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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 1/26/2026 is acknowledged. Claims 1-20 are pending, of which claims 12-20 have been withdrawn as being directed to a non-elected invention. Claims 1-11 are examined herein on the merits for patentability.
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 4 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. The claim recites the limitation "the functionalized PEG" in line 1. There is insufficient antecedent basis for this limitation in the claim. Correction is requested.
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.
Claim(s) 1, 5, 6, 8, 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Tomer et al. (US 2022/0331492) in view of Gasek et al. (Acta Biomater., 2021, 131, 222–235).
Tomer teaches a composition, comprising a hydrogel matrix and microparticles within said matrix, said matrix comprising a cross-linkable protein and a cross-linking agent, wherein said cross-linking agent is able to cross-link said cross-linkable protein, wherein said microparticles comprise a drug (abstract).
The invention is directed to a composition and method for localized treatment of a tissue with controlled drug release, which features fixated beads in a hydrogel matrix. The matrix is preferably cross-linked gelatin that is cross-linked in situ, although optionally a different matrix could be used that is also capable of being cross-linked in situ. Without wishing to be limited to a closed list of benefits, the fixation prevents the beads from migrating and retains their surface area while the beads themselves provide a means for controlled drug release. Preferably, the controlled drug release is also sustained (paragraph 0017).
The composition features encapsulating the drug in polymeric microparticles to achieve zero order release kinetics (paragraph 0018).
The composition comprises a crosslinked gelatin hydrogel matrix containing microparticles. The particles contain a drug. The drug is released from the microparticles, for example and without limitation, optionally by diffusion or erosion mechanism. The rate of release is determined primarily by the material from which the microparticle is comprised of, but also by other parameters such as the type of drug, its solubility, the amount of the encapsulated drug (paragraph 0034+).
The encapsulated drug may optionally comprise one or more of antibiotics, analgesic, anti inflammatory, or anti-tumor drugs (paragraph 0056). See also claim 23.
Example 2 shows release of ciprofloxacin from PLGA microparticles embedded in enzymatically crosslinked gelatin matrix.
In addition the hydrogel preferably shows bioadhesive properties, because the adhesion to tissue is expected to prolong the residence time of the microparticles in the infected site.
Anti-inflammatory or anti-fibrosis treatment include NSAID (paragraph 0083).
Tomer does not specifically recite the adhesiveness of the composition.
Gasek teaches two sealant materials comprised respectively of alginate methacrylate and of gelatin methacryloyl, each functionalized by conjugation with dopamine HCl. Both compounds are cross-linked into easily applied as pre formed hydrogel patches or as in situ hydrogels formed at the wound site utilizing FDA-approved photo-initiators and oxidants. Material testing demonstrates appropriate adhesiveness, tensile strength, burst pressure, and elasticity with no significant cell toxicity in vitro assessments.
The tensile strength of sealants was determined by a DHR-3 rheometer (TA Instruments) based on a modified method of the Standard Test Method for Strength Properties of Tissue Adhesives in Tension, ASTM F2258–05 and the Standard Test Method for Tensile Properties of Plastics, ASTM D638–14 (page 5).
See Figure 4 showing tensile strength results.
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It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a crosslinked gel matrix having the claimed adhesion comprising microparticles, an antimicrobial and an anti-ischemic when the teaching of is taken in view of Gasek. One would have been motivated to do so because Tomer teaches that a cross-linked hydrogel composition comprising microparticles comprises one or more of antibiotics, analgesic, anti inflammatory, or anti-tumor drugs. One of ordinary skill in the art would have had a reasonable expectation of success that a cross-linked gelatin hydrogel would be capable of achieving the claimed adhesion because Gasek teaches that crosslinked gelatin may have a tensile strength in a range of approximately 10-30 kPa.
Claim(s) 1, 5-9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Tomer et al. (US 2022/0331492) in view of Gasek et al. (Acta Biomater., 2021, 131, 222–235), in further view of Zilberman (US 2015/0038424).
The rejection over Tomer in view of Gasek is applied as above.
With regard to claim 7, Tomer and Gasek do not specifically recite ibuprofen as an anti-inflammatory.
Zilberman teaches a bioadhesive formulation, comprising gelatin, alginate and a coupling agent, capable of forming a bioadhesive matrix, which is characterized by rapid curing, optimal viscosity, high bonding strength, flexibility, biocompatibility and biodegradability (abstract).
Representative examples of bioactive agents include… anti-inflammatory agents (paragraph 0259).
Ibuprofen sodium salt …is a commonly used non-steroidal anti-inflammatory drug used in the treatment of pain, fever, dysmenorrhea, osteoarthritis, rheumatoid arthritis, and other rheumatic and nonrheumatic inflammatory disorders, and vascular headaches (paragraph 0353). Two types of drug-eluting samples of bioadhesive matrices were examined: bupivacaine-loaded bioadhesive matrices and ibuprofen-loaded bioadhesive matrices (paragraph 0406).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide ibuprofen as a functionally equivalent anti-inflammatory in the compositions of Tomer in view of Gasek when the teachings of Tomer and Gasek are taken in view of Zilberman. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known NSAID for another, and the results of the substitution would have been predictable, that is sustained release from a hydrogel matrix.
