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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/17/2026 has been entered.
Status of the Claims
Claims 22-23, 28, 30, and 32-41 are pending and under current examination. Claims 27 and 42 are cancelled.
Withdrawn Claim Rejections
All rejections pertaining to claims 27 and 42 are moot because the claims are cancelled in the amendments to the claims filed 7/17/2026.
All rejections not reiterated have been withdrawn.
Claim Objections
Claim 32 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 30. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 33 is objected to because of the following informalities:
Claim 33 recites the abbreviations “HA” and “PEG”. The clarity of the record would be improved if the full definition of the term was provided followed by the abbreviation in parentheses at the first mention of the terms in the claims, as in “hyaluronic acid (HA)” and “polyethylene glycol (PEG)”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 33 is 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 33 recites the limitation “wherein the exterior surface of the protein shell is covalently conjugated with HA and PEG is covalently conjugated to HA”. This renders the claim indefinite because it is not clear if the PEG recited by claim 33 is the PEG of the DSPE-PEG component of the lysosome or if the PEG that is conjugated to HA refers to a separate, additional PEG moiety.
Claim 35 recites the limitation “wherein an effective concentration of the modified gas vesicle is 250pM-1nM”. This renders the claim indefinite because it is not clear what the concentration is referring to. There is no recitation as to what the concentration of gas vesicle is relative to (i.e., the diagnostic agent is a solution comprising the gas vesicle).
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.
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.
Claims 22-23, 28-30, 32, and 34-39 are rejected under 35 U.S.C. 103 as being unpatentable over Lakshmanan et. al. (Nature Protocols, pg. 2050-2080, publication year: 2017, cited in the IDS filed 5/19/2022, of record) in view of Unger (U.S. Patent Application No. 2001/0018072, publication date: 8/30/2001, of record) and Ibsen et. al. (Drug Design, Development and Therapy, pg. 375-388, publication year: 2013, of record).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Regarding claims 22 and 23, Lakshmanan teaches that gas vesicles harvested from the cyanobacterium Anabaena flos-aquae (Ana) comprise a protein shell enclosing a hollow gas-filled interior (pg. 2050, Introduction-Development of the protocol). Lakshmanan teaches that the gas vesicles have a hydrodynamic diameter of about 200nM (pg. 2050 Development of the protocol).
Regarding claim 28, Lakshmanan teaches that the gas vesicles have a hydrodynamic diameter of about 200nM (pg. 2050 Development of the protocol).
Regarding claims 30, 32, and 37 Lakshmanan teaches that gas dissolved in the media surrounding the algae partitions freely in and out of the protein shell of the gas vesicle (pg. 2050, Development of the protocol).
Regarding claim 34, Lakshmanan teaches that the modified algae-derived gas vesicles may be used in clinical diagnostics (pg. 2050 Introduction).
Regarding claim 35, Lakshmanan teaches that the algae-derived gas vesicle may be used for in vivo ultrasound imaging at OD500,ps of about 25 (pg. 2067, Ultrasound imaging of GVs in vivo, step (ix)).
Regarding claims 36, 38, and 39 Lakshmanan teaches the relevant limitations of claim 22 above.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Regarding claim 22, Lakshmanan does not teach that the algae-derived gas vesicle may be encapsulated in a liposome consisting of DOPC and DSPE-PEG, a size of the gas vesicle or a molar ratio of DOPC to DSPE-PEG in the modified gas vesicle. However, this deficiency is cured by Unger and Ibsen.
