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 .
DETAILED ACTION
This application is a 371 of PCT/CN2020/070981 01/08/2020.
Claims 6-7, 9-11 are pending.
Request for Continued Examination
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 4, 2026 has been entered.
Response to Amendments and Arguments
3. The rejection of claim(s) 6-7 under 35 U.S.C. 103 as being unpatentable over Mereu AND Tarran is withdrawn based upon the amendments and the argument that Mereu does not have a clear teaching of anti-inflammatory activity of compound 2, which was a synthetic intermediate.
The rejection of claim(s) 6-7 under 35 U.S.C. 103 as being unpatentable over LeTourneau AND Mereu is maintained but rewritten based upon the amendments. Applicants’ representative’s arguments of March 4, 2026 and the declaration of inventor Yu have been fully considered but are unpersuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). According to the arguments, “Based on LeTourneau it cannot be concluded that the loss of the 2’-OH of the desosamine was a major factor accounting for resistance of its specific A2058-dimethylated bacterial strains. It would therefore not be a fair characterization of LeTourneau to suggest that the loss of the 2’-OH of the desosamine could be an important factor in reducing antibacterial activity of other macrolides.” The examiner disagrees since according to LeTourneau “All new 20-deoxy macrolide derivatives were completely inactive against ermA-positive strain ATCC33591.” Compounds 5a and 5b, which lacked the 2’-OH, were the least potent of all the compound in Table 1 in the antibacterial assay.
According to the arguments since LeTourneau was interested in antibacterial activity, by undertaking the modifications of Mereu it would render the invention “unsatisfactory for its intended purpose” citing MPEP 2143.01. The compounds were well known to posses both anti-inflammatory and antibacterial properties that were tunable by selecting the appropriate substituents. As explained by Mereu “There are growing evidences that macrolide antibiotics may have beneficial effects in chronic inflammatory airway diseases such as asthma, diffuse panbronchiolitis (DPB) and chronic sinusitis that are independent of their anti-bacterial effects.2–4 However, the anti-inflammatory activities seem to be limited to the 14-membered ring macrolides like erythromycin…” If the artisan wants to take an antibacterial 14-membered ring macrolides like erythromycin and make it more anti-inflammatory and less antibacterial there are specific structural modifications that can be done to the structure as shown by Mereu leading to this result. The instant claims merely represent this known modification to the compounds of LeTourneau.
According to the arguments, “Dr. Yu explained that surprising experimental data in the present application have demonstrated unexpected advantageous properties of the claimed compounds. In particular, the claimed compounds, LY101-22, LY101-25, LY101-39, and LY101-45, display no measurable antibacterial activity (MIC > 128 µg/mL) across a broad panel of clinically relevant bacterial strains, whereas LeTourneau's derivatives exhibit moderate antibacterial activity with MIC values ranging from 4 µg/mL to 64 µg/mL against Streptococcus aureus strain ATCC29213.” This is misleading, according to LeTourneau “All new 20-deoxy macrolide derivatives were completely inactive against ermA-positive strain ATCC33591.” Le Tourneaus describes this as inactive. The compounds 5a/5b were the least antibacterial with 64 µg/mL against Streptococcus aureus strain ATCC29213. The loss of antibacterial activity is in line with what is expected from the amino modifications of Mereu. Compounds 5a and 5b, which lacked the 2’-OH, were the least potent of all the compound in Table 1 in the antibacterial assay. If you consider that Erythromycin which has the 2-carbonyl and has an antibiotic activity of 0.5 as per Table 1, and by reducing the carbonyl to 5a/5b its antibacterial activity was 128 fold less, this is an expected resulted. Regarding the amide group, according to Mereu “The best results were achieved with the amide subclass, which never showed toxicity or anti-microbial effect.” The elected species differs from the LeTourneau compound by this amide group. These appear to be expected results. Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989).
