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 .1
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 17, 2026 has been entered.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of Claims
Claims 1, 4, 9, 11, 17-18, 20, and 28-32 are pending.
Response to Arguments
Applicant's arguments filed have been fully considered but they are not persuasive. See below rejection of claims 1, 4, 9, 11, 17-18, 20, and 28-32 over Sasuga (US Pub 799) in view of Oberg and Vogelstein (US Pub 274).
Claim Objections
Claim 9 is objected to because of the following informalities: Claim 9 recites a step (A) without recitation of an additional step (B). Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1, 4, 9, 11, 17-18, 20, and 28-32 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 2019/0167799 (US Pub 799) in view of Oberg et al. In view of Identification of Plasmalogens in the Cytoplasmic Membrane of Bifidobacterium animalis subsp. Lactis Applied and Environmental Microbiology Applied and Environmental Microbiology 78(3):880-4 p. 880- 884 Dec 2011 and U.S. Pub 2018/0161274 A1 (US Pub 274). These references have been cited by the Examiner throughout the prosecution of this case.
Amended claim 1 is directed to a plasmalogen-containing dry solid composition as defined therein.
Regarding claim 1 and the limitations of a plasmalogen is present in an amount of 1.0-4.1 mass%;
and a γ(gamma)-cyclodextrin is present in an amount of 81.0-97.1 mass%, US Pub 799 discloses an ether type glycerophospholipid (i.e., a plasmalogen, see paragraphs 5-7, noting vinyl ether glycerophospholipids are plasmalogen)-containing composition comprising: (in overlapping ranges as follows).
20 mass % or less of ether type glycerophospholipid; and
80 mass % or more of cyclodextrin, see claim 1. See MPEP 2144.05.2 With regard to the γ-cyclodextrin, US Pub 799 discloses γ-cyclodextrin is a preferred embodiment of cyclodextrin, see paragraph 124 and claims 22-23.
Regarding the limitation of a dry solid composition prepared by freeze-drying or spray-drying, US Pub 799 teaches freeze drying and/or spray drying of its plasmalogen-cyclodextrin compound in numerous instances; both freeze and spray drying, see paragraphs 57, 66, 140, claims 19; freeze drying only paragraphs 198, 203, 207, 211, 215.
Note that US Pub 799 teaches its compositions maybe mixed together with other components using known methods to form suspensions and liquid agents. See paragraph 161.
Although US Pub 799 discloses compositions plasmalogen and cyclodextrin per claim 1, it does not teach the use of a pH alkali adjusting agent (a buffer, such as sodium citrate, sodium carbonate, sodium hydrogen phosphate etc.), where the composition would have a pH of 6 to 8 when an aqueous solution added to 10 mL of ion-exchanged water.
The basis for pH adjustment, as claimed is disclosed in Oberg. Oberg discloses “The vinyl ether bond of plasmalogens is easily hydrolyzed under acidic conditions to form an aldehyde, which rapidly reacts to form dimethyl acetals (DMA) in the presence of methanol (Fig. 1).” See page 881, second column. Thus, one of ordinary skill in the art would have a rationale to look towards pH modulating (alkali) agents to prevent the hydrolysis of plasmalogens under acidic conditions. This is especially true where US Pub 799 teaches its plasmalogen and γ-cyclodextrin compositions can be admixed together with liquid components to form suspensions and liquid agents. See paragraph 161.
To do so, as US Pub ‘799 discloses use of cyclodextrins with plasmalogens, US Pub 274 notes a composition comprising a therapeutic agent, cyclodextrin and liposomes, where such liposomes comprise exemplary buffers solutions, including citrate and phosphate buffer solutions, see paragraph 52. Further, per the limitation of claim 1, a pH between 6 and 8, US Pub 274 notes the necessity of ionizable chemical groups, i.e., weakly basic functional groups, with a pKa between 6.5 and 8.5, see paragraph 9 and claim 8.
With regard to the limitation where the pH adjusting agent (e.g., sodium citrate, sodium carbonate, etc.), is found in amounts between 1.9-14.9 mass %, while not explicitly taught by the cited art, because the balance of plasmalogen, γ-cyclodextrin and mass% are taught, along with a desired pH range, a person having ordinary skill in the art (PHOSITA) would routinely optimize the claimed mass% of pH adjusting agent as claimed.
With regard to the limitation of “in following storage for 1 week at 60°C, an amount of plasmalogen in the dry solid composition is 93.1 % to 98.2% of the original amount of plasmalogen in the dry solid composition, these limitations would be necessarily present in a dry composition comprising the core elements of plasmalogen, γ-cyclodextrin and clamed Markush group of buffers (sodium citrate, etc.). Prior art teaching a dry solid composition comprising plasmalogen, γ-cyclodextrin and a member of the Markush of buffers will have the claimed storage stability limitations as recited.
