DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed 08/10/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112 –
Indefiniteness and Broad to Narrow Limitations
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.
Claim 12 is 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 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 12 recites the broad recitations “docetaxel” and “doxorubicin”, and the claim also recites “(DTX)” and “(DOX)” which are the narrower statements of the range/limitations.
The claim(s) 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, and therefore not required, or (b) a required feature of the claims.
The Applicant is encouraged to remove the parentheses from the claims.
Response to Arguments
Applicant's arguments filed 08/10/2026 have been fully considered but they are not persuasive.
Applicant argued that amendments were made to make moot the rejections under 35 USC § 112.
The Examiner responds that claim 12 was not amended. The Applicant is encouraged to correct for broad-to-narrow limitations in the claim.
Claim Rejections - 35 USC § 102 - Anticipation
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-10 and 12-14 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Halbherr et al (US 2022/0265556 A1).
Halbherr taught a liposomal formulation comprising doxorubicin or crystals thereof, in the aqueous inner compartment, and docetaxel in the lipid bilayer [0073, claim 24]. The liposomal formulation comprised phosphatidylcholine, cholesterol and polyethylene glycol [claim 18].
Halbherr anticipates claims 1-10 and 12-14.
Response to Arguments
Applicant's arguments filed 08/10/2026 have been fully considered but they are not persuasive.
Applicant argued that Halbherr neither anticipates the invention, expressly nor inherently. Applicant argued that a “particle modifier” as defined by the Specification, is both a therapeutic, and an ingredient, in the nanoparticle bilayer, in order to adjust properties (partition coefficient, permeation, morphology, pharmacokinetic/pharmacodynamic) of the particle. The Applicant argued that the presence of the particle modifier changes properties of the particle itself.
The Examiner disagrees that Halbherr does not inherently anticipate the instant invention. As per the Applicant’s remarks, the very presence of the particle modifier changes the properties of the particle. The Specification disclosed a particle modifier as existing as both a therapeutic and within the bilayer, as the Applicant stated in the remarks. Halbherr taught docetaxel in the lipid bilayer, as stated in the body of the rejection. As the Applicant has remarked [see page 9 of the Applicant’s remarks], Halbherr also taught docetaxel as a therapeutic.
It appears that the nanoparticles of the instant claims (nanoparticle comprising particle modifiers and therapeutics) and those of the prior art (nanoparticle comprising docetaxel in the bilayer and doxorubicin in the core) would reasonably be expected to have substantially the same physical and chemical properties (particle modifiers as defined by the instant Specification). This is because the instant Specification disclosed a particle modifier as existing as both a therapeutic and within the bilayer, wherein the modifier adjusts properties (partition coefficient, permeation, morphology, pharmacokinetic/pharmacodynamic) of the particle.
Inherent features need not be recognized at the time of the invention. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2112 II. It should be noted that a chemical composition (e.g., nanoparticle having docetaxel in the lipid bilayer, where docetaxel may exist as both a therapeutic and a particle modifier) and its properties (particle modifier, particularly permeation via alteration of the partition coefficient; morphology; pharmacokinetics/pharmacodynamics) are inseparable. If the prior art teaches the identical chemical compounds (in the instant case, located in the lipid bilayer), then the properties that the Applicant discloses and/or claims, are necessarily present.
Applicant cited to the instant Figure 2 to argue that nanoparticles with DOX crystals in the aqueous compartment may be stabilized by the DTX.
The Examiner responds that the invention does not appear patentably distinct from Halbherr, which also has an aqueous compartment of DTX crystals. For purposes of argument only, and not as a basis of rejection, Halbherr taught that the disclosed nanoparticles were particularly stable [see ¶s 0030, 0032, 0057; see also Figs. 15a and 15b].
Applicant argued that the claimed aspect ratio captures the morphology of how the particle modifier works.
The Examiner responds that an aspect ratio is not claimed.
Applicant argued that the word “particle modifier” does not appear in Halbherr, and that no concept equivalent to it appears. In the same paragraph [last paragraph of page 8], Applicant states that Halbherr teaches doxorubicin as a therapeutic.
