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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. See certificate of availability of a certified patent document in a digital library dated Dec 15 2020 with regard to JP 2018-129133 filed in JAPAN on 07/06/2018.
Status of Claims
Claims 1, 4, 5, 9-11, 15, 17-20 and 24-27 are pending.
Response to Arguments
Applicant’s amendment renumbering claim 22 to claim 20, filed August 19, 2025, with respect to the objection of claim 22 following claim 19, has been fully considered and is persuasive. The objection of claim 22 has been withdrawn.
Applicant's arguments filed August 19, 2025 to rebut the rejection of claims 1, 4-5, 9-11, 15, 17-20 as being obvious over US 2019/0167799 in view of Oberg et al. Applied and Environmental Microbiology Applied and Environmental Microbiology; and U.S. Pub 2018/0161274; have been fully considered but they are not persuasive. See detailed rejection below and rebuttal of Attorney response, as well as rejection of new claims 24027..
Maintained and New 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicants are advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1, 4, 5, 9-11, 15, 17-20 and 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 2019/0167799 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. These references have been cited by the Examiner throughout the prosecution of the this invention.
Previously presented claim 1 is directed to a plasmalogen-containing dry solid composition comprising
plasmalogen,
γ-cyclodextrin, and
at least one member selected from the group consisting of sodium citrate, sodium carbonate, sodium hydrogen carbonate, and sodium hydrogen phosphate 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.
In terms of claim interpretation, core elements of a dry solid composition claim 1 comprises and requires:
plasmalogen
γ-cyclodextrin and
the Markush group of buffers (pH alkali adjusting agents) listed therein.
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. Absent a showing of structural limitations, i.e. amounts of the composition components (cyclodextrin, plasmalogen and buffer), the claimed pH range 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.
Regarding claim 1 and the limitations of a plasmalogen and γ (gamma) -cyclodextrin, 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:
20 mass % or less of ether type glycerophospholipid; and
80 mass % or more of cyclodextrin, see claim 1.
Regarding claim 1, 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, 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.
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 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.
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.
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, along with citrate and phosphate buffer) would have found it prima facie obvious to treat the buffered composition 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, 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, 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 and the limitation 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 5 and the limitation the composition comprises plasmalogen in an amount of 0.1 to 10 mass%, US Pub 799 discloses its composition comprises 20 mass % or less of ether type glycerophospholipid, see claim 11.
Regarding claim 9 and the method for producing the plasmalogen composition, comprising plasmalogen, γ-cyclodextrin, a pH adjusting agent, and water 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. 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 10 and the limitation of drying to obtain a dry composition, comprising plasmalogen, γ-cyclodextrin and sodium citrate or sodium phosphate, US Pub 799 discloses where the ether type glycerophospholipid (plasmalogen)-containing composition is subjected to drying, by freeze drying or spray drying, see claims 18-19.
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.
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.
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. 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.
With regard to the drying step (B), 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.
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, 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.
Regarding claim 15 and the limitation the composition comprises plasmalogen in an amount of 0.1 to 10 mass%, US Pub 799 discloses its composition comprises 20 mass % or less of ether type glycerophospholipid, see claim 11.
Claim 17 recites a method of storing plasmalogen, the method comprising:
(i) preparing a plasmalogen-containing dry solid composition comprising
plasmalogen,
y-cyclodextrin, and
at least one member selected from the group consisting of sodium citrate,
sodium carbonate, sodium hydrogen carbonate, and sodium hydrogen phosphate,
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, and
(ii) storing the plasmalogen-containing solid composition
Regarding claim 17 and the method for producing the plasmalogen composition, comprising plasmalogen, γ-cyclodextrin, a pH adjusting agent, and water to prepare a suspension having a pH of 6 to 8, it would be obvious to do so where 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.
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.
While 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.
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. 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. Regarding the storage limitation of claim 17, US Pub 274 teaches a buffer solution can be added to provide pH optimal for storage stability, preferably between about 6.0 and 7.4, more preferably about 6.5. See paragraph 67.
Additionally, 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.
A person having ordinary skill in the art (PHOSITA) would use of pH adjusting agents (i.e. buffer such as sodium citrate/phosphate 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.
Thus, a PHOSITA would have a rationale to look towards pH modulating (alkali) agents to prevent the hydrolysis of plasmalogens under acidic conditions.
Regarding claim 18 and the limitation of 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 claim 19 and the limitation the composition comprises plasmalogen in an amount of 0.1 to 10 mass%, US Pub 799 discloses its composition comprises 20 mass % or less of ether type glycerophospholipid, see claim 11.
Regarding claim 20 and the limitation of storing the plasmalogen-containing composition for at least 4 weeks, a PHOSITA would routinely optimize storage of plasmalogen containing dry compositions for periods of 4 weeks.
Claims 24-27 are the composition according to claims 1, 9, 11 and 17, respectively, wherein, based on 100 mass% of the plasmalogen, the y-cyclodextrin, and the at least one member selected
from the group consisting of sodium citrate, sodium carbonate, sodium hydrogen
carbonate, and sodium hydrogen phosphate:
the plasmalogen is present in an amount of 1 .0-4.1 mass%;
the γ-cyclodextrin is present in an amount of 81.0-97.1 mass%; and
the at least one member selected from the group consisting of sodium citrate,
sodium carbonate, sodium hydrogen carbonate, and sodium hydrogen phosphate is present in an amount of from 1.9-14.9 mass%.
