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 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Election/Restrictions
Applicant’s election of Group I, claims 1-10 and 12-15, in the reply filed on 01/13/2026, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election of:
Afatinib and nintedanib co-encapsulated (species of protein kinase inhibitor)
Substituted ammonium salts of polyanionized sulfated carbohydrates, or triethylammonium sucrose octasulfate (TEA-SOS) (species of trapping agent)
Non-small cell lung cancer (species of cancer)
, in the reply filed on 01/13/2026, is acknowledged.
Claims 16-19 and 21-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 01/13/2026.
Claim Rejections - 35 USC § 112 –
Indefiniteness, Indefinite Language
Broad to Narrow Limitations and Lack of Antecedent Basis
Claims 9, 12 and 15 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.
Regarding lack of antecedent basis, claim 9 recites the limitation "dispersion" in line two. There is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Regarding broad to narrow limitations, 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 recitation “0.20 to 0.80”, and the claim also recites “(i.e., about 20 % to about 80 %) which is the narrower statement of the range/limitation.
In the present instance, claim 15 recites the broad recitation “polyoxyethylene”, and the claim also recites “(i.e., polyethylene glycols) which is the narrower statement of the range/limitation.
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.
Regarding indefinite language, and further regarding claims 12 and 15, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The Applicant is encouraged to remove the indefinite language from the claims.
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, 4, 5-6, 7-8, 9-10, 12-13 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Hong et al (US 2021/0145740 A1), in view each of Chao et al (Journal of Thoracic Oncology, Vol 11, Suppl 4S, 2016, S79-S91) and of Tardi et al (US 2004/0022817 A1).
Hong taught a liposomal sustained-release composition for use in the treatment of non-small cell lung cancer, comprising liposomes with entrapped tyrosine kinase inhibitor, comprising an aqueous interior encompassed by a lipid bilayer and entrapping a tyrosine kinase inhibitor (TKI) [claims 1 and 6]. The tyrosine kinase inhibitor was encapsulated in the aqueous interior of the liposome via a loading method generally comprising a trapping agent [0077], wherein the trapping agent was triethylammonium sucrose octasulfate [0038] (e.g., TEA-SOS). The tyrosine kinase inhibitor was selected from the group consisting of nintedanib or afatinib [0043]. As per Hong, “liposomes” refer to particles characterized by having an aqueous interior space sequestered from an outer medium [0034]; at ¶ [0087], Hong taught a buffer (e.g., reads on a liquid medium).
Hong taught a liposome encapsulating one (TKI), rather than two, as instantly recited; furthermore, Hong did not teach synergy, as recited in claim 1.
Chao taught synergistic antitumor activity of afatinib and nintedanib in non-small cell lung cancer (NSCLC) [title], whereby the combined treatment of afatinib and nintedanib induced significant cell apoptosis in NSCLC cells. Furthermore, the anti-tumor efficacy of the combination of afatinib and nintedanib was better than alone [results].
Since Hong taught treating NSCLC with one TKI, it would have been prima facie obvious to one of ordinary skill in the art to include more than one TKI within Hong. The ordinarily skilled artisan would have been so motivated, because the combined treatment of afatinib and nintedanib induced significant cell apoptosis in NSCLC cells. Furthermore, the anti-tumor efficacy of the combination of afatinib and nintedanib was better than alone, as taught by Chao, at the title and results.
The combined teachings of Hong and Chao did not teach two encapsulated agents.
Tardi taught, at the abstract, compositions which comprise delivery vehicles (e.g., liposomes at [0023]) having stably associated therewith, non-antagonistic (e.g., synergy, at [0024, 0116]) combinations of two or more agents, such as antineoplastic agents, which were useful in achieving non-antagonistic effects when combinations of drugs were administered. This is because there is a strong correlation between the number of agents administered, and cure rates for diseases such as cancer, and because the effects of combinations of drugs are enhanced when the ratio in which they are supplied provides a synergistic effect. Synergistic combinations of agents have also been shown to reduce toxicity due to lower dose requirements, and to increase cancer cure rates [0003-0004].
Since Hong taught the encapsulation of afatinib or nintedanib, and Chao taught that both agents provide a synergistic effect, in the treatment of NSCLC, it would have been prima facie obvious to one of ordinary skill in the art to encapsulate two agents (both afatinib and nintedanib), as taught by Tardi. The ordinarily skilled artisan would have been so motivated, because there is a strong correlation between the number of agents administered and cure rates, and because the effects of drugs are enhanced when they are combined, as taught by Tardi. Further, as taught by Tardi, synergistic combinations of agents have been shown to reduce toxicity, due to lower dose requirements [0003-0004].
The combined teachings of Hong, Chao and Tardi read on claim 1, 7-8 and 15.
Claim 4 is rendered prima facie obvious because Hong taught 100 g drug (TKI, e.g., nintedanib) in a concentration of 15 mg/mL [see claims 2 and 4]. Hong taught the PEG-modified lipid present from 0.0001 mol % to 40 mol % [0037].