Claim(s) 1 and 3-11 are rejected under 35 U.S.C. 103 as being unpatentable over Dang et al. (US 2023/0039279) in view of Tomer et al. (US 2022/0331492).
Dang teaches an inflammation-responsive drug delivery platform comprising of (1) drug-loaded domains (either particles encapsulating anti-inflammatory drugs or conjugated anti-inflammatory drug) with a tailored basal drug release profile and/or (2) a proteases-cleavable hydrogel domain. This invention provides a drug delivery platform which can be customized to cope with an inflammatory disease by changing the configuration of its drug-loaded domain and/or adjusting the plural sensitivity of its protease-triggered domain to tailor its responsiveness and specificity to the disease of interest.
According to a first aspect of the invention, there is provided a drug-loaded protease-responsive hydrogel comprising;
a) a drug encapsulated in particles;
b) a polymer building block comprising of a multi-arm-polyethylene glycol (PEG) with functional moiety; and
c) a bis-functional protease-sensitive crosslinker comprising a protease-cleavable substrate flanked by two spacer sequences containing functional moieties;
wherein said polymer building block of b) forms a gel in the presence of the protease-cleavable crosslinker of c) to entrap the particles of a) (paragraph 0012-3).
In some embodiments the drug is encapsulated in particles comprising a polymeric material selected from the group comprising polycaprolactone, poly (methacrylic acids), polylactic acids, polyvinylpirrolidone, poly(lactic-co-glycolic acid) (PLGA) and gelatin (paragraph 0018).
In some embodiments of the drug-loaded protease-responsive hydrogel of any aspect of the invention, the drug is a steroidal anti-inflammatory drug or a non-steroidal anti-inflammatory drug (NSAID), or derivatives thereof. The drug may be a steroidal anti-inflammatory drug such as Dexamethasone, Fludrocortisone, Methylprednisolone, Prednisolone, Prednisone or Hydrocortisone, or derivatives thereof. Glucocorticoids can be oxidized to add a carboxylic functional group which allows these drugs to be conjugated to the peptide anchors of the invention. Preferably the drug is a NSAID, such as Ibuprofen, Ketoprofen, Diclorofenac, Sunlindac, Piroxicam, or Celecoxib, or derivatives thereof (paragraph 0037).
There is provided a method of treatment comprising administering to a subject in need of such treatment an efficacious amount of the drug-loaded protease-responsive hydrogel of any aspect of the invention or a composition of the invention. In some embodiments the administration is by injection or topical application to the subject. In some embodiments, the treatment is for inflammation-associated diseases such as chronic wounds, inflammatory bowel diseases, arthritis and potentially infection-related conditions for which inflammation management is desirable (paragraph 0046).
Dang does not specifically teach wherein the composition comprises an antimicrobial agent for preventing infection.
Tomer teaches a composition, comprising a hydrogel matrix and microparticles within said matrix, said matrix comprising a cross-linkable protein and a cross-linking agent, wherein said cross-linking agent is able to cross-link said cross-linkable protein, wherein said microparticles comprise a drug (abstract).
The composition comprises a crosslinked gelatin hydrogel matrix containing microparticles. The particles contain a drug. The drug is released from the microparticles, for example and without limitation, optionally by diffusion or erosion mechanism. The rate of release is determined primarily by the material from which the microparticle is comprised of, but also by other parameters such as the type of drug, its solubility, the amount of the encapsulated drug (paragraph 0034+).
The encapsulated drug may optionally comprise one or more of antibiotics, analgesic, anti inflammatory, or anti-tumor drugs (paragraph 0056). See also claim 23.
Example 2 shows release of ciprofloxacin from PLGA microparticles embedded in enzymatically crosslinked gelatin matrix.
In addition the hydrogel preferably shows bioadhesive properties, because the adhesion to tissue is expected to prolong the residence time of the microparticles in the infected site.
Anti-inflammatory or anti-fibrosis treatment include NSAID (paragraph 0083).
It would have been obvious to one of ordinary skill in the art at the time of the invention to further provide an anti-infective agent in the composition taught by Dang when the teaching of Dang is taken in view of Tomer. One would have been motivated to do so because Dang teaches treatment of inflammation-associated diseases such as chronic wounds, inflammatory bowel diseases, arthritis and potentially infection-related conditions for which inflammation management is desirable, and Tomer teaches that a hydrogel matrix comprising microparticles may comprise and anti-infective and anti-inflammatory agent. With regard to the functional limitation wherein the composition is characterized by adhesiveness in the range of 0.1 to 100 kPa as measured by a tack test based on ASTM F2258-05, and the limitations of claims 10-11 directed to release kinetics, it is respectfully submitted that the matrix comprising microparticles is the same structural component as that claimed in the dependent claims, muti-arm PEG. “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
Claim(s) 1, 2, 5 and 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Bege et al. (Eur. J. Pharm. and Biopharm., 2013, 84, p. 99-105) in view of Calabrese (US 2010/0100124).
