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 .
Response to Amendment
Applicant’s response of 11/17/2025 has been received and entered into the application file. Claims 1-2, 10-11, 17, 20, 26, 39, 70, 75-77, 79-80, 83, 85, 87, 89-90 and 92 are pending in this application.
Applicant’s amendments to the Specification and claims have overcome each and every objection, 112(a) and 112(b) rejection previously set forth in the Non-Final Office Action mailed 07/17/2025.
Claim Rejections - 35 USC § 103 (necessitated by amendment)
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 claims 17 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, 17, 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 11/17/2025 have been fully considered and a new reference is incorporated to reject the amended claim 1.
Zhang discloses methods of making platelet membrane-cloaked nanoparticle (PNP) ([0141]). The polymeric cores were prepared by mixing PLGA in organic phase. Then DiD was loaded into the core at 0.1 wt %. The mixture was then stirred, filtered and mixed with platelet membrane vesicles with PLGA particles via sonication ([0141]).
The instant application discloses a similar process – first PLA and R848 were mixed in an organic phase, then the mixture was sonicated. The organic solvent was evaporated overnight, and the resulting solution was mixed with platelet membrane ([016]). One of ordinary skill in the art would immediately envisage that different weight % of each nanoparticle ingredient within a well-known process would be routinely practiced. In re Lilienfeld, 67 F.2d 920, 924 (CCPA 1933) ("It is well established that, while a change in the proportions of a combination shown to be old, such as is here involved, may be inventive, such changes must be critical as compared with the proportions used in the prior processes, producing a difference in kind rather than degree.")
On page 9 of remarks, applicant argues that the combination of cited art does not teach or suggest every element of the present claim 1. As discussed above, all of the routine components of a platelet-membrane nanoparticle are taught by Gu, Zepp and Zhang, including the diameter ranges. One of ordinary skill in the art would routinely experiment with various concentrations of each ingredient within a nanoparticle composition. Per MPEP 2144.05 (II) (A), Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.
On pages 10-13 of remarks, applicant argues that there is no reason to combine the cited art. 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.
On pages 13-18 of remarks, applicant cites the specification to show that the uptake of PNP by the total population of cells in the tumor was significantly higher. Gu teaches the platelet membrane coated nanoparticles; the platelet membranes can be derived from platelet and purified to coat the surface of nanoparticle. Equipped with large numbers of “self-recognized” proteins, the nanoparticle is expected to minimize the in vivo immunogenicity, prolong the circulation time. More importantly, the overexpressed P-Selectin on the platelet membrane can specifically bind to CD44 receptors upregulated on the surface of cancer cells. Taken together, the platelet membrane coated nanoparticle could actively target to tumor site and sequentially deliver anticancer therapeutics to their most active destinations ([0026]). One of ordinary skill in the art would immediately envisage that platelet membrane coated nanoparticles would have more selective activity for cancer cells. Furthermore, the specification cited by the applicant discloses higher uptake for PNP observed among CD45+ leukocytes and CD11c+ dendritic cells, as well as rapid regression followed by a specific treatment called PNP-R848. Claim 1 as currently written is a general description of a platelet coated nanoparticle and is not commensurate in scope of the detailed experiments provided.
On page 18 of remarks, applicant argues that the process taught by Hu is different from instant application. 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
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 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