With regard to the intended use limitation where the claimed dry solid composition is said to have “pH of 6 to 8 when 0.1 g of the dry solid composition is added to 10 ml of ion-exchanged water,” this limitation would be necessarily present in a dry composition comprising the core elements of plasmalogen, γ-cyclodextrin and clamed Markush group of buffers (sodium citrate, etc.). Prior art teaching a dry solid composition comprising plasmalogen, γ-cyclodextrin and a member of the Markush of buffers will have a pH of 6 to 8 when 0.1 g of the dry solid composition is added to 10 ml of ion-exchanged water.
In terms of claim interpretation, the language of the dry solid composition having a “ pH of 6 to 8 when 0.1 g of the dry solid composition is added to 10 ml of ion-exchanged water” is an intended use to achieve a pH range claimed when added to water. Because the claimed amounts are overlapped and therefore taught by the amounts known in the cited, art,, i.e. amounts of the composition components (cyclodextrin, plasmalogen and buffer), the claimed pH range is achieved with the claimed amount of dry solid added to ion-exchanged water, the intended uses will not overcome prior art teaching the claimed composition.
A person having ordinary skill in the art (PHOSITA) following the teachings of US Pub 799 (disclosing an ether type glycerophospholipid (i.e., a plasmalogen) in combination with γ-cyclodextrin, in overlapping mass % amounts, along with citrate and phosphate buffer) would have found it prima facie obvious to treat the buffered composition, where it is envisaged these compositions are reconstituted into suspensions and liquid preparations of US Pub 799, as taught by Oberg to prevent acid hydrolysis of the vinyl ether bond of plasmalogens, where US Pub 274 notes protection of compositions comprising cyclodextrin with buffers such as citrate and buffers, those ionizable groups with a pKa between 6.5 and 8.5. The rationale to support the prima facie case are the prior art elements of a composition comprising plasmalogen, γ-cyclodextrin and buffers (and known to be used ins suspensions and liquid preparations) combined according to known methods, the stabilization to avoid acid hydrolysis of said composition with buffering compounds with a pKa range between 6.5 and 8.5. A PHOSITA would use pH adjusting agents (i.e. buffer such as sodium citrate etc.) to achieve a pH range as claimed with a reasonable expectation of success because the vinyl ether bond of plasmalogens makes them vulnerable to harsh (acidic) conditions, necessitating the use of pH adjust agents (buffers) as claimed.
Regarding claim 4 reciting a powder composition of claim 1, US Pub 799 discloses that the “ether type glycerophospholipid and the cyclodextrin are mixed together to form a clathrate of the ether type glycerophospholipid and the cyclodextrin, the water content can be removed from the clathrate by a well-known drying method such as the freeze drying method or the spray drying method to obtain powder.” See paragraph 140.
Regarding claim 9 and the method for producing the plasmalogen composition, comprising plasmalogen, γ-cyclodextrin, a pH adjusting agent, and water to prepare the suspension having a pH of 6 to 8, it would be obvious to do so where US Pub 799 discloses where ether type glycerophospholipid-(plasmalogen) containing composition described above can be easily produced by, in particular, mixing together 20 mass % or less of ether type glycerophospholipid and 80 mass % or more of cyclodextrin in the presence of water and/or ethanol. See paragraph 65. These mass % amounts taught overlap the claimed mass %. Further, US Pub 274 notes a composition comprising a therapeutic agent, cyclodextrin and liposomes, where such liposomes comprise exemplary buffers solutions, including citrate and phosphate buffer solutions, see paragraph 52. Further, per the limitation of claim 1, a pH between 6 and 8, US Pub 274 notes the necessity of ionizable chemical groups, weakly basic functional groups, with a pKa between 6.5 and 8.5, see paragraph 9 and claim 8.
Regarding claim 11 and the method for improving the stability of plasmalogen, comprising step (A) of mixing at least plasmalogen, γ-cyclodextrin, water and at least one member selected from the group consisting of and including sodium citrate and to prepare a suspension having a pH of 6 to 8, it would be obvious to do so where US Pub 799 discloses where ether type glycerophospholipid-(plasmalogen) containing composition described above can be easily produced by, in particular, mixing together 20 mass % or less of ether type glycerophospholipid and 80 mass % or more of cyclodextrin in the presence of water and/or ethanol. See paragraph 65 of US Pub 799.
