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 .
Claims 1, 2, 4, 5, 8, and 10 have undergone amendments. Claims 3, 6, 7, and 9 have been cancelled. Claims 11-28 are newly added. Thus, Claims 1, 2, 4, 5, 8, and 10-28, submitted on 28 April 2026, represent all claims currently under consideration.
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.
Response to Amendment
The objections to Claims 5 and 8 are withdrawn. Applicant has amended the claims to correct the informalities.
The 35 U.S.C. § 101 rejection of Claims 1, 2, 3, 4, and 10 is maintained. Claims 1 and 2 are a hybrid of a composition and a methods claim, and the methods are not written in the correct format. Methods claims should be written in a manner such as “A method [i.e., to treat urothelial carcinoma] comprising [action to conduct the objective, such as “administering to a patient in need thereof a mitoxantrone hydrochloride liposome”]. See MPEP § 2173.05 (q).
The 35 U.S.C. § 112(b) rejections of Claims 1, 2, 4, 8 and 10 are maintained. The claims as currently written remain in “use” format. The artisan does not know if the claims are directed towards compositions (the mitoxantrone hydrochloride liposome) or a method of using the mitoxantrone hydrochloride liposome for the treatment of cancer. Amending the claims to be either directed towards a composition (mitoxantrone liposome) or a method of using the liposomes will overcome this rejection.
The 35 U.S.C. § 102(a)(1) rejections of Claims 6, 7, and 9 are each withdrawn. Applicant has cancelled the claims, rendering the rejections moot.
The 35 U.S.C. § 103 rejections of Claims 5-9 over Mei in view of Chiang, Dietel, and Park, Pestalozzi in view of Chiang, Dietel, and Park, and Li in view of Pestalozzi, Chiang, and Park, are each withdrawn. Applicant has cancelled Claims 6, 7, and 9, rendering those rejections moot. Applicant argues that Chiang does not teach the specific population which is to be treated, i.e., patients who have failed platinum and PD-1 inhibitors, and also are suffering from systemic, refractory and metastatic disease as defined in the claims, and there is no suggestion or motivation that this population would respond to the mitoxantrone liposome of Mei. Applicant further argues that none of the cited references teach, suggest, or provide a motivation for the treatment of the specific population of urothelial carcinoma patients which are claimed in the examined application. The Examiner finds this argument to be persuasive.
The provisional non-statutory patenting rejections and non-statutory patenting rejections of Claims 6, 7, and 9 are each withdrawn. Applicant has cancelled the claims, rendering each rejection moot.
Response to Arguments
Each of the 35 U.S.C. § 103 rejections of Claims 5-9 are each withdrawn. Applicant has cancelled Claims 6, 7, and 9, rendering the rejection of those claims moot, and Applicant has further amended Claim 5 to specify that the population to be treated is a specific population which has urothelial carcinoma that is resistant to platinum-containing chemotherapy and/or PD-1 inhibitors, or refuses PD-1 inhibitor therapy, or is intolerant to cisplatin. There is no teaching, suggestion, or motivation found in the cited references to utilize mitoxantrone hydrochloride liposomes to treat this specific type of urothelial carcinoma.
Claim Objections
Claim 5 is objected to because of the following informalities: There is no “wherein” prior to each of the limitations describing the urothelial carcinoma to be treated. Appropriate correction is required.
Claim Rejections - 35 USC § 101- Maintained Rejection
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-4, 10-13, and 22-28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter- namely, machine, manufacture, composition of matter, and process claims. The claims as written are directed towards the use of mitoxantrone hydrochloride liposomes. As such, the claims are not directed to a process, machine, manufacture, or composition of matter (See MPEP § 2173.05(q)).
Claim Rejections - 35 USC § 112(b)- Maintained Rejection
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 1, 2, 4, 10-13, and 22-28 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. Claim 1 is indefinite as the claim remains written in a “use” format. The artisan does not know if the claim is directed towards the composition (“mitoxantrone liposome”) or the method of treatment of cancer using the liposomes. There is no action verb such as administering present within this claim actively defining the steps to set forth a method, rendering the claim indefinite. Claim 2 is indefinite because it is unclear what the phrase “a therapeutically effective amount of mitoxantrone hydrochloride liposome to a patient suffering from urothelial carcinoma” means as there is no action verb such as administering prior to this clause. Claims 4, 10-13, and 22-28 are similarly rejected as indefinite as dependent upon an indefinite claim without resolving the underlying issue of indefiniteness.
