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 .
Status of claims
Claims 1-5 and 8-10 are currently amended. Claims 6-7 are original. Claim 11 is new. Claims 1-11 are pending and under examination.
Priority
This application is a 371 of PCT/CN2022/134834, filed on 11/29/2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. CHINA 202211440166.6, filed on 11/17/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/05/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1 and 10 are objected to because of the following informalities:
Claim 1 is objected to for the recitation of “pa” which should be “Pa”. Appropriate correction is needed.
Claim 10 recites “minolevulinic acid hydrochloride”, which is an incorrect spelling. Proper syntax is “aminolevulinic acid hydrochloride”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (b)
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 1-11 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 1 recites “filtration through a filter below 0.22 μm”. It is unclear whether a “filter below 0.22 μm” refers to the nominal pore-size-rating of the filter, the size of the particles retained by the filter, the size of the particles passing through the filter, the diameter of the filter, or other filtration characteristics. This renders claim 1 indefinite.
Claim 1 is indefinite for “70%-90% of a prescribed amount of an injection water” as it does not state what the units of the amount are (e.g. mass%, volume%, mole%). Thus, it is unclear what amount the % would refer to. For the purpose of compact prosecution, the examiner will consider this as % volume.
Claims 2-11 are also indefinite for being dependent to indefinite claim 1.
Claims 4 recites the phrase “related substance”. However, neither the claim not specification define what is or is not considered a “related substance”, which is a broad and undefined term encompassing a wide variety of chemically distinct materials, each having different properties. The claim and specifications fail to provide any structural, functional, or compositional limitation that would define what constitutes a “related substance” to provide the metes and bounds of this phrase. Therefore, the scope of this claim is unclear, and thus indefinite.
Claim 4 recites that the “moisture content is ≤1.0%, and a content of related substances is ≤1.0%”. Although it states that these contents are by mass, it remains unclear what the mass percentage is relative to (e.g., relative to the total weight/volume of the composition, relative to the weight/volume of the active ingredient, etc.), which thus renders the claim indefinite.
Claims 5 and 6 state that the impurities “does not exceed 0.1%” and “does not exceed 0.2%”, respectively. However, it is unclear what is used as the units of percentage (e.g., % molar, % w/w, % v/v, % w/v), thus rendering the claim indefinite.
Claims 5 and 6 state that the impurities “does not exceed 0.1%” and “does not exceed 0.2%”, respectively. However, it is unclear what the percentage is relative to (e.g., relative to the total weight/volume of the composition, relative to the weight/volume of the active ingredient, etc.), thus rendering the claim indefinite.
Claim 5 and 6 recite the phrase “unknown impurities”. However, neither the claim not specification define what is or is not considered a “unknown impurity”, which is a broad and undefined term encompassing a wide variety of chemically distinct materials, each having different properties. The claim and specifications fail to provide any structural, functional, or compositional limitation that would define what constitutes a “unknown impurity” to provide the metes and bounds of this phrase. It is also It is unclear how such impurities will be measured if they are unknown. Therefore, the scope of this claim is unclear, and thus indefinite.
Claim 7 lists the drug content to be “95%- 105% of a labeled amount”. It is unclear whether the labeled amount denotes the absolute mass of drug, an amount per dosage unit, a weight percentage, a weight-per-volume concentration, or another quantity. This renders the claim indefinite.
Claim 7 states that the “content of the aminolevulinic acid hydrochloride is 95%- 105% of a labeled amount”. However, it does not identify the “labeled amount” serving as the reference for the cited percentages, thus rendering the claim indefinite. For purpose of compact prosecution, it will be assumed that any amount satisfies the “labeled amount”.
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.
Claims 3, 7, 9 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sui et al. (CN108261545A).
Claim 3 is a product-by-process claim (MPEP 2113). The claim is considered for the materials and structure it has rather than the process by which it is made. Materially similar products may be made by different processes.
Sui et al. discloses prescriptions and preparation processes of photosensitizer freeze-dried compositions.
Regarding claim 3: Example 8 (i.e., embodiment 8) specifically employs 23.6 g of aminolevulinic acid hydrochloride (“5-aminoketoglutarate hydrochloride”) in a total solution volume of 200 mL. Example 8 dissolves the ingredients in water; fills the mixture into pharmaceutical vials; pre-freezes the filled product; applies vacuum below 20 Pa; raises the temperature in 5°C increments; and continues staged drying until reaching 30°C to obtain the freeze-dried composition.
Regarding Claim 7: An aforementioned 35 U.S.C. 112(b) has been imposed on this claim due to the indefiniteness of “a labeled amount” as recited. Any amount was thus interpreted to satisfy claim 7. Consequently, Sui et al.’s content of aminolevulinic acid hydrochloride (i.e., 23.6 g) as recited in example 8 satisfies the limitations of this claim.
Regarding Claim 9: The reconstitution time of ≤2 minutes is inherent to the formulation of example 8.
Regarding Claim 11: Example 8 additionally employs mannitol, polyvinyl alcohol, PEG 4000, and sodium hydrogensulfite as excipients.
Claim Rejections - 35 USC § 103
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.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries 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 1-4 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Sui et al. (CN108261545A) in view of Kwok et al. (US20080221049A1) in further view of Cesco et al. (US20140088026A1) in further view of Kraus et al. (WO2020264333A1).
Regarding Claim 1:
Sui et al. discloses a photosensitizer freeze-dried composition. Example 8 (i.e., embodiment 8) specifically employs 23.6 g of aminolevulinic acid hydrochloride (“5-aminoketoglutarate hydrochloride”) in a total solution volume of 200 mL, corresponding to approximately 118 mg/mL, which falls within the claimed concentration of 100-200 mg/mL. Example 8 additionally employs mannitol, polyvinyl alcohol, PEG 4000, and sodium hydrogensulfite as excipients; dissolves the ingredients in water; fills the mixture into pharmaceutical vials; pre-freezes the filled product; applies vacuum below 20 Pa; raises the temperature in 5°C increments; and continues staged drying until reaching 30°C to obtain the freeze-dried composition.
However, Sui et al. fails to disclose the following: initially adding 70-90% of the final amount of water for injection and subsequently bringing the solution to a final volume; sterile filtration through a 0.22µm or less; filling 7.5-15 mL in a 50 mL vial; the claimed cooling and heating rates; a 10-20 hour freezing hold; a 100–150-hour primary draying hold; a pressure-rise test; or the claimed nitrogen backfill, shelf-lifting, stoppering, and atmospheric pressure operations.
Kwok et al. discloses stable, sterile pharmaceutical formulations comprising lyophilized tobramycin, wherein the lyophilized tobramycin is in the form of a free-flowing powder. Kwok et al. teaches that the invention can comprise additional active agents [¶60]. Kwok et al. teaches initially placing approximately 80% of the total batch quantity of the sterile water for injection into a compounding tank, adding the active ingredient and stirring until completely dissolved, and subsequently adding water for injection to bring the batch to its final volume. The result pharmaceutical solution is passed through a sterile 0.22 µm filter, filled into sterile vials, and partially stoppered [¶¶63-67]. Kwok et al. further teaches a preferred container capacity of approximately 50 mL and pre-lyophilization fill-volume embodiments including 10 mL, thereby suggesting a fill volume within 7.5 to 15 mL and a 50 mL vial [¶¶24 and 50]. Kwok et al. further multiple embodiments of the following: freezing to -45°C or below, cooling at rates of 0.1-0.5°C/min (corresponding to 6-30°C/hour, thereby overlapping the claimed 5-15°C/hour range); maintaining the frozen product for 10-20 hours; primary drying at a temperature including -15°C; increasing the primary-drying temperature at rates beginning at 0.05°C/min (corresponding to 3°C/hour, falling within the claimed 0.5-5°C/hour range); secondary drying temperatures including 30-35°C; secondary heating rates beginning at 0.1°C/min (corresponding to 6°C/hour, falling within the claimed range of 1-10°C/hour); primary drying pressures of approximately 13-40 Pa, within the claimed maximum of 50 Pa [¶¶32-45]. Kwok et al. teaches that secondary drying temperature may be maintained (on hold) for about 5-30 hours [¶43].
However, Sui et al. and Kwok et al. fail to collectively teach the claimed 100–150-hour primary drying hold or the pressure-rise endpoint test.
Cesco et al. discloses methods of making the lyophilized pulmonary surfactants [¶abstract]. Cesco et al. teaches embodiments of lyophilization cycle where the product is cooled to -50°C, heated to -25°C under vacuum, held at -25°C for 100 hours, heated to 25°C for 6 hours, and evaluated using pressure-rise test to determine whether drying is complete [¶¶49-50 and table 2]. Cesco et al. further teaches that primary drying may extend from 18 to 140 hours [¶49].
However, Sui et al., Kwok et al., and Cesco et al. fail to collectively teach the post-drying shelf-lifting and atmospheric pressure restoration sequence recited in claim 1.
Kraus et al. provides formulations for a drug product comprising a PEGylated CBS protein [¶abstract]. In a non-limiting embodiment [¶¶96-101], Kraus et al. teaches a lyophilization process wherein the chamber is aerated with nitrogen to 800 mbar, which corresponds to 0.8 bar absolute and falls within the claimed 0.1-1.0 BarA range. the vials are then stoppered by lifting the shelves, after which the chamber is aerated with nitrogen gas to atmospheric pressure [¶100].
Regarding Claim 2: In example 8, Sui et al. specifically combines the aminolaevulinic acid hydrochloride with excipients including mannitol, PVA, PEG 4000, and Sodium hydrogensulfite.
Regarding Claim 3: Sui et al. provides the claimed underlying product in example 8 by freeze-drying: an excipient-containing, vial-filled, freeze-dried aminolaevulinic acid hydrochloride formulation at concentrations overlapping with those claims.
Regarding Claim 4: Cesco et al. teaches that the residual moisture content of the formulation may be less than 2% (including 0%) [¶9]. Kwok et al. also teaches that the composition may have less than 2% impurities by weight [¶15].
Regarding Claim 9: Cesco et al. teaches embodiments wherein the average reconstitution time of the formulation was between 8 and 10 seconds [¶111].
Regarding Claim 10: Kwok et al. states that the lyophilized composition is in the form of a free-flowing powder [¶17].
Regarding Claim 11: In example 8, Sui et al. specifically combines the aminolaevulinic acid hydrochloride with excipients including mannitol, PVA, PEG 4000, and sodium hydrogensulfite.
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the aminolaevulinic acid hydrochloride freeze-drying process and formulation of Sui et al. by employing the sterile compounding, 0.22µm filtration, vial-filling, freezing, vacuum, heating rate, drying temperature, and secondary-drying conditions taught by Kwok et al. This is because Kwok et al. teaches those measures as conventional means for producing a stable, sterile, vial-filled lyophilized pharmaceutical product. It would further have been obvious to employ Cesco et al.’s extended primary drying period and pressure-rise endpoint test to promote complete sublimation and objectively confirm completion of drying, and to employ Kraus et al.’s nitrogen backfills, shell-lifting stoppering, and restoration to atmospheric pressure to close the vials under an inert atmosphere and protect the dried product from moisture and oxidative degradation. The cited modifications merely apply known pharmaceutical lyophilization operations according to their established functions, and arranging those conventional operations in the claimed sequence would have amounted to routine process optimization, because the prior art teaches the same general progression of such solution preparation, sterile filtration, vial-filling, freezing, vacuum drying, endpoint confirmation, inert gas backfilling, and stoppering, with the precise ordering and timing ordinarily adjusted to achieve sterility, drying completeness, and product stability, which would thus be the motivation for a person of ordinary skill in the art to pursue such endeavors. A person of ordinary skill in the art would have had a reasonable expectation of success in doing so because Sui et al. already demonstrates that aminolaevulinic acid hydrochloride can be successfully lyophilized, while Kwok et al., Cesco et al., and Kraus et al. teach compatible and routinely adjustable processing and vial-closure parameters for sterile freeze-dried drug products. Selection of values within the disclosed overlapping ranges, including fill volume, cooling and heating rates, drying times, residual moisture, impurity content, and reconstitution time, likewise would have involved no more than routine optimization to obtain predictable improvements in sterility, drying completeness, stability, purity, and reproducibility. Accordingly, the claimed process and resulting freeze-dried composition would have been obvious over the combined teachings of Sui et al., Kwok et al., Cesco et al., and Kraus et al.
