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 .
Receipt is acknowledged of Applicant’s Amendments and Request for Continued Examination filed on 04/09/2026 and 05/04/2026.
Claims 1, and 3 have been amended. Claims 4, 9, 18, 22, and 24 have been cancelled. Non-elected claims are withdrawn for consideration. Claims 1-3, 5-8, 10-17, 19-21, 23, 25 and 44 are pending and presented for examination.
Any previous rejections and/or objections not reiterated herein have been withdrawn in view of amendment and arguments filed on 04/09/2026. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
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) 1-3, 5-8, 10-17, 19-21, 23, 25 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Huffstetler et al. (US 2015/0057509) in view of Lavanant et al. (US 20120150006) and Jorge Peiro Cadahia et al. (J Med Chem, 61, 3503-3515, 2018) are maintained for reasons of record in the previous office action mailed on 02/08/2026.
Huffstetler discloses a sensor (e.g., an optical sensor) that may be implanted within a living animal (e.g., a human) and may be used to measure an analyte (e.g., glucose or oxygen) in a medium (e.g., interstitial fluid, blood, or intraperitoneal fluid) within the animal. The sensor may include a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and one or more therapeutic agents. The one or more therapeutic agents may reduce deterioration of the analyte indicator. The one or more therapeutic agents may be incorporated within the analyte indicator, a membrane covering at least a portion of the analyte indicator, and/or one or more drug eluting polymer matrices, which may be external to or within the sensor housing (abstract). A sensor may include an analyte indicator, which may be in the form of indicator molecules embedded in a graft (i.e., layer or matrix). For example, in an implantable fluorescence-based glucose sensor, fluorescent indicator molecules may reversibly bind glucose and, when irradiated with excitation light (e.g., light having a wavelength of approximately 378 nm), emit an amount of light (e.g., light in the range of 400 to 500 nm) that depends on whether glucose is bound to the indicator molecule. In some embodiments, the indicator molecules 104 may be fluorescent indicator molecule and reversibly bind an analyte (e.g., glucose, oxygen, cardiac markers, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides) (0006 and 0034). In some embodiments, the one or more therapeutic agents may be chemically incorporated with in the drug eluting polymer matrix, membrane, or hydrogel and/or polymer containing the analyte indicator. One or more therapeutic agents may be incorporated within the drug eluting polymer matrix, membrane, or hydrogel and/or polymer containing the analyte indicator via covalent bonds. The drug eluting polymer matrix, membrane, or hydrogel and/or polymer containing the analyte indicator may release the one or more therapeutic agents when one or more of the covalent bonds are broken. The covalent bonds may break in the presence of water (e.g., in the presence of water in the interstitial fluid, blood, or intraperitoneal fluid), or alternatively break through exposure to ultraviolet or visible light (0068). In some embodiment, the drug-eluting polymer matrix may be applied to the sensor housing 102 via dip coating. FIG. 8, the drug-eluting polymer matrix may have a pre-formed shape such as, for example, a ring or sleeve, cylinder, or any suitable monolith (e.g., rectangular) shape (0055). In some non-limiting embodiments, the analyte indicator may be a polymer graft 106 coated, diffused, adhered, or embedded on at least a portion of the exterior surface of the sensor housing. In some embodiments, the analyte indicator (e.g., polymer graft) of the sensor may include indicator molecules and may be distributed throughout the entire graft or only throughout one or more portions of the graft (0033 and 0034). In some embodiments, the one or more therapeutic agents, which may be dispersed within the drug eluting polymer matrix, may include one or more anti-inflammatory drugs, such as, for example, non- - steroidal anti-inflammatory drug (e.g., acetylsalicylic acid (aspirin) and/or isobutylphenylpropanoic acid (ibuprofen)), one or more glucocorticoids, one or more of dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclometasone, fludrocortisone, derivatives thereof, and analogs thereof. The one or more therapeutic agents may reduce the production of hydrogen peroxide by neutrophils and macrophages. In some embodiments, the one or more therapeutic agents may reduce deterioration of the analyte indicator (0064). In some non-limiting embodiments, one or more therapeutic agents may be incorporated within the drug eluting polymer matrix, membrane, or hydrogel and/or polymer containing the analyte indicator via covalent bonds (0068).
Huffstetler fails to disclose drug covalently attached to one or more of the compounds
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and boronic acid-drug conjugates comprising drug covalently attached to a boronic acid moiety.
Lavanant discloses a glucose responsive membrane comprising a nanoporous support substrate and a coating of a glucose responsive hydrogel is covalently attached to a surface of the nanoporous substrate (abstract). The glucose responsive hydrogel advantageously comprises phenylboronic acid functional groups, and reversibly changes its three-dimensional configuration and/or surface properties in response to changes in glucose concentration occurring in the medium contacting the hydrogel under physiological conditions.(0037). In one embodiment, discloses a medical device for the monitoring and/or regulation of glucose levels in a patient including a glucose responsive membrane, which reversibly changes its hydraulic permeability subject to changes in glucose concentration, said membrane comprising a nanoporous support substrate and a biointerface comprising a glucose responsive hydrogel coating covalently attached to a surface of the nanoporous support substrate. The glucose responsive hydrogel advantageously comprises a polymeric matrix functionalized with phenylboronic acid moieties. Said medical device may optionally include means for administration of a quantity of a drug capable of adjusting glucose concentration, according to a determined glucose concentration (0051). The hydrogels may include polymeric matrix of suitable monomer groups, such as methacrylate, acrylate, methacrylamide, acrylamide or vinylic monomer groups, functionalized with the glucose binding moiety, e.g. phenyl boronic acid moieties (0081 and 0114). The phenylboronic acid moieties may be protected or unprotected. Particular examples, include of the structural formula:
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, wherein X=NH, (0086).