Bege teaches examination of the feasibility of nimodipine-loaded PLGA microparticles suspended in Tisseel fibrin sealant as an in situ forming depot system. This device locally placed can be used for the treatment of vasospasm after a subarachnoid hemorrhage. Microparticles were prepared via spray-drying by using the vibration mesh spray technology of Nano Spray Dryer B-90. Spherically shaped microparticles with different loadings and high encapsulation efficiencies of 93.3–97.8% were obtained. Depending on nimodipine loading (10–40%), the particle diameter ranged from 1.9 ± 1.2 µm to 2.4 ± 1.3 µm. Thermal analyses using DSC revealed that nimodipine is dissolved in the PLGA matrix. Also, fluorescent dye loaded microparticles were encapsulated in Tisseel to examine the homogeneity of particles. 3D-pictures of the in situ forming devices displayed uniform particle homogeneity in the seal ant matrix. Drug release was examined by fluorescence spectrophotometry which demonstrated a drug release proportional to the square root of time. A prolonged drug release of 19.5 h was demonstrated under in vitro conditions. Overall, the nimodipine in situ forming device could be a promising candidate for the local treatment of vasospasm after a subarachnoid hemorrhage (abstract).
Bege does not specifically teach wherein the composition further comprises an anti-infective agent.
Calabrese teaches a gel matrix that serves as an excellent tissue adhesive or sealant (paragraph 0019).
A variety of optional ingredients may also be added to the bioabsorbable compositions of the present disclosure, including but not limited to surfactants antimicrobial agents, colorants, preservatives, imaging agents e.g., iodine or barium sulfate, or fluorine, or medicinal agents. In some embodiments, the present compositions may optionally contain one or more bioactive agents. The term “bioactive agent,” as used herein, is used in its broadest sense and includes any substance or mixture of substances that have clinical use. Consequently, bioactive agents may or may not have pharmacological activity per se, e.g., a dye. Alternatively a bioactive agent could be any agent which provides a therapeutic or prophylactic effect, a compound that affects or participates in tissue growth, cell growth, cell differentiation, a compound that may be able to invoke a biological action such as an immune response, or could play any other role in one or more biological processes.
Examples of classes of bioactive agents which may be utilized in accordance with the present disclosure include antimicrobials, analgesics, antipyretics, anesthetics, antiepileptics, antihistamines, anti-inflammatories, cardiovascular drugs, diagnostic agents, sympathomimetics, cholinomimetics, antimuscarinics, antispasmodics, hormones, growth factors, muscle relaxants, adrenergic neuron blockers, antineoplastics, immunogenic agents, immunosuppressants, gastrointestinal drugs, diuretics, steroids, lipids, lipopolysaccharides, polysaccharides, and enzymes. It is also intended that combinations of bioactive agents may be used.
Suitable antimicrobial agents which may be included as a bioactive agent in the present compositions include: triclosan, also known as 2,4,4′-trichloro-2′-hydroxydiphenyl ether; chlorhexidine and its salts, including chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, and chlorhexidine sulfate; silver and its salts, including silver acetate, silver benzoate, silver carbonate, silver citrate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein, and silver sulfadiazine; polymyxin; tetracycline; aminoglycosides such as tobramycin and gentamicin; rifampicin; bacitracin; neomycin; chloramphenicol; miconazole; quinolones such as oxolinic acid, norfloxacin, nalidixic acid, pefloxacin, enoxacin and ciprofloxacin (paragraph 0050+).
The compositions have use in wound closure (including surgical incisions and other wounds), including brain tissue (paragraph 0060+). The compositions described herein can also be used as sealants. When used as a sealant, a compound of the present disclosure can be used in surgery to form a bioabsorbable composition to prevent or inhibit bleeding or fluid leakage both during and after a surgical procedure (paragraph 0062).
It would have been obvious to one of ordinary skill in the art at the time of the invention to further provide an anti-infective agent (e.g. ciprofloxacin) in the compositions comprising nimodipine-loaded PLGA microparticles suspended in fibrin sealant taught by Bege, when the teaching of Bege is taken in view of Calabrese. One would have been motivated to do so, with a reasonable expectation of success, because Calabrese teaches a gel matrix sealant may contain combinations of bioactive agents including be any agent which provides a therapeutic or prophylactic effect, as well as including an antimicrobial agent. One would have been motivated to do so in order to further treat or prevent infection using the sealants of the invention. With regard to the functional limitation wherein the composition is characterized by adhesiveness in the range of 0.1 to 100 kPa as measured by a tack test based on ASTM F2258-05, and the limitations of claims 10-11 directed to release kinetics, it is respectfully submitted that the matrix comprising microparticles is the same structural component as that claimed in the dependent claims, fibrin. “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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