DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/31/2026 has been entered.
Response to Amendment
Applicant’s response of 07/31/2026 has been received and entered into the application file. Claims 1-2, 10-11, 20, 26, 39, 70, 75, 77, 79-80, 83, 85, 87, 89-90 and 92 are pending in this 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.
Claims 1-2, 10-11, 17, 20 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al. (US 2018/0235894 A1), Zepp et al. (US 2018/0256709 A1), and Zhang et al. (US 2018/0169027 A1).
Gu discloses a platelet membrane-coated nanoparticle having an inner core comprising a drug delivery matrix, and an outer shell platelet membrane coating the inner core. The inner core can be any drug delivery matrix capable of delivering a therapeutic agent to a cell. The outer shell platelet membrane can be a natural or synthetic membrane comprising platelet proteins capable of interacting with cancer cells. Also disclosed is a method for treating cancer in a subject that involves administering to the subject a platelet membrane-coated nanoparticle (Abstract). The active drug can be imiquimod ([0095]). The inner core comprises a polymer ([0038]) and polymers can be poly(lactic-co-glycolic acid) (PLGA), polycaprolactam (PCL), polylactic acid (PLA), polyglycolic acid (PGA) ([0047]). Gu teaches that the platelet membrane-coated nanoparticles have diameters from about 10 nm to about 1000 nm ([0040]). The inner core can be biodegradable ([0044]).
Zepp discloses conjugates of immunomodulatory agents and polymers. The conjugates may be contained within synthetic nanocarriers (Abstract). The immunomodulatory agent and polymers or unit thereof are coupled covalently via an amide or ester bond. In some embodiments, these conjugates form part of a synthetic nanocarrier. In general, a polymer, such as polylactide (PLA) or poly(lactic-co-glycolic acid) (PLGA) can be conjugated with an immunostimulatory agent, such as resiquimod (also known as R848), in several ways ([0182]).
Zhang discloses methods, combinations and pharmaceutical compositions for preventing and/or treating infection by a platelet-targeting microbe in a subject. A nanoparticle comprising an inner core comprising a non-cellular material, an outer surface comprising a cellular membrane derived from a platelet and an agent for preventing an infection. (Abstract). The platelet-targeting microbe can bind to a toll-like receptor (Claim 48). The nanoparticle can comprise any suitable inner core such as PLGA, PLA, PGA, PCL, and others ([0046]). The nanoparticle can comprise a plasma membrane derived from a platelet ([0047]). The composition can comprise at least about 1%-99% (w/w) or more of the nanoparticles that comprise an outer surface comprising a platelet cellular membrane ([0059]).
One of ordinary skill in the art would routinely experiment with different concentrations of each component within a nanoparticle composition. Gu clearly teaches that the biodegradable polymer core, outer surface comprising a cellular membrane derived from a platelet, and an immunomodulating agent such as imiquimod are routinely used.
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to arrive at a nanoparticle comprising an inner core, an outer surface derived from a platelet, and an immunomodulating agent that is a toll-like receptor (TLR) agonist. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 2, a polymer is discussed above.
Regarding claim 10, inner core comprising polymers is discussed above.
Regarding claim 11, platelet-derived membrane is discussed above.
Regarding claim and 20, toll-like receptor agonists such as resiquimod and imiquimod are discussed above.
Regarding claim 26, the inner core supporting outer surface would be an obvious function of a nanoparticle. As discussed above, Gu discloses that the inner core is coated with outer shell platelet membrane.
Claims 39, 70, 75-77, 79-80, 83, 85, 87, 89-90, and 92 are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al. (US 2018/0235894 A1), Zepp et al. (US 2018/0256709 A1), and Zhang et al. (US 2018/0169027 A1) as applied to claims 1-2, 10-11, 20 and 26 above, and further in view of Hu et al. (Nanoparticle biointerfacing via platelet membrane cloaking, Nature, 2015 October 1) and Tang (Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-kB activation, Molecular Cancer, 2017).
