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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 20, 2026 has been entered.
Applicants' arguments, filed January 20, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Comments and Notes
The claim amendments filed January 20, 2026 are technically improper as when new claims were added, the last two claims were both numbered 104 and each claim number can only be used once.
In the interesting of compact prosecution, a Notice of Non-Compliant Amendment is not being mailed. In the remainder of this office action, the last two claims will be referred to as 104 and 104* respectively. Failure to properly format future claim amendments may result in the mailing of a Notice of Non-Compliant Amendment.
Claim Rejections - 35 USC § 112 – Written Description
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, 4, 6, 14, 15, 19, 32 – 35, 37, 41, 99, 101, 103, 104 and 104* 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed (MPEP 2163 (II)(3)(A)). A description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112 (MPEP 2163 (I)).
Amended claim 1, from which all other claims depend, newly requires that the gas vesicles, derived from Anabaena, be configured to collapse under pressure so as to affect at least a 2-fold increase in diffusivity of the hydrogel composition and at least a 4-fold increase in the rate of payload release when compared to the composition absent collapse of the Anabaena derived gas vesicle collapse. New claim 103 requires a 4-fold increase in diffusivity of the hydrogel composition.
The specification as filed (¶ [0021] of the PGPub of the instant application) discusses that the collapse pressure profile of the vesicles can be engineered using a gas vesicle protein C (GvpC) protein but this is a general discussion of modulating the collapse pressure profile. This is related to the new claim limitations but does not describe a structure function relationship between the characteristics such as the collapse pressure profile of a given gas vesicle and the changes to the diffusivity and payload release rate of the surrounding hydrogel when such a gas vesicle is exposed to ultrasound. One of ordinary skill can imagine that not only the properties of the gas vesicles such as the forces exerted upon collapse but also the hydrogel itself must be taken into consideration when determining what the effects on the physical properties of the hydrogel would be after collapse of the gas vesicles. The collapse of the exact same gas vesicle in two different hydrogels that vary in the particular polymer(s) used to form the surrounding hydrogel, the concentration of the same polymer(s) or degree of crosslinking at the same polymer concentration and type can alter the degree of change in diffusivity and payload release rate but there in discussion as to any structure-function relationship.
While it is not necessary to demonstrate possession of every species within a claimed genus, there does need to be the disclosure of a representative number of species and the Examiner was unable to locate any information linking the properties of the gas vesicles and their collapse characteristics with hydrogel diffusivity and payload release rate and there is no art appreciated structure function relationship. Therefore possession of the full scope of hydrogel compositions configured in the required manner has not been sufficiently demonstrated and the written description requirement is not full satisfied. The dependent claims fall therewith as no claims are limited to the subject matter whose possession was demonstrated.
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.
Claim(s) 1, 4, 6, 14, 15, 19, 32 – 35, 37, 41, 99, 101, 103, 104 and 104* are rejected under 35 U.S.C. 103 as being unpatentable over Kohane et al. (US2013/0041311) in view of Shapiro et al. (Nat Nanotechnol, 2014) and Bhattarai et al. (Adv Drug Del Rev, 2010). This rejection is MAINTAINED for the reasons of record set forth herein.
Kohane et al. discloses compositions for on demand drug delivery via ultrasound containing a drug depot (polymer scaffold) and drug encapsulated in an encapsulating material that also contains microbubbles that encapsulate one or more gases that enhance drug release when ultrasound is applied compared to the same system in the absence of microbubbles (whole document, e.g., abstract). In one example, an increase in drug release of 3.1-fold was observed (¶ [0256]). The encapsulating material can be liposomes that carry the drug and prevent the premature release of the drug with the hydrogel maintaining both the encapsulating materials and the microbubbles in close proximity to each other and in a relatively constrained location to affect release when ultrasound is applied (¶ [0009]). The drug depot is typically a polymeric material that degrades in the presence of an ultrasound beam with the depot continuing to entrap the remaining entrapped material and drug when the ultrasound is turned off (¶ [0025]). The carrier medium surrounds the encapsulated therapeutic material and microbubbles can disintegrate and/or change pore size when exposed to ultrasounds energy according to changes in the intensity, frequency and duration of the applied ultrasound energy (claims 40 and 46). The drug depot can be formed from precursor components that form a polymeric matrix (¶ [0031]). The hydrogels can be formed from natural or synthetic organic polymers such as polyethylene oxide-polypropylene