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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-20 are the original claims filed on 5/19/2023. In the Reply of 5/1/2026, no claims are amended, canceled or added. Claims 1-20 are all the claims.
Election/Restrictions
2. Applicant’s election without traverse of Group I (Claims 1-12) in the reply filed on 5/1/2026 is acknowledged.
3. Claim 13-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/1/2026.
4. Claims 1-12 are the claims under examination.
Priority
5. USAN 18,320,272, filed 05/19/2023, Claims Priority from Provisional Application 63/365,036, filed 05/20/2022.
Information Disclosure Statement
6. AS of 6/10/2026, a total of one (1) IDS is filed for this application: 12/14/2023. The corresponding initialed and dated 1449 form is considered and of record.
7. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections
Specification
8. The disclosure is objected to because of the following informalities:
a) The use of the term GraphPad Prism, Trizol, Mastercycler, Perfecta, SYBR, Bio-Rad, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
9. Claims 1-12 are objected to because of the following informalities:
a) Claims 1-12 are objected to for claim 2 serving to define the aspect of the invention of claim 1 that is not naturally occurring and which necessarily precedes any of steps (a)-(d) of the instant method invention. Amend claim 1 to incorporate the subject matter of claim 2 and to replace (a)-(d) with (a)-(e).
b) Amend claims 1(d)-9 to recite “to produce the loaded polymeric microparticles in the cytosol of [[in]] the phagocytic cells.
c) Amend claim 1(d) to recite “the loaded polymeric microparticles in the phagocytic cells.”
d) Amend claim 9 to replace “any combination thereof” with “[[any]] a combination thereof” since there is one option for a combination.
e) Amend claim 10 to recite “A phagocytic cell comprising loaded polymeric microparticles made by the method claim 1, wherein the loaded polymeric microparticles are in the cytosol of the phagocytic cell.”
f) Amend claim 11 to replace “a monocytes” with “a monocyte”.
Appropriate correction is required.
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.
10. Claims 5-9 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.
a) Claims 5-6 are indefinite for the term “about.” The specification provides a per se definition with caveats noted by underline at
[0067] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise
If the equivalent value falling within the use of the term “about” for an amount or a range cannot be reasonably determined, then the POSA cannot reasonably determine the full metes and bounds for the invention.
b) A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 recites the broad recitation “metal”, and the claim also recites “metal oxide” which is the narrower statement of the range/limitation.
The claim(s) 7-9 are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim 7, and therefore not required, or (b) a required feature of the claims.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
11. Claims 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim interpretation
Claims 1-9 are drawn to the method for introducing loaded polymeric microparticles into one or more phagocytic cells, the method comprising: a. incubating loaded polymeric microparticles at a first temperature and in a first medium with the one or more phagocytic cells, wherein, during incubation, the loaded polymeric microparticles are taken up by the phagocytic cells into phagosomes, wherein the loaded polymeric microparticles comprise one or more nanoparticles; b. transferring the phagocytic cells containing loaded polymeric microparticles to a second medium at a second temperature at which the loaded polymeric microparticles swell; c. incubating the phagocytic cells at the second temperature, wherein during incubation, the phagosomes rupture in the phagocytic cells; and d. transferring the phagocytic cells to a third medium at a third temperature, to produce the loaded microparticles in the phagocytic cells.
Claims 10-12 are drawn to a phagocytic cell comprising loaded polymeric microparticles made by the method claim 1 in the cytosol of the phagocytic cell.
“microparticle”: the structure for a microparticle is described by its various aspects in the specification as follows:
[0024] Disclosed herein are microfabricated microparticles composed of uncrosslinked linear ploy(N-isopropylacrylamide)(PNIPAM) as phagocytic objects. In one aspect, PNIPAM is a synthetic polymer that can undergo phase transition in water at a lower critical solution temperature (LCST) of around 32° C. In another aspect, PNIPAM chains are typically soluble in water at temperatures well below LCST, but they tend to aggregate and form an insoluble macroscopic gel phase at temperatures above LCST, such as 37° C.