Hu reports on the preparation of polymeric nanoparticles enclosed in the plasma membrane of human platelets, which are a unique population of cellular fragments that adhere to a variety of disease-relevant substrates. The resulting nanoparticles possess a right-side-out unilamellar membrane coating functionalized with immunomodulatory and adhesion antigens associated with platelets. The platelet membrane-cloaked nanoparticles have reduced cellular uptake by macrophage-like cells (Abstract). Hu discloses that vancomycin-loaded nanoparticles were synthesized using a double emulsion process. The inner aqueous phase consisted of vancomycin and NaOH. The outer phase consisted of PLGA polymer dissolved in dichloromethane. The first emulsion was formed via sonication. The resulting emulsion was then emulsified in aqueous solution and the solvent was evaporated. The nanoparticles are then collected via centrifugation (pg 6, last paragraph).
Hu discloses a routinely practiced process called double emulsion process for creating nanoparticles. Additionally, Gu discloses a process for making a platelet membrane-coated nanovehicles (PM-NV). The NV encapsulated with Dox was prepared using a single emulsion method; aqueous phase was added into the organic phase; then the NV was precipitated and washed. To acquire purified platelets membrane, the obtained platelets were added into lysis buffer; then, the mixture was centrifuged; after sonication, the obtained PM and Dox-NV mixture was stirred and maintained overnight ([0119-0120]). And as discussed above, one of ordinary skill in the art practicing these routine processes would experiment with various concentrations of each component within a nanoparticle composition; depending on how the process was executed, various diameter sizes can be experimented as well.
Tang discloses that tetracyclines increase the expression of lipid phosphate phosphatases at the surface of cells. These enzymes degrade circulating lysophosphatidate and therefore doxycycline increases the turnover of plasma lysophosphatidate and decreases its concentrations. Extracellular lysophosphatidate signals through six G protein-coupled receptors and it is a potent promoter of tumor growth, metastasis and chemo-resistance. In this work, Tang used a syngeneic orthotopic mouse model of breast cancer to determine the impact of doxycycline on circulating lysophosphatidate concentrations and tumor growth. Doxycycline decreased plasma lysophosphatidate concentrations, delayed tumor growth and decreased the concentrations of several cytokines/chemokines in the tumor. These results contribute a new dimension for understanding the anti-inflammatory effects of tetracyclines, which make them potential candidates for adjuvant therapy of cancers and other inflammatory diseases (Abstract).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have arrived at the process of claim 39 and additionally using doxycycline as an adjunct therapy for cancer. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 70, Gu discloses drugs to treat cancer ([0094]) as well as a method for treating cancer in a subject that involves administering to the subject a platelet membrane-coated nanovehicle ([0102]).
Regarding claim 75, Gu teaches that the term “subject” refers to humans ([0029]).
Regarding claim 76-77, toll-like receptor (TLR) agonists such as resiquimod and imiquimod are discussed above.
Regarding claims 79-80, Gu discloses that the cancer may be a solid tumor, metastatic cancer, or non-metastatic cancer. The cancer may originate in the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, duodenum, small intestine, large intestine, colon, rectum, anus, gum, head, kidney, liver, lung, and others ([0104]).
Regarding claim 83, Gu discloses that the compositions may be administered intratumorally ([0108]).
Regarding claims 85 and 87, one of ordinary skill in the art would contemplate doxycycline as an add-on therapy for cancer as taught by Tang.
Regarding claim 89, Gu discloses a platelet membrane-coated core-shell nanovehicle, which can sequentially and site-specifically deliver both extracellularly active drugs and intracellularly functional drugs to cancer cells ([0004]). One of ordinary skill in the art would immediately envisage that such a nanoparticle can be administered to a subject as a first, second, third or as any line of treatment for cancer.
Regarding claim 90, Gu discloses that the cancer to be treated can be a chemo-resistant cancer ([0104]).
Regarding claim 92, Gu discloses the tumor targeting capability of platelet membrane nanovehicle (PM-NV); PM-NV exhibited strong fluorescence signal at the tumor site at 6-hour post-injection. As time extended, elevated fluorescence intensity was found at the tumor site of mice treated with PM-NV. Additionally, a prolonged retention time at tumor site was achieved by PM-NV at 48-hour post injection. The enhanced accumulation of PM-NV at tumor site was further validated by the distribution of Dox ([0157]).
