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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
Claims 33-53, submitted 9/18/2025 are currently pending. Claims 33-36 and 53 are currently under examination. Claims 37-52 are withdrawn.
Examiner Note
Applicant submitted a request for interview on 7/27/2026 for 8/11/2026. However, SPE Garyu was scheduled to be out of the office from 8/8/2026 to 8/27/2026. Upon receiving this information and alternatives being offering, Applicant chose to delay any such interview for a later date. Therefore, an interview was not denied but the decision was made to have such an interview when SPE Garyu was available.
Response to Amendment
The affidavit under 37 CFR 1.132 filed 3/30/2016 is insufficient to overcome the rejection of claims 33-36 and 53 based upon 35 U.S.C. 103 as set forth in the last Office action because the affidavit fails to show that the claimed composition is an unexpected result.
Specifically:
Applicant Affidavit, dated 3/30/2026, page 3, item 12 starts with the heading “Synergy cannot be expected in every streptogramin B/A pair.”
This section of the affidavit misconstrues the legal standard for a prima facie case of obviousness. MPEP 2143.02(I) states: “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).”
Consequently, a finding of synergy with every streptogramin B/A pair is not required.
In the instant case, both the synergistic nature of streptogramins A and B was well-known and furthermore well-characterized in the prior art. This includes detailed mechanistic information about how said synergy arises as described by McCafferty et al. (McCafferty, et al. Current opinion in chemical biology 3.6: 672-680 (1999)):
“Separately, streptogramins A and B are bacteriostatic, yet when administered in combination in vivo the antibiotics are bactericidal and their inhibitory action is synergistic. Binding of streptogramin A antibiotics to the ribosome (Ka = 2.5 × 106 M) increases the affinity for streptogramin B up to 40-fold and decreases the affinity for other macrolide antibiotics 8, 11, whereas dual antibiotic binding (A and B bound) is essentially irreversible [9]. It is believed that the binding of type A antibiotics alters the conformation of the rRNA and exposes a high affinity binding site for the type B antibiotic [9].
This year, Porse and Garrett [12•] have shed light on the molecular target of the synergetic streptogramin antibiotics. Resistance to both antibiotics has been linked to RNA A2058 mutation or N-6 base methylation. Photoaffinity experiments indicate that streptogramin B cross-links directly to A2503/U2504 rRNA and induces an internal ribosomal cross-link involving bases G2061/A2062 (Escherichia coli nomenclature) [13]. Secondly, using in vivo and in vitro footprinting experiments with streptogramin A and B bound to wildtype and mutant haloarchael and bacterial ribosomes, Porse and coworkers [13] have determined that streptogramins A and B bind to nucleotides A2058, A2059, and A2503 of the peptidyl transferase loop of the 23S rRNA. Both antibiotics have the same RNA binding site (as shown by their overlapping footprints), suggesting that a unique heterodimeric antibiotic complex forms upon contact with RNA that juxtaposes regions 2058–2062 with 2503–2506, simultaneously bridging the two adjacent strands of the 23S rRNA.” (McCafferty et al., page 673, col. 2, para. 2).
Therefore, any streptogramin A/B combination would be reasonably expected to experience the synergistic outcome disclosed by McCafferty (and Noeske et al.). Again, absolute certainty is not required. Prior art references previously referenced such as Noeske et al. and Robertson et al. are building on knowledge available in the prior art such as McCafferty et al.
Regarding Bacqué et al., this reference is presumably invoked as a teaching away from the pristinamycin IA/flopristin combination. Taking the statements from the affidavit directly, a 25% failure to achieve synergy with modified Streptogramin A molecules does not constitute a teaching away.
First, a 25% failure rate means a 75% success rate, which easily falls within the reasonable expectation of success standard described above.
Furthermore, Bacqué discloses that flopristin, which is common to both Applicant CBA1 and NXL-103 (linopristin-flopristin) is expected to have strong synergy:
PNG
media_image1.png
35
560
media_image1.png
Greyscale
PNG
media_image2.png
20
557
media_image2.png
Greyscale
(Bacqué et al., page 198, Table 6).
