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.
Claim Status – Response to Restriction/ Election Requirement
Claims 20-39 are pending.
Applicant’s election of Group I, claims 20-34, and sucrose at 5-10% w/w and tromethamine buffer, at a concentration of 20-100 mM (pH 8-9), in the reply filed on Dec. 19, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The Applicant merely stated that the groups are so related that there is no search burden. As such, the Applicant is merely claiming there is unity of invention, without pointing out distinctly and specifically why there is unity of invention.
Claims 20-34 are currently active and subject to examination. Claims 35-39 are withdrawn.
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 23-24, 27, 29-30 and 33-34 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.
Regarding claims 23-24, 27, and 29-30, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). “If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.”
Regarding claim 33, the claim recites that “the carbohydrate is selected from trehalose, sucrose, mannitol or lactose.” It is unclear what alternatives are intended to be covered by the claim because “selected from” implies a closed grouping while the conjunction “or” implies an open grouping.
Treatment of claims reciting alternatives is not governed by the particular format used (e.g., alternatives may be set forth as "a material selected from the group consisting of A, B, and C" or "wherein the material is A, B, or C")…
A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim.
MPEP § 2173.05(h).
Claim 34 depends upon claim 33 and does not clarify this ambiguity and is therefore also indefinite.
Appropriate correction is required.
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.”
Claim(s) 20-24 and 28-30 is/are rejected 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)).
Claim 20 is directed towards a fosphenytoin sodium solid composition comprising fosphenytoin sodium and at least one carbohydrate.
Naidu teaches fosphenytoin sodium solid compositions comprising fosphenytoin sodium and at least one carbohydrate (mannitol, lactose, dextrose, or sorbitol):
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798
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Naidu, p. 68.
Therefore, claim 20 is anticipated.
Claim 21 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein the solid composition can be stored at room temperature.
Naidu teaches that the fosphenytoin sodium solid compositions are stable at room temperature (25°C):
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200
761
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Naidu, p. 26;
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543
757
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Naidu, p. 133;
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755
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Naidu, p. 135.
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 composition. As shown in the rejection of claim 20, Naidu teaches that the composition is lyophilized. Therefore, claim 22 is anticipated.
Claim 23 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein the carbohydrate is at least one selected from sugar and oligosaccharide; preferably, the sugar is at least one selected from monosaccharide, disaccharide and sugar alcohol; preferably, the monosaccharide is at least one selected from glucose, galactose and fructose; preferably, the disaccharide is at least one selected from sucrose, lactose, trehalose, maltose and isomaltose; preferably, the sugar alcohol is at least one selected from sorbitol, mannitol, xylitol and maltitol; and preferably, the oligosaccharide is at least one selected from raffinose, stachyose, isomaltooligosaccharide, fructooligosaccharide, mannose oligosaccharide and soybean oligosaccharide.
As shown in the rejection of claim 20, Naidu teaches that the carbohydrate is mannitol, lactose, sorbitol or dextrose, which are sugars/ sugar alcohols.
Therefore, claim 23 is anticipated.
Claim 24 is directed towards the fosphenytoin sodium solid composition according to claim 22, wherein, prior to lyophilization, the weight-to-volume ratio of the carbohydrate in the composition is 1% to 20%, preferably 3% to 15%, and more preferably 5% to 10%.
Naidu teaches that the w/v ratio of carbohydrate in the composition lies within the range of 1% to 20%. For example, Naidu teaches that the composition comprises 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:
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Naidu, p. 66, Table 4.2.
Therefore, claim 24 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, preferably 8 to 9.3, and more preferably 8 to 9.
Naidu teaches that the pH of the fosphenytoin solid compositions after reconstitution is between 8 and 9:
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Naidu, p. 92.
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, preferably 75 mg/mL to 100 mg/mL; and more preferably 75 mg/mL or 100 mg/mL.
Naidu teaches that prior to lyophilization, the concentration of the fosphenytoin sodium is about 98 mg/ mL in the F1-F3 compositions
4.9
g
*
1000
m
g
/
g
*
50
m
L
=
98
m
g
/
m
L
.