Unger teaches that the target gas vesicles may have one or more monolayers and they may be concentric. The vesicles include such entities as liposomes and protein-coated bubbles. The vesicles may encapsulate gases and may comprise a targeting ligand [0033]. The lipids used to form the targeted gas vesicles may include DOPC, DSPE, lipids bearing polymers such as PEG, and any combinations thereof [0108]. The PEG may act as a stabilizing material [0100]. Suitable pegylated lipids include DSPE-PEG5000 [0100]. Unger also teaches that the stabilizing agents may either form or stabilize the vesicles, in either way serving to minimize or substantially prevent the escape of gases until said release is desired [0031]. Unger also teaches that the PEG moiety surrounds the vesicle membrane or skin, and thereby forms a physical barrier to various enzymatic and other endogenous agents in the body whose function is to degrade such foreign materials. DPPE-PEG may provide more vesicles of a smaller size which are safe and stable to pressure when combined with other lipids. The pegylated material, because of its structural similarity to water, may be able to defeat the action of the macrophages of the human immune system, which would otherwise tend to surround and remove the foreign object. The result is an increase in the time during which the stabilized vesicles may function as diagnostic imaging contrast media [0101]. The gas filled vesicles may be less than about 1µm in size [0204]. Ibsen teaches that microbubbles may be encapsulated inside liposomes to protect the microbubble and to ensure the microbubble actuation releases the entire payload. The nested structure presents a smooth outer surface which increases stability of the particle and reduces immune recognition (pg. 382 Microbubble-based drug delivery vehicle designs and Fig. 9F).
Regarding claim 28, Lakshmanan does not teach the zeta potential of the modified gas vesicles.
Regarding claim 30, 32, 37, and 39 Lakshmanan does not teach that the internal gas of the algae-derived gas vesicle is oxygen. However, this deficiency is cured by Unger.
Unger teaches that preferred gases for the gas vesicle are inert and biocompatible, such as nitrogen, carbon dioxide, and oxygen [0162].
Regarding claim 35, Lakshmanan does not teach the effective concentration of modified gas vesicle embraced by the instant claim.
Regarding claims 36, 38, and 39, Lakshmanan does not teach the use of the modified gas vesicle in the diagnosis of any cancers embraced by the instant claims. However, this deficiency is cured by Unger
Unger teaches that the region of a patient to be treated by the disclosed gas vesicle includes diseased tissue, including cancerous tissue and tumors, and that region can be imaged with diagnostic imaging [0043 and 0062]. Unger also teaches that the therapeutic included in the disclosed gas vesicle may include therapeutics to treat malignant melanoma or kidney cancer [0138].
Regarding claim 37, Lakshmanan does not teach the used of the modified gas vesicle in a pharmaceutical composition. However, this deficiency is cured by Unger.
Unger teaches that the therapeutic incorporated into the gas vesicle may be used in the treatment of a malady, affliction, disease, or injury in a patient [0045]. The Examiner considers Unger to therefore read on the limitation “a pharmaceutical composition” embraced by the instant claim 37.
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 22, it would have been prima facie obvious to one of ordinary skill in the art of filing to encapsulate the algae-derived gas vesicle embraced by Lakshmanan in a liposome consisting of DOPC and DSPE-PEG. One would have understood in view of Unger that a targeted gas vesicle may contain more than one concentric layer and that one of those layers may be comprised of lipids, including a combination of DOPC and PEG-modified DSPE[0108], that may act as a stabilizing agent to regulate the release of gases [0031] and in view of Ibsen that microbubbles encapsulated in a liposome increases stability of the particle and reduced immune recognition (pg. 382 Microbubble-based drug delivery vehicle designs and Fig. 9F). It would have been obvious to encapsulate the gas vesicle embraced by Lakshmanan in such a liposome. One of ordinary skill in the art of filing would have been motivated to encapsulate the gas vesicle embraced by Lakshmanan in the liposome embraced by Unger and Ibsen in order to improve the stability of the algae-derived gas vesicle. The artisan of ordinary skill would have had reasonable expectation of success because Ibsen teaches targeted gas vesicles encapsulated in liposomes.
Regarding claims 22 and 28, the particle size and zeta potential are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal particle size and zeta potential of the modified gas vesicles in order to best achieve the desired results as such would provide advantageous therapeutic effect. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Lakshmanan teaches that conventional imaging agents based on microbubbles are limited by size and physical instability (pg. 2050, Introduction). The Examiner considers it prima facie obvious to optimize the particle size and zeta potential of the modified gas vesicles embraced by Lakshmanan to lie within the range embraced by the instant claims, absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the particle size and zeta potential would directly impact the stability of the vesicles and ability to label the desired target and therefore be an optimizable variable.
