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 .
Election/Restrictions
Applicant’s election without traverse of invention group I, claims 1-3 and 12, in the reply filed on 04/28/2026is acknowledged.
Claims 4-9, 11 and 13-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 04/28/2026.
Claims 1-9, 11-20 are pending claims 1-3 and 12 are under examination.
Priority
Acknowledge is made that this application is national stage of international patent application PCT/CN2023/081594, filed on 03/15/2023; which claims priority from Chinese Patent Application CN202210300041.7, filed on 03/25/2022.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/25/2024 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 2-3 and 12 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 2 recites the broad recitation “a neutral phospholipid, a negatively charged phospholipid and sphingomyelin (SM)”, and the claim also recites preferably phosphatidylcholine or sphingomyelin, such as hydrogenated soybean phosphatidylcholine (HSPC), distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), sphingomyelin, hydrogenated sphingomyelin (HSM), which is the narrower statement of the range/limitation.
In the present instance, claim 2 recites the broad recitation “a combination of a neutral phospholipid and a negatively charged phospholipid”, and the claim also recites “preferably a combination of a phosphatidylcholine and a phosphatidylglycerol, such as DSPC and distearoylphosphatidylglycerol (DSPG), HSPC and DSPG, or HSPC and dipalmitoylphosphatidylglycerol (DPPG)” which is the narrower statement of the range/limitation.
In the present instance, claim 2 recites the broad recitation “polyethylene glycol-modified lipid”, and the claim also recites “preferably a phospholipid which is modified by polyethylene glycol and is the same type as the phospholipid that constitutes the liposome membrane; preferably, the polyethylene glycol has a molecular weight of 500 Dalton to 10,000 Daltons, more preferably 2000 to 5000 Daltons” which is the narrower statement of the range/limitation.
In the present instance, claim 2 recites the broad recitation “sodium salt solution, a potassium salt solution and an ammonium salt solution, and the acid radical ion contained in the salt solution is selected from the group consisting of sulfate radical, chloride ion, phosphate radical, hydrogen phosphate radical, dihydrogen phosphate radical, sucrose octasulfate radical, citrate radical, gluconate radical, methanesulfonate radical, acetate radical, oxalate radical and 4-hydroxyethyl piperazine ethanesulfonate radical”, and the claim also recites “preferably one or more selected from the group consisting of sulfate radical, chloride ion, hydrogen phosphate radical, dihydrogen phosphate radical, sucrose octasulfate radical and acetate radical, more preferably sulfate radical or a combination of sulfate radical, chloride ion, phosphate radical, hydrogen phosphate radical and dihydrogen phosphate radical; more preferably, the salt solution is an ammonium sulfate, a solution of a combination of sodium sulfate and a salt of phosphate buffer, a solution of a combination of sodium chloride and a salt of phosphate buffer, or solution of a combination of ammonium sulfate and a salt of phosphate buffer” which is the narrower statement of the range/limitation.
In the present instance, claim 2 recites the broad recitation “2:1 to 15:1”, and the claim also recites “preferably 2:1 to 10:1, preferably 2.5:1 to 10:1” which is the narrower statement of the range/limitation.
In the present instance, claim 2 recites the broad recitation “5:1 to 80:1”, and the claim also recites “10:1 to 50:1” which is the narrower statement of the range/limitation.
In the present instance, claim 2 recites the broad recitation “100 to 800 mM”, and the claim also recites “200 to 600 mM” which is the narrower statement of the range/limitation.
In the present instance, claim 3 recites the broad recitation “10 to 200 nm”, and the claim also recites “preferably 30 to 150 nm, and more preferably 50 to 100 nm” which is the narrower statement of the range/limitation.
In the present instance, claim 3 recites the broad recitation “0.1 to 3 mg/ml”, and the claim also recites “preferably 0.1 to 2 mg/ml” which is the narrower statement of the range/limitation.
In the present instance, claim 3 recites the broad recitation “more than 85%”, and the claim also recites “such as more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%” which is the narrower statement of the range/limitation.
In the present instance, claim 12 recites the broad recitation “10 to 200 nm”, and the claim also recites “preferably 30 to 150 nm, and more preferably 50 to 100 nm” which is the narrower statement of the range/limitation.
In the present instance, claim 12 recites the broad recitation “0.1 to 3 mg/ml”, and the claim also recites “preferably 0.1 to 2 mg/ml” which is the narrower statement of the range/limitation.
In the present instance, claim 12 recites the broad recitation “more than 85%”, and the claim also recites “such as more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%” 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 2 cite parenthesis “(including hydrogenated phospholipids obtained by hydrogenating the above phospholipids)”, 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).