glycol block copolymers or agarose amongst others and crosslinked via covalent, ionic or hydrogen bonds to create a 3-D open lattice that entraps water to form a gel (¶¶ [0035] and [0048]). The encapsulating materials can be microparticles (generally defined as 0.5 microns ≤ x ≤ 100 microns) or nanoparticles (generally defined as 30 – 500 nm) and preferably are liposomes (¶¶ [0066] and [0075]). The lipid film of the envelope of the gas bubbles can be 1 - 100 nm thick and about 1 nm thick in a preferred embodiment (¶ [0089]) with a gas core of pharmacologically acceptable with the amount of gas contained with the microparticles depending on the type of gas (¶¶ [0117] – [0119]). The hydrogel characterization experiments described in ¶¶ [0199] and [0200] used various volumes of microbubbles with the highest amount being 12.9% microbubbles by volume. The effect of adding increasing amounts of microbubbles is shown in Figure 2C with increases the release magnitude and the number of cycles over which the that increase resulting from increasing amounts of microbubbles (¶ [0256]) and also led to more rapid depletion of the dye (¶ [0257]) that was used to study release from the hydrogels. A wide variety of drugs can be delivered including antibiotics which can be small molecules but also biologics such as cellular material, DNA, RNA, siRNA or vaccines among others (¶ [0120] onward, such as ¶¶ [0121] and [0123]). The dosage forms can be administered by injection and suitable dosage forms include solutions or suspensions (¶ [0151]) and that typical carriers for injection include sterile water, saline or phosphate buffered saline (¶ [0152]).
The presence of gas vesicles (GVs) rather than microbubbles in the hydrogel is not disclosed.
Shapiro et al. discloses biogenic gas vesicles that are more stable due to their free diffusion of gases into them, allowing for ultrasound imaging of the particles and particle collapse at specific hydrostatic pressures (abstract, p 2, ¶ 2). Hydrogels of 1% agarose containing GVs and clustering of the GVs increase echogenicity (p 6, ¶ 6 – 7 and p 4, ¶ 1). The GVs are cylindrical or biconical in shape with maximal diameters of 45 – 450 nm and typical lengths of 100 – 600 nm (p 2, ¶ 2). Use of two species of GVs, including Anabaena flos-aquae which reads on Anabaena derived gas vesicles, with different collapse pressure profiles in the gels allows for sequential contrast to distinguish different populations at different frequencies (p 3, ¶ 4). The GVs can collapse and show up to 10+ fold less echogenicity (acoustic contrast) in the collapsed state (Figure 1F). The GVs can have different collapse profiles pre-collapse, after collapse at 300 kPa and after, collapse pressures of 650 kPa and both 300 kPa and 650 kPa were selected and collapse amounts could be determined from a comparison of given pressure values and resulting echogenicity (figure 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the biogenic Anabaena derived GVs of Shapiro et al. in the drug delivery system of Kohane et al. in place of the gas filled microbubbles of Kohane et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because GVs provide more stable ultrasound collapsible materials compared to microbubbles and that the collapse pressure of the materials can be varied to provide for additional control over rupture of the structures when ultrasound energy is applied. The ultrasound induced rupture alters the structure of the surrounding material to enable enhanced release of the therapeutic agent contained within the drug depot. When a plurality of materials are used to prepare the drug depot, the initial properties of the drug depot and/or the drug depot after ultrasound exposure can be tailored based on the desired properties of the drug depot. The claimed particle sizes overlap or lie within the claimed ranges and such ranges are prima facie obvious absent evidence as to the criticality of the claimed size (see MPEP 2144.05). “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05. As disclosed by Kohane et al., the loading of the acoustic response structure alters the magnitude of release and number of cycles over which that increase was seen, rendering the amount of gas vesicles present in the hydrogel system a results effects variable that one of ordinary skill in the art would routinely optimize depending on the magnitude of release and/or number of cycles required for a particular application. The mechanism of drug release taught by Kohane et al. requires alteration in the hydrogel structure that will alter both the diffusivity and payload release rate from the surrounding hydrogel. One of ordinary skill in the art would optimize the performance of the system depending on the desired release characteristics and there is no evidence of record as to the criticality of the amount of alteration in the diffusivity and/or payload release rate from the hydrogel. The drug delivery system requires administration to actually deliver the therapeutic agent and Kohane et al. discloses that injection in a carrier such a sterile water can be used to deliver the drug delivery system so one of ordinary skill would add such an aqueous medium, such as those disclosed by Kohane et al. which are amongst such carriers that are known to those of ordinary skill in the art, to the system so that it can be administered.
The relative pore (or mesh) size of the hydrogel and the size of material to be delivered as required by claim 1 is not disclosed.