A new ground of rejection appears below.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
4. Claim(s) 6-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wu “Inhibitory effect of erythromycin derivative on expression of NF-κB in active T lymphocytes” Zhonghua Fengshibingxue Zazhi 2007, Volume: 11 Issue: 7 Pages: 406-409 (abstract only) Wu I AND Wu “Effects of erythromycin derivatives without antibacterial activity on T lymphocyte proliferation in vitro” Zhongguo Yike Daxue Xuebao 2006, Volume: 35, Issue: 6 Pages: 597-599 (abstract only) Wu II in view of Tarran, Robert “Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion.” American Journal of Physiology, 2013, 304(6, Pt. 1), L746-L756 (cited on the IDS). 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:
Determining the Scope and Contents of the Prior Art
Wu I discloses that (9S)-9-Dihydroerythromycin A is an anti-inflammatory agent:
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“Effect of erythromycin derivative, 9(S)-hydroxyerythromycin, on expression of nuclear factor (NF)-κB in active T lymphocytes was elucidated, and its potential role in treatment of rheumatoid arthritis (R A) was elevated. Jurkat T cells were exposed to 100 pmol/L tumor
necrosis factor (TNF)-α with or without pretreatment with 3, 10, 30 or 100 μg/mL of erythromycin or 9(S )-hydroxyerythromycin 1 h at 37°. The expression of NF-κB was measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Erythromycin and 9(S )-hydroxyerythromycin decreased the expression of NF-κB mRNA and protein in a dose-related fashion. The treatments with erythr omycin (100 μg/mL) and 9(S )-hydroxyerythromycin (100 μg/mL) resulted in about 36% and 45% reduction of N F-κB mRNA (P<0.01), resp., and meanwhile, 46% and 56% reduction of NF-κB protein could be observed (P<0.01). Erythromycin and its derivative, 9(S)-hydroxyerythromycin, have anti-inflammatory activity, presumably via an interaction with the NF-κB signaling pathway in active T lymphocyte, which may be a potential treatment for RA.”
Wu II also discloses The objective was to study the effect of erythromycin derivatives without antibacterial activity on the proliferation of T lymphocytes in vitro and to evaluate their anti-inflammatory mechanism. T lymphocytes were treated with erythromycin and 9 erythromycin derivatives within the dose range of 3 to 100μg/mL for 24 h. The inhibitory effects of erythromycin and 9 erythromycin derivatives on the prolife ration of T lymphocytes cultured in vitro were determined by MTT assay. The proliferation of T lymphocytes was inhibited by erythromycin, clarithromycin, N-demethyl erythromycin, 9 (S)-hydroxyl erythromycin, and 12- numbered-ring erythromycin derivative, and 50% inhibitory concentrations were 606.28±35.43, 431.62±25.60, 367.31±32.60, 425.62±32.08, and 176.38±10.42μmol/L, resp. The IC50 of 12- numbered-ring erythromycin derivative was significantly lower than that of erythromycin and clarithromycin. Erythromycin and its derivatives could inhibit the proliferation of T lymphocytes, which may be related with the anti-inflammatory activity to some extent.”
Tarran teaches desosamine modification in macrolide antibiotics to remove their antibacterial properties but to still maintain their anti-inflammatory immunomodulatory effects. Tarran explains on page L746 col. 2 a similar goal as Wu:
In addition to being antibiotic, macrolides also have immunomodulatory and anti-inflammatory properties. For example, they have successfully been used to treat diffuse panbronchiolitis, COPD, and CF, likely by also acting in an immunomodulatory role (14, 29, 31, 41). More specifically, macrolides have been shown to affect NF-KB and ERK MAPK activation, decrease IL-8 secretion, and decrease MUC5AC expression with efficacy in the micromolar range (22). Since chronic antibiotic usage can induce bacterial resistance, it has been proposed that a nonantibacterial macrolide would be therapeutically beneficial in treating chronic airway disease without inducing bacterial resistance. Accordingly, we designed a novel macrolide, 2’-desoxy-9-(S)- erythromycylamine (GS-459755), that has negligible antibacterial ability.