Regarding claim 22, the molar ratio of DOPC and DSPE-PEG is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal molar ratio in order to best achieve the desired results as such would provide advantageous size and stability effect. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Unger teaches that the pegylated lipid has a direct effect on the stability of the gas vesicles [0100]. The Examiner considers it prima facie obvious to optimize the molar ratio of lipids encapsulating the gas vesicle , absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the amount of pegylated lipid would have a direct effect on the size and stability of the gas vesicles and therefore be an optimizable variable.
Regarding claim 30, 32, and 37, and 39 it would have been prima facie obvious to one of ordinary skill in the art of filing that the oxygen in the gas vesicle embraced by Lakshmanan may be oxygen. One would have understood in view of Unger that a targeted gas vesicle may encapsulate an inert biocompatible gas such as oxygen. It would have been obvious to one of ordinary skill in the art of filing to include a biocompatible gas such as oxygen in the gas vesicles embraced by Lakshmanan. One of ordinary skill in the art of filing would have been motivated to include oxygen in the gas vesicles embraced by Lakshmanan in order to provide the therapeutic benefits of the oxygen to the tissues targeted by the gas vesicles. The artisan of ordinary skill would have had reasonable expectation of success because Unger teaches that targeted gas vesicles may comprise oxygen as the encapsulated gas. See MPEP 2144.07.
Regarding claim 35, the effective concentration of modified gas vesicle used as a diagnostic agent is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal concentration of modified gas vesicle in order to best achieve the desired results as such would provide advantageous diagnostic effect. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Lakshmanan teaches that the signal rendered by the modified gas vesicles is dependent on the concentration of gas vesicles used as a contrast agent and may be modified by raising or lowering the concentration of gas vesicles (pg.2075, Table 5). The Examiner considers it prima facie obvious to optimize the concentration of gas vesicle used as a diagnostic agent, absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the concentration of gas vesicle used as a diagnostic agent is directly correlated to a signal rendered by the gas vesicle and therefore be an optimizable variable.
Regarding claims 36, 38, and 39 it would have been prima facie obvious to one of ordinary skill in the art of filing that the diagnostic modified gas vesicle embraced by Lakshmanan may be used to target kidney cancer or malignant melanoma. One would have understood in view of Unger that a gas vesicle may be used to target the treatment of kidney cancer and malignant melanomas. It would have been obvious that the algae-derived gas vesicles embraced by Lakshmanan may also be used in diagnostic imaging of the same regions. One of ordinary skill in the art of filing would have been motivated to utilize the gas vesicles embraced by Lakshmanan in the diagnosis of kidney cancer and malignant melanomas in order to provide a more targeted diagnostic method. The artisan of ordinary skill in the art of filing would have had reasonable expectation of success because Unger teaches that modified gas-vesicles of similar structure to those embraced by Lakshmanan may be used to target kidney cancer and malignant melanomas.
Regarding claim 37, it would have been prima facie obvious to one of ordinary skill in the art of filing that the algae-derived gas vesicle embraced by Lakshmanan may be used in a pharmaceutical composition. One would have understood in view of Unger that a similar modified gas vesicle may be combined with a therapeutic agent to target specific cancers. It would have been obvious to include a therapeutic agent with the gas vesicle embraced by Lakshmanan. One of ordinary skill in the art of filing would have been motivated to include a therapeutic agent with the gas vesicle embraced by Lakshmanan in order to provide additional therapeutic benefit to the specific tissue targeted by the gas vesicle. The artisan of ordinary skill in the art of filing would have had reasonable expectation of success because Unger teaches that modified gas vesicles may incorporate therapeutics targeting specific cancers.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Lakshmanan et. al. (Nature Protocols, pg. 2050-2080, publication year: 2017, cited in the IDS filed 5/19/2022, of record) in view of Unger (U.S. Patent Application No. 2001/0018072, publication date: 8/30/2001, of record) and Ibsen et. al. (Drug Design, Development and Therapy, pg. 375-388, publication year: 2013, of record), as applied to claims 22-23, 28-30, 32, and 34-39 above, and further in view of Arpicco et. al. (Molecules, pg. 3193-3230, publication year: 2014, of record) and Choi et. al. (ACS Nano, pg. 8591-8599, publication year: 2011, of record).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Lakshmanan, in view of Unger and Ibsen, teaches the relevant limitations of claim 22 and 27 above. Lakshmanan also teaches that the exterior of the gas vesicle may be modified via chemical conjugation of chemical moieties, such as polymers, to the lysine residues on the protein shells of the gas vesicles (pg. 2053, Modification and functionalization of GVs) and that gas dissolved in the media surrounding the algae partitions freely in and out of the protein shell of the gas vesicle (pg. 2050, Development of the protocol).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Lakshmanan does not teach a hyaluronic acid covalently conjugated to the exterior surface of the protein shell and PEG covalently conjugated to the hyaluronic acid. However, this deficiency is cured by Arpicco and Choi.