This falls within the claimed range and as such, claim 29 is anticipated (MPEP 2131.03).
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, preferably 75 mg/mL to 100 mg/mL; and more preferably 75 mg/mL.
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. Therefore, claim 30 is anticipated.
Claim(s) 20-29 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 is directed towards a fosphenytoin sodium solid composition comprising fosphenytoin sodium and at least one carbohydrate.
Mengshujuan teaches a fosphenytoin sodium solid composition comprising fosphenytoin sodium 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.
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 composition. As shown in the rejection of claim 20, Mengshujuan teaches a lyophilized composition. Therefore, claim 22 is anticipated.
Claim 23 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein the carbohydrate is at least one selected from sugar and oligosaccharide. As shown in the rejection of claim 20, Mengshujuan teaches that the carbohydrates are mannitol (sugar) and sulfobutyl-beta-cyclodextrins (oligosaccharide). Therefore, claim 23 is anticipated.
Claim 24 is directed towards the fosphenytoin sodium solid composition according to claim 22, wherein, prior to lyophilization, the weight-to-volume ratio of the carbohydrate in the composition is 1% to 20%, preferably 3% to 15%, and more preferably 5% to 10%. As shown in the rejection of claim 20, Mengshujuan teaches that the composition comprises 20 mg/mL mannitol and 100 mg/mL sulfobutyl-beta-cyclodextrins for a carbohydrate content of 12%, which falls within the claimed range. Therefore, claim 24 is anticipated.
Claim 25 is directed towards the fosphenytoin sodium solid composition according to claim 20, wherein the solid composition further comprises a buffer. Claim 26 is directed towards the fosphenytoin sodium solid composition according to claim 22, wherein the solid composition further comprises a buffer. As shown in the rejection of claim 20, Mengshujuan teaches a lyophilized fosphenytoin sodium solid composition which comprises TRIS buffer. Therefore, claims 25-26 are 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; preferably, the phosphate, hydrophosphate, dihydrogen phosphate, bicarbonate, carbonate, borate and pyrophosphate are independently a sodium salt and/or a potassium salt; the trialkylamine is trimethylamine; preferably, prior to lyophilization, a concentration of the buffer is 10 to 150 mM, and more preferably 20 to 100 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, preferably 8 to 9.3, and more preferably 8 to 9. 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, preferably 75 mg/mL to 100 mg/mL; and more preferably 75 mg/mL or 100 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 from trehalose, sucrose, mannitol or lactose; and the pH of the lyophilized composition before lyophilization or after reconstitution is 8 to 9.
The claim is interpreted as not to limit the carbohydrate to trehalose, sucrose, mannitol or lactose because the alternative limitation is ambiguous. The claim appears to read on a composition comprising at least one carbohydrate selected from trehalose, sucrose, mannitol or lactose.
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
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.
Claim(s) 20-24 and 28-32 is/are rejected 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.
The rejection of claims 20-24 and 28-30 above as anticipated by Naidu is incorporated herein by reference. As such, these claims were 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 14 days; preferably, 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 14 days; preferably, 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.
One of ordinary skill in the art would have a reasonable expectation of success that the fosphenytoin composition of claim 20 would generate no impurity A, B or C after 14 days at 25°C and 60% relative humidity and 40°C and 75% relative humidity because 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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Naidu, p. 166 of PDF.1
Therefore, claims 31-32 were prima facie obvious at the time of filing.
Claim(s) 20-34 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 20-29 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 20-29 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 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, preferably 75 mg/mL to 100 mg/mL; and more preferably 75 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 14 days; preferably, 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 14 days; preferably, 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 14 days 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 14 days because 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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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:
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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.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
1 Phenytoin rel impurity A (2,2-Diphenylglycine), Phenytoin rel impurity B (2,2-Diphenyl-2-ureidoacetic acid), and phenytoin (5,5-diphenylimidazolidine-2,4-dione) are Impurity A, Impurity B, and Impurity C, respectively.