR-2092 to a patient who has not yet developed the PJI but is at risk thereof, in an effort to to reduce the likelihood of said patient developing a PJI. As stated by MPEP 2144.05, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” As further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
As such, claims 14-15 are also rejected as prima facie obvious.
Claims 1-4 and 9-12 are ADDITIONALLY rejected under 35 U.S.C. 103(a) as being unpatentable over Ma et al (J Med Chem 59:6645-6657, 2016; of record), Fisher et al (Diagnostic Microbiology and Infectious Disease 97:115040, 2020; of record) and Renick et al (“Efficacy of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic, in rodent models of bacterial infection” Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) 2007, Poster F1-2105; of record) in view of Lucet et al (Antimicrobial Agents and Chemotherapy 34:2312-2317, 1990; of record), Niska et al (Antimicrobial Agents and Chemotherapy 57:5080-5086, 2013; of record), Garrigos et al (Antimicrobial Agents and Chemotherapy 54:5251-5256, 2010; of record) and Saleh-Mghir et al (Antimicrobial Agents and Chemotherapy 55:4589-4593, 2011; of record), all in further view of Roy et al (J Arthroplasty 29:564-568, 2014).
As amended, claim 1 is drawn to a method for treating or preventing prosthetic joint infections (PJI) or alleviating PJI-related symptoms, comprising intra-articularly administering a therapeutic agent to a joint cavity of a patient in need thereof, wherein the therapeutic agent is a compound of Formula (I) (aka TNP-2092, CBR-2092):
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As taught by Ma et al, “Staphylococcus aureus and coagulase-negative staphylococci (CoNS) are responsible for the majority of PJIs” wherein “[t]he treatment strategy for staphylococcal PJIs involves a prolonged rifampin-based combination therapy” (Page 6645, Column 1), further identifying “the recommended PJI regimen [of] rifampin plus a fluoroquinolone (ciprofloxacin or levofloxacin)” (Page 6647, Column 2). However, as further taught by Ma et al, “[r]ifampin is a member of the rifamycin family” and “pathogens develop resistance to rifamycins rapidly” (Page 6646, Column 1). Additionally, an “antagonistic effect between rifampin and the fluoroquinolone has been observed in vitro and in vivo with different members of the fluoroquinolone class and against different pathogens” (Page 6647, Column 1).
As such, Ma et al teach the “dual action molecule 1 (TNP-2092, CBR-2092) based on rifamycins” (Page 6646, Column 1) to take “advantage of the proven efficacy of the rifamycin combinations against PJIs and at the same time to alleviate the problems associated with the use of drug combinations” (Page 6646, Column 2). In particular, Ma et al teach that, based on “[p]reclinical studies of the in vitro and in vivo activities of 1” (Page 6650, Column 2), “[t]he dual-action molecule 1 has demonstrated advantages over rifampin and fluoroquinolone combinations in several aspects”, namely:
“First, it possesses potent and balanced activity against three cellular targets RNA polymerase, DNA gyrase, and topoisomerase IV in S. aureus and CoNS. Second, it is not a substrate of fluoroquinolone efflux systems and has a low propensity for resistance development. Third, 1 exhibits potent activity against drug resistant pathogens including those resistant to one or both parent drugs and demonstrates better efficacy and resistance development profile than rifamycin + fluoroquinolone combinations in both in vitro and in vivo biofilm models. Fourth, 1 appears able to alleviate certain safety concerns associated with its parent antibiotic classes such as CYP3A4 induction and hERG inhibition.” (Page 6652 Column 2 to Page 6653, Column 1).
And, further considering that, “[i]n completed human phase I single and multiple ascending dose clinical trials of an intravenous formulation, 1 demonstrates good pharmacokinetic and safety profiles”, Ma et al propose TNP-2092 for “further clinical development for the treatment of PJIs and other persistent bacterial infections” (Page 6653, Column 1).