For clarity, Noeske et al. discloses the structure of flopristin:
PNG
media_image3.png
204
269
media_image3.png
Greyscale
(Noeske et al., page 5270, Fig. 1)
And this is identical to entry 15 of Bacqué wherein R = F:
PNG
media_image4.png
266
652
media_image4.png
Greyscale
(Bacqué et al., page 193, Scheme 12)
Furthermore, Bacqué teaches that every single variant of Pristinamycin I experiences the predicted synergy to varying degrees:
PNG
media_image5.png
712
782
media_image5.png
Greyscale
(Bacqué et al., page 194, Table 1)
Consequently, a person of ordinary skill in the art would find pristinamycin IA a perfectly viable component of a streptogramin A/B combination.
No teaching away is present in Bacqué; only evidence that certain modifications to Streptogramin A molecule can affect binding to the bacterial ribosome to the point where synergism is lost. The chemical arts are unpredictable and a person of ordinary skill in the art would expect that not every chemical modification of a natural compound would be well-tolerated. This evidence does not alter the reasonable expectation of success established by prior art such as McCafferty et al. and does not teach away from the combination of pristinamycin IA and flopristin.
Applicant Affidavit, dated 3/30/2026, page 4, item 16 starts with the heading “CBA1 shows unexpected results that cannot be extrapolated from the prior art”.
MPEP 2144.09(VII) states: “However, a claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. It is the differences, in fact, in their respective properties which are determinative of nonobviousness. If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc).”
In this case, flopristin and pristinamycin IA structures are both known in the prior art being disclosed by Robertsen et al. and Noeske et al.:
PNG
media_image6.png
341
295
media_image6.png
Greyscale
(Robertsen et al., page 24, Fig. 8)
PNG
media_image3.png
204
269
media_image3.png
Greyscale
(Noeske et al., page 5270, Fig. 1)
Greater than expected results are a factor in the obviousness analysis as described by MPEP 716.02(a)(I): “"A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).”
However, expected beneficial results are an indicator of obviousness according to MPEP 716.02(c)(II): “"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) (Claims at issue were directed to a process of sterilizing a polyolefinic composition which contains an antioxidant with high-energy radiation. Although evidence was presented in appellant’s specification showing that particular antioxidants are effective, the Board concluded that these beneficial results would have been expected because one of the references taught a claimed antioxidant is very efficient and provides better results compared with other prior art antioxidants.).”
In this case, the benefit of Streptogramin A/B combinations are well-known as described above. More specifically, this exact improvement range is documented and therefore expected: “ In in vitro studies of NXL-103 showed a 4-fold higher activity than Synercid® and 2-fold higher activity than pristinamycin (Goldstein et al., 2005, Felmingham et al., 2005). The advantage of NXL-103 is that it can be administered orally, it is less prone to select for resistance, and shows less severe side-effects than Synercid®, which are limited to nausea, vomiting, and dizziniess (Politano and Sawyer, 2010).” (Mast et al., page 46, col. 1, para. 1).
The mean MIC improvement of Applicant CBA1 is 1.6 fold over the next closest tested composition, which happens to be NXL-103 discussed above. Overlooking the lack of error bars/error analysis with the CBA1/NXL-103 comparison, a 1.6-fold improvement is less than the improvement that NXL-103 enjoyed over Synercid®. Consequently, this can be fairly categorized as an obvious improvement in the context of what is known about Streptogramin A/B combinations and the mechanism of action of said Streptogramins.
Applicant offers an alternate analysis for a head-to-head comparison on Applicant Affidavit, dated 3/30/2026, page 6, item 24, but this still results in only a 2-fold improvement, which is still well within what previous improvements would predict for yet another improved combination. Furthermore, this analysis lacks error analysis and error bars. Therefore, the true improvement may be less than 2-fold as indicated by section 24.
As discussed above, Bacqué fails to teach away from the Pristinamycin IA/flopristin combination. Because a subset of researchers created a Pristinamycin IA derivative such as linopristin does not indicate to the person of ordinary skill in the art that Pristinamycin IA itself is now. MPEP 2145(X)(D)(1) is instructive here: “Furthermore, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.") (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023) ("Although Oez [the prior art] used a white pigment with a cross-linking polymer, it does not discourage a skilled artisan from using the white pigment without a cross-linking polymer or lead the skilled artisan in a direction divergent from the path taken in the Appealed Patents. Thus, Oez's disclosure is substantial evidence that supports the Board's finding that Oez does not teach away from the proposed combination.").
