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 .
Withdrawn Rejections:
Applicant's amendments and arguments filed on 05/11/2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claims 17-37 are pending and under examination.
Claim Rejections - 35 USC § 112
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 32 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 32 recites the broad recitation rhabdomyosarcoma, and the claim also recites “alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, pleomorphic rhabdomyosarcoma” 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.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 17-26, 28-30 and 32, 34, 35, 37 are rejected under 35 U.S.C. 103 as being unpatentable over Willerding et al. (“Method of hyperthermia and tumor size influence effectiveness of doxorubicin release from thermosensitive liposomes in experimental tumors”, Journal of Controlled Release 222 (2016) 47-55) in view of Dou et al. (“To heat or not to heat: Challenges with clinical translation of thermosensitive liposomes”, Journal of Controlled Release 249 (2017) 63–73; cited in IDS).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Willerding et al. teaches Systemic chemotherapy of solid tumors could be enhanced by local hyperthermia (HT) in combination with thermosensitive liposomes (TSL} as drug carriers. In such an approach, effective HT of the tumor is considered
essential for successful triggering local drug release and targeting of the drug to the tumor. To investigate the effect of HT method on the effectiveness of drug delivery, a novel laser-based HT device designed for the use in magnetic resonance imaging (MRI) was compared systematically with the frequently used cold light lamp and water bath HT. Long circulating phosphatidyldiglycerol-based TSL (DPPG2-TSL) with encapsulated doxorubicin. Experiments were performed in male Brown Norway rats with a syngeneic soft tissue sarcoma (BN 175) located on both hind legs. One tumor was heated while the second tumor remained unheated as a reference. Six animals were investigated per HT method. DPPG2-TSL were injected i.v. at a stable tumor temperature above 40ºC. Thereafter, temperature was maintained for 60 min (abstract). Lipid composition of all TSL formulations used in the present study was DPPC/DSPC/DPPG2 50:20:30 (mol/mol) (DPPG2-TSL) (page 48, section 2.2). The tumor model is soft tissue sarcoma cell (page 48, section 2.4). The temperature of HT is from 40-44.3 ºC (page 50, section 3.2).
Dou et al. teaches thermosensitive liposome formulation with DOX (abstract). A lysolipid-containing thermosensitive liposome formulation of doxorubicin provides rapid release of drug following heating to temperatures in the range of mild hyperthermia. This formulation has been commercialized under the trade name ThermoDox®, and was built on earlier research on traditional temperature-sensitive liposomes (page 64, section 1.1). Hyperthermia involves raising the temperature of body tissue to approximately 39 °C to 45 °C (page 65, left column). The tumor size is 3-7cm and the ThermoDox® is at a dose of 50 mg/m2 (page 66, 2nd paragraph). The liposomal
doxorubicin (i.e. Doxil®) has generally been administrated intravenously at 40–50mg/m2 every 28 days for approximately three treatment cycles (page 67, section 2).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Willerding et al. is that Willerding et al. do not expressly teach dose amount and tumor size. This deficiency in Willerding et al. is cured by the teachings of Dou et al.
Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Willerding et al., as suggested by Dou et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to have dose of liposome-dox at about 20 to about 80 mg/m2 because this is optimization under prior art condition or through routing experimentation. MPEP 2144.05. Under guidance from Dou et al. teaching liposome-dox at 50 mg/m2 and produce instant claimed invention with reasonable expectation of success.
Regarding claims 17-20, 26, 29, prior art teaches a method of treating soft tissue sarcoma by administration of DPPG2-TSL-dox at dose of 50 mg/m2 together with local hyperthermia (HT). No lysolipid is required.
Regarding claims 21-25, Willerding et al. teaches effective HT (at temperature of 40-44.3 ºC ) of the tumor is considered essential for successful triggering local drug release and targeting of the drug to the tumor, it is within skill of one artisan in the art to choose the timing for heat treatment (HT), for example, shortly before, during or after administration of liposome-dox so there is sufficient period of time (e.g. 60 min ) for the drug release. One artisan in the art would not start heat treatment more than 30 min before administration of liposome-dox because heating treatment is for drug release, more than 30 min without liposome-dox in the tumor is not for intended use; and one artisan in the art knows when to start heat through routing experimentation, for example, at about 10 min before the liposome-dox so the local temperature is stabilized form 40-44 ºC upon the administration of liposome-dox. MPEP 2144.05.