Bhattarai et al. hydrogels based on chitosan as the scaffold material that can provide sustained, local delivery of a variety of therapeutic agents (whole document, e.g., abstract). The most important parameters that regulate diffusion of the encapsulated therapeutics out of a hydrogel are the material’s pore or mesh size and the hydrodynamic size of the drug (p 85, col 1, ¶ 2). A range of hydrogel systems have been explored for small molecular weight drugs to larger biomolecules such as nucleic acids, peptides and proteins (p 85, col 1, ¶ 4). The choice of hydrogel material, network conformation and drug loading mechanism must be made to complement the properties of the drug (¶ bridging p 91 and 92). Typical mesh sizes for biomedical hydrogels range from 5 – 100 nm in the swollen state, which are much larger than the size of most small molecule drugs (p 85, col 2, ¶ 4). Diffusion of such drugs is not significantly retarded in the swollen state although macromolecules such as proteins or peptides have a sustained release due to their hydrodynamic radii, unless the swollen hydrogel is designed appropriately to obtain the desired macromolecular diffusion rate (p 85, col 2, ¶ 4). Environmental stimulation of gels such as by gels that swell in response to pH and temperature effectively open pores for enhanced diffusion of the entrapped therapeutic under predetermined conditions (p 93, col 1, ¶ 1). If the retardation of drug release using cross-linked hydrogels is not sufficient to slow the release rate for long term applications, another release system may be incorporated into the hydrogel such as drug containing micro- or nano-capsules (p 85, col 1, ¶ 6). Small molecules can be loaded by slow diffusion into the gel depending on the porosity of the hydrogel, the size of the drug and the chemical properties of the hydrogel and drug although larger therapeutics are not able to migrate through the small pores of the hydrogel (p 92, col 1, ¶ 2). Larger drugs and bioligand payloads must be entrapped during the gelation process (p 92, col 1, ¶ 3) and such payload molecules will only release upon hydrogel swelling, dissolution or degradation of the hydrogel (p 93, col 1, ¶ 3) that surrounds such payload molecules.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to vary the hydrogel pore size and to load the hydrogel with a payload material that is larger in hydrodynamic size than the size of the pores. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because such a relative size of the payload to be released and the hydrogel pore size will limit the ability of the payload to diffuse out of the hydrogel in the absence of external stimuli such as in the system of Kohane et al. When the properties of the surrounding material are altered such as by the application of ultrasound to change pore size as taught by Kohane, payload molecules will then be able to diffuse out of the hydrogel over time given the altered properties of the material. That the average pore size of the material containing the payload molecule is smaller than the average diameter of the payload molecule means that one of ordinary skill in the art would expect little payload release from the material. Some molecules require entrapment within a structure such as a liposome as disclosed by Kohane et al. to meet this constraint and not release the drug from the hydrogel as prepared. The properties of the hydrogel can be changed by, for example, application of ultrasound to rupture the microbubbles present in the drug delivery system of Kohane et al. to bring about release of the entrapped material. Such rupture can increase the pore size of the hydrogel material, and increasing the pore size of the material in such a manner will increase the diffusion of the payload material out of the drug depot. Therefore, the pore size of the hydrogel is a results effective parameter that one of ordinary skill in the art would routinely optimize depending on particular payload (e.g., large or small molecule and whether the therapeutic agent is present within a structure such as a liposome or not to retain the payload molecule in the drug depot) and the desired release after changes to the hydrogel pore size brought about by the application of ultrasound and subsequent rupture of the microbubbles present in the drug delivery system of Kohane et al. and Shapiro et al. The typical hydrogel pore sizes of 5 – 100 nm of Bhattarai et al. overlaps with the claimed size as the pores must be smaller than the less than about 20 nm hydrodynamic radius of the payload molecules to prevent diffusion in the initial material. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. There is no evidence of record as to the criticality of the claimed hydrodynamic radius of the plurality of payload molecules. While Bhattarai et al. focuses on chitosan, the processes discussed therein also apply to other hydrogel materials such as those prepared by a plurality of polymers as required by the instant claims.
As to the amount of payload molecules and/or gas vesicles released over time as required by claim 14, that is determined by the properties of composition. Having payload molecules and/or gas containing particles that are larger than the pores will act to limit diffusion and release of the materials prior to ultrasound application. The presence of such structures will also act to “block” the pores and/or channels present in the material as required by instant claim 33. One of ordinary skill in the art would routinely optimize the material in order to limit release of these materials in the absence of ultrasound to maximize the amount of the therapeutic agent and the gas containing structures that are used to alter the properties of the material and bring about enhanced drug release after ultrasound application when therapeutic agent is triggered.
