DETAILED ACTION
Claims 1-5, 7-24 are currently pending. Claims 1-5, 7-18 and 24 are currently under examination.
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 .
Withdrawn Rejections
The prior rejection of claim 7 is withdrawn in light of Applicant’s clarification that the phrase release half-life is the time it takes for 50% of nitric oxide to be released from the biocompatible material, which the Examiner finds persuasive.
Examiner’s Note
Applicant's amendments and arguments filed 01/16/2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. In the Applicant’s response, filed 01/16/2026, it is noted that claim 1 has been amended and claim 24 is newly added. No new matter has been added.
Modified Rejections:
The following rejections are modified based on Applicant’s claim amendments and newly added claims.
Claim Rejections - 35 USC § 112 (b)
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 and 24 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.
Claims 1 and 24 contains the limitation of ratio of nitric oxide donor to silk fibroin nanoparticles. It is unclear if the ratio is the nitric oxide donor to silk fibroin in the nanoparticle or if it is the ratio of the nitric oxide donor to the silk fibroin nanoparticle as a whole, thus including the amount of silk fibroin, nitric oxide donor and any additional ingredients in the nanoparticles. The ratio thus has unclear metes and bounds. For examination purposes the amount of nitric oxide donor to the amount of silk fibroin will be used. It would be remedial to remove “nanoparticles” in the limitation of “nitric oxide donor to silk fibroin nanoparticles” to clearly define the ratio of the nitric oxide donor to the amount of silk fibroin.
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) 1-3, 5, 9, 11-18 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0305765 (previously applied) in view of WO 2013/169538 (previously applied) and Huerta (Huerta, Sergio, Future Sci. OA (2015) 1(1), FSO44, previously applied).
Regarding claims 1 and 24, the limitation of a biocompatible material comprising a drug embedded in silk fibroin nanoparticles is met by the ‘765 publication teaching nanoparticle for drug delivery that include fibroin polypeptide and a drug (abstract). The drug is taught as incorporated into the nanoparticles that include fibroin, wherein silk fibroin is taught [0012].
The limitation of wherein the ratio of drug to silk fibroin nanoparticle is about 2:1 to about 1:4 or about 1.5:1 to about 1:1.5 met by the ‘765 publication teaches 2-75% drug [0143] and the coatings may be 0.1% or 10% Silk fibroin or a ration of silk fibroin to chitosan (Table 1). As MPEP 2144.05 recites “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine optimization”. The ‘765 publication teaches ranges of both the active agent and silk fibroin to form the nanoparticles and additionally teaches the blends lead the drug release [0201], thus it would have been prima facie obvious to one of ordinary skill in the art to optimize the amount of drug and silk fibroin in the nanoparticles to obtain the desired release rate.
Regarding claim 5, the limitation of wherein the silk fibroin nanoparticle have diameter of about 300 nm to about 500 nm is met by the ‘765 publication teaching the nanoparticle has a diameter of about 1nm to 500 nm [0013].
Regarding claim 9, the limitation of wherein the drug is from about 5% to about 15% by weight of the biocompatible material is met by the ‘765 publication teaching the pharmaceutical compristion includes at least 0.1 wt% of the drug such as 2-75% of the drug [0143]. As MPEP 2144.05 recites “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine optimization”.
Regarding claim 11, the limitation of wherein the biocompatible material further comprises a drug is met by the ‘765 publication teaching combinations of drugs being used [0016].
Regarding claims 12-13 and 16-18, the limitation of a biocompatible material produced by the method comprising mixing a drug composition comprising the drug and a binary solvent with a silk fibroin to form a first composition comprising the biocompatible material and isolating the biocompatible material form the first compristion is met by the ‘765 publication teaching preparing the nanoparticles by preparing a composition that includes silk fibroin, the one or more drugs and a carrier, wherein the carrier may be solvent such as water, ethanol or combinations thereof, dispersing the composition a surface, lyophilizing the surface to remove the carrier, wherein dried dots of the compristion include silk fibroin and the drug are formed on the surface to form the nanoparticles, the dots may be washed and buffered ([0030] ([0145]). The nanoparticles may be purified by centrifugation and removal of the supernatant [0101]. MPEP 2113 - “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
The ‘765 publication does not specifically teach nitric oxide donor (claim 1) wherein the nitric oxide donor is S-nitrosothiol compound (claim 2) selected from a group including S-nitroso-N-acetyl-penicillamine and S-nitroso-N-acetyl cysteine (claim 3 and 14-15).
The ‘538 publication teaches nanoparticles are provided that comprise S-nitrosothiol groups containing molecules encapsulated within the nanoparticles (abstract). S-nitrosothiol encapsulated within the nanoparticle include S-nitroso-N-acetyl cysteine [0019]. The nanoparticle comprises for example chitosan [0020]. The nanoparticles can be used to treat the disease or disorder that is treatable with nitric oxide [0036].
