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 .
Claim Status
Claims 1-30 are pending and currently under examination.
Priority
Examiner acknowledges Applicant’s claim for the following priority:
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Information Disclosure Statement (IDS)
The IDS (1) filed on 19 March 2025 has been considered by the examiner. A signed copy is enclosed.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section.”
Claim Objections
Claims 9 and 26 are objected to because of the following informalities:
Claim 9 recites “poly(N-isopropylacrylamide” without the closing parenthesis.
Claim 26 is drawn to the ophthalmic composition in a form suitable for “…intravitreal or retrobulbar administration, or in a form suitable for intravitreal administration.” The repetition of intravitreal administration is assumed to be a typographical error.
Appropriate correction is required.
Claim Rejections
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 4, 6, 9, 12, 20, 22, 26, and 29 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 4 and 20 are rejected under 35 USC 112(b) as indefinite because the scope of the limitation “the therapeutic agent is an ophthalmic drug used to treat, prevent or diagnose an ocular disease” is unclear when considered together with the recited closed group. The recited group is limited to: a chemotherapeutic agent, an anti-glaucoma agent, an anti-angiogenesis agent, an anti-infective agent, an anti-inflammatory agent, a growth factor, an immunosuppressant agent, an anti-allergic agent, each of which are identified by therapeutic or prophylactic activity whereas the claim additionally characterizes the selected agent as being used to diagnose an ocular disease. It is unclear whether the diagnostic-use language requires a selected agent to possess diagnostic capability, whether a diagnostically labeled form of a listed therapeutic agent is intended, or whether ‘diagnose’ is surplus claim language and only treatment or prevention is required. Accordingly, the metes and bounds of claims 4 and 20 cannot be determined with reasonable certainty.
Claims 6 and 22 are rejected under 35 USC 112(b) as indefinite because the recited term ‘toposide’ does not have a reasonably ascertainable meaning in the pharmaceutical art. The claim separately recites etoposide and it is unclear whether ‘toposide’ identifies a different active agent, a trade name formulation of etoposide, or a typographical error. Consequently, the metes and bounds of claims 6 and 22 cannot be determined with reasonable certainty.
Claim 9 is rejected under 35 USC 112(b) as indefinite for the following reasons:
Claim 9 recites poly(D,L-lactide-co-caprolactone) (PCL). Because poly(D,L-lactide-co-caprolactone) is ordinarily identified as PLCL, not PCL (which ordinarily identifies polycaprolactone), it is unclear whether the limitation contained within the parenthesis is meant as an optional limitation, to further clarify the preceding limitation, or is a limitation in itself.
Claim 9 recites ‘polygalactic acid’ and further recites this compound in the specification. This recited term does not have a reasonably established meaning in the polymer or pharmaceutical arts. It is unclear if this is a typographical error and applicant intended poly(lactic acid) (PLA), poly(glycolic acid) (PGA), or poly(lactic-co-glycolic acid) (PLGA), particularly because PLA, PGA, and PLGA are separately recited in the claim. Accordingly, the scope of claimed polymer genus cannot be determined with reasonable certainty.
Claim 9 recites “triblock copolymers (e.g., PLGA-PEG-PLGA, PEG-PLGA-PEG). It is unclear whether the limitation contained within the parenthesis is meant as an optional limitation, to further clarify the preceding limitation, or is a limitation in itself. Of note to Applicant: that which is claimed in parenthesis is not a limitation of the metes and bounds of the claim.
Claim 9 recites “derivatives thereof including oxidized, reduced, mono substituted, disubstituted, multi-substituted derivatives” fails to define the permissible modifications to the listed polymers. The claim does not identify the substitution sites, permissible substituents, degree of substitution, extent of oxidation or reduction, or the structural relationship required for a modified polymer to remain a ‘derivative.’ It is additionally unclear whether ‘mono,’ ‘di,’ and ‘multi’ refer to the number of substituted atoms, functional groups, monomer units, or substituent types. Because the listed polymers are chemically diverse and these terms do not have a single art-recognized scope applicable to the entire group, a skilled artisan cannot determine with reasonable certainty which modified polymers are encompassed by the claimed derivative terminology.
Claims 12 and 26 are rejected under 35 USC 112(b) as indefinite because both claims include ‘subcutaneous administration,’ yet depend from claims requiring intraocular administration. This creates an internal inconsistency within these claims and therefore, the metes and bounds are not reasonably clear.
Claim 29 is rejected under 35 USC 112(b) as indefinite because the limitation “in a range of about 0.0269 mg/kg” is unclear. First, the specification does not define the term ‘about.’ Second, the claim recites a range followed by a single number. Therefore, it is unclear what number +/- 0.0269 mg/kg would constitute infringement and one of ordinary skill could not determine the metes and bounds of this claim.
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.
Claims 1, 2, 4-17, and 19-27 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (cited in Applicant’s 19 March 2025 IDS as “Homotypic cell membrane-cloaked biomimetic nanocarrier for the targeted chemotherapy of hepatocellular carcinoma,” published 12 August 2019) in further view of Godse (“Intravitreal galactose conjugated polymeric nanoparticles of etoposide for retinoblastoma,” published 30 November 2020).
Liu discloses a drug nanocarrier utilizing a homotypic cancer cell membrane for targeted chemotherapy of hepatocellular carcinoma (HCC) with excellent active targeting ability (abstract). The biometric platform, Liu discloses, not only effectively treats HCC, but also provides a sound strategy for the treatment of other cancers via changes in the corresponding homotypic cancer cell membrane (abstract). Liu further discloses that by applying homotypic cancer cell membrane as cloak for nanomaterials to generate desirable drug nanocarriers by suitable strategies, the surface protein interactions of the homotypic cancer cell membrane endow the nanocarrier with excellent homotypic targeting ability and remarkable immunocapability, allowing the nanocarrier to prolong circulation time and improve in vivo drug delivery efficiency (p. 5829).
Regarding claim 1 –
Liu teaches an HCC cell membrane-biometric drug nanocarrier constructed by coating PLGA nanoparticles with an HCC cell membrane (derived from HepG2 cancer cell membranes) and further encapsulating doxorubicin (Doc) into the nanoparticles (p. 5829). Therefore, Liu teaches a nanoparticle comprising therapeutic agent contained within a core surrounded by a nanoparticle coated with a membrane derived from a cancer cell membrane.
Liu does not expressly disclose a membrane derived from an ocular tumor or ocular cancer, but explicitly provides motivation for seeking alternative cancer-coating membranes to treat additional cancer types. The limitations of instant claim 1 are further made obvious by the teachings of Godse.
Godse teaches an intravitreal nanoparticle delivery system specifically to target retinoblastoma (abstract). Godse loads etoposide into PLGA nanoparticles and modifies the surface of the nanoparticles to increase uptake and cytotoxicity against retinoblastoma cells (abstract). Godse therefore establishes that:
Retinoblastoma was a known target for surface-modified nanoparticles;
PLGA was a suitable carrier for intravitreal retinoblastoma therapy;
Etoposide was a known therapeutic cargo for the PLGA core;
Increasing particle association and uptake by retinoblastoma cells was a recognized objective in the art.
Regarding claim 2 –
Godse identifies retinoblastoma as the cancer being treated by PLGA nanoparticles while Liu expressly teaches adapting its platform to other cancers by selecting the corresponding homologous cancer cell membrane.
Regarding claim 4 –
Liu teaches nanoparticles loaded with doxorubicin and Godse teaches nanoparticles loaded with etoposide. Both doxorubicin and etoposide are chemotherapeutic agents used to treat cancer.
Regarding claims 5 and 6 –
Godse expressly teaches etoposide as a chemotherapeutic agent for treatment of retinoblastoma, an ocular cancer.
Regarding claims 7, 8, 9, and 10 –
Liu and Godse both expressly teach PLGA as the nanoparticle carrier.
Regarding claim 11 –
Liu prepares its membrane-coated nanoparticles by combining 2 mg PLGA nanoparticle core with 0.5 mg cell membrane material (p. 5836). This produces a core-to-membrane weight ratio of approximately 4:1, which falls within the instantly claimed range. The separately recited “about 1:1” alternative does not avoid the broader overlapping range claimed.
Regarding claim 12 –
Godse teaches an intravitreal retinoblastoma nanoparticle formulation. Because the claimed routes are alternatives, the intravitreal embodiment of Godse satisfies this claim.
Regarding claim 13 –
Godse expressly teaches formulations for intraocular injection.
Regarding claim 14 –
Liu teaches treating cancer using drug-loaded, cancer cell membrane-coated PLGA nanoparticles. Godse teaches etoposide-loaded PLGA nanoparticles for intravitreal treatment of retinoblastoma. It would have been obvious to intraocularly administer the modified Liu composition to a subject with retinoblastoma for the reasons stated above.
Regarding claim 15 –
Godse identifies retinoblastoma as the cancer being treated by PLGA nanoparticles while Liu expressly teaches adapting its platform to other cancers by selecting the corresponding homologous cancer cell membrane.
Regarding claim 16 –
Liu directly compares HepM-PLGA particles with bare particles, reporting that the HepM-PLGA particles exhibited 4- to 5-fold stronger uptake compared to the bare particles (p. 5830). The increased uptake limitation of claim 16 is therefore expressly taught by Lui and would also inherently result when Liu’s homotypic targeting principle is applied to retinoblastoma cells.
Regarding claim 17 –
Liu expressly teaches the cancer cell membrane-coated nanoparticle targets the corresponding homologous cancer cell. Applying Liu’s principle to retinoblastoma, as taught by Godse, would target the composition to retinoblastoma cells.
Regarding claims 19-22 –
Godse expressly teaches etoposide as a chemotherapeutic agent for treatment of retinoblastoma, an ocular cancer. Applying Liu’s principle to retinoblastoma, as taught by Godse, would lead to the selection of etoposide as a known ocular chemotherapeutic agent.
Regarding claims 23 and 24 –
Liu and Godse both expressly teach PLGA as the nanoparticle carrier.
Regarding claim 25 –
Liu prepares its membrane-coated nanoparticles by combining 2 mg PLGA nanoparticle core with 0.5 mg cell membrane material (p. 5836). This produces a core-to-membrane weight ratio of approximately 4:1, which falls within the instantly claimed range. The separately recited “about 1:1” alternative does not avoid the broader overlapping range claimed.
Regarding claim 26 –
Godse teaches an intravitreal retinoblastoma nanoparticle formulation. Because the claimed routes are alternatives, the intravitreal embodiment of Godse satisfies this claim.
Regarding claim 27 –
Godse expressly teaches formulations for intraocular injection.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify Liu’s therapeutic drug-loaded, cancer cell membrane-coated PLGA nanoparticles by using a membrane derived from a retinoblastoma cell and formulating the resulting nanoparticles for intravitreal administration, as taught by Godse. Liu expressly teaches its cancer cell membrane-coated nanoparticle platform can be adapted to treat other cancers by changing the nanoparticle coating to the corresponding homotypic cancer cell membrane. Godse teaches retinoblastoma is an intraocular cancer treatable using intravitreally administered PLGA nanoparticles loaded with etoposide and identifies human retinoblastoma cells as the intended cellular target. One of ordinary skill would have therefore been motivated to replace Liu’s HepG2 membrane targeting hepatocellular carcinoma with a cancer cell membrane derived from a human retinoblastoma cell membrane when adapting Liu’s nanoparticle platform to Godse’s intraocular retinoblastoma treatment. The modification would have predictably combined Godse’s established intravitreal PLGA/etoposide delivery system with Liu’s homologous cancer cell-targeting nanoparticle demonstrating enhanced cellular uptake, drug delivery efficacy, and therapeutic efficacy. The skilled artisan would have a reasonable expectation of success because Liu expressly teaches the cancer cell membrane coating is a generalizable platform in which the membrane may be changed to the correspond to the cancer being treated while Godse demonstrates that the drug-loaded PLGA nanoparticles are suitable for intravitreal delivery to target retinoblastoma.
Therefore, claims 1, 2, 4-17, and 19-27 would have been obvious over Liu in view of Godse.
Claims 3 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Liu and Godse as applied to claims 1, 2, 4-17, and 19-27 above, and further in view of Grayson (cited in Applicant’s 19 March 2025 IDS as “Retinoschisin, the x-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb-1 cells,” publication year 2000).
As discussed above, Liu in view of Godse renders obvious a composition comprising a nanoparticle coated with a membrane derived from an ocular cancer, a core comprising a therapeutic agent, and a method of use. While neither Liu nor Godse expressly disclose retinoschisin in the membrane coating as recited in claims 3 and 18, this limitation is made obvious by Grayson.
Grayson teaches differentiated retinoblastoma cell (Weri-Rb1 cells) is a photoreceptor-like human retinoblastoma cell line that expresses RS1 mRNA and produces retinoschisin protein (p. 1873). Furthermore, Grayson detects retinoschisin protein in both undifferentiated and differentiated Weri-Rb1 cell lysates and in the corresponding culture media (p. 1876). Thus, Grayson teaches Weri-Rb1 cells contain and release retinoschisin.
In view of Grayson, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to select Weri-Rb1 cells as the retinoblastoma cell membrane source when implementing the combined teachings of Liu and Godse. Weri-Rb1 was a known human retinoblastoma cell line and possessed photoreceptor-like characteristics, including expression and production of the retina-associated protein retinoschisin. Selection of Weri-Rb1 cells would have therefore provided both the homologous retinoblastoma cell membrane called for in Liu’s nanoparticle platform, retinoblastoma taught by Godse, and the retinoblastoma cell protein characteristic taught by Grayson. A person of ordinary skill would have reasonably expected the membrane material obtained from retinoschisin-containing Weri-Rb1 cells to retain retinoschisin among the cellular proteins associated with the isolated coating material. Liu demonstrates the source cell proteins are preserved during extraction and membrane coating and Grayson establishes that retinoschisin is present in the selected retinoblastoma source cells.
Therefore, claims 3 and 18 would have been obvious over Liu in view of Godse and Grayson.
Claims 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Liu and Godse as applied to claims 1, 2, 4-17, and 19-27 above, and further in view Lam (US2011/0286915 A1, published 24 November 2011).
For the reasons previously stated, Liu in view of Godse renders obvious intraocular administration of a drug-loaded nanoparticle, including an etoposide-loaded polymeric nanoparticle, for treatment of retinoblastoma. While neither Liu nor Godse expressly disclose the specific therapeutic treatment as recited in claims 28-30, this limitation is made obvious by Lam.
Lam teaches a nanoscale drug carriers administered to a subject for treatment of cancers such as retinoblastoma ([0103]). Lam further teaches the interior core of the nanocarriers are filled with hydrophobic therapeutic drugs such as etoposide (claims 1, 3, and 9). Finally, Lam teaches the therapeutic drugs within the nanocarriers are administered at a daily dose range of 0.01 mg/kg to 500 mg/kg ([0114]). The claimed range of approximately 0.01-0.04 mg/kg falls entirely within the range taught by Lam.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to administer the etoposide-loaded nanoparticles of the combined Liu/Godse method at a dosage within the range taught by Lam. Lan teaches the administered dosage depends upon the requirements of the patient, severity of the disease, therapeutic compound, and adverse effects. Lam further directs the practitioner to begin with a smaller dosage and increase the dosage in small increments until the optimum effect is obtained. A person of ordinary skill would have therefore been motivated to select a low dosage within the disclosed range for intravitreal administration because local administration directly exposes the ocular tumor to the therapeutic agent and because minimizing exposure to a cytotoxic agent would reduce the risk of ocular toxicity. Furthermore, and in view of Lam’s teachings, the selection of a dosage within the claimed range (claim 28) would have amounted to routine optimization of a known result-effective variable. The selection of a specific dosage within a previously disclosed range, including approximately 0.0269 mg/kg (claim 29), would have been obvious through the incremental dose optimization taught by Lam. The claimed value has not been shown to represent a critical threshold or to produce an unexpected result.
Therefore, claims 28-30 would have been obvious over Liu in view of Godse and Lam.
Conclusion
Claims 1-30 are rejected. No claim is allowed.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Julia A. Rossi whose telephone number is (571)272-0138. The examiner can normally be reached M-Th 7:30-5:30 (MST).
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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.
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/JULIA A. ROSSI/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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