Tarran focused upon the 2’ -OH group on the desosamine. Starting with the compound 1, compound 7 lacking the 2’-OH was made:
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“Fig. 1. Synthesis of GS-459755, a nonantibiotic macrolide. 9-Amino-9-deoxo erythromycin
(compound 1; erythromycylamine) was converted into 2’-desoxy-9-(S)-erythromycylamine (compound 7; GS-459755) by a 6-step process (see EXPERIMENTAL PROCEDURES).”
“Since erythromycylamine has therapeutic potential, we developed a novel macrolide-based molecule with significantly diminished antimicrobial activity against several common pathogens, which we termed GS-459755 (Fig. 1). Our findings indicated that the efficacy of GS-459755 in the sheep TMV model was comparable to erythromycylamine and azithromycin (Figs. 2 and 3), suggesting that it was independent of the antibacterial properties.” [Page L752] “In conclusion, we have developed a novel macrolide, GS- 459755, that has significantly reduced antibacterial activity while retaining other key attributes of the macrolide family. Like the antibiotic macrolides erythromycylamine and azithromycin, this compound can protect against HNE-induced mucus stasis and ASL volume depletion, possibly by protecting bronchial epithelial cells from proteolytic activation of ENaC. On the basis of this data, we propose that such nonantibacterial macrolides may be suitable for chronic treatment of CF and COPD patients without inducing bacterial resistance.” [Conclusions]
Determining the Differences Between the Prior Art and the Instant Claims
The difference between the of Wu and the compound LY101-45 of the instant claim 6, is the 2’-OH group on the desosamine. The compound of Wu has the 2’OH while the instantly claimed compound does not.
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Considering objective evidence present in the application indicating obviousness or nonobviousness
The compound Ly101-45 is a dehydroxy analog of (9S)-9-Dihydroerythromycin A above differing only by the removal of an -OH group. One of ordinary skill would be motivated to make the compounds of the invention because he or she would expect the compounds to have the same property as anti-inflammatory or immunomodulator compound. As discussed above Tarran shows that removal of the -OH further lessens the antibacterial activity which was the primary goal of Wu. This provides a reason for one of ordinary skill in the art to choose the compound and modify it in the same manner.
The suggestion in the prior art to formulate a compound lacking an -OH in this narrow field of macrolides possessing a structurally defined desosamine with reduced antibacterial activity is a strong motivation to make this change. Since a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, a prima facie case of obviousness of the claimed chemical compound exists. [MPEP 2143 B]
5. Claim(s) 6-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over LeTourneau, Nicolas “Synthesis and antibacterial activity of desosamine-modified macrolide derivatives.” Bioorganic & Medicinal Chemistry Letters, 2012, 22(14), 4575-4578 AND Mereu, A.; “Design, synthesis and in vivo activity of 9-(S)-dihydroerythromycin derivatives as potent anti-inflammatory agents.” Bioorganic & Medicinal Chemistry Letters, 2006, 16(22), 5801-5804. 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:
Determining the Scope and Contents of the Prior Art
Letourneau teaches the compound 5a/b on page 4577:
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R is H.
According to LeTourneau “All new 20-deoxy macrolide derivatives were completely inactive against ermA-positive strain ATCC33591. This result argues against any considerable contribution of a steric clash between N-6 methyl groups of A2058 and 20-OH of macrolide derivative to erm-mediated resistance.” 5a and 5b were the least potent of all the compound in Table 1:
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Mereu explains that the purpose of the study was to make macrolides with anti-inflammatory properties without antibacterial properties as discussed on page 5801:
There are growing evidences that macrolide antibiotics may have beneficial effects in chronic inflammatory airway diseases such as asthma, diffuse panbronchiolitis (DPB) and chronic sinusitis that are independent of their anti-bacterial effects.2–4 However, the anti-inflammatory activities seem to be limited to the 14-membered ring macrolides like erythromycin and clarithromycin, and 15-membered ring macrolides like azithromycin, but are not shared by 16-membered ring macrolide like josamycin.5
Great caution must be used for administering anti-microbial drugs as anti-inflammatory agents for chronic treatment in order to avoid selecting microbial resistance. A better approach would involve chemical modification of the basic structure in order to enhance effects on the inflammatory cascade and avoid anti-microbial activity.