Regarding step (B), US Pub 799 teaches freeze drying and spraying drying its plasmalogen and cyclodextrin compositions. See paragraphs 57, 66, 140, claims 19; freeze drying only paragraphs 198, 203, 207, 211, 215.
Although US Pub 799 discloses compositions plasmalogen and cyclodextrin per claim 1, it does not teach the use of a pH alkali adjusting agent (a buffer, such as sodium citrate, etc.), where the composition would have a pH of 6 to 8 when an aqueous solution. Note that US Pub 799 teaches its plasmalogen and γ-cyclodextrin compositions can be admixed together with liquid components to form suspensions and liquid agents. See paragraph 161.
However a person having ordinary skill in the art (PHOSITA) would use of pH adjusting agents (i.e. buffer such as sodium citrate etc.) to achieve a pH range as claimed with a reasonable expectation of success because the vinyl ether bond of plasmalogens makes them vulnerable to harsh (acidic) conditions, necessitating the use of pH adjust agents (buffers) as claimed.
Oberg discloses “The vinyl ether bond of plasmalogens is easily hydrolyzed under acidic conditions to form an aldehyde, which rapidly reacts to form dimethyl acetals (DMA) in the presence of methanol (Fig. 1).” See page 881, second column. Thus, a PHOSITA would have a rationale to look towards pH modulating (alkali) agents to prevent the hydrolysis of plasmalogens under acidic conditions.
To do so, as US Pub ‘799 discloses use of cyclodextrins with plasmalogens, US Pub 274 notes a composition comprising a therapeutic agent, cyclodextrin and liposomes, where such liposomes comprise exemplary buffers solutions, including citrate and phosphate buffer solutions, see paragraph 52 of US Pub 274. Further, per the limitation of claim 11, a pH between 6 and 8, US Pub 274 notes the necessity of ionizable chemical groups, weakly basic functional groups, with a pKa between 6.5 and 8.5, see paragraph 9 and claim 8.
A PHOSITA following the teachings of US Pub 799 (disclosing an ether type glycerophospholipid (i.e., a plasmalogen) in combination with γ-cyclodextrin, along with citrate and phosphate buffer) would have found it prima facie obvious to treat the buffered composition of US Pub 799, whose dry compositions can be admixed with liquids to form suspensions and liquid formulations in need of pH stabilization, as taught by Oberg to prevent acid hydrolysis of the vinyl ether bond of plasmalogens, where US Pub 274 notes protection of compositions comprising cyclodextrin with buffers such as citrate and buffers, noting the necessity of using ionizable groups with a pKa between 6.5 and 8.5. The rationale to support the prima facie case are the prior art elements of a composition comprising plasmalogen, γ-cyclodextrin and buffers combined according to known methods, stabilization to avoid acid hydrolysis of said composition with buffering compounds with a pKa range between 6.5 and 8.5.
Note with regard to the limitations of mass % of the plasmalogen, γ-cyclodextrin, choice of pH adjusting agent (sodium citrate, etc.), these limitations are discussed above to be taught by US Pub 799. See above rejection of claim 1 where these limitations are identical to those of claim 1.
Regarding claim 17 and the method for storing plasmalogen the method comprising (i) preparing the composition according to claim 1, (ii) storing the plasmalogen-containing solid composition for at least one week, as detailed above, the cited prior art discloses the claimed composition of claim 1. Regarding step (i), the preparation of a composition of claim 1 is discussed above and taught the prior art as detailed above.
Regarding the limitation of claim 17 (ii) of storage of the plasmalogen containing dry solid composition for at least one week, a PHOSITA would routinely optimize storage of plasmalogen containing dry compositions for periods of at least 1 week. US Pub 799 teaches its composition comprising plasmalogen and cyclodextrin is intended for long-term storage, i.e. periods of at least 1 week. See paragraph 144.
Regarding claim 18 and the limitation of a powder composition, US Pub 799 discloses that the “ether type glycerophospholipid and the cyclodextrin are mixed together to form a clathrate of the ether type glycerophospholipid and the cyclodextrin, the water content can be removed from the clathrate by a well-known drying method such as the freeze drying method or the spray drying method to obtain powder.” See paragraph 140.
Regarding claims 20 and 32 and the limitation of storing the plasmalogen-containing composition for at least 4 weeks or at least 2 weeks (respectively), a PHOSITA would routinely optimize storage of plasmalogen containing dry compositions for periods of at least 2 or 4 weeks. US Pub 799 teaches its composition comprising plasmalogen and cyclodextrin is intended for long-term storage, i.e. periods of at least 1 week. See paragraph 144.