Claims 5, 8, and 14-16 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. Claim 5 recites the limitation "the urothelial cancer" in line 3. There is insufficient antecedent basis for this limitation in the claim as all previous references have been to urothelial carcinoma. The Examiner suggests amending this to read “the urothelial carcinoma” to overcome this rejection. Claims 8 and 14-16 are similarly rejected as indefinite as they do not resolve the underlying issue of indefiniteness.
Claim 10 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. Claim 10 is indefinite because it contains a parenthetical (“(e.g. sulfate, citrate, or phosphate)”), causing indefiniteness as to whether these ions are required parts of the invention or merely representative of ions that can be used to practice the invention.
Claim 10 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. In (iii) of Claim 10, it is unclear if what follows the e.g., is a necessary part of the invention or merely representative of preferred embodiments, causing indefiniteness.
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. Claim 12 is indefinite because it is unclear what “mitoxantrone hydrochloride liposome contains 1-2 mg/mL of active ingredient, based on mitoxantrone. 1 mg/mL of active ingredient based on mitoxantrone” refers to. The claim also contains two periods.
Claim 13 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. Claim 13 is indefinite because it is unclear what the clause “based on mitoxantrone 1 mg/mL of active ingredient, based on mitoxantrone” refers to.
Claims 17-21 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. The claims are indefinite as each claim depends on Claim 7, which has been cancelled. It is unclear what claim these should be dependent upon.
Claim 28 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. Claim 28 is indefinite because of the limitation of “about 40-60 nm”. “About” is not defined in the specification, causing indefiniteness as to the error associated with the nanoparticle size.
Claim Rejections - 35 USC § 112(d)- Maintained Rejection
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 28 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 28 depends on Claim 10, which requires that the mitoxantrone liposomes meet one of the 5 groups of stipulations, one of which is (v) the phospholipid bilayer of the mitoxantrone hydrochloride liposome contains hydrogenated soy lecithin, cholesterol, and distearoylphosphatidylethanolamine modified with polyethylene glycol 200 in a mass ratio of 3:1:1, the mitoxantrone hydrochloride forms an insoluble precipitate with the multivalent acid anion in the liposome, and the particle size of the liposome is about 60 nm. However, Claim 28 is broader than this limitation as the claims states that the particle size is about 40-60 nm. As this limitation claims a broader particle size than what is found in (v), Claim 28 is broader, and thus does not further limit Claim 10. 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 § 102- Maintained Rejection
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 2, 4, 10-13, and 22-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li (US 2016/0235671; Publication Date: 18 August 2016).
Li a liposomal pharmaceutical preparation containing a multivalent ionic drug and use thereof in the treatment of diseases, in which the liposome has a size of about 30-80 nm, and the phospholipid bilayer has a phospholipid with a Tm higher than body temperature, so that the phase transition temperature of the liposome is higher than the body temperature (Abstract). Examples of said phospholipid include but are not limited to phosphatidylcholine, HSPC, DPPC, or DSCP, or any combination thereof (Paragraph 0012). In another aspect, the present invention provides a liposomal pharmaceutical composition which comprises a drug of interest, especially a multivalent ionic drug, in a liposomal preparation of the present invention. Therefore, the present invention relates to a liposomal pharmaceutical preparation having a size of 30-80 nm, wherein the liposomal pharmaceutical preparation comprises a multivalent ionic drug as active ingredient, the phospholipid bilayer comprises a phospholipid with a Tm higher than body temperature such that the phase transition temperature of the liposome is higher than the body temperature. Preferably, the peaks of size of the liposomes are centered around 35-75 nm, especially around 40-60 nm (Paragraph 0017). Example 3 (Paragraph 0052) discloses mitoxantrone hydrochloride liposomes. Example 18 (Paragraph 0071) demonstrates use of these liposomes in the treatment of a mouse model of soft tissue sarcoma (S180 tumor cells). The mice were administered via IV injection (Paragraph 0072). Mitoxantrone liposomes with DPPC, cholesterol, and DSPE-PEG2000 at a weight ratio of 3:1:1 were prepared (Example 5, Paragraph 0054). The liposomal formulations can have a multivalent counter ion, which preferably includes the sulfate ion (Claim 31).