Exemplary glucose responsive hydrogels are phenylboronic acid hydrogels comprising 3-(acrylamido)phenylboronicacid) or 2-(acrylamido)phenylboronicacid as the phenylboronic acid moiety (0090 and claim 26, reads on instantly claimed compounds). According to illustrated FIG.1B, methacrylate or acrylate or methacrylamide or acrylamide or vinylic monomers functionalized with active ester groups (11), and optionally, (ii) monomers such as non-functionalized methacrylate or acrylate or methacrylamide or acrylamide or vinylic monomers and/or cross-linkers, such a cross-linker groups of formula (VII) and suitable active ester functional groups include active ester groups of the structural formulae
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or
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(0126-0128). Additional disclosure includes that, the glucose responsive membranes comprising phenylboronic acid-based glucose responsive hydrogel are particularly advantageous for the use in medical device applications for the monitoring or regulation of glucose levels, e.g. insulin, may be delivered by the medical device.
Cadahia is made of record to illustrate that it is well known in the art to generate drug conjugates comprising 4-methylphenylboronic acid promoieties linked to the drug via a carbonate linkage or a direct C-N bond. In particular, it is disclosed a series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) synthesis and evaluated for therapeutic efficacy with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drug via a carbonate linkage or a direct C-N bond (abstract).
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Activation under pathophysiological concentrations of H202 proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physiochemical and pharmacokinetic assays.
It would have been obvious to one of ordinary skill in the art at the time the invention was to incorporate compounds comprising 3-(acrylamido)phenylboronic acid) or 2-(acrylamido)phenylboronic acid as the phenylboronic acid moiety into Huffstetler's sensor composition. The person of ordinary skill in the art would have been motivated to make those modifications because Lavanant teaches glucose responsive hydrogels based on phenylboronic acid or derivatives show good properties for resistance to flux of molecules such as water and insulin, and exhibit good selectivity for glucose, are sensitive to glucose under physiological conditions, show significant glucose response, and respond reversibly and reproducibly to high and low glucose concentrations (0082) and reasonably would have expected success because glucose responsive membranes comprising phenylboronic acid based glucose responsive hydrogel are particularly advantageous for the use in medical device applications for the monitoring or regulation of glucose levels.
It would have been obvious to one of ordinary skill in the art at the time the invention was to incorporate boronic acid-drug conjugates comprising drug covalently attached to a boronic acid moiety into Huffstetler's composition. The person of ordinary skill in the art would have been motivated to make those modifications because Cadahia teaches that selected candidates (MTX) and (ATM) showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model and reasonably would have been expected success because the
prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and ATM while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients.
Response to Applicant’s Arguments
Applicant arguments filed on 04/09/2026 have been fully considered but they are not persuasive. Applicant argues that neither Huffstetler nor Cadahia discloses a boronic acid-drug conjugate comprising a boronic acid moiety and a drug covalently attached to the boronic acid moiety, and Lavanant does not disclose or suggest incorporation of a boronic acid-drug conjugate into a polymer for use in a sensor. This argument is not persuasive since Huffstetler reference is relied upon to show that it is known in the art to a sensor that includes analyte indicator molecules, and one or more therapeutic agents incorporated within the drug eluting polymer matrix, membrane, or hydrogel and/or polymer containing the analyte indicator via covalent bonds, while Cadahia shows an equivalence that is recognized in the art to the prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drug via a carbonate linkage or a direct C-N bond that would read on a boronic acid-drug conjugate comprising a boronic acid moiety and a drug covalently attached to the boronic acid moiety. Lavanant discloses a medical device for the monitoring and/or regulation of glucose levels in a patient comprising: an implantable member comprising a glucose responsive membrane, said membrane comprising a nanoporous support substrate and a biointerface comprising a glucose responsive hydrogel coating covalently attached to a surface of the nanoporous support substrate, said glucose responsive hydrogel advantageously comprises a polymeric matrix functionalized with phenylboronic acid moieties (0051 and claim 36). And FIG.1B, illustrates methacrylate or acrylate or methacrylamide or acrylamide or vinylic monomers functionalized with active ester groups (11), and optionally, (ii) monomers such as non-functionalized methacrylate or acrylate or methacrylamide or acrylamide or vinylic monomers and/or cross-linkers. These phenylboronic acid functionalized polymeric matrix having activated ester groups when reacted with drug molecules would obviously generate boronic acid-drug conjugate comprising a boronic acid moiety and a drug covalently attached to the boronic acid moiety as shown by Huffstetler reference to a sensor that includes analyte indicator molecules, and one or more therapeutic agents may be incorporated within the drug eluting polymer matrix, membrane, or hydrogel and/or polymer containing the analyte indicator via covalent bonds. Consistent with this reasoning, it would have obvious to have selected the various combinations of features claimed from within the prior art disclosure, specifically with a boronic acid-drug conjugate core comprising drug covalently attached to the boronic acid moiety of polymeric matrix, to arrive at the instantly claimed compositions.
Conclusion
No claims are allowed at this time.
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/J.R.S/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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