Regarding claims 28-31, where following periods of storage for 2 weeks at 60° C, plasmalogen in the dry solid composition is 89.7% to 96.4% of the original amount of plasmalogen, 4 weeks at 60°C, an amount of plasmalogen in the dry solid composition is 87.4% to 94.5% of the original amount of plasmalogen, these limitations would be necessarily present in a dry composition comprising the core elements of plasmalogen, γ-cyclodextrin and clamed Markush group of buffers (sodium citrate, etc.). Prior art teaching a dry solid composition comprising plasmalogen, γ-cyclodextrin and a member of the Markush of buffers will have the claimed storage stability limitations as recited.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states the presently claimed invention have been amended to be consistent with the specification’s Examples so that the invention exhibits unexpectedly superior storage results not disclosed in the cited art, and the present claims are commensurate in scope with those results.
The Attorney response summarizes claim 1 by reciting the particular limitations of plasmalogen, γ-cyclodextrin, the claimed pH adjusting components (sodium citrate etc.) in the claimed mass %, and claimed property of pH of 6 to 8 when 0.1 g of dry solid composition is added to 10 mL of ion-exchanged water; prepared by the claimed freeze-dried or spray dried method, reciting the claimed storage property at the claimed storage conditions.
The Attorney response states, as opposed to the claimed composition, the plasmalogen contained in a dry composition that does not comprise γ-cyclodextrin or a pH adjusting agent, degrades after long term storage.
The Attorney response states per the claimed invention, when the plasmalogen contained in a dry composition comprises plasmalogen, y-cyclodextrin, and the pH alkali adjusting agents recited in claim 1, the result is an unexpectedly very stable composition, even after long-term storage in a dry state. The Attorney response references Figures 4-6 as support.
The Attorney response states these results would not be predicted or expected from the cited prior art, where the claimed solid dry composition and clamed method of making the solid composition is commensurate in scope with these working Examples.
In response, the issue of glycerophospholipid (plasmalogen) stability is recognized in the art, which is addressed by US Pub 799. US Pub 799 teaches glycerophospholipid (plasmalogen) is easily degraded because the vinyl ether bond with in the structure or the polyunsaturated fatty acid included therein is considerably oxidized. See paragraph 10.
US Pub 799 teaches its inventors found that “by including ether type glycerophospholipid [plasmalogen] in cyclodextrin, ether type glycerophospholipid having, even in powder form, high thermal stability, high oxidation stability, and high storage stability can be produced.” See paragraph 28. US Pub 799 teaches a method for producing such a stable composition by a method that involves freeze drying or spray drying. See paragraph 57. Because the prior art recognizes the advantages of a plasmalogen and cyclodextrin dry composition as having high thermal, oxidation and high thermal stability, the Attorney arguments that its working Examples and Figures 4-6, noting the stability of plasmalogen and cyclodextrin versus plasmalogen alone is unexpected, is contradicted by the teachings in the cited prior art.
The Attorney response states, the claims have been amended to recite unexpectedly superior results of following storage for 1 week at 60°C, the amount of plasmalogen in the dry solid composition is 93.1 % to 98.2% of the original amount of plasmalogen in the dry solid composition. See also Attorney statements regarding claims 28-32 with reported storage values at 2 and 4 week periods as per Table 8 of the specification.
As detailed above, these limitations would be necessarily present in a dry composition comprising the core elements of plasmalogen, γ-cyclodextrin and clamed Markush group of buffers (sodium citrate, etc.). Prior art teaching a dry solid composition comprising plasmalogen, γ-cyclodextrin and a member of the Markush of buffers, in overlapping amounts, will have the claimed storage stability limitations as recited.
The Attorney response states per the Kotoura Declaration, where water is absent from a dry solid composition, hydrolysis cannot occur during storage and the concept of pH does not arise and therefore a PHOSITA would not have predicted the presence of the pH adjusting agent to improve the storage stability of a plasmalogen during storage as a dry composition.
In response, as detailed above, the issue of plasmalogen stability is addressed in the cited prior art, where US Pub 799 teaches plasmalogen stability via forming compositions by freeze or spraying drying it with cyclodextrins as claimed. Also noted is that US Pub 799 envisages reformulation of its dry compositions into suspensions and liquid preparations, necessitating pH adjusting agents as claimed.
Conclusion and Correspondence
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a 371 of PCT/JP2019/026550 07/04/2019
FOREIGN APPLICATIONS
JAPAN 2018-129133 07/06/2018
2 MPEP 2144.05 Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions
