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.
Response to Amendments and Arguments
2. The objection to the specification for errors with the structural drawings is withdrawn based upon the amendments. The rejections and objections of canceled claims are withdrawn. The rejections of claim 7, based upon the dependence upon claim 1, are withdrawn based upon the amendment changing the dependency to claim 6. The rejections of claims 6-7 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn based upon the amendments.
The rejection of claim(s) 6-7 under 35 U.S.C. 103 as being unpatentable over Mereu AND Tarran is maintained. Applicants’ representative’s arguments of August 12, 2025 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). Applicant’s representative argues that Tarran’s compounds have a “variety of differences of chemical structure” compared to the compounds of Mereu and that the goal of Mereu, developing anti-inflammatory agents was different than that of Tarran. The structures are nearly identical with the same erythromycin structure. Tarran describes the class of compounds on page L746 col. 2, “Macrolide antibiotics typically used in the clinic are characterized by the presence of a macrocyclic lactone ring containing 14 or 15 atoms to which one or two sugars are attached via glycosidic bonds (34).” The ring is the same, the sugars are the same and the substituents on both nearly the same. The compounds in Mereu and Tarran have the same basic structure.
According to the arguments Tarran does not “provide evidence concerning any anti-inflammatory effects.” This is factually incorrect, both Merreu and Tarran were concerned with making anti-inflammatory macrolides. Tarran explicity states that the compounds prepared were “nonantibacterial macrolides may be suitable for chronic treatment of CF and COPD patients without inducing bacterial resistance.” Both CF and COPD are inflammatory conditions. According to the arguments, “Terran[sic] attributed no significance to this aspect of the structure [the hydroxy group] of its compound and provided no data concerning the effect of the presence or absence of this specific group on anti-inflammatory effects or antibiotic activity.” [Remarks page 8]. This is rebutted by the direct statement of Tarran quoted in the rejection, “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.” The sole difference between compound 1 and compound 7 in Terran is the 2’-OH, and the effect on antibacterial activity is clear. The title of Table 1 on page L750 is “GS-459455 has ≤1,000-fold less antibacterial activity than azithromycin”. With respect to data for anti-inflammatory activity, Terran evaluated the compounds in a cellular models of chronic lung inflammation. “Neutrophilia frequently occurs in chronic lung disease and human neutrophil elastase (HNE) induces mucus stasis by activating the epithelial sodium channel (ENaC), we tested the ability of GS- 459755 to protect against HNE-induced mucus stasis…..GS-459755 pretreatment protected against HNE-induced ASL volume depletion in human bronchial epithelial cells (HBECs). [T]he amiloride-sensitive transepithelial voltage, a marker of ENaC activity, was diminished by macrolide pretreatment.” The activity is shown in the various tables in Tarran and was so robust that Tarran suggests that the compounds may be useful for the treatment of chronic inflammatory diseases CF and COPD. As explained by Tarran, these macrolides have two basic types of biological activity, antibiotic and/or anti-inflammatory activity. Tarran page L746 col. 2:
As antibiotics, they inhibit bacterial protein synthesis by binding to the bacterial ribosomal 50S subunit, which interferes with transpeptidation/translocation (21). They are often used to treat gram-positive bacteria such as Streptococcus pneumoniae and some gram-negative bacteria including Haemophilus influenzae (21). 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).
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 while maintaining “other key attributes of the macrolide family” 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]
The rejection of claim(s) 6-7 under 35 U.S.C. 103 as being unpatentable over LeTourneau AND Mereu is maintained. Applicants’ representative’s arguments of August 12, 2025 have been fully considered but are unpersuasive. Applicants’ representative’s arguments of August 12, 2025 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.
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.
3. Claim(s) 6-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over 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 AND 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
Mereu teaches the macrolide compounds with the amino group of the elected species and others in claim 6 including compounds 2, 3, 16 and 17”
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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.
Starting with the standard desosamine 3’ dimethylamino group in compounds like 1 and 2, the group was modified:
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“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”
“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.
Tarran in a similar study 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 Mereu:
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 compounds of Mereu and the compounds of the instant claim 6, Table A, is the 2’-OH group on the desosamine. The compound of Mereu have the 2’OH while the instantly claimed compounds do not.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The compounds of the instant claim 6, Table A, are analogs of the compounds discussed 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 Mereu. 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 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]
4. 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
Letourneou teaches the compound 5a 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 teaches the macrolide compounds with the amino group of the elected species and others in Table A as discussed above. Mereu explains that the purpose of the study was to make macrolides with anti-inflammatory properties without antibacterial 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. 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 of LeTourneau and the elected species and others is the identity of the groups on the amino in the desosamine. The compounds of Mereu have the acetamide groups and other amines of compounds Ly 101-22, Ly 101-25, and Ly 101-45.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The compounds of the instant claim 6, Table A, are analogs of the compounds discussed above differing only by the identity of the amino group substituents from the Letourneau compound. 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. 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 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
5. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
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