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 17-32 are pending and under examination.
Priority
Acknowledge is made that this application is national stage of international patent application PCT/EP2022/072844, filed on 08/16/2022; which claims priority from European patent application EP21191825.5, filed on 08/18/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/01/2024 is being considered by the examiner.
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.
Claims 20, 25-26 and 29-32 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.
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 20 recites the broad recitation ”DPPGn”, and the claim also recites “DPPG2” which is the narrower statement of the range/limitation;
claim 26 recites the broad recitation “soft tissue sarcoma”, and the claim also recites “undifferentiated pleomorphic sarcoma (UPS), liposarcoma (well differentiated
liposarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma), leiomyosarcoma, synovial sarcoma, angiosarcoma, epithelioid sarcoma, malignant peripheral nerve sheath tumor (MPNST), rhabdomyosarcoma (alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), solitary fibrous tumor, myxofibrosarcoma, fibrosarcoma, uterine sarcoma (uterine leiomyosarcoma, endometrial stromal sarcoma), desmoplastic small round cell sarcoma (DSRCT), desmoids, kaposi sarcoma or bone sarcoma, preferably Ewing sarcoma, osteosarcoma or chondrosarcoma” which is the narrower statement of the range/limitation.
claim 29 recites the broad recitation “local hyperthermia, regional hyperthermia or superficial hyperthermia”, and the claim also recites “regional deep hyperthermia” which is the narrower statement of the range/limitation.
claim 30 recites the broad recitation “7 to 28 days”, and the claim also recites “21 days” which is the narrower statement of the range/limitation.
claim 31 recites the broad recitation “premedication”, and the claim also recites “a compound selected from the group comprising steroids, dexrazoxane, and/or HI-receptor antagonist” which is the narrower statement of the range/limitation.
Claim 32 recites the broad recitation “15 mol % up to 55 mol %”, and the claim also recites “25 mol % up to 35 mol %”, 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 25 recites about 45 after the termination, and it is unclear what “45” indicates. For compact prosecution purpose, “45” is examined as “45 min”.
Claim 26, the claims cite parenthesis, and it is unclear if the subject matter contained within the parenthesis is further limiting or not. A parenthetical expression is simply a word or string of words which contains relevant yet non-essential information and are non-restrictive which means that the phrase may be removed from the sentence without changing the meaning of the sentence. Parenthetical expressions are not permissible which do not contribute to clearness or exactness in stating Applicant’s invention (Ex parte Cahill, 1893 C. D., 78; 63 O. G., 2125).
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 17-22 and 31 are rejected under 35 U.S.C. 102)(a)(1) as being anticipated by 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).
The limitation of claims 17-20 is met by Van Valenberg disclosing a method of treating bladder cancer by Local release of doxorubicin (DOX) from phosphatidyldiglycerol based thermosensitive liposomes (DPPG2-TSL-DOX) potentiated by hyperthermia (HT) and dose of DPPG2-TSL-DOX is 60 mg/m2 (abstract, material and methods). No lysolipid is required.
The limitation of claims 21-22 is met by Van Valenberg disclosing HT (heat treatment) at 43ºC (page 77. Right column, last paragraph), the heat treatment is either before, after or concomitantly with start administration of DPPG2-TSL-DOX.
The limitation of 31 is met by Van Valenberg disclosing premedication dexamethasone (page 77, right column, 3rd paragraph).
Claim(s) 17-18 and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by 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).
The limitation of 17-18 and 22 is met by Dou et al. disclosing a method of treating cancer by administration of thermosensitive liposome formulation with DOX at a dose of 50 mg/m2 together with Hyperthermia involves raising the temperature of body tissue to approximately 39 °C to 45 °C (page 64, section 1.1; page 65, left column; page 66, 2nd paragraph).
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 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, Willerding et al. teaches DPPC/DSPC/DPPG2 50:20:30 (mol/mol) (DPPG2-TSL), thus, the DPPG2 is 30 mol%.
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 and 31 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, 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) and Gabizon (US20100297216).
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]).
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 predication. This deficiency in Willerding et al. is cured by the teachings of Judson et al. and Gabizon.
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. and Gabizon, 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.
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.
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 17-32 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 17-32 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.
Conclusion
No claim is allowed.
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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/JIANFENG SONG/Primary Examiner, Art Unit 1613