In this report, we describe the preliminary results regarding a study aimed at the design and synthesis of a new class of erythromycin derivatives provides with potent in vivo anti-inflammatory properties. Several compounds were prepared and tested in an iterative approach in order to enhance the anti-inflammatory activity but at the same time eradicating the anti-bacterial effect.
“Several compounds were prepared and tested in an iterative approach in order to enhance the anti-inflammatory activity but at the same time eradicating the anti-bacterial effect.” “During this study, we have found that erythromycin anti-bacterial activity can be reduced by structural modifications at different functional groups:
(1) C-3’ dimethylamino modification,
(2) Cladinose removal,6
(3) C-9 carbonyl modification.” [Page 5801 col. 2]
“Among all the possible C-9 carbonyl modifications in erythromycins, we selected the reduction to secondary alcohol.9 C-9 carbonyl reduction increased metabolic stability and played an important role in reducing the anti-bacterial effect, which was completely eliminated by the concomitant modification of the dimethylamino group.7”
Regarding the C-3’ dimethylamino modification, “Functionalization of the desosamine sugar by introduction of a C-3’ substituent was envisaged as a suitable modification. The amino group was demethylated following two protocols…..We finally devised another class of compounds featuring a substituent connected to the desosamine sugar through an amide bond in C-3’ position. This modification completely suppressed the unwanted anti-bacterial effect.” [Page 5802].
According to Mereu, “All the compounds were soluble, nontoxic and, except for compounds 8 and 10, no effect was observed on several bacterial strains.18 Most of these compounds are as effective as erythromycin (i.e., aminomethylthiazoles 6, 7, and 11 or benzylamine 8)…..The best results were achieved with the amide subclass, which never showed toxicity or anti-microbial effect. Their anti-inflammatory properties were improved ranging from 66% inhibition of cladinose-free acetamide 17” The acetamide is the amino group of the elected species.
Determining the Differences Between the Prior Art and the Instant Claims
The difference between the compound 5a a of LeTourneau and LY 101-45 is the reduction of the carbonyl group.
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The additional compounds Ly 101-25 and Ly 101-22 differ by the amino group on the sugar 3’ position.
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Considering objective evidence present in the application indicating obviousness or nonobviousness
The compounds Ly 101-45, Ly 101-22 and Ly 101-25 of the instant claim 6 are analogs of the compound 5a/5b discussed above differing only by the identity of the amino group substituents from the Letourneau compound or the reduction of the C-9 carbonyl from the compounds of LeTourneau. One of ordinary skill would be motivated to make the compounds of the invention because he or she would expect the compounds to have the same property as anti-inflammatory or immunomodulator compound. As discussed above LeTourneau shows that removal of the -OH further lessens the antibacterial activity which was the primary goal of Mereu. “Similarly to 20-deoxygenated macrolide derivatives; 3’-desmethyl macrolide derivatives 3a,b and 6d showed lower antibacterial activity in the native strain of S. aureus.” This accounts for the change in the compound Ly-101-25. This provides a reason for one of ordinary skill in the art to choose the claimed species and modify it in the same manner.
The suggestion in the prior art to formulate a compound lacking an -OH and having the acetamide or a desmethyl amino group in this narrow field of macrolides possessing a structurally defined desosamine with reduced antibacterial activity is a strong motivation to make this change. The combination of removing the -OH and making acetamide would strongly reduce the antibacterial activity as both groups have this effect. Since a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, a prima facie case of obviousness of the claimed chemical compound exists. [MPEP 2143 B]
Conclusion
6. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
