-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 .
This application was transferred to Primary Examiner Alma Pipic in Art Unit 1617.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 13, 2025 has been entered.
Priority
This application is a continuation of 16/007,874 filed on 06/13/2018, which claims benefit in provisional application 62/519,103 filed on 06/13/2017.
Claim Status
Claims 1-20 are pending. Claims 11-20 stand withdrawn as drawn to the non-elected invention. Accordingly, claims 1-10 are under current examination.
Withdrawn Claim Rejections - 35 USC § 103
Rejections of claims 1 and 3-10 over the combination of Campbell et al. (ACS Macro Lett. 2015, 4, 312-316), Annabi et al. (Adv. Mater. 2014, 26, 85-124), Luo (Pub. No.: US 2012/0040397; Pub. Date: Feb. 16, 2012), and Subotic et al. (Ind. Eng. Chem. Res. 1997, 36, 1302-1309) and rejection of claim 2 over Campbell et al. (ACS Macro Lett. 2015, 4, 312-316), Annabi et al. (Adv. Mater. 2014, 26, 85-124), Luo (Pub. No.: US 2012/0040397; Pub. Date: Feb. 16, 2012), Subotic et al. (Ind. Eng. Chem. Res. 1997, 36, 1302-1309), and Jaiswal et al. (Colloids and Surfaces B: Biointerfaces 81 (2010) 185-194) are withdrawn because applicant’s arguments are persuasive.
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.
Claims 1-10 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 1 is indefinite because the scope of “from 25°C to from 32 °C to 42 °C” is not clear. A range of temperatures should be expressed by reciting the two end points, such as “from 25 °C to 42 °C”. The range is not clear from the claimed phrase.
Claims 9-10 are indefinite because the claims depend from an indefinite base claim.
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 1, 3-5, 9, 10, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Junginger (EP 1 095 650 A1 Published May 2, 2001) and Kluijtmans (EP 1 961 411 A1 Published August 27, 2008).
The claims encompass a stimulus responsive carrier comprising:
a body of polymeric components comprising a copolymer comprising units derived from N-isopropylacrylamide, N-vinylpyrrolidone, and acrylic acid, wherein the body of the polymeric component is thermo-responsive; and
a second component disposed within the body of the polymeric component, the second component comprising a hydrogel comprising a combination of denatured protein and a synthetic protein wherein the hydrogel comprises methacrylated gelatin polymer (GelMA),
wherein a single volume of the second component is disposed within the body of the polymer component such that the second component is partially or entirely embedded within the body of the polymeric component,
wherein the second component has different composition than the polymeric component,
wherein the average hydrodynamic diameter of the stimulus-responsive carrier decreases by an amount of from 10% to 50% when the stimulus-responsive carrier undergoes transition from a swollen, hydrated state to a shrunken, dehydrated state, and
wherein the polymer component is selected to produce a decrease in the average hydrodynamic diameter of the stimulus-responsive carrier when the stimulus-responsive carrier is exposed to an increase in temperature of from 25°C to 42°C; and
wherein the stimulus-responsive carrier further comprises an active agent disposed within the body of the polymeric component or within the hydrogel of the second component and wherein the active agent is a growth factor.