[0035]. In another aspect, the first medium can be a cell culture medium, the second medium can be a cell culture medium, phosphate buffered saline (PBS), or any combination thereof, and the third medium can be a cell culture medium. In one aspect, and without wishing to be bound by theory, the first temperature should be above the glass transition temperature of the polymeric material in the microparticles,
[0036] In any of these aspects, the microparticles are non-toxic and are not biodegradable.
[0038] …In another aspect, the polymeric microparticle can include or be made from poly(N-isopropylacrylamide) (PNIPAM),), a copolymer thereof, a derivative thereof, or any combination thereof. In one aspect, the copolymer of PNIPAM can be PNIPAM-fluorescein.
Example 2: Results and Discussion
Characterization of Microparticles
[0188] Two types of microparticles were fabricated and used as phagocytic objects in this study. One type was made of a commercial uncrosslinked linear PNIPAM with a molecular weight of 40 kDa. To fluorescently label the microparticles, red fluorescent sulfate-modified polystyrene nanoparticles with a diameter of 100 nm were dispersed in the microparticles. A microcontact-printing method that was previously developed was modified to fabricate the microparticles. Specifically, a thin film of PNIPAM containing the nanoparticles was spin-coated onto a PDMS stamp carrying an array of 5 μm-radius pillars using an aqueous solution of PNIPAM and the nanoparticles. The resultant film on the pillars was then transferred onto a glass coverslip via a conformal contact, generating an array of circular microparticles over a centimeter-wide printing area. The microparticles had an average radius of 5.07±0.03 μm (from 60 microparticles in three samples). The microparticles were visible in both bright-field and fluorescence images (FIGS. 2A(i)-2A(iii)), indicating that the microparticles were composed of both PNIPAM and the nanoparticles. Moreover, the microparticles were highly uniform in size, shape, and fluorescence intensity. To further characterize the morphology, the microparticles were imaged with SEM (FIGS. 2B(i)-2B(ii)), revealing a disk-like shape with a thickness much smaller than the diameter. To determine the thickness of the microparticles, the same microparticles as mentioned above were printed on a thin film of PVA, and the resulting film was manually cut with a razor blade across the microparticle array (FIG. 2C(i)). Using the cross-sectional images of the cut-through microparticles (FIG. 2C(ii)), the average thickness of the microparticles was determined to be 1.2±0.1 μm (from 42 microparticles in three samples). To demonstrate that the microparticles were not soluble in an aqueous environment at 37° C., the microparticles were printed on a PVA-coated glass coverslip and then soaked in PBS at 37° C. for 7 d. The PVA film was used to release the microparticles from the coverslip surface because it is soluble in water. As shown in FIGS. 2D(i)-2D(iii), the soaked microparticles were circular in shape and highly uniform in size. The random distribution of the soaked microparticles indicates that they were indeed released from the coverslip surface. Moreover, some microparticles were moving when imaged, suggesting that the soaked micro-particles had a spherical shape. It was hypothesized that the original disk-shaped microparticles were released from the coverslip surface upon addition of 37° C. PBS and that the released microparticles became hydrated and transformed into a spherical shape driven by surface area minimization during the period of soaking. This hypothesis is consistent with the observation that the soaked microparticles, with an average radius of 2.3±0.3 μm (from 30 microparticles in 3 samples), were much smaller than the lateral radius of the original disk-shaped microparticles. Moreover, the soaked microparticles exhibited bright fluorescence, indicating that the nanoparticles were trapped in the hydrated PNIPAM matrix of the microparticles. To examine if the microparticles were soluble in an aqueous solution at a lower temperature, the micro-particles printed on a PVA-coated glass coverslip were released with a prewarmed complete cell culture medium (37° C.) and further incubated for 3 h at 37° C. The microparticles in the complete medium were then imaged in the ambient environment at 22° C. The temperature of the complete medium gradually decreased (FIG. 2E(i)). The microparticles initially exhibited a compact and bright appearance at 35.6° C. (FIG. 2E(ii)), swelled in size and dimmed in fluorescence at 29° C. (FIG. 2E(iii)), and then quickly (within 1 min) and almost simultaneously disappeared at 28.5° C. (FIG. 2E(iv)). By repeating this experiment three times, the temperature at which the microparticles just disappeared was determined to be 28.8±0.3° C. This type of microparticles were used throughout this study unless otherwise noted.