Regarding claim 28, since Dou et al. teaches liposome-dox treating of tumor size of 3-7cm, it is obvious for (DPPG2-TSL-dox) treating tumor size of at least 4 cm.
Regarding claim 30, it is obvious for one of ordinary skill in the art to optimize the treatment cycle by routing experimentation or under prior art condition. Under guidance from Du et al. teaching 28 days treatment cycle, it is obvious for one of ordinary skill in the art to have treatment of 7 to 28 days.
Regarding claim 32 and 37, Willerding et al. teaches DPPC/DSPC/DPPG2 50:20:30 (mol/mol) (DPPG2-TSL), thus, the DPPG2 is 30 mol%.
Regarding claim 34, Willerding et al. teaches reginal deep hyperthemia.
Regarding claim 35, one arisen would have been motivated to adjust and optimize the frequence of treatment through routing experimentation to have treatment cycle every 21 days, especially in the absence of showing criticality of claimed range. MPEP 2144.05.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 27, 31, 33 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Willerding et al. (“Method of hyperthermia and tumor size influence effectiveness of doxorubicin release from thermosensitive liposomes in experimental tumors”, Journal of Controlled Release 222 (2016) 47-55) in view of Dou et al. (“To heat or not to heat: Challenges with clinical translation of thermosensitive liposomes”, Journal of Controlled Release 249 (2017) 63–73; cited in IDS), as applied for the above 103 rejection for claims 17-26, 28-30 and 32, 34, 35, 37, further in view of Judson et al. (“Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL®/CAELYX®) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcomaa study by the EORTC Soft Tissue and Bone Sarcoma Group”, European Journal of Cancer 37 (2001), 870-877; cited in IDS), Gabizon (US20100297216) and Luukkonen et al. (US20030191048).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Willerding et al. and Dou et al. teaching have already been discussed in the above 103 rejection and are incorporated herein by reference.
Judson et al. teaches treatment of advanced or metastatic soft tissue sarcoma by liposome doxorubicin (title and abstract).
Gabizon teaches a method of treating malignancies in a subject in need of treatment comprising administering to the subject a high loading dose of a pegylated liposomal doxorubicin (PLD) (abstract). Premedication: Pre-medication was administered as follows: On day 1 granisetron 3 mg (or ondansetron 8 mg) IV will be given within 30 minutes prior to treatment (according to its datasheet). Patients with acute symptoms of nausea and/or vomiting, will also receive premedication of dexamethasone 8 mg IV. All other antiemetic therapy will be given depending on how patients tolerate the infusion and physician discretion ([0020]).
Luukkonen et al. teaches compound that modulates Kaposi sarcoma by a mechanism other than inhibition of type I sigma receptor is selected from a group consisting of daunorubicin, doxorubicin, interferon alpha, retinoids, and taxol (claim 17).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Willerding et al. is that Willerding et al. do not expressly teach metastatic cancer and premedication as well as specific sarcoma. This deficiency in Willerding et al. is cured by the teachings of Judson et al., Gabizon and Luukkonen et al.
Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Willerding et al., as suggested by Judson et al., Gabizon and Luukkonen et al. and produce the instant invention.
One of ordinary skill in the art would have been motivated to treat metastatic cancer by DPPG2-TSL-dox because metastatic cancer is treated by liposome-dox as suggested by Judson et al., thus, it is obvious for one of ordinary skill in the art to treat metastatic cancer by DPPG2-TSL-dox and produce instant claimed invention with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to administer premedication before administration of liposome-dox because premedication helps to reduce size effects as suggested by Gabizon. Since it is advantage to reduce side effects of cancer treatment, it is obvious for one of ordinary sill in the art to administer premedication before administration of liposome-dox and produce instant claimed invention with reasonable expectation of success.
Regarding claim 33, under guidance from Luukkonen et al. teaching Kaposi sarcoma treated by doxorubicin; it is obvious to teat Kaposi sarcoma with liposome comprising doxorubicin.
Regarding claim 36, Gabizon teaches premedication dexamethasone which is synthetic steroid.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Argument:
Applicants argue that Willerding et al. does not teach treating human subject.
