DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 14 August 2026, has been entered.
Status of Claims
Claims 1, 4, 7, 9, 18, and 20-21 are amended.
Claims 10, 13-15, 17, and 19 have been cancelled.
Claims 1, 4, 7, 9, 11-12, 18, and 20-22 are pending and under consideration in the instant Office Action to the extent that dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) is the species of helper lipid.
Objections Withdrawn
Objection to Drawings
Applicant’s Replacement Sheet 1, submitted on 14 August 2026, has overcome the objection to the drawing presented in the Office Action mailed on 17 June 2025. Accordingly, the relevant objection is withdrawn.
Rejections Withdrawn
Rejections pursuant to 35 U.S.C. § 102
The rejection of claim 1 under 35 U.S.C. § 102(a)(1) is withdrawn in view of Applicant’s amendments to claim 1.
Rejections pursuant to 35 U.S.C. § 103
The rejections of claims 1, 4, 7, 9, 11-12, 18, and 20-22 under 35 U.S.C. § 103 are withdrawn in view of Applicant’s amendments to the claims and in favor of the new grounds of rejection set forth below. The rejection of claims 10, 13-15, 17, and 19 under 35 U.S.C. § 103 has been rendered moot by Applicant’s cancellation of the claims.
New Grounds of Objection
Claim Objections
Claims 1 and 9 are objected to because they each recite an extraneous comma following the preamble “A nanocarrier comprising” and the commas should be removed.
Appropriate correction is required.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 20 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 20 recites the SLNP of claim 18 to have a Zav size of 102.00 nm and a Zeta potential of -9.9 mV. However, claim 9, from which claim 18 and subsequently claim 20 depend, recites the SLNP to have a Zav size of 99.00 nm and a Zeta potential of -11.2 mV. A SLNP cannot simultaneously have two different sizes and potentials, therefore claim 20 fails to include all of the limitations of the claim upon which it depends. A dependent claim must be rejected under 35 U.S.C. 112(d) if it omits an element from the claim upon which it depends or it fails to add a limitation to the claim upon which it depends. MPEP 608.01(n)(III).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 4, 7, 9, 11-12, 18, and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Kratz (U.S. Patent No. 7,902,144 B2, published on 8 March 2011) as evidenced by Casares et al. (J. Exp. Med. 2005, 202 (12), 1691.) in view of Mura et al. (J. Control. Release 2015, 208, 25., hereafter referred to as Mura), Ji et al. (Cancer Biol. Ther. 2012, 13 (4), 206., hereafter referred to as Ji), and Serda et al. (U.S. Patent Application Publication No. US 2020/0375912 A1, published on 3 December 2020, hereafter referred to as Serda).
Kratz teaches a “carrier molecule” capable of treating cancer comprising at least one anthracycline, a class of anticancer drugs, and at least one albumin-affinitive substance which is linked to the anthracycline via an acid labile linkage (claims 1 and 25). Among the anthracyclines taught by Kratz is doxorubicin (col. 3, line 63). One embodiment of the carrier molecule uses stearic acid as the albumin-affinitive substance (claims 20-21 and col. 36, lines 33-34). Later in that embodiment, Kratz teaches stearic acid linked to doxorubicin via reaction between doxorubicin and stearic acid hydrazide, resulting in stearic acid linked to doxorubicin via a hydrazone linker (labeled DOXO-SAH, col. 42, line 39 - col. 43, line 24). The bond between the albumin-affinitive substance and anthracycline in the carrier molecule is described as “acid-labile” (claim 7), therefore DOXO-SAH is determined to be equivalent to a prodrug and has an identical structure to the “ICD prodrug” of instant claim 1 (vide infra).
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DOXO-SAH reproduced from Kratz, claim 18
Kratz further teaches “pharmaceutical products and diagnostic kits” containing the compounds disclosed (col. 1, lines 8-12). The kits contain the compounds taught by Kratz, as well as a method of detecting the carrier molecules and/or determining the distribution of the carrier molecules through the body of the subject (col. 33, lines 31-36).
The phrase “immunogenic cell death (ICD)” in instant claim 1 describing the claimed doxorubicin-containing prodrug is a description of the form of cell death induced by the compound. This is an inherent property of doxorubicin, as evidenced by Casares et al. See MPEP § 2112.01. "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Following cleavage of the acid labile hydrazone linker, doxorubicin is the active pharmaceutical ingredient, its structure is known in the art, and its inducement of ICD has been reported (vide supra).