Arpicco teaches that nanoparticles may be modified by EDC-coupling of hyaluronic acid to the surface (pg. 3201, 4.1 Polymeric Nanoparticles and pg. 3204 Table 2). Arpicco also teaches that hyaluronic coating naturally targets particles to cells expressing specific receptors and gives particles stealth properties (pg. 3201, 4. HA Decorated Particles). Choi teaches that hyaluronic acid nanoparticles accumulate in the liver. Choi also teaches that PEGylation of the hyaluronic nanoparticles effectively reduce liver uptake and increase the circulation time in the blood, leading to selective accumulation of the nanoparticles to the tumor site (pg. 8592, Introduction).
Lakshmanan does not teach that the internal gas of the algae-derived gas vesicle is oxygen. However, this deficiency is cured by Unger.
Unger teaches that preferred gases for the gas vesicle are inert and biocompatible, such as nitrogen, carbon dioxide, and oxygen [0162].
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art of filing to include a PEG moiety covalently bound to a hyaluronic acid moiety that is covalently bound to the protein surface of the gas vesicle embraced by Lakshmanan. One would have understood in view of Arpicco that hyaluronic acid may be covalently attached to particles in order to target the particles to cells expressing specific receptors (pg. 3201, 4. HA Decorated Particles) and in view of Choi that PEGylation of hyaluronic acid nanoparticles reduces liver uptake of the nanoparticles and increases the circulation time in the blood, leading to selective accumulation of the nanoparticles to the tumor site (pg. 8592, Introduction). It would have been obvious to modify the surface of the algae-derived gas vesicle embraced by Lakshmanan with a PEG-modified hyaluronic acid moiety. One of ordinary skill in the art of filing would have been motivated to conjugate a PEG-modified hyaluronic acid moiety to the surface of the algae-derived gas vesicle in order to reduce liver uptake and increase circulation time and targeting of the gas vesicle. The artisan of ordinary skill would have had reasonable expectation of success because Lakshmanan teaches that gas vesicles may be modified by chemical conjugation to polymers (pg. 2053, Modification and functionalization of GVs).
It would have been prima facie obvious to one of ordinary skill in the art of filing that the oxygen in the gas vesicle embraced by Lakshmanan may be oxygen. One would have understood in view of Unger that a targeted gas vesicle may encapsulate an inert biocompatible gas such as oxygen. It would have been obvious to one of ordinary skill in the art of filing to include a biocompatible gas such as oxygen in the gas vesicles embraced by Lakshmanan. One of ordinary skill in the art of filing would have been motivated to include oxygen in the gas vesicles embraced by Lakshmanan in order to provide the therapeutic benefits of the oxygen to the tissues targeted by the gas vesicles. The artisan of ordinary skill would have had reasonable expectation of success because Unger teaches that targeted gas vesicles may comprise oxygen as the encapsulated gas. See MPEP 2144.07.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Lakshmanan et. al. (Nature Protocols, pg. 2050-2080, publication year: 2017, cited in the IDS filed 5/19/2022, of record) in view of Unger (U.S. Patent Application No. 2001/0018072, publication date: 8/30/2001, of record) and Ibsen et. al. (Drug Design, Development and Therapy, pg. 375-388, publication year: 2013, of record), as applied to claims 22-23, 28-30, 32, and 34-39 above, and further in view of Sachar et. al. (Journal of Pharmacology and Experimental Therapeutics, pg. 267-275, publication year: 2016, of record).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Lakshmanan, in view of Unger and Ibsen, teaches the relevant limitations of claims 22 and 39 above.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Lakshmanan does not teach that the modified algae-derived gas vesicles may be co-administered with protoporphyrin IX. However, this deficiency is cured by Sachar.