The teachings of Junginger are related to a delivery system for active ingredients which comprises a swellable phase defining at least one void comprising an active ingredient, wherein the active ingredient may be substantially enclosed by the swellable phase, optionally with a degradable layer present between the gel phase and the active ingredient (Abstract). One objective is to obtain a delivery system that keeps the dosage form mechanically fixed at the
site of action (paragraph 0005). Another objective is to get an appropriate time controlled drug release profile with a suitable lag time, which is necessary for absorption of certain compounds
such as peptide drugs (paragraph 0006). In some cases, e.g. with peptide drugs, a suitable lag time is mandatory to inactivate enzyme activities and to open tight junctions. Thereafter,
a burst release is necessary in which substantially the whole amount of drug can be released in a very short period of time, for example in order to achieve optimal bioavailability of the active ingredients, e.g. peptide drugs (paragraph 0008). It has now been found that the above-mentioned objectives can be met by a delivery system comprising a swellable phase, such as a superporous hydrogel (SPH) phase and/or a swellable superporous hydrogel composite (SPHC) phase, defining at least one void suitable to contain an active ingredient. Preferably, the dimensions of the delivery system and the chemical composition of the phases it comprises are chosen such that application of the system in a lumen results in swelling of the phase(s), which results in mechanical fixing of the system at a predetermined site in the lumen, such as of the gut (paragraph 0009). Preferably the SPH or the SPHC is a polymer or copolymer of ethylenically unsaturated monomers, preferably of N-isopropylacrylamide (NIPAM), N-vinyl pyrrolidone (VP), and acrylic acid (AA), among other (paragraph 0033). The diameter of the system in swollen state depends strongly on the envisaged application, in particular it depends on the size of the lumen it is applied to. The size of the non-swollen release system is determined by the diameter of the system in swollen state in combination with the swelling ratio of the swellable material. This combination should be such that mechanical fixation of the system at the desired
site in the lumen can take place (paragraph 0039). Generally, the size of the swollen system will
be from several mm to several cm, preferably 1-5 cm, more preferably 2-4 cm. The cross-sectional diameter of the swollen system has to be sufficient to fix the system at the desired site in the lumen (paragraph 0040). Examples of active compounds are provided in paragraphs 0066 and 0067. Polymers that can be used for time-controlled release comprise HPMC, MC, and other cellulose derivatives. Release can be modified by the thickness of these layers (paragraph 0071). In an embodiment of a core inside the body, the first phase is a body in a cup-shaped form and the second phase is a plug. The plug and the body can be made from the same material (paragraphs 0076-0079). Additionally, the outer surface of the core can be coated with appropriate excipients such as swellable matrices that let the drug be released after a desirable lag time, so that a time-controlled release profile will be achieved (paragraph 0103).
Junginger does not teach a growth factor and methacrylated gelatin polymer.
The teachings of Kluijtmans are related to a controlled release composition comprising a cross-linked gelatin and at least one therapeutic protein (Abstract). A controlled release composition or a hydrogel can be prepared from synthetic or natural polymers, where natural polymers include cellulose derivatives and gelatin, among others (paragraph 0010). The at least one therapeutic protein is enclosed in the three-dimensional network formed by chemically crosslinked gelatin. Examples of proteins include growth factors (paragraph 0011). Gelatin may be natural or recombinant (paragraph 0012). An important feature of controlled release compositions is that the polymer used in hydrogel formation should be biodegradable and does not require invasive surgical methods to be removed after complete release of pharmaceuticals. Biodegradability could be required to release the pharmaceutical used in the composition (paragraph 0028). In case of chemical crosslinking, the used gelatin is provided with a chemical linker and subsequently subjected to a linking reaction. The gelatin is chemically modified with a crosslinkable group (paragraph 0038). The crosslinkable group is preferably methacrylate and such methacrylated gelatin is very useful in preparing a controlled release composition (paragraph 0039). Methacrylated gelatin is especially preferred in combination with a therapeutic protein because crosslinking of methacrylated gelatin can be performed in the presence of a therapeutic protein without crosslinking the therapeutic protein (paragraph 0046). The speed of degradation of the obtained product depends on the amount of crosslinks: the more cross-links the slower the degradation. The release profile of the used pharmaceutical can be from several hours (diffusion controlled) to weeks or months (controlled by degradation speed). A combination of both mechanisms can also occur. (paragraph 0047). The controlled release composition may comprise gelatin in combination with a synthetic polymer (paragraph 0053).
The teachings of Junginger and Kluijtmans are related to controlled release compositions comprising a hydrogel and a therapeutic peptide, 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 formed a controlled release system comprising a swellable phase defined by at least one void, wherein the void comprises an active ingredient substantially enclosed by the swellable phase and a degradable layer present between the gel phase and the active ingredient, with a reasonable expectation of success because Junginger teaches a controlled release system comprising a swellable phase defined by at least one void, wherein the void comprises an active ingredient substantially enclosed by the swellable phase and a degradable layer present between the gel phase and the active ingredient. It would have been obvious to have formed the system with a single void that comprises the active ingredient enclosed by a degradable layer present between the gel phase and the active ingredient because “at least one” includes one and Figures 3 and 4 exemplify a system with a single core surrounded by a swellable phase.