In response to this argument: this is not persuasive. Willerding et al. teaches animal test, and animal test even in vitro test is sufficient to establish the obviousness of treating human subject, thus, the 103 rejection is still proper.
Applicants argue that Willerding et al. has different type of liposome from that of Dou et al., thus, Dou et al. can not be relied on for teaching amount of liposome. All related arguments are incorporated herein by reference.
In response to this argument: this is not persuasive. Both Willerding et al. and Dou et al. teaches liposome-dox, there is no evidence to show the dose amount would be significantly different from each other, For example, Van Valenberg (" DPPG2-Based Thermosensitive Liposomes with Encapsulated Doxorubicin Combined with Hyperthermia Lead to Higher Doxorubicin Concentrations in the Bladder Compared to Conventional Application in Pigs: A Rationale for the Treatment of Muscle-Invasive Bladder Cancer", International Journal of Nanomedicine, 75-88, 07 Jan 2021; cited in IDS) teaches dose of dose of DPPG2-TSL-DOX is 60 mg/m². Furthermore, one artisan in the art would have been motivated to optimize the dose under routing experimentation to have claimed range of about 20 to about 80 mg/m2, especially in the absence of showing criticality of claimed range. MPEP 2144.05.
Double Patenting
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 17-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10251838 in view of Willerding et al. (“Method of hyperthermia and tumor size influence effectiveness of doxorubicin release from thermosensitive liposomes in experimental tumors”, Journal of Controlled Release 222 (2016) 47-55), Dou et al. (“To heat or not to heat: Challenges with clinical translation of thermosensitive liposomes”, Journal of Controlled Release 249 (2017) 63–73; cited in IDS), Judson et al. (“Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL®/CAELYX®) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma a study by the EORTC Soft Tissue and Bone Sarcoma Group”, European Journal of Cancer 37 (2001), 870-877; cited in IDS) and Gabizon (US20100297216). The reference patent teaches a method of treating cancer (soft tissue sarcoma) by administering thermal sensitive liposome comprising phosphatidyloligoglycerol and doxorubicin (claim 15), in view of Willerding et al. teaching DPPC/DSPC/DPPG2 50:20:30 (mol/mol) (DPPG2-TSL) and the temperature of HT from 40-44.3 ºC; Dou et al. teaching liposome-dox at 50 mg/m2, Judson et al. teaching treatment of advanced or metastatic soft tissue sarcoma by liposome doxorubicin; Gabizon teaching premedication; it is obvious for one of ordinary skill in the art to produce applicant’s claimed invention with reasonable expectation of success.
Claims 17-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18004182 in view of Willerding et al. (“Method of hyperthermia and tumor size influence effectiveness of doxorubicin release from thermosensitive liposomes in experimental tumors”, Journal of Controlled Release 222 (2016) 47-55), Dou et al. (“To heat or not to heat: Challenges with clinical translation of thermosensitive liposomes”, Journal of Controlled Release 249 (2017) 63–73; cited in IDS), Judson et al. (“Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL®/CAELYX®) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma a study by the EORTC Soft Tissue and Bone Sarcoma Group”, European Journal of Cancer 37 (2001), 870-877; cited in IDS) and Gabizon (US20100297216). The copedning application teaches aa thermal sensitive liposome DPPG2-TSL-dox (claims 1 and 3), in view of Willerding et al. teaching DPPC/DSPC/DPPG2 50:20:30 (mol/mol) (DPPG2-TSL) and the temperature of HT from 40-44.3 ºC for the treatment of soft tissue sacroma; Dou et al. teaching liposome-dox at 50 mg/m2; Judson et al. teaching treatment of advanced or metastatic soft tissue sarcoma by liposome doxorubicin; Gabizon teaching premedication; it is obvious for one of ordinary skill in the art to produce applicant’s claimed invention with reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments:
Applicants argue the same as the above 103 rejection.
In response to this argument: this is not persuasive. For the same response to argument as for the above 103 rejection, the double patenting rejections are still proper.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIANFENG SONG. Ph.D. whose telephone number is (571)270-1978. The examiner can normally be reached M-F 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian-Yong Kwon can be reached at (571)272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANFENG SONG/Primary Examiner, Art Unit 1613
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