Sachar teaches that a stable precursor for protoporphyrin IX can be administered orally or locally as a therapy for early malignant lesions of the skin, bladder, breast, stomach, and oral cavity. The photodynamic effects of protoporphyrin IX may also be used for cancer diagnosis (pg. 272, PPIX-Based Strategies for Diagnosis and Therapy).
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to combine two compositions, each of which is taught by the prior art to be useful for the same purpose (modified gas vesicles and protoporphyrin IX for photodynamic cancer therapy and imaging), in order to form a third composition to be used for the very same purpose. See MPEP 2144.06-I.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Lakshmanan et. al. (Nature Protocols, pg. 2050-2080, publication year: 2017, cited in the IDS filed 5/19/2022, of record) in view of Unger (U.S. Patent Application No. 2001/0018072, publication date: 8/30/2001, of record) and Ibsen et. al. (Drug Design, Development and Therapy, pg. 375-388, publication year: 2013, of record), as applied to claims 22-23, 28-30, 32, and 34-39 above, and further in view of Zhu et. al. (Methods in Enzymology, pages 267-274; publication year: 2013, of record).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Lakshmanan teaches that the algae-derived gas vesicles may be prepared by first lysing collected cultures of Anabaena flos-aquae, isolating the gas vesicles by centrifugation, and resuspending in PBS for use and storage (pg. 2059, steps (xii-xvii)). The molar ratio of DOPC and DSPE-PEG has been rendered obvious in the rejection of claim 22 above.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Lakshmanan does not teach that the algae-derived gas vesicles may be combined with a solution of DOPC and DSPE-PEG in chloroform to form a liposome. However, this deficiency is cured by Unger and Zhu.
Unger teaches that the gas vesicles may be prepared by suspension of the surfactant, such as a lipid, in an organic solvent, followed by evaporation of the solvent, resuspension in an aqueous suspension, sonication and centrifugation [0188]. Zhu teaches that lipids may first be dissolved in chloroform when forming lipid vesicles (pg. 270, section 4.2).
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to utilize the aqueous solution of gas vesicle isolated by the method embraced by Lakshmanan in the method of forming lipid gas vesicles embraced by Unger. One would have understood in view of Unger and Zhu that the lipids intended to form a liposome gas vesicle may first be dissolved in an organic solvent such as chloroform and then resuspended in an aqueous suspension. It would have been obvious that DOPC and DSPE-PEG combined in chloroform may then be added to the aqueous suspension of gas-vesicles obtained by the method embraced by Lakshmanan. One of ordinary skill would have been motivated to combine the two methods in order to produce a lipid-encapsulated algae-derived gas vesicle. The artisan of ordinary skill would have had reasonable expectation of success because Unger teaches that lipids dissolved in an organic solvent may be combined, the solvent evaporated, and then resuspended in an aqueous solution to form a gas vesicle.
Response to Arguments
Applicant's arguments filed 7/17/2026 have been fully considered but they are not persuasive.
On page 6, Applicant argues that the broad exemplary list of Unger does not provide a reasoned teaching to select DOPC and DSPE-PEG as the entire liposome composition for encapsulating Lakshmanan’s algae-derived protein-shell gas vesicles. This is not found persuasive. In response, simply because the prior art “discloses a multitude of effective combinations does not render any particular formulation less obvious." Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). "[P]icking and choosing may be entirely proper in the making of a 103, obviousness rejection." In re Arkley, 455 F.2d 586, 587 (CCPA 1972). Please also refer to MPEP 2123 (I), which states: “a references may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments”. In the instant case, Unger teaches that the lipids used to form the targeted gas vesicles may include DOPC, DSPE, lipids bearing polymers such as PEG, and any combinations thereof [0108] and may act as stabilizing materials [0031]. Therefore, one of ordinary skill in the art would have reasonably concluded that the lipids used to form the gas vesicle may consist of DOPC, DSPE, and lipids bearing polymers such as PEG. Furthermore, it is noted that Applicants do not identify secondary consideration demonstrating criticality or anything unexpected regarding the combination or molar ratio of DOPC and DSPE-PEG.
On page 6, Applicant argues that the specific stabilization taught by Unger does not support the rationale of selecting DOPC and DSPE-PEG. This is not found persuasive. In response, the Examiner respectfully draws attention to MPEP 2123 (II), which states: “disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments”. In the instant case, Unger teaches that DOPC and DSPE-PEG may be present as lipids in the gas vesicle and specifically names DSPE-PEG5000 as a suitable pegylated lipid. Unger also teaches that the pegylated lipid has a direct effect on the size and stability of the gas vesicle. One of ordinary skill in the art would have therefore reasonably chosen DOPC and DSPE-PEG as the lipids present in the gas vesicle and would have recognized the amount of DSPE-PEG as a result effective variable. Therefore, the argument is not persuasive and the rejection is maintained.
On page 6, Applicant argues that the cited prior at does not provide a reasonable expectation that omission of Unger’s DPPA stabilizer would produce the claimed modified gas vesicles having an average particle size of 290-330nm. This is not found persuasive. In response, please refer to MPEP 2141.03(I) regarding the factors to consider when determining level of ordinary skill: “A person of ordinary skill in the art is also a person of ordinary creativity, not an automation.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. Please also refer to MPEP 2143.02 (I), which states: “conclusive proof of efficacy is not required to show a reasonable expectation of success” and MPEP 2143.02 (II), which states: “obviousness does not require absolute predictability, but at least some degree of predictability is required”. In the instant case, as described in the obviousness rejection above, one of ordinary skill in the art would have recognized in view of the teachings of Lakshmanan and Unger that the particle size and zeta potential would directly impact the stability of the vesicles and ability to label the desired target and therefore be an optimizable variable.
On page 6, Applicant argues that Ibsen does not support the rationale of selecting DOPC and DSPE-PEG. This is not found persuasive. 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).
On page 7, Applicant argues that the routine-optimization rationale is inapplicable because the cited prior art does not establish the general conditions of the claimed invention. This is not found persuasive. In response, the Examiner respectfully draws attention to MPEP 2123 (II), which states: “disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments”. Please also refer to MPEP 2141.03(I) regarding the factors to consider when determining level of ordinary skill: “A person of ordinary skill in the art is also a person of ordinary creativity, not an automation.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. In the instant case, Unger teaches that DOPC and DSPE-PEG may be present as lipids in the gas vesicle and specifically names DSPE-PEG5000 as a suitable pegylated lipid. Unger also teaches that the pegylated lipid has a direct effect on the size and stability of the gas vesicle. Thus, Unger teaches the general conditions of the identity of the lipids, pegylation to stabilize the liposome, and the relationship between size, stability, and lipid identity. One of ordinary skill in the art would have therefore reasonably chosen DOPC and DSPE-PEG as the lipids present in the gas vesicle and would have recognized the amount of DSPE-PEG as a result effective variable. Therefore, the argument is not persuasive and the rejection is maintained.
On page 7, Applicant argues that the disclosures of Lakshmanan, Unger, and Ibsen do not provide a reasonable expectation that the gas vesicles would predictably yield the structure of the amended claim 22, including the defined 4:1 DOPC/DSPE-PEG liposome and average particle size of 290-330nm. This is not found persuasive. In response, please refer to MPEP 2141.03(I) regarding the factors to consider when determining level of ordinary skill: “A person of ordinary skill in the art is also a person of ordinary creativity, not an automation.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. Please also refer to MPEP 2143.02 (I), which states: “conclusive proof of efficacy is not required to show a reasonable expectation of success” and MPEP 2143.02 (II), which states: “obviousness does not require absolute predictability, but at least some degree of predictability is required”. As described in the obviousness rejection above, one of ordinary skill in the art would have recognized that the lipid vesicle may contain DOPC and DSPE-PEG and would have recognized that both the ratio of DOPC:DSPE-PEG and particle size were result effective parameters that a person of ordinary skill in the art would routinely optimize. Therefore, one of ordinary skill in the art could have reasonably chosen DOPC and DSPE-PEG as the components of the lipid vesicle and optimized both the ratio of DOPC:DSPE-PEG and particle size.
Conclusion
No claims are allowed.
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ELIZABETH ANNE MEYERSExaminer, Art Unit 1617
/KATHERINE PEEBLES/Primary Examiner, Art Unit 1617
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