Huerta teaches nitric oxide has a role in cancer therapeutics either as a single agent or in combination with other antineoplastic compounds. NO might be used to overcome tumor cell resistance to conventional treatments (abstract). Two compounds typically used as antineoplastic agents are S-nitroso-N-acetylpenicillamine (SNAP) and S-nitroglutathione (page 4, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to use SNAP nitric oxide generating agent in the silk fibroin particles taught by the ‘765 publication because the ‘765 publication teaches silk fibroin particles which may comprise any active ingredient in the treatment of cancer and Huerta teaches nitric oxide such as SNAP being used as antineoplastic agents to treat cancer. One of ordinary skill in the art before the filing date of the claimed invention would have a reasonable expectation of success as the ‘765 publication teaches the use of any active ingredient in nanoparticles and the ‘538 publication teaches that it is known to encapsulate S-nitrothiol groups in nanoparticles, wherein Huerta teaches SNAP is an S-nitrothiol. One of ordinary skill in the art before the filing date of the claimed invention would be motivated to use SNAP in the nanoparticles as the ‘765 publication teaches the silk fibroin particles for the treatment of cancer and Huerta teaches SNAP to be used to treat cancer as an antineoplastic agent.
Claim(s) 4, 10 and 12-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0305765, WO 2013/169538 and Huerta as applied to claims 1-3, 5, 9, 11-18 and 24 above, and further in view of CN 107041875 (Applicant provided).
As mentioned in the above 103(a) rejection, all of the limitations of claims 1-3, 5, 9, 11-18 and 24 are taught by the combination of the ‘765 publication, the ‘538 publication and Huerta.
The combination of reference does not specifically teach hydrophobic core wherein the majority of the nitric oxide donor is present in the hydrophobic core of the silk fibroin nanoparticles (claim 4).
The combination of references does not specifically teach wherein the biocompatible material has a negative charge of about -25 mV to about -30 mV (claim 10).
The ‘875 publication teaches silk protein nanoparticles [0002]. The nanoparticles are used for drug accumulation at targeted tumor sites and overcome drug intracellular drug delivery and achieve controlled and sustained release [0007]. Silk fibroin has been shown to possess several unique properties such as biocompatibility, tunable biodegradation and stabilization making it a potential drug delivery vehicle capable of delivering a range of therapeutic drugs [0007]. The drug and silk fibroin are taught as dissolved in a binary mixed solvent of ethanol and acetone. The resulting suspension is frozen, thawed and centrifuged to obtain silk fibroin nanoparticles loaded with the drug [0016]. The particles are dissolved in a binary solvent of ethanol and acetone (3>2) added dropwise thereto under gentle stirring, freeze dried, thawed in water, the nanoparticles were collected by centrifugation, washed to remove impurities and freeze dried [0052]. Zeta potential is taught to be-27 and -25.5 [0078]. The SF form random coil/helix to beta-sheet because of the mutual hydrophobic interaction between the drug and Silk fibroin macromolecules. The beta-sheet formation induced by drug may be beneficial or their entrapment of silk fibroin nanoparticles, thus causing slow drug release effect in subsequent applications [0082].
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to use a binary solvent mixture to form the silk fibroin nanoparticles as the ‘765 publication teaches a combination of solvents may be used to form the nanoparticles and the ‘875 publication specifically teaches the desire to use a binary solvent mixture to form drug containing silk fibroin particles. One of ordinary skill in the art before the filing date of the claimed invention would have an expectation of success of a drug being held in the hydrophobic core of the nanoparticle as the ‘875 publication teaches the drug encapsulated in the hydrophobic core of silk fibroin nanoparticles. One of ordinary skill in the art before the filing date of the claimed invention would have an expectation of success in having the zeta potential claimed as the ’765 publication teaches silk fibroin nanoparticles and the ‘875 publication teaches known zeta potential of silk fibroin nanoparticles. One of ordinary skill in the art before the filing date of the claimed invention would have an expectation of success as the ‘765 publication and the ‘875 publication are both directed to the formation of drug containing silk fibroin nanoparticles formed by a solution of silk fibroin, drug and solvent and containing the steps of centrifuging and freeze drying.
Claim(s) 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0305765, WO 2013/169538 and Huerta as applied to claims 1-3, 5, 9, 11-18 and 24 above, and further in view of Privett (Privett, Benjamin et al, Nitric Oxide 26 (2012) pgs. 169-173, previously applied).
As mentioned in the above 103(a) rejection, all of the limitations of claims 1-3, 5, 9, 11-18 and 24 are taught by the combination of the ‘765 publication, the ‘538 publication and Huerta.