As to the porosity, the materials of Kohane et al. and Shapiro et al. necessarily have a porosity. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
Applicants traverse this rejection on the grounds that the applied references alone or in combination fail to teach or suggest the instant claimed elements, such as a plurality of Anabaena derived gas vesicles comprising at least 5% volume per volume of the hydrogel composition. The gas vesicles in Shapiro are at concentrations as low as 150 pM to 1.2 nM that correspond the gas volume fractions of ~0.01 – 0.1% which was sufficient to produce robust contrast so a skilled artisan would lack any reason to increase the gas vesicle concentration to ≥5% v/v levels claimed.
These arguments are unpersuasive. As discussed above, the primary reference Kohan et al. discloses the effects on variation in the amount of ultrasound responsive structures present in the hydrogel with the highest volume added corresponding to 12.9% microbubbles by volume. No explanation as to how the molar concentration of gas vesicles in Shapiro et al. was converted to a volume by volume number that would seem to require some consideration as to the size of the gas vesicles, has been set forth to verify the correctness of the calculation. Even if the calculations are correct, such values are the minimum required values without any indication that higher levels could not be used. The values are for use as contrast agents for imaging purposes and imaging is not the reason for adding ultrasound responsive structures to the materials of Kohane et al. Kohane et al. explicitly provides guidance as to the amount and reason to vary the amount of ultrasound responsive structures present in the drug delivery system and there is no evidence of record as to the criticality of the claimed amounts of Anabaena derived gas vesicles in the composition.
Applicants also argue that the at least 2-fold increase in hydrogel diffusivity upon and at least 4-fold increase in payload release rate gas vesicle collapse is not taught or suggested by cited references. These features are shown in various figures and examples in the disclosure as filed.
These arguments are unpersuasive. The explicit, implicit and inherent teachings of the applied prior art and the knowledge of one of ordinary skill in the art must be taken into account when evaluating the obviousness of the claimed invention. Kohane et al. discloses that the carrier medium can disintegrate and/or change pore size when exposed to ultrasound energy (claims 40 and 46), which will result in increases in diffusivity and payload release rate after exposure to ultrasound that will result in collapse of the microbubbles. The data in specification does not provide evidence of unexpected results that outweigh the prima facie case of obviousness.
Applicants argue that the disclosure of Bhattarai relating to a hydrogel based on chitosan does not remedy the deficiencies of Kohane and Shapiro.
As discussed in greater detail above, Kohane and Shapiro are not deficient as alleged by Applicants so Bhattarai need not cure the alleged deficiencies of Kohane and Shapiro.
Claim(s) 1, 4, 6, 14, 15, 19, 32 – 35, 37, 41, 99, 101, 103, 104 and 104* are rejected under 35 U.S.C. 103 as being unpatentable over Kohane et al., Shapiro et al. and Bhattarai et al. as applied to claims 1, 4, 6, 14, 15, 19, 32 – 35, 37, 41, 99, 101, 103, 104 and 104* above, and further in view of Pluen et al. (Biophysical J, 1999). This rejection is MAINTAINED for the reasons of record set forth herein.
Kohane et al. and Shapiro et al. and Bhattarai et al. are discussed above.
Explicit discussion of the porosity of the hydrogels such as those comprised of agarose is not given.
Pluen et al. discloses that as the Kozeny factor increases (less torturous more oriented pores, i.e., lower agarose/polymer matrix amount) so does porosity (ϵ) and that a 2% agarose gel already has a porosity of 0.9805 (98.5%) (p 545, top of col 2 and p 548, col 2, ¶ 3) so a 1% gel would have a higher porosity due to the lower amount of matrix material.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to optimize the porosity of the hydrogel encapsulating the drug. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because factors such as the porosity will affect the diffusion rate of the material and the amount and size of the pores that are present. Hydrogels can readily achieve the porosity values of instant claim 15 and given the relationship to diffusion and drug delivery rates, before and after ultrasound exposure that alters porosity, one of ordinary skill in the art would routinely optimize the porosity of the hydrogel material. There is no evidence of record as to the criticality of the claimed porosity values.
Applicants argue that the disclosure of Pluen relating to tuning hydrogel porosity does not remedy the deficiencies of Kohane, Shapiro and Bhattarai.
As discussed in greater detail above, Kohane, Shapiro and Bhattarai are not deficient as alleged by Applicants so Pluen need not cure the alleged deficiencies of Kohane, Shapiro and Bhattarai.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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