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Sui et al. (CN108261545A) in view of Kwok et al. (US20080221049A1) in further view of Cesco et al. (US20140088026A1) in further view of Kraus et al. (WO2020264333A1) in further view of Puskas et al. (US20140249098A1).
Sui et al., Kwok et al., Cesco et al., and Kraus et al. collectively teach all required limitations of claims 1-4 and 9-11.
However, Sui et al., Kwok et al., Cesco et al., and Kraus et al. fail to collectively teach all required limitations of claim 5-7.
Puskas et al. relates to a process for producing pharmaceutical compositions [¶abstract]. Puskas et al. teaches that the compositions may be prepared via freeze-drying [¶79].
Regarding Claims 5 and 6: Puskas et al. teaches that impurities of the composition should be less than 2 wt.-%, more preferably less than 1 wt.-% [¶11].
Regarding Claim 7: Puskas et al. teaches that the dosage form, preferably the tablet, of the invention preferably has contents of active agent which lie within the concentration of 90 to 110%, preferably 95 to 105% of the average content of the active agents [¶120].
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to further modify the freeze-dried formulation of Sui et al., Kwok et al., Cesco et al., and Kraus et al. to provide the impurity and active agent levels taught by Puskas et al. All of the above references are directed to freeze-drying/lyophilization techniques, and Puskas et al. teaches that such freeze-dried compositions may have a purity and drug content overlapping the claimed amount. A person of ordinary skill in the art would have been motivated to combine the above teachings of Puskas et al. into the teaching of the primary references because minimizing impurities and maintaining potency within 95-105% of the labeled amount predictably improve pharmaceutical purity, stability, dosage accuracy, and batch-to-batch consistency. Puskas et al.’s preferred total impurity levels of less than 0.1%, at which each individual known impurity necessarily does not exceed 0.1% and the largest individual unknown impurity does not necessarily exceed 0.2%. A person of ordinary skill in the art would have had a reasonable expectation of success because impurity and potency levels are routinely controlled through conventional purification, formulation, filling, and lyophilization adjustments, and selecting values within Puskas et al.’s disclosed ranges would have amounted to no more than routine optimization yielding predictable results.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Sui et al. (CN108261545A) in view of Kwok et al. (US20080221049A1) in further view of Cesco et al. (US20140088026A1) in further view of Kraus et al. (WO2020264333A1) in further view of Kim et al. (US20200146974A1).
Sui et al., Kwok et al., Cesco et al., and Kraus et al. collectively teach all required limitations of claims 1-4 and 9-11.
However, Sui et al., Kwok et al., Cesco et al., Kraus et al. fail to collectively teach all required limitations of claim 8.
Kim et al. relates to a composition for injection [¶abstract]. Kim et al. teaches that The composition of the present disclosure is prepared prior to a process of freeze-drying [¶21]. Kim et al. teaches that the composition may be in powder form and prepared via freeze-drying [¶¶24, 25].
Regarding Claim 8: Kim et al. Teaches that the composition may have a pH of 3-5 [¶27].
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to adjust the pH of the freeze-dried aminolaevulinic acid hydrochloride formulation of Sui et al., Kwok et al., Cesco et al., Kraus et al. to a pH of 3, as taught by Kim et al. This is because Kim et al. identifies this pH as suitable for a freeze-dried injectable pharmaceutical composition. A person of ordinary skill in the art would have been motivated to select and optimize the pH within the disclosed range to promote suitable drug stability, solubility, manufacturability, and product consistency. A person of ordinary skill in the art would have had a reasonable expectation of success in doing so because pH is a routinely controlled formulation parameter that can be predictably adjusted using conventional acids and bases, and selecting the shared endpoint of pH=3 would have required no more than routine optimization absent any evidence of criticality or unexpected results.
Conclusions
No claim is found allowable
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Arya A. Bazargani, Ph.D.
Patent Examiner
Art Unit 1613
/MARK V STEVENS/Primary Examiner, Art Unit 1613
Prosecution Insights