The Examiner maintains that Halbherr appears to anticipate the instant invention, and does so by inherency. In that case, Halbherr does not need to explicitly state the words “particle modifier”. By the Applicant’s admission, Halbherr taught doxorubicin as a therapeutic. As was written in the body of the rejection, Halbherr’s doxorubicin was located in the core of the nanoparticle, and the docetaxel was located in the lipid bilayer. These teachings of Halbherr anticipate the Applicant’s claims, especially at claim 1, and at claim 12, where the structure of the nanoparticle is detailed. The Applicant has not identified how, or why, Halbherr does not anticipate the claimed invention, where the property of the modifier stays with the compound, and where the exact nanoparticle as found in the prior art appears to be the claimed nanoparticle. The Applicant’s arguments against the teachings of Halbherr are found non-persuasive.
Applicant argued that the Examiner-cited paragraph [0073] disclosed location only (regarding docetaxel), and that the surrounding paragraphs assign docetaxel to combination therapy (e.g., with doxorubicin). Applicant argued that Halbherr’s claim 18 does not recite docetaxel as a bilayer component.
The Examiner responds that paragraph [0073] clearly defines docetaxel as a lipid bilayer component: “It is therefore particularly preferred, if the liposomal doxorubicin formulation comprises individual liposomes which in the aqueous inner compartment comprise doxorubicin; and in the lipid bilayer comprise docetaxel.”
Regarding Halbherr’s claim 18, the claim recites that the liposome comprises “at least” phosphatidylcholine, cholesterol and a PEG-lipid conjugate. The claim does not recite that the liposome is limited to the aforementioned components. Furthermore, it does not appear that the claimed nanoparticle (having two therapeutics; Applicant’s remarks state that the particle modifier may also act as a therapeutic; and, there is a therapeutic in the core) and the prior art nanoparticle (therapeutic in the core and one in the bilayer) appear patentably distinct.
Applicant argued that Halbherr’s composition does not have the claimed property (e.g., particle modifier).
The Examiner disagrees, because a compound (docetaxel in the lipid bilayer) and its properties (modifier of the nanoparticle) are not separate, as was previously discussed. Applicant’s arguments are not persuasive.
In response to the Applicant's argument that Halbherr fails to show certain features of the invention, it is noted that the features upon which the Applicant relies (i.e., resultant predominately elongated population of particles having an elongated structure with an aspect ratio between about 1 and 4) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See MPEP 2145.
Applicant argued against Halbherr’s teachings as inherent, because Halbherr taught that the disclosed liposomes were preferred to have a mean relative circularity. Applicant cited Halbherr at ¶ [0037].
The Examiner responds that Halbherr is not limited to preferred embodiments, but was, rather, relied upon as a broad disclosure. Halbherr is prior art for all that it contains, including nonpreferred and alternative embodiments, as they also constitute prior art. See MPEP 2123 I and II.
Applicant argued that the reliance of Halbherr’s claim 24 for a teaching of docetaxel in the lipid bilayer is misplaced.
The Examiner responds that Halbherr’s teachings of docetaxel in the lipid bilayer was established in Halbherr’s ¶ [0073] (see the above discussion; e.g., Examiner’s rebuttal to Applicant’s arguments regarding the location of docetaxel). Halbherr’s claim 24 was relied upon to reject the instant claim 13, which recites a crystalized therapeutic in the core region. In the instant case, Halbherr taught encapsulated doxorubicin crystals.
Applicant argued that Halbherr’s ¶ [0073] discloses presence without function.
The Examiner maintains that the function (particle modifier) of Halbherr’s docetaxel in the lipid bilayer (presence) is a property that is inherent to the compound, and to its location in the membrane.
The Applicant’s arguments are found non-persuasive. The 35 USC § 103 rejection is maintained.
Claim Rejections - 35 USC § 103 - Obviousness
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.
Claim(s) 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Halbherr et al (US 2022/0265556 A1).
Halbherr et al is believed to be anticipatory as described above, but in the interest of completeness of prosecution, purely arguendo, and for the purposes of this ground of rejection only, Halbherr will be interpreted as if it is not anticipatory.
In that case, claims 1-10 and 12-14 are rendered prima facie obvious over the teachings of Halbherr, because it is prima facie obvious to combine prior art elements according to known methods, in order to yield predictable results. In the instant case, all the claimed elements (e.g., nanoparticle, first layer surrounding core, particle modifier, therapeutics present within core) were known in the prior art (e.g., Halbherr) and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would yield nothing more than predictable results (e.g., a liposomal formulation comprising doxorubicin or crystals thereof, in the aqueous inner compartment, and docetaxel in the lipid bilayer) to one of ordinary skill in the art. MPEP 2143.A.
Halbherr reads on claims 1-10 and 12-14.
Claim 11 is rendered prima facie obvious because Halbherr taught nucleic acids [0069].