Significantly, Fisher et al similarly teach that “[o]verall, TNP-2092 inhibitory activity was as good as or better than that of rifampin against S. aureus and S. epidermis” and “[a] similar pattern was observed when comparing TNP-2092 and rifampin bactericidal activities against S. aureus and S. epidermis” (Page 5, Column 1), specifically investigating “the in vitro activity of TNP-2092 against 80 PJI-associated staphylococcal isolates grown planktonically and in biofilms” (Page 2, Column 1). As such, Fisher et al conclude that “TNP-2092 is a promising hybrid antimicrobial agent that exhibits equivalent or superior inhibitory and bactericidal activity against planktonic and biofilm forms of PJI-associated S. aureus and S. epidermidis clinical isolates compared to rifampin and ciprofloxacin alone or in combination in vitro” (Page 7, Column 2).
Lastly, Renick et al – assessing “the efficacy of CBR-2092 in a variety of rodent models of infection, including... a chronic biofilm-associated infection model for indwelling medical devices” (Introduction), in which “[t]eflon catheter segments (1 cm) were exposed... to... S aureus cultures... to establish biofilms” and then “implanted SC on the backs of female Balb/c mice” (Methods and Materials) and “25 mg/kg” (Panel 9) “[t]reatments were initiated 7 days post-surgery by bid IP injections for up to 14 days” (Methods and Materials) – teach that “CBR-2092 demonstrated superior efficacy and resistance profiles against infections with wild-type, fluoroquinolone-resistant and rifampin-resistant S. aureus strains” (Summary and Conclusions) compared to rifampin, gatifloxacin, or levofloxacin (Panels 8 and 9). Additionally, “CBR-2092 exhibited continued suppression of the catheter-localized infections after therapy was withdrawn” (Abstract; see also Panel 8).
And a variety of prior art demonstrate that agents which show efficacy in foreign body infection also show efficacy in prosthetic joint infection. For example:
(a) Lucet et al teach that “regimens including rifampin... in combination with vancomycin... in were an effective treatment for foreign body infection due to methicillin-resistant S. aureus” (Abstract), while Niska et al teach that “vancomycin-rifampim combination therapy has enhanced efficacy against an experimental Staphylococcus aureus prosthetic joint infection” (Title); and
(b) Garrigos et al, recognizing that “[t]he treatment of prosthetic joint infections caused by methicillin-resistant Staphylococcus aureus (MRSA) continues to be a challenge”, teach the efficacy of “daptomycin... in combination with rifampin” in the treatment of foreign-body infection by MRSA using “a rat foreign-body infection model” (Abstract), supporting its use “against device-related infection caused by rifampin-resistant or -susceptible MRSA strains” (Page 5255, Column 2), while Saleh-Mghir et al teach that “[u]sing a methicillin-resistant Staphylococcus aureus (MRSA) knee prosthesis infection in rabbits... combining rifampin with daptomycin was highly effective” (Abstract).
As such, it would have been prima facie obvious to administer TNP-2092/CBR-2092 for the treatment of PJI with a reasonable expectation of success. In particular, it would have been obvious to do so considering that Ma et al teach that TNP-2092 is more effective than rifampin and fluoroquinolone (the mainstay of PJI treatment) against S. aureus and S. epidermis – and, in particular, as further taught by Fisher et al, against PJI-associated staphylococcal isolates – suggesting TNP-2092/CBR-2092 for “further clinical development for the treatment of PJIs and other persistent bacterial infections” (Ma et al, Page 6653, Column 1). Moreover, Renick et al specifically demonstrate the efficacy of TNP-2092/CBR-2092 in an in vivo foreign body infection model for indwelling medical devices due to Staphylococcus aureus which, as further demonstrated by Lucet et al and Niska et al and/or Garrigos et al and Saleh-Mghir et al is reasonably predictive of a likelihood of success in treating PJI infection.