[0189] The other type of microparticles used in this study were made of a PNIPAM derivative, which was synthesized by randomly copolymerizing N-isopropylacrylamide and fluorescein-O-acrylate as described previously. The copolymer, named PNIPAM-fluorescein hereafter, had a N-isopropylacrylamide-to-fluorescein mole ratio of 98:1 and a molecular weight of 5.12 kDa and was intrinsically green fluorescent. Microparticles made of PNIPAM-fluorescein alone were fabricated as described previously.
The POSA could reasonably conclude that the scope of microparticles recited in the claims exceeds what the specification teaches for the starting material of a polymeric microparticle.
“swell”/”swelled”/”ruptured”: the specification is clear in teaching that the swelling/rupturing of a loaded polymeric microparticle-containing phagosome in a phagocytic cell is theoretical and “a presumed mechanism of action” for the method invention as explained in [0185-0196] based on Flory-Huggens modeling.
[0208] Equation 11 provides a mathematical expression for surface tension in the phagosomal membrane as a function of radius of the phagosome and the cold-shock temperature.
The POSA cannot reasonably ascertain whether the swelling feature of the invention is predicated on the use of uncrosslinked linear PNIPAM with a molecular weight of 40 kDa and PNIPAM-fluorescein derivative at specific and select temperatures or that any microparticle structure can be applied to the equation or the Flory-Huggins model to formulate a surface tension for the corresponding loaded copolymeric microparticle and the phagocytic phagosome in order to facilitate phagosomal rupture.
Based on the interpretation of the claim scope, the method invention exceeds the breadth and scope beyond what is taught for the method invention by the specification as filed. Because applicant seeks patent protection for all such methods and phagocytic cells derived therefrom, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
The scope of the claimed genus is discussed herein above and that encompasses the indefiniteness rejections of the claims.
State of the Art
Cheng (ACS Appl Mater Interfaces. 2023 May 24;15(20):24244-24256. Epub 2023 May 15) with shared authorship to the inventorship of the claims teaches the working examples for a generic method outlined in the claims. Cheng relies on the Flory-Huggens model for predicting phagosomal rupture in monocytes from loaded microparticles under specific formulation of the particle under specific transitional phase temperatures to achieve a method limited by the unpredictability of the model inherent to the method performance itself.
The art recognizes the Flory-Huggins (FH) model is highly predictive qualitatively but often struggles with exact quantitative accuracy unless fitted to experimental data. It is best viewed as a foundational thermodynamic framework rather than an exact predictive tool. The predictive power of the model entirely hinges on the Flory-Huggins interaction parameter (χ), where χ is heavily dependent on temperature and often varies across different compositions (volume fractions).
It often fails to quantitatively predict complex transitions, such as Lower Critical Solution Temperatures (LCST), without empirical fitting. It severely underestimates or misses strong, specific interactions like hydrogen bonding, which frequently leads to inaccurate solubility limits. The model relies on a "lattice" mean-field assumption, which ignores complex monomer packing, chain connectivity, and localized spatial structures (Bussamra et al. (Separation and Purification Technology, Volume 255, 15 January 2021, 117636); Zhang et al. (Phys. Rev. Lett. 119, 017801 – Published 6 July, 201); and Panayiotou et al (Ind. Eng. Chem. Res. 2007, 46, 2628-2636).
It is asserted that neither the specification nor the state of art at the time of filing disclosed the reliability of predicting surface tension interactions based on the Flury-Higguns model relied on by Applicants in alleging the universal conditions for a method outlined in steps (a)-(d) of the instant claimed invention.
The lack of predictability for the claimed invention as a whole does not place Applicants in possession of the invention much less render the claims obvious.
Conclusion
13. No claims are allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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, Wu Julie can be reached at 571-272-5205. 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.
LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
Prosecution Insights