It would have been obvious to have formed the swellable phase from a copolymer of N-isopropylacrylamide, N-vinyl pyrrolidone, and acrylic acid because Junginger teaches that a copolymer of N-isopropylacrylamide, N-vinyl pyrrolidone, and acrylic acid is a suitable for making the swellable phase.
It would have been obvious to have selected a therapeutic peptide as the active agent because Junginger teaches that therapeutic peptides are suitable for delivery with the controlled release system. Junginger does not limit the therapeutic peptide. It would have been obvious to have selected a growth factor as the therapeutic peptide, with a reasonable expectation of success because Kluijtmans teaches that growth factors are therapeutic peptides that are suitable for controlled release delivery from a hydrogel. The selection of a known material based on its suitability for its intended purpose supports obviousness.
It would have been obvious to have formed the degradable layer from HPMC or MC because Junginger teaches HMPC and MC as suitable materials for making the degradable layer. Junginger also teaches that HPMC, MC, and cellulose derivatives are used for time controlled release. Junginger further teaches that the outer surface of the core can be coated with swellable matrices that let the drug be released after a desirable lag time so that a time controlled release profile is achieved. Therefore, it would have been obvious to have formed the degradable layer between the therapeutic peptide core and the swellable material from a material that provides time controlled release of the therapeutic peptide. It would have been obvious to have modified Junginger’s composition by replacing the cellulose derivatives in the degradable layer with methacrylated gelatin, with a reasonable expectation of success because Kluijtmans teaches controlled release of a therapeutic protein from a hydrogel matrix wherein the hydrogel matrix is formed from a cellulose derivative or methacrylated gelatin. Replacing a cellulose derivative with methacrylated gelatin in the degradable layer would have been obvious because the two are known as equally suitable for encapsulating therapeutic peptides to provide controlled release of the therapeutic peptides. Replacing one equivalent with another to obtain predictable results supports obviousness. Junginger requires the layer to be degradable and provide controlled release, and methacrylated gelatin meets both of these criteria. Furthermore, Kluijtmans teaches that degradation rete and release rate of the therapeutic peptide from methacrylated gelatin may be varied by varying the degree of crosslinking in the methacrylated gelatin hydrogel matrix. It would have been obvious to vary these parameters through routine experimentation in order to obtain a hydrogel that provides target release rate of the therapeutic peptide.
The claimed stimulus-responsive carrier is obvious over the controlled release system of Junginger modified in view of Kluijtmans because the prior art system comprises:
-a swellable phase defining one void wherein the swellable phase is formed from a copolymer of N-isopropylacrylamide, N-vinylpyrrolidone, and acrylic acid (relevant to the claimed body of a polymer component comprising units derived from N-isopropylacrylamide, N-vinylpyrrolidone, and acrylic acid); the swellable phase is made from the same copolymer as claimed body and it would have been reasonable to expect the swellable phase to be thermo-responsive; Junginger’s monomers are identical to claimed monomers therefore they are thermos-responsive; and
-the void enclosing a core, the core comprising a growth factor coated with a layer made from methacrylated gelatin (a second component disposed within the body of the polymeric component, the second component comprising a hydrogel comprising methacrylated gelatin polymer wherein carrier comprises a growth factor disposed within the hydrogel of the second component).
It is apparent that the swellable phase has a different composition from the core.
The two “wherein” phrases at the end of the claim describe carrier properties and it would have been reasonable to expect the prior art system to have the same properties as claimed carrier because the two are made from the same materials. The claimed decrease in hydrodynamic diameter of the carrier and the polymeric component is a property that depends on the material from which the carrier and the polymeric component are formed, and the skilled artisan would have expected the prior art carrier and the polymeric component to have the same properties as claimed when tested under the same conditions.
The configuration of the prior art system meets the limitation that requires a single volume of the second component disposed within the body of the polymer component such that the second component is partially or entirely embedded within the body of the polymeric component.
Combining prior art elements according to known methods to obtain predictable results supports obviousness.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Junginger and Kluijtmans as applied to claims 1, 3-5, 9, 10, and 21 above, and further in view of Roth (WO 96/11671 Published April 25, 1996).
The claim requires the stimulus-responsive carrier of claim 1 wherein the stimulus responsive carrier has an average hydrodynamic diameter of 500 nm to 500 microns in the swollen, hydrated state.
The teachings of Junginger and Kluijtmans are relied upon as summarized above. Junginger teaches that the delivery system can be employed in a variety of lumina in humans, animals, as well as in plants (paragraph 0049) including the lungs (paragraph 0072). However, Junginger does not teach diameter ranges of the delivery system that are suitable for lumina in the lungs.
The teachings of Roth are related to encapsulation of biologically active proteins within biodegradable, biocompatible polymeric microparticles which are appropriately sized to infiltrate and remain trapped within the capillary beds and alveoli of the lungs for the purpose of targeted delivery to these regions of the body followed by administration to a patient by infusion or injection (Abstract). The purpose is to provide a means for locally administering bioactive molecules to tissues or cells in a patient in a controlled sustained manner (page 4 lines 20-24). The microparticle has a diameter which is selected to lodge in particular regions of the body. For example, a microparticle selected to lodge in a capillary will have diameter of 10-25 microns. In various applications, the sizes may range from 0.2 to 100 microns (paragraph bridging pages 14-15). Biologically active molecules include growth factors (paragraph bridging pages 19-20).
The teachings of Roth and Junginger modified by Kluijtmans are related to particles comprising a growth factor encapsulated in a polymer wherein the particles are intended for controlled release of a biologically active molecule by administering to a subject wherein the particles lodge into a lumen of the lungs. 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 skilled in the art before the effective filing date of the claimed invention to have formulated Junginger’s particles as modified by Kluijtmans for administration to the lumen of the lungs, with a reasonable expectation of success because Junginger teaches that the particles are suitable for controlled release delivery of an active agent to the lumen of the lung. Junginger does not teach particle sizes of particles suitable for lodging into lumina of the lungs. It would have been obvious to have formulated the particles to have particle sizes in the range of 0.2-100 microns when swollen and hydrated in order to lodge the particles into the lumina of the lungs, with a reasonable expectation of success because Roth teaches that particles in the range of 0.2-100 micron diameter are suitable for controlled release of a bioactive agent into the lumina of the lungs by lodging the particles into the lumina of the lungs. The claimed range is obvious because it overlaps with 0.2-100 microns. The skilled artisan would have understood that the particles would have to have said diameter in the swollen, hydrated state because the particles would have to be in the swollen hydrated state upon administration to the subject.
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Junginger and Kluijtmans as applied to claims 1, 3-5, 9, 10, and 21 above, and further in view of Jiang (US 2011/0097277 Published April 28, 2011).
The claims require the stimulus-responsive carrier of claim 1 further comprising one or more magnetic nanoparticles within the body of the polymeric component or within the hydrogel of the second component, and wherein the one or more magnetic nanoparticles are coated with the hydrogel of the second component.
The teachings of Junginger and Kluijtmans are relied upon as summarized above, however they do not teach the limitations of claims 6 or 7.
The teachings of Jiang are related to nanoparticles comprising a core and a surface having a plurality of zwitterionic polymers grafted thereto (paragraphs 0006-007). Targeting ligands such as growth factors may be immobilized on the surface of the nanoparticles (paragraph 0138). Magnetic nanoparticles (MNPs) have many attractive properties, often combining low toxicity with excellent magnetic properties. Recently, "theranostics", which incorporate both therapy and diagnosis, are attracting significant attention and may revolutionize current medical treatments. To achieve this goal, MNPs can work as multifunctional carriers to selectively accumulate at the target site, cure disease by certain mechanisms (either hyperthermia or drug release) and be detected using non-invasive diagnosis modality such as magnetic resonance imaging (MRI). Multifunctional MNPs can typically be formed from magnetic cores and surface coating. Magnetic cores are iron oxide nanoparticles which are detectable by MRI and can be manipulated by a magnetic field, while an ideal surface coating can carry a therapeutic reagent, prevent MNPs from being cleared from the blood circulation, and provide functional groups for conjugation of targeting ligands. Thus, the surface coating plays a key role in achieving multifunctional MNPs (paragraph 0161).
