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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/18/2025 has been entered.
Priority
The instant application filed on 07/15/2022 is a 371 of PCT/JP2021/001434 filed on 01/18/2021 which finds support for claim 13, and which claims priority to U.S. Provisional Application No. 63/115,666 filed on 11/19/2020 which finds support for claims 1-3, 8, and 11-12. Therefore, the effective filing date for claims 1-3, 8, and 11-12 is 11/19/2020, and the effective filing date for claim 13 is 01/18/2021.
Status of the Claims
Claim 3 has been amended. Claims 3, 8, 11-13, and 32-35 are pending and currently under examination (claim set filed on 06/18/2025).
Withdrawal of Rejections
The response and amendments filed on 06/18/2025 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s response to arguments section.
Briefly, the previous claim rejections under 35 U.S.C. 103 have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection have been set forth below.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 112(a), New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 3, 8, 11-13, and 32-35 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 3 has been amended to recite “non-recombinant bacteria”; however, there is no support for non-recombinant bacteria in the instant Specification as originally filed. Therefore, the recitation of “non-recombinant bacteria” is new matter and should be removed from the instant claim (see, e.g., MPEP 608.04).
Claims 8, 11-13, and 32-35 are included in this rejection for depending on rejected claim 3 and failing to rectify the noted deficiency.
Examiner’s Response to Arguments
Applicant stated that support for the claim 3’s amendments can be found throughout the original application (remarks, page 5); however, there is no support in the instant Specification for Applicant’s amendment of “non-recombinant bacteria”. Therefore, this amendment is considered new matter and rejected under 35 U.S.C. 112(a).
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 112(a), Enablement
Claims 3, 8, 11-13, and 32-35 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
In re Wands (858 F2d, 721, 727, 8 USPQ 2d 1400, 1404 (Fed Cir. 1988)), the issue of enablement in molecular biology was considered. It was held that the following factors should be considered to determine whether the claimed invention would require the skilled artisan undue experimentation:
Amount of experimentation necessary;
Amount of direction or guidance presented;
Presence or absence of working examples;
Nature of the invention;
State of the prior art;
Relative skill of those in the art;
Predictability or unpredictability of the art; and
Breadth of the claims.
Independent claim 3 recites:
A composition for producing isoalloLCA from 3-oxo-A4- LCA, comprising an active ingredient and a carrier that is acceptable pharmacologically or as a food or drink, wherein the active ingredient is selected from the group consisting of: (a) a first bacterium having a polynucleotide encoding bacterial 3-oxo-5a-steroid-4-dehydrogenase (EC 1.3.99.5) (5AR) and a second bacterium having a polynucleotide encoding 3β-hydroxysteroid dehydrogenase (3βHSDH); (b) a third bacterium having a polynucleotide encoding 5AR and a polynucleotide encoding 3βHSDH, and (c) a combination thereof, the first bacterium, the second bacterium, and the third bacteria are non-recombinant bacteria, and independently selected from the group consisting of Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae.
Nature of the invention: The invention is directed towards a bacterial composition for producing isoalloLCA from 3-oxo-A4- LCA, wherein the bacteria non-recombinantly expresses 5AR and/or 3βHSDH.
Breadth of the claims: As claimed, the composition consists of bacteria non-recombinantly expressing 5AR and/or 3βHSDH, wherein the bacteria are selected from the group consisting of Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae.
Amount of direction or guidance presented: The instant specification states that the invention pertains to “A composition for converting 3-oxo-A4- LCA to 3-oxoalloLCA, comprising: a bacterium having a polynucleotide encoding 3-oxo-5a-steroid-4-dehydrogenase (5AR) as an active ingredient” (see, e.g., instant specification, pg. 6, lines 13-16), and “A composition for converting 3-oxoalloLCA to isoalloLCA, comprising: a bacterium having a polynucleotide encoding 3β-hydroxysteroid dehydrogenase (3βHSDH) as an active ingredient” (see, e.g., instant specification, pg. 6, lines 21-24). Moreover, the instant specification states “The present invention also relates to the use of at least one bacterium selected from the group consisting of a bacterium having a polynucleotide encoding 5AR, a bacterium having a polynucleotide encoding 3βHSDH, and a bacterium having a polynucleotide encoding 5AR and 3βHSDH” (see, e.g., instant specification, pg. 10, lines 1-5). Additionally, the instant Specification states that the polynucleotides encoding the enzymes may be “natural DNA or RNA, may be a DNA or RNA in which a mutation has been artificially introduced into a natural DNA or RNA, or may be a DNA or RNA composed of an artificially designed nucleotide sequence” (see, e.g., instant specification, pg. 56, lines 25-26 & pg. 57, lines 1-4), and the polynucleotides can be inserted into a vector for replication in a host cell (see, e.g., instant specification, pg. 58, lines 23-26). Based on the statement that the DNA may be artificially designed, one of ordinary skill in the art would readily understand that this DNA would need to be recombinantly expressed within bacteria.