The rejected claims are directed to a drug (liposomal mitoxantrone) with an intended use (a treatment for urothelial cancer) and the doses of the usage. As Li teaches liposomal mitoxantrone, and shows its anti-cancer activity, this renders the claims anticipated as the intended use of the claimed invention does not result in a structural difference between the claimed invention and the prior art (See MPEP § 2112.02 (II)).
Claims 1, 2, 4, 10-13, and 22-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mei (US 2020/0197534; Publication Date: 25 June 2020).
Mei methods and compositions where an inducer of cell death (ICD-inducer)-inducing agent (e.g., doxorubicin, oxaliplatin, mitoxantrone etc.) and an IDO pathway inhibitor are integrated into a nanocarrier that allows systemic delivery (Abstract). It is believed that a mitoxantrone (MTX) encapsulated nanocarrier provides a more potent ICD stimulus than the free drug (Paragraph 0011). It is noted that the use of both mitoxantrone-only and mitoxantrone-IND liposomes were extremely effective in a 4T1 breast cancer model (See, e.g., Example 8), and much better than the results with a Doxil equivalent liposome delivering doxorubicin only. In the 4T1 model, the mitoxantrone-only liposome was so effective that an additional effect for cholesterol-IND was not observed, reflecting the possibility that the 4T1 triple negative breast cancer model may represent a TN cancer subset in which hIDO-1 does not play a major role (Paragraph 0456). In certain embodiments, the use of liposomes containing mitoxantrone where the lipid bilayer does not contain IND or other IDO inhibitor. In certain embodiments the liposome formulations are the same as liposome formulations described herein comprising IND, but the lipid bilayer components do not comprise a conjugated IDO inhibitor (Paragraph 0460). Particular embodiments of the invention include a nanovesicle drug carrier wherein said cargo comprises mitoxantrone (Paragraph 0055). Further embodiments for these nanovesicle drug carriers comprise a cargo-trapping agent, selected from the group consisting of citric acid, triethylammonium sucrose octasulfate, ammonium sulfate, an ammonium salt, a trimethylammonium salt, and a triethylammonium salt (Paragraph 0061). The nanoparticle drug carrier can comprise a phospholipid including phosphatidylcholine (Paragraph 0086). The route of administration includes intravenous administration (Paragraph 0194). A “nanovesicle” refers to a “lipid vesicle” having a diameter (or population of vesicles having a mean diameter) ranging from about 10 nm up to about 500 nm. In certain embodiments, a nanovesicle has a diameter ranging from about 10 nm up to about 80 nm (Paragraph 0260).
The rejected claims are directed to a drug (liposomal mitoxantrone) with an intended use (a treatment for urothelial cancer) and the doses of the usage. As Mei teaches liposomal mitoxantrone, and shows its anti-cancer activity, this renders the claims anticipated as the intended use of the claimed invention does not result in a structural difference between the claimed invention and the prior art (See MPEP § 2112.02 (II)).
Double Patenting- Maintained Rejection
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. 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, 2, 4, 10-13, and 22-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,357,728 (Patent Date: 14 June 2014) (‘728).
Claim 1 of ‘728 is drawn to a liposome comprising a bilayer, inner water phase and metal cation ionophore in the outer phase, wherein the inner water phase comprises sulfobutyl ether cyclodextrin, one or more active compounds selected from a group which includes mitoxantrone, and one or more of sodium ion, potassium ion, and calcium ion, wherein the sulfobutyl ether cyclodextrin forms precipitate with the active compound in the inner water phase.
The rejected claims are directed to a drug (liposomal mitoxantrone) with an intended use (a treatment for urothelial cancer) and the doses of the usage. As ‘728 teaches liposomal mitoxantrone, and shows its anti-cancer activity, this renders the claims anticipated as the intended use of the claimed invention does not result in a structural difference between the claimed invention and the prior art (See MPEP § 2112.02 (II)).
Conclusion
Claims 1, 2, 4, 5, 8, and 10-28 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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, Andrew Kosar can be reached at 571-272-0913. 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.
/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
Prosecution Insights