Kratz does not teach delivery of the doxorubicin prodrug via a nanocarrier, the nanocarrier being a solid-lipid nanoparticle (SLNP), the components comprising the SLNP, the size of nanoparticles, nor the SLNP comprising a toll-like receptor agonist. These deficiencies are offset by the teachings of Mura, Ji, and Serda.
Mura teaches the utility of using lipid-based prodrug nanocarriers in the treatment of cancer, including as a method of reducing widespread toxicity and improved targeting of anticancer drugs (Abstract and Introduction, pg. 25). Among the nanocarriers taught is a SLNP formulated with Taxol linked to cholesterol as a prodrug (pg. 36, left col., final paragraph) and cholesterol linked to butyric acid as part of the lipid matrix making up the core of a SLNP (pg. 37, right col., second paragraph). Unmodified cholesterol was also taught to be a useful component of nanocarriers, including as a stabilizer in the formation of liposomes (pg. 26, right col., second paragraph), modifier of therapeutic efficacy in liposomes containing doxorubicin (pg. 34, left col., first paragraph), and in a variety of other nanoscale lipid-based anticancer prodrugs, shown in Table 1 (pg. 28). Another lipid used in liposome nanocarriers is 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), which Mura teaches to enhance the hydrolysis of prodrugs, increasing the rate of production of free anticancer drugs (pg. 37, right col., para. 1).
Mura also teaches the “superior efficacy of peptide-decorated [nanoparticles] compared with the non-functionalized ones” when treating pancreatic cancer models with gemcitabine prodrugs (pg. 29, right col., first paragraph). In addition, several examples are provided of SLNPs comprising receptor targeting molecules, such as epidermal growth factors (EGF) (pg. 26, right col., final paragraph), the frizzled (FZD) protein receptors, which are overexpressed in pancreatic cancer (pg. 29, right col., first paragraph), and low-density lipoprotein (LDL) receptors, which are overexpressed in a number of tumors (pg. 34, right col., third paragraph).
Finally, Mura teaches the utility of using phospholipids in nanoparticle lipid prodrugs – in Table 1, several examples of prodrugs are provided which employ oleic acid, palmitic acid, linoleic acid, and glycerol substituted phospholipids. The incorporation of palmitate in nanoparticles comprising the anticancer drug paclitaxel demonstrated higher tolerability in subjects, allowing for higher doses and better control of tumor growth (pg. 36, left col., para. 2). The incorporation of oleic acid and linoleic acid was also associated with increased effectiveness in killing cancer cells (pg. 36, left col., para. 3-4). Incorporation of oleic acid into liposomes was also taught to increase lipid solubility, enabling incorporation of a prodrug into an injectable nanoemulsion that displayed greater therapeutic effectiveness than the analogous free drug (pg. 36, right col., final para.).
Ji teaches nanoparticles which utilize the peptide RGD to target pancreatic cancer (Abstract). Integrin avβ3, a transmembrane receptor, is taught to be overexpressed in many types of cancer; particularly in pancreatic cancer, integrin avβ3 is “expressed not only on primary tumors, but also on metastatic tumors” (pg. 207, left col., second paragraph). Nanoparticles made from the protein bovine serum albumin (BSA), termed BSANP, were conjugated to RGD peptides with the goal of increasing BSANP uptake in pancreatic cancer cells. As demonstrated in Figure 5 (pg. 209) and discussed on pg. 212 (right col., second paragraph), the nanoparticles conjugated to RGD peptides “selectively accumulate in BxPC-3 [pancreatic cancer] cells when compared with BSANPs without RGD conjugation.” The RGD-conjugated BSANPs were measured to have diameters in the range of 94-166 nm, with an average of 130 nm, and zeta potentials of -31 mV (pg. 207, Results, Preparation and characterization of RGD-conjugated BSANP). Ji teaches that the size of nanoparticles plays a crucial role in their interactions with cells and nanoparticles with diameters in the range of ~100-200 nm have “the best properties for cellular uptake” (pg. 212, right col., para. 1).
The BSANPs were subsequently loaded with the anticancer drug gemcitabine to assess anticancer activity (Results, pg. 207). The cytotoxicity of BSANPs against BxPC-3 cells was assessed with and without gemcitabine and with and without the integrin avβ3 targeting RGD peptide and subsequently compared to a control and free gemcitabine (pg. 212-213, figures 10 and 12). The nanoparticles that contained the anticancer drug and were conjugated to RGD peptides displayed the greatest anticancer properties (Conclusion, pg. 213).
Guidelines on the obviousness of similar and overlapping ranges, amounts, and proportions are provided in MPEP § 2144.05. With respect to claimed ranges which “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). These guidelines apply to the diameter of particles taught by Ji, which encompass the values recited in instant claims 1, 9, and 20, rendering them obvious.
Serda teaches a method of producing lipid coated nanoparticles that inhibit or treat cancer (spec. para. [0005-0009] and claims 31-36). The disclosed nanoparticles contain one or more molecules in a lipid layer coating the core that aid cancer targeting by activating antigens, binding antigens, or are themselves antigen-presenting cells (spec. para. [0005]). Among the lipids disclosed in the outer layer are 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (claim 14). Serda further teaches the nanoparticle lipid coating to contain one or more molecules that is/are a ligand(s) for a toll-like receptor (TLR), including TLR-2, TLR-3, TLR-4, TLR-7, and TLR-9 (claims 4, 6, and 17), such as a toll-like receptor agonist (spec. para. [0019]). Following the targeting of cancer cells, the invention of Serda can subsequently deliver drugs from the nanoparticle core, such as doxorubicin or oxaliplatin, to treat cancer (Example 3).
It would have been prima facie obvious to a person having ordinary skill in the art, before the effective filing date of the instant application, to combine the teachings of Kratz, Mura, Ji, and Serda to arrive at the claimed invention because the use of known techniques to improve similar devices in the same way yields predictable improvements. With respect to Kratz, the invention does not disclose the use of nanocarriers to deliver the doxorubicin prodrug DOXO-SAH, however, Mura teaches the technique of delivering doxorubicin-containing prodrugs encapsulated in nanoparticles and described nanoparticles as offering advantages as a delivery method, which would yield a predictable improvement. As a matter of convenience and economy, it would have been obvious to one of ordinary skill in the art to modify the kits taught by Kratz to include the doxorubicin prodrug in SLNPs. In addition, Mura teaches the use of DPPC as a helper lipid to enhance hydrolysis of the prodrug, increasing the rate of anticancer drug release, and phospholipids, including oleic acid and linoleic acid, to improve subject tolerability of compositions and improve therapeutic efficacy, which an artisan would be motivated to incorporate into their invention for improvement.
An artisan would have been further motivated to modify the above teachings with those of Ji because the Ji teaches RGD-associated nanoparticles to have improved uptake in targeted cancer cells as compared to other nanoparticles, improving therapeutic effectiveness. Ji also taught the preferable size of nanoparticles for improved cellular uptake, which an artisan would be motivated to use for improved therapeutic effectiveness in their invention. Further, in view of the teachings of Serda one of ordinary skill in the art would be motivated to utilize TLR agonists in their SLNPs to improve targeting for subsequent drug delivery because Serda teaches that TLR agonists enhance the ability of nanoparticles to deliver anticancer agents to the intended target. Serda wrote “[TLR] agonists enhance or otherwise favorably influence the engagement of T-cell subsets to…make certain cells better targets for immune-mediated destruction” (Serda, spec. para. [0074]).
Finally, the zeta potential of the SLNPs containing ICD-prodrugs would be obvious because it is an inherent property of the nanoparticles (see evidentiary reference Kamble et al. ChemistrySelect 2022, 7 (1), 2365.). See MPEP § 2112.01. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Because the nanocarrier composition and size is obvious in view of the above teachings, the zeta potential is prima facie obvious as well. As a result, there is a reasonable expectation of success in arriving at the invention of claims 1, 4, 7, 9, 11-12, 18, and 20-22 in view of the teachings of Kratz, Mura, Ji, and Serda.
Response to Arguments
Applicant's arguments filed 14 August 2026, have been fully considered but they are not persuasive.
Applicant argues in the section titled “Rejection under 35 USC §102(a)(1)” on pg. 6 that Kratz does not anticipate the nanocarrier recited in instant claim 1. The relevant rejection has been withdrawn in view of Applicant’s amendment to claim 1 and the argument is considered moot.
Applicant argues in the section titled “Rejection under 35 USC §103 (claims(s) 1, 4, 7, 9-15, 18, and 20-22)” on pg. 6 that none of the references cited in the rejection presented in the previous Office Action “teach the claimed invention as a whole and thus do not render the claims obvious under current law”. Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sean J. Steinke, Ph.D., whose telephone number is (571) 272-3396. The examiner can normally be reached Mon. - Fri., 09:00 - 17:00 ET.
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/S.J.S./
Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
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