Privett teaches controlled NO storage using NO donors including S-nitroso-N-acetylpenicillamine (page 1, second paragraph). The short half-life of less than 10 seconds of NO in physiological milieu prevents deliver at infection sites. NO particles are taught to release over extended periods from minutes to days, allowing for more targeted NO delivery thus ensuring more lethal concentrations of NO (page 170, second column, last paragraph). NO donors tend to release their NO payload more quickly, especially in aqueous media (page 171, first column, first paragraph). Nanoparticle size is taught. Release of .09 umol/mg release per particle (page 171, first column second paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to optimize the release half life of the nitric oxide and the amount of nitric oxide released as the ‘765 publication teaches the result of the drug release is based on the composition and structure of the coating and the release mechanism, the drug release if a mechanism of diffusion from the silk fibroin particles wherein the amount of drug may be present over a wide range, thus teaching the drug release rate if an optimizable parameter. It would have been obvious to one of ordinary skill in the art to optimize the drug release as Privett teaches NO particles releasing over periods of over minutes to days being desired, thus teaching a desired release rate overlapping with the instant claims wherein the ‘765 publication teaches the release amount and rate to be an optimizable parameter. As MPEP 2144.05 recites “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine optimization”.
Response to Arguments:
Applicant’s arguments have been fully considered and are not deemed to be persuasive.
112(b):
Applicant argues claim 6 limitations have been amended to include I claim 1. The weigh ratio is based on the relative weight of nitric oxide donor and silk fibroin nanoparticle used to produce the biocompatible material and thus the ratio is clear.
In response, it is unclear if the ratio is the nitric oxide donor to silk fibroin in the nanoparticle or if it is the ratio of the nitric oxide donor to the silk fibroin nanoparticle as a whole, thus including the amount of silk fibroin, nitric oxide donor and any additional ingredients in the nanoparticles. This if further demonstrated by the instant specification teaching the ratio is the nitric oxide donor to silk fibroin [0060], thus clearly demonstrating the ratio is the nitric oxide donor to silk fibroin, wherein the instant claims include silk fibroin nanoparticles, thus making it unclear if the ratio is the total amount of nanoparticles formed of silk fibroin or directed to the amount of silk fibrion only. The ratio thus has unclear metes and bounds. For examination purposes either interpretation will be deemed to read on the instant claims.
103: The ‘765 publication (Mathur), the ‘538 publication (Nacharaju) and Huerta
Applicant argues that even if the skill artisan was to start with the teaching of the ‘765 publication the weight ratio ranges of drug to silk fibroin is from 0.1 to 750, compared to the claimed with ratio range of about 2:1 toa bout 1:4. The range taught by the ‘765 publication is much broader than that of the instant claims and the teachings of the ‘765 publication are not directed one way or another to use higher or lower amounts.
In response, the ‘765 publication teaches 2-75% drug [0143] and the coatings may be 0.1% or 10% Silk fibroin or a ratio of silk fibroin to chitosan (Table 1). As MPEP 2144.05 recites “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine optimization”. The ‘765 publication teaches ranges of both the active agent and silk fibroin to form the nanoparticles and additionally teaches the blends lead the drug release [0201], thus it would have been prima facie obvious to one of ordinary skill in the art to optimize the amount of drug and silk fibroin in the nanoparticles to obtain the desired release rate. Applicant has not demonstrated criticality of the claimed range, thus the rejection is maintained.
Applicant presents data regarding the criticality of the range wherein Applicant has disclosed that the mass ratio of nitric oxide donor to silk fibroin is important with respect to obtaining the highest loading capacity of the nitric oxide done in the silk fibroin nanoparticles. Table 2 page 24 of the instant specification summarized the results.
In response, Applicant provides data for the SNAP:SF ratio of 2:1, 1:1, 1:2 and 1:4 measuring the encapsulation efficiency and the loading capacity. Applicant has not provided data for outside the claimed range and thus has not demonstrated criticality as there is no comparison date. If Applicant is intending to demonstrate superiority at the 1:1 ration the claims are not commensurate in scope and additionally the 1:4 ratio demonstrates the best encapsulation efficiency.
Applicant argues the additionally claims are dependent upon claim 1 and thus patentably in view of the arguments above.
In response, Applicant’s arguments regarding instant claim 1 are addressed as first presented.
Conclusion
No claims are allowed.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNDSEY MARIE BECKHARDT whose telephone number is (571)270-7676. The examiner can normally be reached Monday-Thursday 9am to 4pm and Friday 9am to 2pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian-Yong Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LYNDSEY M BECKHARDT/Examiner, Art Unit 1613
/BRIAN-YONG S KWON/ Supervisory Patent Examiner, Art Unit 1613