A person of ordinary skill in the art is not required to begin their inquiry into Streptogramin A/B combinations with the work of Bacqué. They are free to use any and all reference material including Bacqué. Based on the prior art, the combination of Pristinamycin 1A and flopristin falls under the rationale of simple substitution of one known element for another to obtain predictable results. As described above, both compounds individually behave as one of ordinary skill in the art would expect, and therefore substitution of flopristin into Pristinamycin as disclosed by Robertsen (Robertsen, page 24, para. 1 and Fig. 8) in place of Pristinamycin IIA or substitution of Pristinamycin IA into NXL-103 as disclosed by Noeske ((Noeske et al., page 5270, Fig. 1) in place of linopristin is equally obvious.
Applicant Affidavit, dated 3/30/2026, page 8, item 26 starts with the heading “CBA1 shows unexpected results that cannot be foretold by the cited references”.
The legal standard for obviousness is addressed above.
The degree of efficacy is also addressed above.
Regarding the issue of efficacy against antibiotic resistant strains, the MIC values for CBA1 compared to linopristin-flopristin are within 2-fold and the disclosed Ranges overlap. Furthermore, one of ordinary skill in the art would expect that an antibiotic not currently in broad use would initially have fewer resistance issues than currently deployed antibiotics.
Sabtu et al. (Sabtu, et al. British medical bulletin 116.1:105 )) discloses that:
“Resistance to an antibiotic occurs when a microorganism is able to grow or survive in the presence of a concentration of antibiotic that is usually sufficient to inhibit or kill organisms of the same species. The terms ‘susceptible’ and ‘resistant’ relating to antibiotics are usually used in clinical practice to infer the likely success or failure of treatment. Resistance is more likely when the concentration required to inhibit or kill microorganisms exceeds that achievable in a patient.
Microorganisms can be either intrinsically resistant to an antibiotic or develop resistance following exposure to that antibiotic (acquired resistance). Resistance can develop as a result of mutation or direct transfer of genes encoding a resistance mechanism. Transfer of resistance genes can occur by a variety of mechanisms including conjugation (transfer of genes carried on
plasmids, which are also known as mobile genetic elements), transformation (direct transfer of naked DNA) or transduction (transfer of similar DNA by bacteriophage).5 Genetic material, including antibiotic resistance genes, can spread very effectively between bacteria, even those of unrelated species.” (Sabtu et al., page 106, col. 1, para. 4).
Therefore, a person of ordinary skill in the art would expect an undeployed antibiotic to face fewer resistance challenges, especially if one of the two components has been out of active use for an extended period of time.
Cassir et al. (Cassir, et al. Frontiers in microbiology 5: 551 (2014)) discloses this strategy: “The increasing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is limiting the options for effective antibiotic therapy. Moreover, this alarming spread of antimicrobial resistance has not been paralleled by the development of novel antimicrobials. Resistance to the scarce new antibiotics is also emerging. In this context, the rational use of older antibiotics could represent an alternative to the treatment of MDR bacterial pathogens. It would help to optimize the armamentarium of antibiotics in the way to preserve new antibiotics and avoid the prescription of molecules known to favor the spread of resistance (i.e., quinolones). Furthermore, in a global economical perspective, this could represent a useful public health orientation knowing that several of these cheapest “forgotten” antibiotics are not available in many countries. We will review here the successful treatment of MDR bacterial infections with the use of old antibiotics and discuss their place in current practice.” (Cassir et al., Abstract).
Cassir even discloses Pristinamycin as such a potential drug:
“Pristinamycin, derived from Streptomyces pristinaespiralis, is an oral streptogramin antibiotic made up of two synergistic but structurally unrelated components, pristinamycin IA and pristinamycin IIA. It was discovered over 50 years ago (Cooper et al., 2014).
Although the data are limited, pristinamycin is a well-tolerated and effective alternative for the treatment of BJI due to Gram-positive bacteria including MRSA and VRE (Dancer et al., 2003; Ng and Gosbell, 2005; Ruparelia et al., 2008; Reid et al., 2010). The extended use of pristinamycin for BJI and other infections requires further evaluation.
Many enterococcal species, including those that are vancomycin-resistant though not including Enterococcus faecalis, are also susceptible to pristinamycin (Collins et al., 1993). In France, resistance to pristinamycin has remained low over the last 40 years, and typical susceptibility rates amongst staphylococci are 98% in the community (Quentin et al., 2001) and 93% in hospitals (Leclercq et al., 2003). But, also concerned by MLS resistance genes, the use of pristinamycin could favor the horizontal spread of resistance.” (Kassir et al., page 7 col. 1, para. 5).
Between the disclosures of Sabtu and Kassir, it is not unexpected that a newly deployed combination of Streptogramin A/B would have favorable resistance metrics. In the case, the metrics are expected beneficial results and not unexpectedly superior to those metrics of NXL-103.
For these reasons, the affidavit is insufficient to overcome the rejection of claims 33-36 and 53 based upon 35 U.S.C. 103.
Maintained Claim Rejections - 35 USC § 103
Maintained rejections
Claims 33 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Robertsen (Robertsen, et al. Antibiotics 8.4: 157 (2019)) in view of Noeske (Noeske, et al Antimicrobial agents and chemotherapy 58.9: 5269-5279 (2014)) as evidenced by Mast (Mast, et al. International Journal of Medical Microbiology 304.1:44-50 (2014)).
Regarding claim 33, claim 33 recites “A composition comprising pristinamycin IA (PIA) or a pharmaceutically acceptable salt thereof; and flopristin or a pharmaceutically acceptable salt thereof.”
Robertsen discloses that the antibiotic pristinamycin is composed of two substances: pristinamycin IIA and pristinamycin IA (Robertsen, page 24, para. 1 and Fig. 8). Mast further discloses that pristinamycin II congeners are of the streptogramin A type and pristinamycin I congeners are of the streptogramin B type (Mast 2014, page 45, Fig. 1).
Robertsen does not disclose the case where streptogramin A component is flopristin and the streoptogramin B component is pristinamycin IA. However, Noeske discloses two products, Synercid and NXL 103, wherein streptogramin type A molecules (dalfopristin and flopristin) are combined with streptogramin type B molecules (quinupristin and linopristin) to result in functional antibiotics (Noeske, page 5269, col. 2, para 2). Mast discloses that “In the beginning, pristinamycin was only introduced as a drug in France, Belgium, the Netherlands, and Germany.”, so the combination of pristinamycin IIA and pristinamycin IA has been used as a drug as well (Mast 2014, page 45, col. 1, para. 3)
Noeske further discloses that: “Streptogramins A and B must be used in combination, due to the fact that the individual streptogramin components exert a bacteriostatic effect, whereas their combination is bactericidal.” (Noeske, page 5269, col. 2, para 2). Noeske shows how streptogramins A and B interact with A2062 of the 70S bacterial ribosome, but do not appear to interact with each other in any meaningful way (Noeske, page 5260, Fig. 1).
It would have been obvious to a person of ordinary skill in the art before the effective file date of the claimed invention to combine pristinamycin IA as disclosed by Robertsen with flopristin as disclosed by Noeske to arrive at the invention recited in claim 33. A person of ordinary skill in the art would have a reasonable expectation of success in combining these two molecules for at least two reasons. First, both molecules have been used in known antibiotics already. Second, each molecule must have exhibited the necessary streptogramin A and B activity in those antibiotics. MPEP 2144.06(I) states: “’It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Specifically, the binding affinity of streptogramin B molecules is known to increase in the presence of streptogramin A molecules. (Noeske, page 5271, col. 1, para. 1). Based on the activity of NXL 103 using flopristin and the activity of pristinamycin using pristinamycin IA, each molecule had sufficient individual efficacy to make those antibiotics active; therefore, a person of ordinary skill in the art would expect flopristin to bind to the bacterial ribosome and increase in the affinity pristinamycin IA for said ribosome in a similar manner as other streptogramin antibiotics, resulting in an active antibiotic.
Consequently, claim 33 is obvious over Robertsen in view of Noeske as evidenced by Mast and rejected.
Regarding claim 35, claim 35 recites: “A kit or a packaged article, comprising a first composition comprising pristinamycin IA or a pharmaceutically acceptable salt thereof; and a second composition comprising flopristin or a pharmaceutically acceptable salt thereof; and instructions for administering the first composition and the second composition in a method for treating an infection caused at least in part by a bacterium in a subject.”
This claim is very similar to claim 33, except for the addition of instructions for use.
MPEP 2111.05(I)(B) states: “Where a product merely serves as a support for printed matter, no functional relationship exists.” The MPEP also states: “For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864.”
Furthermore, MPEP 2111.05 states: “"[O]nce it is determined that the limitation is directed to printed matter, [the examiner] must then determine if the matter is functionally or structurally related to the associated physical substrate, and only if the answer is ‘no’ is the printed matter owed no patentable weight." In re DiStefano, 808 F.3d at 850, 117 USPQ2d at 1268.
Consequently, in this situation, the printed matter is owed no patentable weight and claim 35 is rejected on the same grounds as claim 33 above.
Regarding claim 36, claim 35 is obvious as described above. Claim 36 recites: “The kit or packaged article of claim 35 wherein the instructions include administering to the subject the first composition and the second composition simultaneously, administering the first composition before the second composition is administered, or administering the first composition after the second composition is administered.”
MPEP 2111.05(I)(B) states: “Where a product merely serves as a support for printed matter, no functional relationship exists.” The MPEP also states: “For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864.”
Furthermore, MPEP 2111.05 states: “"[O]nce it is determined that the limitation is directed to printed matter, [the examiner] must then determine if the matter is functionally or structurally related to the associated physical substrate, and only if the answer is ‘no’ is the printed matter owed no patentable weight." In re DiStefano, 808 F.3d at 850, 117 USPQ2d at 1268.
Consequently, in this situation, the printed matter is owed no patentable weight and claim 36 is rejected on the same grounds as claim 33 above.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Robertsen (Robertsen, et al. Antibiotics 8.4: 157 (2019)) in view of Noeske (Noeske, et al Antimicrobial agents and chemotherapy 58.9: 5269-5279 (2014)) as evidenced by Mast (Mast, et al. International Journal of Medical Microbiology 304.1:44-50 (2014)) as applied to claim 33 above, and further evidenced by Politano (.Politano, et al. Current opinion in investigational drugs (London, England: 2000) 11.2: 225 (2010)) and Abdel-Hamid ( Abdel-Hamid et al, Journal of pharmaceutical and biomedical analysis 32.6: 1167-1174 (2003)).
Regarding claim 34, claim 33 is rejected as described above. Claim 34 recites the limitation: “The composition of claim 33 wherein the PIA:flopristin ratio is in the range from about 1:99 to about 99:1 by weight.”
Robertsen discloses that the two substances pristinamycin IIA and pristinamycin IA are produced and used in a 70:30 ratio (Robertsen, page 24, para. 1). Additionally, Politano discloses that “NXL103 is a 70/30 mixture of streptogramin A/streptogramin B components” (Politano, Abstract), and Abdel-Hamid discloses that “Synercid is a combination of two semisynthetic pristinamycin derivatives, quinupristin and dalfopristin in 30:70 (w/w) ratio.” (Abdel-Hamid, Abstract).
Consequently, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to try a formulation of 70/30 flopristin to pristinamycin IA. A person of ordinary skill in the art would be motivated to try this ratio because the above described streptogramin antibiotics use this ratio.
This ratio lies within the range provided for claim 34. MPEP 2131.03 (I) states: “"If the prior art discloses a point within the claimed range, the prior art anticipates the claim." UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 687, 2023 USPQ2d 448 (Fed. Cir. 2023). Due to the nature of claim 33, anticipation is not appropriate, but instead supports a finding of obviousness.
Therefore, claim 34 is obvious over Robertsen in view of Noeske, as evidenced by Mast, Politano, and Abdel-Hamid and rejected.
Claim 53 is rejected under 35 U.S.C. 103 as being unpatentable over Robertsen (Robertsen, et al. Antibiotics 8.4: 157 (2019)) in view of Noeske (Noeske, et al Antimicrobial agents and chemotherapy 58.9: 5269-5279 (2014)) as evidenced by Mast (Mast, et al. International Journal of Medical Microbiology 304.1:44-50 (2014)) as applied to claim 33 above, further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 53, claim 33 is obvious as described above. Claim 53 further recites a carrier, vehicle, excipient or diluent. Chaudhari discloses a variety of excipients and motivation of a person of ordinary skill in the art to include them depending on the specific need (Chaudhari, page 28, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the composition of claim 33 with the excipients disclosed by Chaudhari to arrive at the claimed invention. A person of ordinary skill in the art would have a reasonable expectation of success: “Excipients can be considered as indispensable component of medicinal products and in most of the formulations they are present in greater proportion with regards to active pharmaceutical ingredient, as it forms the bulk of the formulation it is always necessary to select an excipient which satisfies the ideal properties for a particular excipient.” (Chaudhari, page 22, col. 1, para. 2).
Consequently, claim 53 is obvious over Robertsen in view of Noeske as evidenced by Mast as applied to claim 33 above, and further in view of Chaudhari and rejected.
Response to Arguments
Applicant's arguments filed 7/27/2026 have been fully considered but they are not persuasive.
“We disagree with the contention that any combination of any streptogramin B with any streptogramin A would be expected to be a synergistic combination.”
MPEP 2143.02(I) states: “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).”
Consequently, a finding of synergy with every streptogramin B/A pair is not required.
Regarding the argument of unexpected superiority, MPEP 2144.09(VII) states: “However, a claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. It is the differences, in fact, in their respective properties which are determinative of nonobviousness. If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc).”
In this case, flopristin and pristinamycin IA structures are both known in the prior art being disclosed by Robertsen et al. and Noeske et al.:
PNG
media_image6.png
341
295
media_image6.png
Greyscale
(Robertsen et al., page 24, Fig. 8)
PNG
media_image3.png
204
269
media_image3.png
Greyscale
(Noeske et al., page 5270, Fig. 1)
Greater than expected results are a factor in the obviousness analysis as described by MPEP 716.02(a)(I): “"A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).”
However, expected beneficial results are an indicator of obviousness according to MPEP 716.02(c)(II): “"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) (Claims at issue were directed to a process of sterilizing a polyolefinic composition which contains an antioxidant with high-energy radiation. Although evidence was presented in appellant’s specification showing that particular antioxidants are effective, the Board concluded that these beneficial results would have been expected because one of the references taught a claimed antioxidant is very efficient and provides better results compared with other prior art antioxidants.).”
In this case, the benefit of Streptogramin A/B combinations are well-known as described above. More specifically, this exact improvement range is documented and therefore expected: “ In in vitro studies of NXL-103 showed a 4-fold higher activity than Synercid® and 2-fold higher activity than pristinamycin (Goldstein et al., 2005, Felmingham et al., 2005). The advantage of NXL-103 is that it can be administered orally, it is less prone to select for resistance, and shows less severe side-effects than Synercid®, which are limited to nausea, vomiting, and dizziniess (Politano and Sawyer, 2010).” (Mast et al., page 46, col. 1, para. 1).
The mean MIC improvement of Applicant CBA1 is 1.6 fold over the next closest tested composition, which happens to be NXL-103 discussed above. Overlooking the lack of error bars/error analysis with the CBA1/NXL-103 comparison, a 1.6-fold improvement is less than the improvement that NXL-103 enjoyed over Synercid®. Consequently, this can be fairly categorized as an obvious improvement in the context of what is known about Streptogramin A/B combinations and the mechanism of action of said Streptogramins.
Applicant offers an alternate analysis for a head-to-head comparison on Applicant Affidavit, dated 3/30/2026, page 6, item 24, but this still results in only a 2-fold improvement, which is still well within what previous improvements would predict for yet another improved combination.
“We disagree with the assertion that it would have been obvious to modify the streptogramin combinations taught in the prior art to arrive at the combination of PIA and flopristin.”
In the instant case, both the synergistic nature of streptogramins A and B was well-known and furthermore well-characterized in the prior art. This includes detailed mechanistic information about how said synergy arises as described by McCafferty et al. (McCafferty, et al. Current opinion in chemical biology 3.6: 672-680 (1999)):
“Separately, streptogramins A and B are bacteriostatic, yet when administered in combination in vivo the antibiotics are bactericidal and their inhibitory action is synergistic. Binding of streptogramin A antibiotics to the ribosome (Ka = 2.5 × 106 M) increases the affinity for streptogramin B up to 40-fold and decreases the affinity for other macrolide antibiotics 8, 11, whereas dual antibiotic binding (A and B bound) is essentially irreversible [9]. It is believed that the binding of type A antibiotics alters the conformation of the rRNA and exposes a high affinity binding site for the type B antibiotic [9].
This year, Porse and Garrett [12•] have shed light on the molecular target of the synergetic streptogramin antibiotics. Resistance to both antibiotics has been linked to RNA A2058 mutation or N-6 base methylation. Photoaffinity experiments indicate that streptogramin B cross-links directly to A2503/U2504 rRNA and induces an internal ribosomal cross-link involving bases G2061/A2062 (Escherichia coli nomenclature) [13]. Secondly, using in vivo and in vitro footprinting experiments with streptogramin A and B bound to wildtype and mutant haloarchael and bacterial ribosomes, Porse and coworkers [13] have determined that streptogramins A and B bind to nucleotides A2058, A2059, and A2503 of the peptidyl transferase loop of the 23S rRNA. Both antibiotics have the same RNA binding site (as shown by their overlapping footprints), suggesting that a unique heterodimeric antibiotic complex forms upon contact with RNA that juxtaposes regions 2058–2062 with 2503–2506, simultaneously bridging the two adjacent strands of the 23S rRNA.” (McCafferty et al., page 673, col. 2, para. 2).
Therefore, any streptogramin A/B combination would be reasonably expected to experience the synergistic outcome disclosed by McCafferty (and Noeske et al.). Again, absolute certainty is not required. Prior art references previously referenced such as Noeske et al. and Robertson et al. are building on knowledge available in the prior art such as McCafferty et al.
“We disagree with the conclusion that the superior antibacterial activity exhibited by the combination of PIA and flopristin was expected or could have been predicted.”
Regarding the argument of unexpected superiority, MPEP 2144.09(VII) states: “However, a claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. It is the differences, in fact, in their respective properties which are determinative of nonobviousness. If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc).”
In this case, flopristin and pristinamycin IA structures are both known in the prior art being disclosed by Robertsen et al. and Noeske et al.:
PNG
media_image6.png
341
295
media_image6.png
Greyscale
(Robertsen et al., page 24, Fig. 8)
PNG
media_image3.png
204
269
media_image3.png
Greyscale
(Noeske et al., page 5270, Fig. 1)
Greater than expected results are a factor in the obviousness analysis as described by MPEP 716.02(a)(I): “"A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).”
However, expected beneficial results are an indicator of obviousness according to MPEP 716.02(c)(II): “"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) (Claims at issue were directed to a process of sterilizing a polyolefinic composition which contains an antioxidant with high-energy radiation. Although evidence was presented in appellant’s specification showing that particular antioxidants are effective, the Board concluded that these beneficial results would have been expected because one of the references taught a claimed antioxidant is very efficient and provides better results compared with other prior art antioxidants.).”
In this case, the benefit of Streptogramin A/B combinations are well-known as described above. More specifically, this exact improvement range is documented and therefore expected: “ In in vitro studies of NXL-103 showed a 4-fold higher activity than Synercid® and 2-fold higher activity than pristinamycin (Goldstein et al., 2005, Felmingham et al., 2005). The advantage of NXL-103 is that it can be administered orally, it is less prone to select for resistance, and shows less severe side-effects than Synercid®, which are limited to nausea, vomiting, and dizziniess (Politano and Sawyer, 2010).” (Mast et al., page 46, col. 1, para. 1).
The mean MIC improvement of Applicant CBA1 is 1.6 fold over the next closest tested composition, which happens to be NXL-103 discussed above. Overlooking the lack of error bars/error analysis with the CBA1/NXL-103 comparison, a 1.6-fold improvement is less than the improvement that NXL-103 enjoyed over Synercid®. Consequently, this can be fairly categorized as an obvious improvement in the context of what is known about Streptogramin A/B combinations and the mechanism of action of said Streptogramins.
Applicant offers an alternate analysis for a head-to-head comparison on Applicant Affidavit, dated 3/30/2026, page 6, item 24, but this still results in only a 2-fold improvement, which is still well within what previous improvements would predict for yet another improved combination.
“We disagree with the assertion that the combination of PIA and flopristin is a product of routine optimization.”
This line of reasoning does not appear in the rejections above, but will be addressed anyway.
While the number of chemical modifications is theoretically infinite, the prior art in this area discloses a finite number of characterized Streptogramin A and B molecules. It is not unreasonable to use this finite list as a starting point of combinations to explore for additional combinations to add to the available pool of antibiotics.
Furthermore, MPEP 2144.05(II)(B) states: “However, in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421, 82 USPQ2d at 1397 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.” (Emphasis added).
While this reasoning was not invoked in the prior office action, one might reasonably conclude that the Pristinamycin IA-flopristin combination was actually the product of routine optimization of readily available and documented Streptogramin molecules.
Conclusion
No claim is allowed.
Claims 33-36 and 53 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/JEANETTE M LIEB/ Primary Examiner, Art Unit 1654
Prosecution Insights