Response to Arguments
Applicant's arguments filed 08/10/2026 have been fully considered but they are not persuasive.
Applicant reiterated the arguments of the rejection over Halbherr.
The Examiner maintains the rebuttal of the arguments of the rejection over Halbherr.
Applicant argued that the Office Action never explained why the skilled artisan would place docetaxel in Halbherr’s bilayer for the purpose of modifying the particle.
The Examiner responds that Halbherr taught docetaxel placed in the lipid bilayer. The property of particle modifier is interpreted as inherent [previously discussed; see the above rationale].
In response to the Applicant's argument that, rather than Halbherr’s placement of docetaxel in the bilayer as a second hydrophobic chemotherapy drug, the claimed invention places a compound in the first layer for a different purpose: to adjust the partition coefficient of the loading molecule, tune permeation through the outer layer, and adjust particle morphology, the Examiner responds that the fact that the Inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability, when the differences would otherwise be obvious. See MPEP 2145.
Applicant argued that Applicant’s results are not predictable, in view of Halbherr’s small, spherical particles. Applicant argued that Halbherr teaches away from the claimed invention, whose hallmark is an elongated particle population.
The Examiner disagrees. As previously discussed, Halbherr’s particle morphology was preferred, but Halbherr is not limited to preferred embodiments. Further, Halbherr is not considered to teach away because the disclosure does not criticize, discredit, or otherwise discourage that which is claimed.
Applicant argued that the Examiner’s entire treatment of claim 11 was one sentence. Applicant cited to Halbherr’s ¶ [0069] to argued a generic, laundry-list of active components. Applicant argued that Halbherr did not teach working examples involving a nucleic acid.
The Examiner responds that claim 11 recites a core comprising nucleic acid as a therapeutic. One sentence was sufficient to reject the claim. Further, Halbherr is not required to disclose working examples, as efficacy is not a requirement for prior art. Halbherr is presumed operable for that which it discloses; the burden is on the Applicant to provide facts rebutting the presumption of Halbherr’s operability. See MPEP 2121 I-III.
Finally, the Examiner is not persuaded by the Applicant’s argument regarding Halbherr’s ¶ [0069], because the list is at most 6 lines long, wherein the first line is “The active component can be selected from the group consisting of”. At line two, there is listed “nucleic acids”. The list presents “a finite number of identified, predictable solutions”, expressly including at least a nucleic acid as a therapeutic, as instantly claimed in claim 11. The Applicant has failed to provide a persuasive reason as to why it would not have been within the skill of the ordinarily skilled artisan to try the limited number of active agents to arrive at the claimed nanoparticle, which would allow for a nucleic acid in the core, as described in Halbherr.
Applicant argued unexpected results in that the co-encapsulated lip-dtx/dox formulation showed significantly higher cytotoxicity than free dtx/dox, lip-dtx or lip-dox.
The Examiner disagrees that the data is unexpected. For purposes of discussion only, and not as a basis of rejection, Halbherr taught [0068] the possibility of encapsulating other actives with doxorubicin, for a synergistic effect upon release. As previously discussed, and also at [0068], Halbherr taught two actives, one encapsulated in the core, and one in the bilayer, where independent of size and morphology of the liposomes, encapsulation is advantageous to the active agents [0061], in order to lower the dosage and to limit side effects. Liposomes also alter the tissue distribution and uptake of drugs, in a therapeutically favorable way. Additionally, liposomes transport encapsulated active components directly to the disease site, including to tumor cells, where the active components are directly released from the liposome at the treatment site.
Since the liposomal membrane is structurally similar to biological membranes, the liposomes merge with the cellular membranes. Upon merging, the liposomal contents are emptied into the cell where the active components act. The active components then accumulate at the desired target [0003-0004]. Therefore, it is not unexpected that liposomes are therapeutically more favorable than the unencapsulated drug, and it is not unexpected that two chemotherapeutics are higher in cytotoxicity than one chemotherapeutic.
The Applicant’s arguments of unexpectedness are non-persuasive, and the Obviousness rejection is maintained.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Halbherr et al (US 2022/0265556 A1), in view of Briuglia et al (Drug Deliv and Transl Res, 2015, 5, 231-242).
The 35 U.S.C. 103 rejection over Halbherr was previously described.
Additionally, at ¶ [0050] Halbherr taught at least 3 mol % PEG (reads on the claim 15 limitation of the amount of PEG).
At Example 1, Halbherr taught a 60:40 weight ratio of DSPC to cholesterol, which is a molar ratio of 42:58, as calculated below:
1. Molar Masses
DSPC = 790.15 g/mol
Cholesterol = 386.65 g/mol
2. Assume a Total Mass of 100 g (for simplicity, based on the 60:40 weight ratio)
Mass of DSPC = 60 g
Mass of Cholesterol = 40 g
3. Moles of Each Component
Moles of DSPC: 60 g ÷ 790.15 g/mol = 0.0759 mol
Moles of Cholesterol: 40 g ÷ 386.65 g/mol = 0.1034 mol
4. Molar Ratio
DSPC mol %: 0.0759 ÷ 0.1793 x 100 = 42.3 %
Cholesterol mol % : 0.1034 ÷ 0.1793 x 100 = 57.7 %
At a weight ratio of 60:40, the molar ratio of DSPC to cholesterol is approximately 42:58.
As such, Halbherr was not specific the 77:20 molar ratio of PC to cholesterol, as instantly recited in claim 15.
Nevertheless, Briuglia taught the formulation of liposomes comprised of variable molar ratios of phospholipids (e.g., DSPC) and cholesterol, including at ratios of DSPC:cholesterol at 80-20 [abstract].
Regarding the amounts of phospholipid and cholesterol, the differences in the claimed subject matter and the prior art are 42.3 mol % phospholipid and 57.7 mol % cholesterol, as taught by Halbherr; versus a molar ratio of PC:cholesterol at about 77:20, as instantly claimed.
Halbherr is not silent as the amounts of the phospholipid and cholesterol. As discussed, Halbherr taught the phospholipid to cholesterol molar ratio at 42.3:57.7. However, Halbherr did not teach the claimed ratio of 77:20. Nevertheless, Briuglia, taught that these ingredients are useful in a molar ratio of PC:cholesterol of 80:20, which overlaps that which is instantly recited. These ingredients, and their amounts, are recognized to have different effects (greater or less formulation of liposomes, as taught by Briuglia at the abstract) with changing amounts used. Thus, the general condition (the molar ratio) is known and the amounts of these ingredients are recognized to be result effective. As such, result effective variables can be optimized by routine experimentation, and it would have been prima facie obvious to have optimized the amounts of the phosphatidylcholine and cholesterol present in the composition of Halbherr, as taught by Briuglia et al. See MPEP 2144.05.
Further regarding the instant claim 15, the claim requires 77 mol % phosphatidylcholine. Bruiglia taught 80 mol % phosphatidylcholine. The ordinarily skilled artisan would have been motivated to have modified this to have been 77 mol % phosphatidylcholine. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). In this case, the general conditions of combining PC and cholesterol to manufacture liposomes have been taught by the prior art [e.g., Bruiglia et al at the abstract; see also Halbherr at claim 18]; as such, it would not have been inventive for the skilled artisan to have discovered the optimum amount of phosphatidylcholine via routine experimentation.
With the combined teachings of Halbherr and Bruiglia, the ordinarily skilled artisan would have had a reasonable expectation of success in arriving at the claimed molar ratio of PC:cholesterol.
Response to Arguments
Applicant's arguments filed 08/10/2026 have been fully considered but they are not persuasive.
Applicant argued that Briuglia tested the 80:20 ratio, but it was not selected as optimal. Applicant argued that Briuglia identified the 70:30 ratio as optimal.
The Examiner reminds the Applicant that prior art is relevant for all that it discloses, and that non-preferred and alternative embodiments (e.g., the 80:20 ratio) also constitute prior art. See MPEP 2123 I and II.
Applicant argued that the Examiner’s reasoning for the result effective variable rationale is not enough.
The Examiner disagrees. The rationale to modify the variables is to form the liposome, as was discussed in the body of the rejection.
Applicant argued that Briuglia’s liposomes contained no particle modifier, and no docetaxel.
The Examiner reminds the Applicant that Briuglia was not relied upon for the liposomes having the instantly recited differences, as that was a feature taught by the combination of the references. One cannot show nonobviousness by attacking references individually, where the rejections were based on combinations of references. See MPEP 2145. In the instant case, Halbherr taught liposomes comprised of PC, cholesterol, docetaxel and doxorubicin. Briuglia was relied upon to teach amounts of PC and cholesterol.
The Applicant’s traversal over Briuglia is found non-persuasive, and the rejection over Briuglia is maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/CELESTE A RONEY/Primary Examiner, Art Unit 1612