The instant specification does not provide guidance regarding Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae non-recombinantly expressing 5AR and/or 3βHSDH.
Presence of absence of working examples: The instant specification provides examples for extracting and sequencing DNA from bacterial strains isolated from centenarians (see, e.g., instant specification, pg. 117), as well as the production of 5AR and 3βHSDH deletion mutants in P. merdae through recombinant techniques (see, e.g., instant specification pgs. 118-119). The instant specification provides examples using liquid chromatography-tandem mass spectrometry to identify bile acids in centenarians (see, e.g., instant specification, pg. 136 & Table 7), and shows that levels of iso-LCA, 3-oxoLCA, isoalloLCA, allo-LCA, and 3-oxoallo-LCA are significantly elevated in centenarians (see, e.g., instant specification, pg. 138, lines 9-11); however, the instant specification does not specifically show that Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae non-recombinantly expresses 5AR and/or 3βHSDH within the gut of centenarians in order to elevate the production of iso-LCA, 3-oxoLCA, isoalloLCA, allo-LCA, and 3-oxoallo-LCA. Moreover, the instant Specification states that some of the listed bacteria display the ability to accumulate isoalloLCA, suggesting that these bacterial strains display both 5AR and3βHSDH activity. However, suggesting that the bacterial species express 5AR and 3βHSDH is not the same as the bacterial species actually expressing these enzymes.
Based on the Applicant’s disclosure, the Applicant would not be enabled for non-recombinantly expressing 5AR and/or 3βHSDH in Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae. The instant specification does not provide sufficient evidence that the bacterial species are non-recombinantly expressing 5AR and/or 3βHSDH.
State of the prior art: Regarding the expression of 5AR, Anderson (WO 1991/017251; Date of Publication: November 14, 1991 – previously cited) teaches the recombinant expression of 5AR in bacteria such as E. coli, B. subtilis, S. typhimurium, S. marcescens, and various Pseudomonas species (see, e.g., Anderson, pg. 3, lines 31-35 & pg. 28, lines 6-11). Regarding expression of 3βHSDH, Devlin (A Biosynthetic Pathway for a Prominent Class of Microbiota-Derived Bile Acids; 2015 – previously cited) teaches the recombinant expression of 3βHSDH genes in E. coli (see, e.g., Devlin, “Coning and expression of candidate 3α- and 3β-HSDH genes”, pg. 9).
The prior art does not teach non-recombinantly expressing 5AR and 3βHSDH in Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae.
Relative skill of those in the art: Based on the state of the prior art, the relative skill of those in the art pertaining to non-recombinantly expressing 5AR and/or 3βHSDH in Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae is low.
Predictability or unpredictability of the art: The level of unpredictability within the art is high, as there is no prior art that shows that Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae non-recombinantly expresses 5AR and/or 3βHSDH.
Amount of experimentation necessary: Since the prior art does not teach that Parabacteroides goldsteinii, Parabacteroides merdae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides unformis, Alistipes finegoldii, Alistipes onderdonkii, Odoribacter laneus, Odoribacteraceae, Parabacteroides distasonis, Corynebacterium striatum, Gordonibacter pamelaeae, Emergencia timonensis, and Lachnospiraceae non-recombinantly expresses 5AR and/or 3βHSDH, one of ordinary skill in the art would have undue experimentation in order to determine if these bacteria naturally express 5AR and/or 3βHSDH. Therefore, the amount of experimentation is high.
Dependent claims 8, 11-13, and 32-35 are rejected for depending on rejected independent claim 3 and failing to rectify the noted deficiencies.
Conclusion
Claims 3, 8, 11-13, and 32-35 are rejected.
No claims are allowed.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/NGHI V NGUYEN/Primary Examiner, Art Unit 1653