--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 .
Applicant’s response dated May 15, 2026 is acknowledged.
Priority
This application is a CON of PCT/IL2023/050121 filed on 02/02/2023, which claims benefit in provisional application 63/306,156 filed on 02/03/2022.
Claim Status
Claims 1-20 are pending and examined.
Election/Restriction
Applicant’s election of poly[2-(methacryloyloxy)ethyl phosphorylcholine] as the species of compound of formula I, and a combination of therapeutic agents sulfamethoxazole and ellagic acid, which act in synergy, as a species of therapeutic agent, in the reply filed on May 15, 2026, is acknowledged.
Claims 1-20 read on the elected species.
The requirement is still deemed proper and is therefore made FINAL.
Accordingly, no claims are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being withdrawn to a non-elected invention, and non-elected species of the invention, there being no allowable generic or linking claims.
Response to the restriction requirement of March 18, 2026 was timely filed.
Claims 1-20 are examined on the merits.
The elected species was searched and no relevant prior art was found. The elected species lacks enablement and an enablement rejection is made. In the interest of compact prosecution, the search was expanded to the remaining species and the full scope of all claims was examined and considered.
Claim Rejections – 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The applicants' attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; (8) the quantity of experimentation necessary.
(1)The nature of the invention: The elected species of the claimed invention is a method for treating biofilm in a subject in need thereof, the method comprising administering to the subject a liposome comprising: (a) at least one bilayer-forming lipid; (b) poly[2-(methacryloyloxy)ethyl phosphorylcholine] as the species of compound of formula I; (c) a positively-charged lipidic agent, incorporated within a lipid bilayer and/or on a surface of the liposome; and (d) a combination of therapeutic agents sulfamethoxazole and ellagic acid, bonded to a surface of the liposome and/or within a lipid bilayer and/or core of the liposome, wherein the active agents act in synergy. Claim 16 is drawn to a method for treating biofilm in a subject in need thereof, the method comprising administering to the subject a liposome comprising: (a) at least one bilayer-forming lipid; (b) a polymeric compound having the general formula (I) as shown in claim 1; (c) a positively-charged lipidic agent, incorporated within a lipid bilayer and/or on a surface of the liposome; and (d) at least two therapeutically active agents, each independently bound to a surface of the liposome and/or within a lipid bilayer and/or core of the liposome; and wherein said at least two therapeutically active agents act in synergy. Claim 19 is drawn to the method of claim 19, wherein said first and second therapeutically active agents act in synergy.
(2) The state of the prior art: Synergistic combinations of polyphenols and antibiotics were known in the art. For example, Haghjoo (Advances in Bioscience and Biotechnology, 2013, 4, 959-967) teaches synergistic effects of green tea polyphenols and antibiotics against pathogens (Abstract).
(3) The relative skill of those in the art is high.
(4) The predictability or unpredictability of the art: Synergy is by nature unpredictable unless there is some clear biochemical basis for expecting it.
(5) The breadth of the claims: The claims read on any at least two therapeutic agents that act in synergy. The elected species reads on sulfamethoxazole and ellagic acid that act in synergy.
(6) The amount of direction or guidance presented: The application as filed does not provide any guidance that provides a biochemical basis for expecting sulfamethoxazole and ellagic acid to act in synergy.
(7) The presence or absence of working examples: The specification provides a working example of a composition comprising sulfamethoxazole and ellagic acid, however the working examples does not provide a clear synergistic effect of the combination of sulfamethoxazole and ellagic acid. Since synergism is unexpected in the absence of a known biochemical basis for expecting it, the results that are relied on to support an assertion of synergy should be of statistical significance. MPEP 716.02(b) sets forth the burden Applicant bears in establishing that alleged unexpected results are sufficient to overcome a prima facie case of obviousness, and makes clear that the differences in results must be unexpected, unobvious, and of both statistical and practical significance. In the instant case, to demonstrate synergy the Applicant relies on an example where the effect of SMX and SMX/EA on pyocyanin production in P. aeruginosa was examined using PEG-LUVs and the exemplary pMCP-LUVs in comparison with free antimicrobial agents SMX, SMX/EA, and EA and the results are presented in Figure 11A. The specification states that the results show the inhibitory effect of the exemplary pMPC-LUVs loaded with the exemplary antimicrobial agents SMX and SMX/EA on pyocyanin production in P. aeruginosa biofilms. The results are also described as showing that the delivery of combined SMX/EA induces a significant reduction in pyocyanin production with 15% decrease already of observed for administered PEG-LUVs loaded with the combination of SMX/EA and a decrease of up to about 65% in pyocyanin production in the presence of pMPC-LUVs loaded with SMX/EA.
In order to show a greater than additive effect of SMX and EA, applicant is required to provide the effect of each drug separately and the effect of the combination. The results presented in Figure 11A are not sufficient to show that SMX and EA act in synergy because the effect of the combination of free drugs SMX and EA is not statistically significant compared to the two drugs when tested separately. The shaded regions and their corresponding error bars for EA and SMX/EA clearly overlap. The specification does not provide a comparison among LUVs comprising the SMX/EA combination and LUVs comprising each drug separately. The only comparison between the LUVs is pMPC-LUVs and PEG-LUVs where both contain the combination of SMX and EA.
The applicant also tested the therapeutic agents on eradication of bacterial biofilms and reported the data in Figures 14A-C and 15B.
The data in Figures 14A-C are not sufficient because Figure 14A provides the effects of free SMX and the combination of free SMX/EA where there is a clear overlap between the data points. The applicant did not provide the effects of free EA. SMX/EA and SMX loaded LUVs having either PEG or pMPC were tested, and it clear from the graph that data for SMX-LUVs overlap with data for SMX/EA-LUVs. Applicant did not provide data for LUVs loaded with EA only. Figure 14B does not provide comparative data. Similar data was provided in Figures 14C and 15B where it is apparent that data for free SMX overlaps with data for free SMX/EA combination. Data for SMX-LUVs, having either PEG or pMPC, overlap with data for SMX/EA-LUVs, having either PEG or pMPC.
(8) The quantity of experimentation necessary: Claims 16 and 20 broadly require two therapeutic agents that act in synergy. The elected species requires a combination of SMX and EA that act in synergy. Based on the breadth of the claims and the elected species, the nature of the invention, the unpredictable nature of synergy in the absence of biochemical explanations for it, the lack of any such explanation in the specification as filed, and the failure to provide a working example of statistical significance showing synergy between two therapeutic agents generally and synergy between SMX and EA, one of skill in the art could not make a composition having mixture of active agents commensurate in scope with the claims, i.e. in which two therapeutic agents act in synergy and a composition having a mixture of SMX and EA that act in synergy.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 and 6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 recites the limitation "said substituent" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 3 provides support for “said at least one substituent”.
Claim 6 recites the limitation "said bilayer-forming lipid" in lines 2 and 4. There is insufficient antecedent basis for this limitation in the claim. Claim 1 provides support for “said at least one bilayer-forming lipid”.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
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.
Claims 1, 3, 4, 6-14, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Klein (WO 2018/150429 A1 Published August 23, 2018 – of record in IDS).
The claims encompass a method for treating biofilm in a subject in need thereof, the method comprising administering to the subject a liposome comprising components (a)-(d).
The teachings of Klein are related to a liposome for use delivering a therapeutically active agent to a subject in need thereof. The liposome comprises (a) at least one bilayer-forming lipid, (b) a polymeric compound having the general formula I, and (c) a therapeutically active agent incorporated in the liposome and/or on the surface of the liposome (Abstract). The therapeutically active agent includes antimicrobials (page 4 lines 16-18). According to some embodiments, the delivering is effected by parenteral systemic administration, by intraarticular
administration, the liposome is for use in the treatment of a synovial joint disorder selected
from the group consisting of arthritis, bursitis, carpal tunnel syndrome, fibromyositis, gout,
locked joint, tendinitis, traumatic joint injury, and joint injury associated with surgery (page 4 lines 19-27). According to an aspect of some embodiments, there is provided a method of delivering a therapeutically active agent to a subject in need thereof, the method comprising administering to the subject a liposome comprising at least one bilayer-forming lipid, a polymeric compound according to any of the respective embodiments described herein, and a therapeutically active agent incorporated in the liposome and/or on the liposome, thereby delivering the therapeutically active agent to a subject in need thereof. In some embodiments of, the use of the liposome and/or method described herein is for treating a medical condition treatable by the therapeutically active agent, according to any of the respective embodiments described, in the subject (page 10 lines 8-17). Examples of therapeutically agents include amphotericin B, where cryptococcosis is an example of a fungal disease treatable with amphotericin B (paragraph bridging pages 43-44). Scheme 1 on page 61 shows the synthesis of the polymeric compound of formula
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Table 1 teaches liposome compositions where one liposome contains HSPC (hydrogenated soy phosphatidylcholine), pMPC (polymer of formula depicted above), and 1,2-stearoyl-3-trimethylammonium propane (page 64 lines 9-18).
Regarding claims 1 and 7-12, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have administered a liposomal composition to a patient having a joint injury associated with surgery in order to delivery an active agent to the subject, with a reasonable expectation of success because Klein teaches using a liposomal composition to deliver an active agent to a patient in need thereof wherein the patient has a traumatic joint injury associate with surgery. It would have been obvious to have formed the liposomal composition with HSPC, pMPC, 1,2-stearoyl-3-trimethylammonium propane, and an active agent because Klein teaches an example of a liposomal composition that contains HSPC, pMPC, and 1,2-stearoyl-3-trimethylammonium propane, and also teaches that such liposomal compositions may be used to deliver an active agent to a patient in need thereof. It would have been obvious to have selected amphotericin B as the active agent because Klein teaches amphotericin B as a therapeutic agent that may be delivered using said liposomes.
Klein’s method reads on a method of treating biofilm in a subject in need thereof because Klein’s subject is considered at risk for a disease and administering the liposomal composition as described above would have prevented or inhibited biofilm from forming because the method administers amphotericin B which is a known antifungal agent. Instant application defines “treating” as inhibiting, preventing or arresting the development of a pathology (disease, disorder or condition) and/or causing the reduction, remission, or regression of pathology, where “preventing” is defined as keeping a disease, disorder, or condition from occurring in a subject who may be at risk for the disease, but has not yet been diagnosed as having the disease.
HSPC meets the limitation that requires at least one bilayer-forming lipid, pMCP meets the limitation of the claimed polymeric compound having the general formula I, 1,2-stearoyl-3-trimethylammonium propane meets the limitation of a positively-charged lipidic agent, and amphotericin B is a therapeutically active agent.
Regarding claims 3 and 4, Klein teaches 1,2-stearoyl-3-trimethylammonium propane.
Regarding claim 6, it would have been obvious to have formed the liposome having the bilayer-forming lipid and the polymeric compound in the range of molar ratios from 5:1 to 5000:1, with a reasonable expectation of success because Klein teaches such range of molar ratios as suitable (page 4 line 30-31). The claimed range is obvious because it overlaps with Klein’s range.
Regarding claim 13, amphotericin B is an antimicrobial agent that is effective in treating said biofilm.
Regarding claim 14, it would have been obvious to have formulated the composition with anthromycin or azotomycin, with a reasonable expectation of success because Klein teaches anthromycin and azotomycin as suitable active agents (page 42 lines 11-15). Anthromycin and azotomycin are known antibiotics and a composition comprising said drugs would have treated bacterial biofilm when administered to the subject.
Regarding claims 17 and 18, it would have been obvious to have formulated the liposomes as a part of a pharmaceutical composition comprising a plurality of said liposomes and a pharmaceutically acceptable carrier, with a reasonable expectation of success because Klein teaches that the liposomes may be administered to the subject as a part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier (page 47 lines 6-14). The skilled artisan would have understood that the composition would comprise a plurality of liposomes.
Claims 15, 16, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Klein as applied to claims 1, 3, 4, 6-14, 17, and 18 above, and further in view of Schwarz (Antimicrobial Agents and Chemotherapy, Volume 50, Number 1, January 2006, 113-120).
The claims further limit the method of claim 1.
The teachings of Klein are relied upon as summarized above, however they do not teach the limitations of claims 15, 16, 19, and 20.
The teachings of Schwarz are related to the efficacy of amphotericin B in combination with flucytosine against flucytosine-susceptible or flucytosine-resistant isolates of cryptococcus neoformans during disseminated murine cryptococcosis (Abstract). The study demonstrated the beneficial effect of the addition of flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the C. neoformans isolate is resistant to flucytosine (Abstract). The combination of AMB and FC was evaluated by checkerboard studies against 30 clinical isolates of C. neoformans including three FC-resistant iso lates and found in vitro synergy of the combination in both FC-susceptible and FC-resistant isolates (page 116 bottom of right column). In conclusion, it was demonstrated that the higher efficacy of the addition of FC to AMB compared to monotherapies against both FC-susceptible and FC-resistant isolates of C. neoformans even for the control of cerebral infection. These results show that a combination of AMB and FC could be beneficial for patients with disseminated cryptococcosis due to FC-resistant isolates of C. neoformans (page 119 end of right column).
The teachings of Klein and Schwarz are related to compositions comprising amphotericin B and their use for treating cryptococcosis, and it would have been obvious to have combined their teachings because they are in the same field of endeavor. It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition in Klein by adding flucytosine, with a reasonable expectation of success because it was known from Schwarz that higher efficacy of amphotericin and flucytosine is observed when the two drugs are administered in combination compared to administering each drug separately. Modifying Klein would have improved the drug formulation and provided a composition having a synergistic combination of amphotericin B and flucytosine. Combining prior art elements according to known methods to obtain predictable results supports obviousness.
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Klein as applied to claims 1, 3, 4, 6-14, 17, and 18 above, and further in view of Redelmeier (US 2011/0274625 A1 Published November 10, 2011).
The claims further limit the method of claim 1.
The teachings of Klein are relied upon as summarized above. They do not teach limitations of claims 2 and 5.
The teachings of Redelmeier are related to liposomal compositions comprising a therapeutic agent (Abstract). The liposomes are formed form phospholipids. A sterol such as cholesterol, alpha-tocopherol, dicetyl phosphate, and stearlyamine may be added for stabilization of liposomes (paragraph 0055).
The teachings of Klein and Redelmeier are related to therapeutic liposomes and it would have been obvious to have combined their teachings because they are in the same field of endeavor. It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified Klein’s liposomes by including cholesterol and stearylamine in order to further stabilize the liposomes, with a reasonable expectation of success because it was known from Redelmeier that cholesterol and stearylamine may be added to liposomes for stabilization. Combining prior art elements according to known methods to obtain predictable results supports obviousness.
Conclusion
No claims are allowed.
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/ALMA PIPIC/Primary Examiner, Art Unit 1617
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