However, Ma et al teach “single iv doses of 5-25 mg/kg” (Page 6652, Column 2), “10, 25, or 40 mg/kg, iv, b.i.d.” (Page 6652, Column 2), and “40 mg/kg, iv, b.i.d.” (Page 6652, Column 2) administration as opposed to intra-articular administration.
Yet, as taught by Roy et al – investigating “joint and serum levels of vancomycin following intra-articular (IA) or intravenous (IV) administration, and to compare the concentrations achieved in the joint fluid” – “Both IA and IV vancomycin achieved therapeutic levels in the synovial fluid of the knee, but IA delivery of vancomycin resulted in peak levels that were many orders of magnitude higher, and also resulted in therapeutic serum levels” (Abstract), leading Roy et al to conclude that “[d]aily IA injection into the knee as compared to IV infusion achieves and maintains vastly superior and therapeutic vancomycin levels in the synovial fluid throughout the interval between doses” (Page 567, Column 1).
Accordingly, based further on Roy et al, it would have been prima facie obvious to modify the method of Ma et al so as to administer TNP-2092, CBR-2092 intra-articularly as opposed to intravenously. It would have been obvious to do so to provide vastly superior and therapeutic vancomycin levels in the synovial fluid, with a reasonable expectation of success.
For all the foregoing reasons, claim 1 is rejected as prima facie obvious.
Claim 2 is drawn to the method of claim 1, comprising administering the therapeutic agent “at a dosing frequency optionally selected from: once daily, once every 2 days...” and so on.
As drafted, claim 2 merely requires the administration of the therapeutic agent “at a dosing frequency” but does not require that dosing frequence to be “once daily, once every 2 days...” and so on, each of which is defined by the claim to be optional.
At the outset, any method of treating a disease/disorder/condition comprising the administration of a therapeutic agent entails a dosing frequency, even if that frequency is once.
Furthermore, as discussed above, Renick et al teach the administration of “25 mg/kg” (Panel 9) TNP-2092/CBR-2092 “by bid IP injections for up to 14 days” (Methods and Materials) which entails a dosing frequency.
As such, claim 2 is also rejected as prima facie obvious.
Claim 3 is drawn to the method of claim 1, wherein the therapeutic agent is administered for a duration of 1 day to about 6 months, during which the dosing frequency is the same or is changed.
As discussed above, Renick et al teach the administration of “25 mg/kg” (Panel 9) TNP-2092/CBR-2092 “by bid IP injections for up to 14 days” (Methods and Materials) which entails a duration of about 7 days during which the dosing frequency is the same.
As such, claim 3 is also rejected as prima facie obvious.
Claim 4 is drawn to the method of claim 1, comprising about 10 mg to about 300 mg of the compound of formula (I).
As discussed above, Renick et al teach the administration of “25 mg/kg” (Panel 9) TNP-2092/CBR-2092 “by bid IP injections for up to 14 days” (Methods and Materials) which equates to a human equivalent dose of about 2.0 mg/kg or about 120 mg to about 160 mg.
As such, claim 4 is also rejected as prima facie obvious.
Claims 9-10 are drawn to the method of claim 1, wherein the PJI are caused by Gram-positive bacteria (claim 9), more specifically Staphylococcus aureus and/or coagulase-negative staphylococcal (claim 10).
As discussed above, Ma et al teach that “Staphylococcus aureus and coagulase-negative staphylococci (CoNS) are responsible for the majority of PJIs” (Page 6645, Column 1). Moreover, Renick et al teach “the efficacy of CBR-2092 in a variety of rodent models of infection, including... a chronic biofilm-associated infection model for indwelling medical devices” (Introduction), in which “[t]eflon catheter segments (1 cm) were exposed... to... S aureus cultures... to establish biofilms” and then “implanted SC on the backs of female Balb/c mice” (Methods and Materials).
As such, claims 9-10 are also rejected as prima facie obvious.
