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 .
Priority
This Application is a 371 of PCT/CN2020/133822, filed Dec. 4, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Jan. 7, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status – Response to Restriction/ Election Requirement
Claims 20-25 and 27-39 are pending. Claims 20-25 and 26-34 are currently active and subject to examination. Claims 35-39 are withdrawn.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claim(s) 20-24 and 28-30 under 35 U.S.C. 102(a)(1) as being anticipated by Naidu (Dept. of Pharmaceutics, KCP, Bangalore, 2006, p. 1-170 (of record, cited in prior office action)) is withdrawn.
The rejection of claim(s) 20-24 and 28-32 under 35 U.S.C. 103 as being unpatentable over Naidu (Dept. of Pharmaceutics, KCP, Bangalore, 2006, p. 1-170 (of record, cited in prior office action)), as applied to claims 20-24 and 28-30 above is withdrawn.
The rejection of claim(s) 23-24 under 35 U.S.C. 102(a)(1) as being anticipated by Mengshujuan et al. (CN106265501 A, published January 4, 2017 (of record, IDS June 2, 2023)) is withdrawn.
The rejection of claims 23-24, 27, 29-30 and 33-34 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn.
The above rejections were overcome by Applicant’s amendments to the claims.
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 22 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.
The term “fast” in claim 22 is a relative term which renders the claim indefinite. The term “fast” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what constitutes a “fast lyocycle.” The specification merely states that “the lyophilization process #6 of the present invention are very fast, and the lyophilization time is shortened to about 2 days.” (p. 29). It is unclear what lyophilization times are fast or not.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.”
The rejection of claim(s) 20-22, 25, 27-29 and 33 under 35 U.S.C. 102(a)(1) as being anticipated by Mengshujuan et al. (CN106265501 A, published January 4, 2017 (of record, IDS June 2, 2023)) is maintained.
Response to Arguments
The Applicant argues that the recitation of 5-10 w/v% carbohydrate content prior to lyophilization distinguishes the present claims from Mengujuan (Remarks, p. 9). These arguments were fully considered but are not persuasive. The recitation “prior to lyophilization, the weight-to-volume ratio of the carbohydrate in the composition is 5% to 10%” is a product-by-process limitation, as it defines a property of an aqueous solution from which the claimed solid is prepared rather than a property of the claim solid itself. Determination of patentability is based on the product itself and the patentability of the product does not depend on its method of production (see MPEP § 2113).
The recited weight-to-volume ratio imparts no identifiable structure to the claimed solid composition. Claim 20 recites no concentration of fosphenytoin sodium, no concentration of buffer, and no fill volume, and therefore the pre-lyophilization weight-to-volume ratio does not define any ratio, proportion or other structural attribute of the resulting solid. Lyophilized solids having identical composition are obtained from solutions having differing carbohydrate weight-to-volume ratios by corresponding adjustment of the fosphytoin sodium concentration or fill volume.
Megshujuan teaches a lyophilized fosphenytoin sodium solid composition comprising fosphenytoin sodium, tromethamine (TRIS) buffer, mannitol (a sugar alcohol) and sulfobutyl-beta-cyclodextrin, prepared at pH 8.0 (Translation, Spec., pp. 3-4). The composition of Mengshujuan therefore appears to be the same as, or substantially the same as the claimed solid composition. The additional presence of cyclodextrin does not distinguish, as claim 20 uses the transitional phrase “comprising.” Where the claimed and prior art appear to be substantially identical, the burden is on the applicant to establish that the prior art product does not necessarily possess the characteristics of the claimed product (see MPEP § 2112.01).
Reiterated Rejection
Claim(s) 20-22, 25, 27-29 and 33 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mengshujuan et al. (CN106265501 A, published January 4, 2017 (of record, IDS June 2, 2023)).
Claim 20 recites:
A fosphenytoin sodium solid composition, comprising fosphenytoin sodium and at least one carbohydrate, wherein the solid composition is a lyophilized composition, and prior to lyophilization, the weight-to-volume ratio of the carbohydrate in the composition is 5% to 10%, wherein the solid composition further comprises a buffer, wherein the at least one carbohydrate is selected from the group consisting of monosaccharide, disaccharide and sugar alcohol.
Mengshujuan teaches a fosphenytoin sodium solid composition comprising fosphenytoin sodium, Tris buffer and at least one carbohydrate (cyclodextrin and mannitol):
2, freeze-drying preparation for injection
Keeping solution temperature at 4 DEG C, prepare the fosphenytoin sodium water solution Han 75mg/ml, wherein every ml adds 2.42mgTRIS, the while of continuously stirred, add the sulfobutyl-beta-cyclodextrins of 100mg/ml amount, stirs 2 hours, add 20mg/ml Mannitol, regulates pH to 8.0 with 5N hydrochloric acid solution, adds 0.5% activated carbon adsorption thermal source, loads in cillin bottle after filtration sterilization, Every bottle of 2ml～10ml, lyophilization, seal, prepare lyophilized injectable powder.
Mengshujuan, Translation, Specification, p. 3-4.
The recited weight-to-volume ratio imparts no identifiable structure to the claimed solid composition. Claim 20 recites no concentration of fosphenytoin sodium, no concentration of buffer, and no fill volume, and therefore the pre-lyophilization weight-to-volume ratio does not define any ratio, proportion or other structural attribute of the resulting solid. Lyophilized solids having identical composition are obtained from solutions having differing carbohydrate weight-to-volume ratios by corresponding adjustment of the fosphytoin sodium concentration or fill volume.
Megshujuan teaches a lyophilized fosphenytoin sodium solid composition comprising fosphenytoin sodium, tromethamine (TRIS) buffer, mannitol (a sugar alcohol) and sulfobutyl-beta-cyclodextrin, prepared at pH 8.0 (Translation, Spec., pp. 3-4). The composition of Mengshujuan therefore appears to be the same as, or substantially the same as the claimed solid composition. The additional presence of cyclodextrin does not distinguish, as claim 20 uses the transitional phrase “comprising.” Where the claimed and prior art appear to be substantially identical, the burden is on the applicant to establish that the prior art product does not necessarily possess the characteristics of the claimed product (see MPEP § 2112.01).
Therefore, claim 20 is anticipated.
Claim 21 is directed towards the fosphenytoin sodium solid composition of claim 20, wherein the solid composition can be stored at room temperature. Mengshujuan teaches that in comparison to the product currently on the market which requires refridgeration, the product that they describe can be stored at room temperature:
The beneficial effects of the present invention is, it is provided that the pharmacy intermediate product of new fosphenytoin sodium, it is even at low pH Under also there is good short-term normal temperature storage stability, can facilitate that pharmaceutical factory continues to be configured to including injection various doses Type； Its injection being configured to, in the case of physiological pH, has good long-term normal temperature storage stability, thus right Blood vessel irritation is less, and compliance and the toleration of use are more preferable.
Mengshujuan, Translation, Specification, p. 3.
Therefore, claim 21 is anticipated.
Claim 22 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein the solid composition is a lyophilized through a fast lyocycle without a primary drying process. As shown in the rejection of claim 20, Mengshujuan teaches a lyophilized composition and the lyophilization process does not appear to impact the structure of the final product. Therefore, claim 22 is anticipated.
Claim 27 is directed towards the fosphenytoin sodium solid composition according to claim 25, wherein the buffer is one or more selected from phosphate buffer, hydrophosphate buffer, dihydrogen phosphate buffer, bicarbonate buffer, carbonate buffer, boric acid buffer, borate buffer, amino acid buffer, trialkylamine buffer, tromethamine buffer, pyrophosphate buffer, Glycyl Glycine (glycylglycine) buffer; the trialkylamine is trimethylamine; and wherein prior to lyophilization, a concentration of the buffer is 10 to 150 mM.
As shown in the rejection of claim 20, Mengshujuan teaches a lyophilized fosphenytoin sodium solid composition which comprises TRIS (tromethamine) buffer. The concentration is about 20 mM (
2.42
m
g
=
20
m
M
*
1
m
L
*
121.14
g
/
m
o
l
).
Therefore, claim 27 is anticipated.
Claim 28 is directed towards the fosphenytoin sodium solid composition according to claim 22, wherein the pH of the fosphenytoin sodium solid composition prior to lyophilization or after reconstitution is 8 to 10. As shown in the rejection of claim 20, Mengshujuan teaches a lyophilized fosphenytoin sodium solid composition which is pH adjusted to pH 8.0 prior to lyophilization. Therefore, claim 28 is anticipated.
Claim 29 is directed towards the fosphenytoin sodium solid composition according to claim 22, wherein, prior to lyophilization, the concentration of the fosphenytoin sodium is 75 mg/mL to 150 mg/mL. As shown in the rejection of claim 20, Mengshujuan teaches a lyophilized fosphenytoin sodium solid composition with a fosphenytoin sodium concentration of 75 mg/mL which falls within the claimed range. Therefore, claim 29 is anticipated.
Claim 33 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein the solid composition is a lyophilized composition comprising fosphenytoin sodium, a buffer and at least one carbohydrate; the buffer is tromethamine; the carbohydrate is selected the group consisting of trehalose, sucrose, mannitol and lactose; and the pH of the lyophilized composition before lyophilization or after reconstitution is 8 to 9.
As shown in the rejection of claim 20, Mengshujuan teaches a lyophilized composition comprising fosphenytoin sodium, tromethamine and mannitol, wherein the pH of the lyophilized composition before lyophilization is 8.0.
Therefore, claim 33 is anticipated.
Claim Rejections - 35 USC § 103 – Previously Presented
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The rejection of claim(s) 20-25 and 27-34 under 35 U.S.C. 103 as unpatentable over Mengshujuan et al. (CN106265501 A, published January 4, 2017 (of record, IDS June 2, 2023)), as applied to claims 20-22, 25, 27-29 and 33 above, and further in view of Naidu (Dept. of Pharmaceutics, KCP, Bangalore, 2006, p. 1-170 (of record, cited in prior office action)) is maintained.
Response to Arguments
The Applicant argues that the prior art teaches away from using a buffer, citing US 2007/0244074 A1 (Remarks, p. 9). These arguments were fully considered but are not persuasive.
The prior art as a whole does not teach away from the use of buffers in lyophilized fosphenytoin sodium compositions. As shown in the 102 rejection above, Mengshujuan, the primary reference, contains the very element that ‘074 supposedly discourages. Mengshujuan teaches a lyophilized fosphenytoin sodium composition containing TRIS, published a decade after ‘074. The skilled artisan is presumed to be aware of the art as a whole, and there is no need to “modify Mengshujuan to add a buffer” because the buffer is already there.
Applicant’s reliance on the ‘074 publication is not persuasive because the ‘074 publication is directed towards aqueous parenteral solutions and attributes the increase in diphenylhydantoic acid to alkaline hydrolysis of the prodrug in solution (¶¶ 0016, 0022-0025). Each of Examples 1-3 is a liquid formulation stored for 3 to 6 months. The claims at issue and the cited prior art are drawn to a lyophilized solid composition, in which the water necessary for hydrolysis described in ‘074 has been removed. ‘074 nowhere criticizes, discredits or discourages the use of a buffer in a lyophilized fosphenytoin composition and furthermore it acknowledges the lyophilized composition of WO 9904798 at ¶008 without commenting on buffering.
Reiterated Rejection
Claim(s) 20-25 and 27-34 is/are rejected under 35 U.S.C. 103 as unpatentable over Mengshujuan et al. (CN106265501 A, published January 4, 2017 (of record, IDS June 2, 2023)), as applied to claims 20-22, 25, 27-29 and 33 above, and further in view of Naidu (Dept. of Pharmaceutics, KCP, Bangalore, 2006, p. 1-170 (of record, cited in prior office action)).
The rejection of claims 20-22, 25, 27-29 and 33 as anticipated by Mengshujuan is incorporated herein by reference. As such, these claims were prima facie obvious at the time of filing.
Claim 23 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein the carbohydrate is a monosaccharide and wherein the monosaccharide is at least one selected from glucose, galactose and fructose. Claim 24 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein the carbohydrate is a disaccharide, and wherein the disaccharide is at least one selected from the group consisting of sucrose, lactose, trehalose, maltose and isomaltose.
As shown in the rejection of claim 20, Mengshujuan teaches a similar carbohydrate, mannitol. While Mengshujuan does not teach the carbohydrates of claims 23 and 24, one of ordinary skill in the art would have a reasonable expectation of success to use the claimed monosaccharides and disaccharides in the composition because fosphenytoin sodium solid compositions are commonly known in the art to comprise these monosaccharides and disaccharides.
For example, Naidu teaches fosphentytoin sodium solid compositions comprising glucose (dextrose) and lactose:
PNG
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747
798
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Greyscale
Naidu, p. 68.