Regarding claims 24-27 and the limitation of plasmalogen present in an amount of 1 .0-4.1 mass% and the γ-cyclodextrin is present in an amount of 81.0-97.1 mass%; and
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:
20 mass % or less of ether type glycerophospholipid; and
80 mass % or more of cyclodextrin, see claim 1.
Regarding the limitation of mass % amounts of buffer present in the composition, while not necessarily reciting exact amounts, where the art teaches ranges of plasmalogen and γ-cyclodextrin that overlap those claimed AND teaches an optimal pH range that overlaps the claimed pH range, it would be routine for a PHOSITA to optimize the mass% amounts of buffers (citrate and phosphate) so to arrive at the claimed pH range as claimed to achieve a stable composition.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states new claims 24-27, recite that the plasmalogen is present in an amount of 1.0-4.1 mass%; the γ-cyclodextrin is present in an amount of 81.0-97.1 mass%; and the at least one member selected from the group consisting of sodium citrate, sodium carbonate, sodium hydrogen carbonate, and sodium hydrogen phosphate is present in an amount of from 1 .9-14.9 mass%, based on 100 mass% of those materials.
The Attorney response states claims 24-27 are commensurate in scope with the unexpected results of the claimed invention, as they are the mass percentages of the specification’s Examples (referencing Tables 4 and 6 and consistent with values of paragraphs 59-61).1
The Attorney response notes claim 1 is representative of the invention’s broader scope2, where these examples are said to result in cyclodextrin, and the pH alkali adjusting agents recited in claim 1, with an unexpectedly very stable composition compared to compounds that do not comprise γ-cyclodextrin or a pH adjusting agent, even after long-term storage in a dry state. See Figs 4-6 of the specification. See also the Attorney response referencing page 3 of the Kotoura Declaration.
The Attorney response states per the previously submitted Kotoura Declaration when plasmalogen is contained in a dry solid composition (absent water), hydrolysis cannot occur during storage, and the concept of pH does not even arise in the first place, i.e., a dry composition during storage, where the vinyl ether bond would be hydrolyzed during the storage period, and it would not have been expected that there would be a resulting degradation of the plasmalogen. (See Declaration pages 2-3). The Attorney response states it is an unexpected that a dry composition would be hydrolyzed, as such degradation was unknown (see Declaration page 3).
In response, the alleged unexpected results of dry storage stability argued to overcome the prima facie case of obviousness are not commensurate in scope with the claimed invention.3
Initially it is pointed out that claims 1, 9, 11 and 17 are far broader in scope than the working examples of Figures 4-6 (as well as Tables 4, 6 and 7) said to demonstrate unexpected results to overcome the prima facie case of obviousness.
New claims 24-27, that depend from claims 1, 9, 11 and 17 respectively, are said to be limited to a particular commensurate scope to the Examples of Figures 4-6 (examples of Tables 4, 6 and 7). However, claims 24-27 remain broader in scope than the exemplifications of Figs 4-6 and Tables 4, 6 and 7, while they recite they are limited to 100 mass % of plasmalogen, y-cyclodextrin and pH adjusting agent, they nonetheless depend from claims 1, 9, 11 and 17 where said composition broadly comprises the 100 mass% components of plasmalogen, y-cyclodextrin and pH adjusting agent. Thus, even new claims 24-27 can further comprise additional components/excipients, as they depend from claims 1, 9, 11 and 17, which are broader in scope than the specific examples said to provide unexpected results of stability limited specifically to plasmalogen, y-cyclodextrin and pH adjusting agent.
The Attorney response rebuts the Examiner’s reliance upon Sasuga (US Pub 779) to add a buffer such as citrate/carbonate/phosphate to a dry composition when the purpose of the addition is to prevent hydrolysis of the plasmalogen to be dissolved in an acidic liquid (reference Kotoura Declaration pages 3-4).
With regard to the statements regarding a dry composition where it would be unexpected to added a pH adjusting agent to a dry composition, it is noted that what would be noted to be a dry composition to a person of skill in the art, by all appearances, appearing dry under normal storage conditions, can nonetheless absorb atmospheric moisture, and subject the “dry” composition to moisture degradation, while nonetheless still giving the appearance of a dry composition.
Conclusion and Correspondence
No claims are allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 As disclosed in these paragraphs, for the plasmalogen, the amount is 0.1 to 10 mass%; for the y-cyclodextrin, the amount is about 40-95 mass%; for the pH alkali adjusting agent, the amount is about 0.5 to 20 mass%.
2 Claim 1 recites a plasmalogen-containing dry solid composition comprising plasmalogen, γ-cyclodextrin, and at least one member selected from the group consisting of sodium citrate, sodium carbonate, sodium hydrogen carbonate, and sodium hydrogen phosphate, 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.
3 MPEP 716.02(d) Unexpected Results Commensurate In Scope with the Claimed Invention