Claims 11-12 are drawn to the method of claim 1, wherein the prosthetic joint infections (PJI) comprise early PJI, acute hematogenous PJI, and chronic PJI (claim 11) and, more specifically, early PJI occurring within about 3 months after the patient in need undergoes a prosthetic joint replacement surgery, or acute hematogenous PJI occurring within about 4 weeks after the surgery (claim 12).
As discussed above, Renick et al teach the administration of TNP-2092/CBR-2092 “7 days post-surgery by bid IP injections for up to 14 days” (Methods and Materials) “demonstrated superior efficacy and resistance profiles against infections with wild-type, fluoroquinolone-resistant and rifampin-resistant S. aureus strains” (Summary and Conclusions), which entails treatment of infection occurring within about 3 months.
Accordingly, it would have been prima facie obvious to administer TNP-2092/CBR-2092 for the treatment of early PJI occurring within about 3 months after the patient in need undergoes a prosthetic joint replacement surgery with a reasonable expectation of success
As such, claims 11-12 are also rejected as prima facie obvious.
Claims 13-15 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ma et al (J Med Chem 59:6645-6657, 2016; of record), Fisher et al (Diagnostic Microbiology and Infectious Disease 97:115040, 2020; of record) and Renick et al (“Efficacy of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic, in rodent models of bacterial infection” Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) 2007, Poster F1-2105; of record) in view of Lucet et al (Antimicrobial Agents and Chemotherapy 34:2312-2317, 1990; of record), Niska et al (Antimicrobial Agents and Chemotherapy 57:5080-5086, 2013; of record), Garrigos et al (Antimicrobial Agents and Chemotherapy 54:5251-5256, 2010; of record) and Saleh-Mghir et al (Antimicrobial Agents and Chemotherapy 55:4589-4593, 2011; of record), all in further view of Roy et al (J Arthroplasty 29:564-568, 2014) as applied to claims 1-4 and 9-12 above, in further view of Chao et al (Chinese Journal of Tissue Engineering Research 18(48):7714-7718, 2014).
Claim 13 is drawn to the method of claim 1, wherein the patient in need is a patient who has not yet developed the PJI but is at risk thereof.
As discussed above, the prior art teach the method of claim 1. However, the prior art do not teach the treatment of a patient who has not yet developed the PJI but is at risk thereof.
Yet, as taught by Chao et al – exploring “the efficacy and safety of rifampicin compbined with levofloxacin for preventing periprosthetic joint infection after total hip arthroplasty” – only four out of 150 “patients, who accepted primary total hip arthroplasty” and “[a]fter discharge... were treated orally with rifampicin (0.15 g, three times/d) and levofloxacin (0.1 g, three times/d) for six weeks... suffered from periprosthetic joint infection at the last followed-up” compared to 13 out of 150 patients that “accepted the same surgical procedure” but were not treated with rifampicin or levofloxacin.
Considering that rifampicin and pefloxacin are related to the rifamycin and quinolone components that make up the conjugate TNP-2092, CBR-2092, it would have been prima facie obvious to a person of ordinary skill in the art that the method of Ma et al could be applied to a patient who has not yet developed the PJI but is at risk thereof. It would have been obvious to do so in an effort to reduce the likelihood of said patient developing a PJI with a reasonable expectation of success thereof.
As such, claim 13 is also rejected as prima facie obvious.
Claims 14-15 are directed to the method of claim 13, wherein the therapeutic agent is administered for a duration of 1 day to 14 days (claim 14), wherein first administration is the day on which the subject undergoes the prosthetic joint replacement surgery (claim 15).
For the same reasons as discussed above, it would have been prima facie obvious to determine the optimal dosing regimen in administering TNP-2092, CBR-2092 to a patient who has not yet developed the PJI but is at risk thereof, in an effort to to reduce the likelihood of said patient developing a PJI. As stated by MPEP 2144.05, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” As further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
As such, claims 14-15 are also rejected as prima facie obvious.
Conclusion
The new ground(s) of rejection presented in this Office action are necessitated by Applicant’s amendments to the claims. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
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