Therefore, claims 23-24 were prima facie obvious at the time of filing.
Claim 30 is directed towards the fosphenytoin sodium solid composition according to claim 22, wherein, after reconstitution, the concentration of the fosphenytoin sodium is 75 mg/mL to 150 mg/mL.
Mengshujuan teaches that the lyophilized product can be reconstituted for injection:
Preferably in the purposes of fifth aspect present invention, pharmaceutical preparation is injection (e.g., injection with small volume, infusion solutions Agent, freeze-drying preparation for injection etc.), tablet, capsule. Preferably wherein, in addition to fosphenytoin sodium and sulfobutyl-beta-cyclodextrins, Infusion solution can also include NaCl or glucose
Mengshujuan, Translation, Specification, p. 3.
While Mengshujuan does not teach the concentration after reconstitution, it is commonly known in the art to resuspend lyophilized fosphenytoin sodium to a concentration between 75 mg/mL to 150 mg/mL.
For example, Naidu teaches that each vial was initially filled with 2 mL of the solution prior to lyophilization (Naidu, p. 69), and that the vial was reconstituted with 2 mL water for injection (Naidu, Specification, p. 71). As such the concentration of fosphenytoin sodium remained at about 98 mg/mL. Furthermore, Mengshujuan teaches that an aqueous solution of fosphenytoin sodium preferably has a fosphenytoin concentration of 75 mg/mL (Mengshujuan, Translation, Specification, p. 2).
Therefore, claim 30 was prima facie obvious at the time of filing.
Claim 31 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein no Impurity A, Impurity B or Impurity C is generated in the fosphenytoin sodium solid composition after being placed at 25°C and 60% relative humidity for 3 months. Claim 32 is directed towards, the fosphenytoin sodium solid composition according to claim 20, wherein no Impurity A, Impurity B or Impurity C is generated in the fosphenytoin sodium solid composition after being placed at 40°C and 75% relative humidity for 3 months.
While Mengshujuan does not teach the precise stability of the lyophilized composition in these conditions, one of ordinary skill in the art would have a reasonable expectation of success to obtain a lyophilized composition comprising fosphenytoin sodium and a carbohydrate wherein no Impurity A, Impurity B or Impurity C is generated in the fosphenytoin sodium solid composition after being placed at 25°C and 60% relative humidity for 3 motnhs or no Impurity A, Impurity B or Impurity C is generated in the fosphenytoin sodium solid composition after being placed at 40°C and 75% relative humidity for 3 motnhsbecause it is known in the art that lyophilized compositions comprising fosphenytoin sodium and carbohydrates are highly stable.
For example, Naidu teaches that no impurities are detected for formula F2 and F3 after being placed at 40°C and 75% relative humidity for 2 months:
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666
1051
media_image2.png
Greyscale
Naidu, p. 166 of PDF.
Therefore, claims 31-32 were prima facie obvious at the time of filing.
Claim 34 is directed towards the fosphenytoin sodium solid composition according to claim 33, wherein, prior to lyophilization, the concentration of the fosphenytoin sodium is 75 mg/mL or 100mg/mL, the concentration of the buffer is 20 to 100 mM, and the weight-to-volume ratio of the carbohydrate in the composition is 5% to 10 %.
Mengshujuan teaches a fosphenytoin sodium solid composition wherein prior to lyophilization, the concentration of the fosphenytoin sodium is 75 mg/mL, the concentration of the buffer is about 20 mM and the weight-to-volume ratio of the carbohydrate is 12% (10% cycodextrin and 2% mannitol) (Mengshujuan, Translation, Specification, p. 3-4).
While Mengshujuan does not teach a fosphenytoin sodium solid composition wherein the w/v ratio of the carbohydrate is 5 to 10%, one of ordinary skill in the art would have a reasonable expectation of success to adjust the w/v ratio to 5 to 10% because lyophilized fosphenytoin solid compositions comprising 5 to 10% carbohydrate are commonly known in the art.
For example, Naidu that stable lyophilized compositions comprising 0.9803, 2.4507, or 4.4113 g of mannitol in a total volume of 50 mL, which is about 2 w/v%, 5 w/v% or 9 w/v%, respectively:
PNG
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155
646
media_image3.png
Greyscale
Naidu, p. 66, Table 4.2.
Therefore, claim 34 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