The teachings of Jiang and Junginger modified by Kluijtmans are related to targeted drug delivery using an active agent encapsulated in a polymer and it would have been obvious to have combined them 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 controlled release system of Junginger as modified by Kluijtmans by conjugating the growth factor to a magnetic nanoparticle, with a reasonable expectation of success because it was known from Jiang that magnetic nanoparticles can be used to selectively accumulate at a target site and treat a disease by drug release. The purpose of Junginger is to target a drug to a specific site in intestinal, vaginal, nasal, oral, rectal, or ear cavities, the colon and the lung (paragraph 0072), and the skilled artisan would have been motivated to conjugate the drug such as a therapeutic peptide to a magnetic nanoparticle in order to ensure its delivery to the target sits. One of skill in the art would have been further motivated to use magnetic nanoparticles because Jiang teaches the particles maybe detected by non-invasive methods such as MRI and can be manipulated by a magnetic field. One of skill would have had a reasonable expectation of success modifying Junginger by conjugating a growth factor to a magnetic nanoparticle because it was known from Jiang that a magnetic nanoparticle may be conjugated to a targeting ligand such growth factors.
The limitations of claims 6 and 7 are met because Junginger’s controlled release system modified in view of Kluijtmans and Jiang comprises a core comprised of magnetic nanoparticles conjugated to a growth factor wherein the core is coated by methacrylated gelatin. Therefore, the controlled release system comprises magnetic nanoparticles coated with the hydrogel of the second component.
Combining prior art elements according to known methods to obtain predictable results supports obviousness.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Junginger and Kluijtmans as applied to claims 1, 3-5, 9, 10, and 21 above, and further in view of Saltzman (US 2006/0002971 A1 Published January 5, 2006).
The claims encompass the stimulus-responsive carrier of claim 1, further comprising a targeting agent on an outer surface of the stimulus-responsive carrier, wherein the targeting agent is capable of binding to a target.
The teachings of Junginger and Kluijtmans are relied upon as summarized above, however they do not teach the limitations of claim 8.
The teachings of Saltzman are related to polymeric microparticles that encapsulate therapeutic compounds and have targeting ligands directly bound to the microparticle surface (Abstract). Targeting greatly increases specificity, while not decreasing therapeutic load, such as DNA vaccines, drugs, peptides, proteins, or antigens. Another advantage is that more than one material can be encapsulated and/or coupled to the surface of the microparticle. This may be a therapeutic and/or targeting material. In some cases, it may be advantageous to provide for an initial delivery of molecules coupled to the surface of the microparticles, with a second encapsulated therapeutic load being delivered following phagocytosis or degradation of the microparticle (paragraph 0015).
The teachings of Saltzman and Junginger modified by Kluijtmans are related to a therapeutic protein encapsulated in a polymeric particle 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 skilled in the art before the effective filing date of the claimed invention to have modified Junginger’s controlled release system as modified by Kluijtmans by adding a targeting ligand to the surface of the system, with a reasonable expectation of success because it was known from Saltzman that adding a targeting ligand to a particle comprising encapsulated therapeutic peptide increases targeting specificity of the particle while not decreasing therapeutic load. The purpose of Junginger is to target drugs to a specific site in lumina of a human or animal and the skilled artisan would have been motivated to modify Junginger in view of Saltzman because such modification would have resulted in an improvement of Junginger’s controlled release delivery system.
Combining prior art elements according to known methods to obtain predictable results supports obviousness and the selection of a known material based on its suitability for its intended purpose supports obviousness.
Conclusion
No claims are allowed.
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/ALMA PIPIC/Primary Examiner, Art Unit 1617