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 Arguments filed on 10/31/2025.
Claims 1, 23 and 25 have amended.
Claims 9, 18, 22, 24, 34, 38, and 40 have been cancelled. Claims 26-33 and 35-37, 39 and 41-43 are withdrawn from consideration for non-elected invention. Accordingly, claims 1-8, 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Any previous rejections and/or objections not reiterated herein have been withdrawn in view of amendments and arguments filed on 10/31/2025. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
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 1-8, 10-17, 19-21 and 44 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. Specifically, the boronic acid-drug conjugate comprising :
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, the term “X” has not been clearly defined so that one of ordinary skill in the art would know what structures are included and/or excluded by the term. Therefore, the claims are considered to be indefinite. Applicants are suggested to include the specific agents that are embraced by the term “X” which have clear support in the specification. Thus, the claims and claims 1-8, 10-17, 19-21 and 44 which depend from it which do not rectify the issue are considered to be indefinite.
Claims 1-8, 10-17, 19-21 and 44 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.
The term “in close proximity to the polymer” in claim 1 is a relative term which renders the claim indefinite. The term “in close proximity” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear to what extent or distance the drug conjugate is incorporated into the polymer to maintain the close proximity in the sensor. Thus, the claims and claims 1-8, 10-17, 19-21 and 44 which depend from it which do not rectify the issue are considered to be indefinite.
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) 1-8, 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).
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 within 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).
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 attached to a surface of the nanoporous substrate (abstract). In one embodiment, discloses the design and manufacture of porous membranes which are responsive to external stimuli, and to blood analyte monitoring and drug delivery devices comprising the membranes, in particular for the monitoring of glucose and for the treatment of patients with diabetes (0001). 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 phenylboronic acid moieties may be protected or unprotected. Particular examples, include of the structural formula:
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and
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, wherein X=NH, R1=H (0086). Exemplary glucose responsive hydrogels are phenylboronic acid hydrogels comprising 3-(acrylamido)phenylboronic acid) or 2-(acrylamido)phenylboronic acid as the phenylboronic acid moiety (0090 and claim 26, reads on instantly claimed compounds). Additional disclosure includes that, advantageously hydrogels according to the present invention show significant response to changes in glucose concentration, showing reversible and reproducible swelling properties subject to changes in glucose concentration. Hydrogels are able to provide good resistance to flow of water, and molecules such as insulin, due to their particular cross-linked matrix structure.
Cadahia discloses 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 H2O2 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 are highly stable and are resistant to heat, they can therefore be easily sterilized, e.g. by autoclave, or gamma radiation. A further advantage of the use of phenylboronic acid-based hydrogels over glucose responsive hydrogels containing proteins such as glucose oxidase or lectins is that problems due to leakage of the of the proteins from the gel can be avoided (0083) and reasonably would have expected success because glucose responsive membranes show significant response to changes in glucose concentration at physiological conditions. Advantageously, glucose responsive membranes can provide good selectivity for glucose, and reversible and reproducible swelling properties subject to changes in glucose concentration and provide good resistance to flux of water, and molecules such as insulin.
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.
Conclusion
No claims are allowed at this time.
Claim 1 is currently amended, wherein X is completely deleted. Therefore, as amended, drug is covalently attached to one or more of the compounds via a linking group required new ground of rejection.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGADISHWAR RAO SAMALA whose telephone number is (571)272-9927. The examiner can normally be reached Monday-Friday 9am-6pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Hartley G Michael can be reached at 571 272 0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.R.S/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618