Gu evaluates and discloses the tumor targeting capability of a platelet-membrane coated nanoparticle. In a cancer patient, such targeting capability and enhanced accumulation of cancer drugs at tumor site would subsequently and likely increase the survival rate of a cancer patient. One of ordinary skill in the art would routinely experiment with a platelet-membrane coated nanoparticle comprising an immunomodulating agent to determine cancer targeting capability as well as survival rate of cancer patients.
Response to Arguments
Applicant’s arguments filed 07/31/2027 have been fully considered but is not found to be persuasive.
On page 10 of remarks, applicant argues that resiquimod at a level of about 1 to about 10 weight percent is not taught. Applicant continues to argue that two of the three cited references do not teach resiquimod. Per MPEP 2145 (IV), One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. Zepp reference was incorporated to teach that immunomodulating agents that is a TLR agonist such as resiquimod is routinely practiced within the art. One of ordinary skill in the art would routinely consider any and all immunomodulating agents within a nanoparticle composition for the possible treatment of cancer. Furthermore, Zhang teaches various ways to prepare platelet membrane-cloaked nanoparticles (PNP). Docetaxel-loaded PLGA nanoparticle cores were prepared via a nanoprecipitation process - 10 wt% docetaxel was added to 5 mg PLGA in acetone and precipitated ([0142]). One of ordinary skill in the art would immediately envisage that 10 wt% of an active ingredient can be used within platelet-membrane derived nanoparticles. Applicant argues that there would be endless possible ratios of each component within a nanoparticle if routinely experimenting. The Examiner does not understand the argument. If there are endless ratios through routine experimentation, why is the Applicant’s weight ratio any significant? Is the claimed ratio in claim 1 more efficacious compared to other ratios? The Examiner cannot determine the significance.
On pages 12-13 of remarks, applicant argues that there is no motivation to combine prior art reference teachings. The applicant, again, attacks each reference individually. The argument is discussed above. Zepp clearly teaches that resiquimod can be delivered within a nanocarrier ([0182]). One of ordinary skill in the art would immediately envisage that resiquimod can be delivered within a platelet-membrane coated nanoparticle as well from combined teachings of prior art references.
On pages 14-18, applicant cites various paragraphs from instant specification then concludes by saying superior technical properties as compared with comparable nanoparticles without platelet membrane coating. Gu discloses that a platelet membrane-coated nanoformulation was developed for delivery of TRAIL and Dox. By taking advantage of the specific affinity between platelets and cancer cells, nanoformulations with platelet membrane coating can efficiently deliver active ingredients to cancer cells ([0161]). The advantages of platelet membrane-coated nanoparticles are not new information. Instead of citing the obvious advantage or feature of platelet membrane-coated nanoparticle, the Examiner encourages applicants to explain how their specific weight ratio within the nanoparticle imparts some unexpected results or advantages.
On page 19, applicant argues that resiquimod is covalently conjugated in Zepp. However, Zepp teaches that immunomodulatory agent, antigen, and/or targeting moiety can be noncovalently associated with a polymeric matrix ([0203]).
On page 21, applicant argues that the method taught in Hu is different. The instant application utilizes a nanoemulsion process. Gu teaches that methods of encapsulating drugs into particles are known in the art ([0048]). Gu discloses that the NV encapsulated with Dox was prepared using a single emulsion method ([0119]). Likewise, one of ordinary skill in the art would utilize routine processes to create nanoparticles. In claim 39, an immunomodulating agent is contacted with a polymer to form an organic phase, then the organic phase is mixed with an aqueous phase to form a primary emulsion. However, a process for making a nanoparticle is routinely practiced by one of ordinary skill in the art. Gu discloses many methods of encapsulating drugs into particles, not limited to, spray drying, interfacial polymerization, hot melt encapsulation, phase separation encapsulation, solvent evaporation microencapsulation, coacervation, phase inversion nanoencapsulation among others ([0048]). Gu discloses a method – a polymer with an active agent is mixed in an organic phase, then the organic phase is suspended in an aqueous solution. The resulting emulsion is stirred, then organic solvent is removed. Then the emulsion is collected ([0061]). The process of making a nanoparticle in claim 39 is routinely practiced and obvious.
Therefore, claims remain rejected.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN SEUNGJAI KWON whose telephone number is (571)272-7737. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
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, Robert A. Wax can be reached at 571-272-0623. 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.
/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
Prosecution Insights