Regarding claims 2-3 and 12, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 1-3 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (CN106474067A, machine translation) in view of Xu et al. (“Development of Long-Circulating pH-Sensitive Liposomes to Circumvent Gemcitabine Resistance in Pancreatic Cancer Cells”, Pharm Res (2016) 33:1628–1637; cited in IDS) as evidenced by Curry et al. (“Calculated Optimal Cooling Rates for Ram and Human Sperm Cryopreservation Fail to Conform with Empirical Observations”, BIOLOGY OF REPRODUCTION 51, 1014-1021 (1994)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Zheng et al. teaches a polyethylene glycol modified gemcitabine or a salt thereof
liposome, comprising gemcitabine or its salt, lipoid substance modified by
polyethylene glycol and phospholipids double-molecular layer, lipid double molecule
layer material comprises phospholipids and cholesterol. gemcitabine or a salt thereof
encapsulated in the phospholipids double-molecular layer, modified lipid of the lipid
substance polyethylene glycol substance in the phospholipids double-molecular layer,
exposed outside the phospholipids double-molecular layer of polyethylene glycol, lipid
material phospholipid, cholesterol, modified by polyethylene glycol and parts by
weight of gemcitabine or its salt are respectively 60-120 parts; 10-60 parts, 0.2-6 parts
and 2-10 parts. gemcitabin modified by polyethylene glycol of this invention or its salt
to liposome, liposome modified by polyethylene glycol, which not only can reduce the
interaction between the liposome fusion, aggregation, sedimentation and so the
occurrence of the phenomenon, but also can effectively reduce the speed and degree
of the mononuclear macrophage uptake, prolonged systemic circulation time. The
invention further claims a preparation method and application of the liposome (abstract).
The weight of the phospholipids, the cholesterol, the lipid substance modified by polyethylene glycol and the gemcitabine or its salt are respectively 60-120 parts; 10-60 parts, 0.2-6 parts and 2-10 parts (page 3, last paragraph). In the invention, gemcitabine or its salt can be formed in gemcitabine or its salt into PBS solution PBS solution, then gemcitabine or its salt PBS solution with phospholipids, cholesterol and polyethylene glycol modified lipid substance. The invention, gemcitabine or its salt in PBS solution, the concentration of gemcitabine or its salt is 7.5mg/mL-15mg/mL (page 7). The liposome comprising gemcitabine is 50nm-500nm or 100nm-200nm (page 6; page 11, Table 1).
Xu et al. teaches pH-sensitive liposomes (PSL) containing
a high content of gemcitabine (abstract). A blank PSL for drug loading, (DOPE: CHEMS: DSPEmPEG2000 = 6: 4: 0.3, 10 mg in total) were obtained using the TFHE method. A phosphate buffer (0.5 ml, pH 7.4, 10 mM with osmotic pressure being adjusted to 300 mOsm for low DL or 200 for high DL using NaCl) was used to hydrate the lipid thin film. After 45 min of hydration with stirring, liposomes were extruded through a 200 nm membrane to reduce their size, and the liposomal pellet obtained by ultra-centrifugation at 186,000×g for 1 h at 4°C (page 1630, left column 3rd paragraph). A lower DL PSL was prepared by re-suspending the liposome pellet (aqueous core, 300 mOsm) (page 1630, left column, last paragraph).
Curry et al. teaches PBS (NaCl 160 mM, Na2HPO4 8 mM, NaH2PO4·2H2O 2 mM, pH 7.4, 300 mOsm) (page 1015, left column. 2nd paragraph).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Zheng et al. is that Zheng et al. do not expressly teach concentration of salt solution 50-800 nM. This deficiency in Zheng et al. is cured by the teachings of Xu 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 Zheng et al., as suggested by Xu et al., and produce the instant invention.
Zheng et al. teaches a liposome composition comprising phospholipids, the cholesterol, the lipid substance modified by polyethylene glycol and the gemcitabine or its salt (in PBS) are respectively 60-120 parts; 10-60 parts, 0.2-6 parts and 2-10 parts. As liposome, the aqueous core (comprising gemcitabine or its salt and PBS) is encapsulated by liposome membrane, and this is also evidenced by Xu et al. teaches aqueous core in liposome. Zheng et al. is silent about molar concentration of salt solution 50-800 nM,
One of ordinary skill in the art would have been motivated to have PBS concentration 50-800 nM because this is optimization through routing experimentation or under prior art condition. MPEP 2144.05. Under guidance from Xu et al. teaches PBS (300 mOsm, 160+8+2=170 nM total salt of NaCl and phosphate as evidenced by Curry et al.) for liposome comprising gemcitabine), it is obvious for one of ordinary skill in the art to have PBS concentration 170 nM (50-800nM) and produce instant claimed invention with reasonable expectation of success. Alternative, since Xu et al. teaches PBS (300 mOsm, 160+8+2=170 nM total salt of NaCl and phosphate as evidenced by Curry et al.) for liposome comprising gemcitabine as solution suitable as liquid core for gemcitabine in liposome. It is obvious for one of ordinary skill in the art to PBS concentration 170 nM (50-800nM) and produce instant claimed invention with reasonable expectation of success.
Regarding claim 1-2, prior art teaches a liposome composition comprising phospholipids, the cholesterol, the lipid substance modified by polyethylene glycol and the gemcitabine or its salt (in PBS 170 nM) are respectively 60-120 parts; 10-60 parts, 0.2-6 parts and 2-10 parts. And the aqueous core (comprising gemcitabine or its salt and PBS) is encapsulated by liposome membrane. When the phospholipids is 100 parts, cholesterol is 20 parts, the lipid substance modified by polyethylene glycol is 1 part, gemcitabine is 2 part; the ratio of phospholipids to cholesterol is 100:20 = 5:1, the ratio of total lipid to gemcitabine is (100+20+1) ;2 = 121:1 =60.5:1. According to claim 2 (section (3), lipid substance modified by polyethylene glycol is considered long-circulating functional material, since amount of lipid substance modified by polyethylene glycol in the total lipid is 1 /(120+20+1)=1/121=0.01%.
Regarding claims 3 and 12, Zheng et al. teaches a liposome size of 100nm to 200nm.
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.
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
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