The Examiner notes that the mole percentage of nintedanib is 0.0508 %, calculated as thus:
Molar mass of nintedanib: 539.64 g/mol
Moles of nintedanib: 100 g ÷ 539.64 g/mol = 0.1853 mol
Volume of solution: if the concentration is 15 mg/ml, then 100 g (100,000 mg) of nintedanib would require a total volume of 100,000 mg ÷ 15 mg/mL = 6,666.7 mL = 6.67 L
Moles of solvent (water): Assuming the density of the solution is approximately 1g/mL (like water), the total mass is = 6,666.7 g. The mass of water is total mass minus solute mass (6,666.7g - 100g = 6,566.7g). Moles of water = 6,566.7 g ÷ 18.015 g/mol = 364.5 mol.
Mole percentage: (moles Nintedanib ÷ (moles Nintedanib + moles Water)) X 100 = (0.1853 ÷ (0.1853 + 364.5) x 100 = 0.0508 %
The instant claim 4 recites a ≥ 1 molar ratio of lipid to PKI.
Hong taught the PEG-modified lipid present from 0.0001 mol % to 40 mol %; and, the PKI at 0.0508 %. A prima facie case of obviousness exists because of overlap, as discussed above.
Claim 5 is rendered prima facie obvious because Tardi taught two drugs encapsulated in a single liposome at a 10:1 ratio [0038, 0041, 0046]. The motivation to combine Tardi with the combined teachings of Hong and Chao was previously discussed.
Claim 6 is rendered prima facie obvious because Hong taught a mean particle diameter between about 50 nm and about 400 nm [claim 1].
The instant claim 6 recites a mean particle size between 4.5 nm to 450 nm.
Hong taught a mean particle diameter between about 50 nm and about 400 nm. A prima facie case of obviousness exists because of overlap, as previously discussed.
Claims 9-10 are rendered prima facie obvious because Tardi taught HEPES buffered saline, which includes NaCl (a tonicity modifier), at a pH of 7.4 [0074]; Tardi taught water at [0173]. The motivation to combine Tardi with the combined teachings of Hong and Chao was previously discussed.
The instant claim 10 recites a pH of about 5-8. Tardi taught a pH of 7.4. A prima facie case of obviousness exists because of overlap, as discussed above.
Claim 12 is rendered prima facie obvious because Tardi taught that the non-antagonistic effect was exhibited over at least 20 % of the concentration range such that 20-80 % of the cells were affected in an in vitro assay [claim 6], where synergy is established in the fa (e.g., fraction of affected cells) range of 0.2-0.8 [0105]. The motivation to combine Tardi with the combined teachings of Hong and Chao was previously discussed.
Claim 13 is rendered prima facie obvious because Tardi taught two agents encapsulated in a single liposome, with synergism maintained over 24 hours (in plasma) after in vivo administration [Example 5, at ¶ 0230]. The motivation to combine Tardi with the combined teachings of Hong and Chao was previously discussed.
The instant claim 13 recites maintenance of synergism for at least one hour after in vivo administration.
Tardi taught synergism maintained over 24 hours after in vivo administration. A prima facie case of obviousness exists because of overlap, as discussed above.
Claim 14 is rendered prima facie obvious because Hong taught the trapping agent inside of the liposome [0006].
Claim(s) 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Hong et al (US 2021/0145740 A1), in view each of Chao et al (Journal of Thoracic Oncology, Vol 11, Suppl 4S, 2016, S79-S91) and of Tardi et al (US 2004/0022817 A1) and further in view of Kung et al (WO 86/04232).
The 35 U.S.C. 103 rejection over Hong, Chao and Tardi was previously discussed.
Additionally, Hong taught phospholipids, generally, and cholesterol at 2-4 mol % [0035-0036; see also Table 1 and 3]; however, did not teach at least 10 mol % phosphatidylcholine, as recited in claim 2.
Kung taught liposome compositions and methods thereof, whereby liposomes are prepared with vesicle-forming lipids, typically including between about 20-80 % phosphatidylcholine [page 12, lines 10-15].
Since Hong generally taught phospholipids, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Hong, 20-80 % phosphatidylcholine, as taught by Kung. The ordinarily skilled artisan would have been motivated to include vesicle forming lipids, and amounts thereof, for the preparation of liposomes, as taught by Kung.
The instant claim 2 recites at least 10 mol % phosphatidylcholine.
The instant claim 3 recites 0-60 mol % sterol.
Kung taught 20-80 % phosphatidylcholine. Hong taught 2-4 mol % cholesterol. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art", a prima facie case of obviousness exists. MPEP 2144.05 A.
Nonstatutory Double Patenting
A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-10 and 12-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-11, 13-14, 16, 18-26 and 28 of copending Application No. 17/998, 063, which has issued as a U.S. Patent.
Although the claims at issue are not identical, they are not patentably distinct from each other because the species (liposome formulations for the treatment of cancers) recited in the claims of the issued patent falls within the genus (compositions and methods for delivery of anticancer agents) recited in the claims of the instant application, and thus read on the instant claims.
Conclusion
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/CELESTE A RONEY/Primary Examiner, Art Unit 1612
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