DETAILED ACTION
Status of Application
Claims 1-20 are pending
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election with traverse of Group I, claims 1-10, drawn to a composition comprising a glucuronidase and a phenol, as submitted in communication filed on 06/23/2026 is acknowledged.
Applicant’s traverse is on the grounds that it would not pose an undue burden on the Examiner nor constitute a non-coextensive search, to examine all the claims together, because the elected invention I is used in the non-elected method of invention II.
Applicant’s arguments have been fully considered but not deemed persuasive to withdraw the restriction requirement. It is noted that it would be erroneous to assume that a reference that teaches a composition would necessarily teach a method. Therefore, contrary to Applicant’s assertions, a comprehensive search of all the claims would require sequence and class/subclass searches which are not necessarily co-extensive as well as different keyword searches in the patent/non-patent literature. Thus, an examination of all the claimed inventions would impose an undue burden on the Office. The requirement is deemed proper and therefore is made FINAL.
Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 06/23/2026.
Claims 1-10, are at issue and will be examined to the extent they encompass the elected invention and species.
Priority
Acknowledgment is made of applicant’s claim for domestic priority under 35 U.S.C. 119 (e) to provisional Application No. 63/517,235 filed on 08/02/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/27/2024 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 07/30/2024 have been reviewed and are accepted by
the examiner for examination purposes.
Claim Objections
Claim 8 is objected to due to the recitation of “wherein the phenol is a tannin, phenolic acid, stilbene, lignan, or flavonoid”. It should be amended to recite: “wherein the phenol is a tannin, a phenolic acid, a stilbene, a lignan, or a flavonoid”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
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.
Claim 7 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.
Claim 7 is indefinite in the recitation of “wherein the glucuronidase has increased stability, as compared to wild-type human glucuronidase”, for the following reason: It is unclear how the glucuronidase in the recited claim is different from wild-type glucuronidase, since there are no structural limitations in regard to the claimed glucuronidase. For examination purposes, claim 7 will be interpreted as a duplicate of claim 1. Correction is required.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow.
Claims 1-10 are directed in part to a genus of any glucuronidase and any phenol, wherein said glucuronidase is effective at increasing bioavailability or reabsorption of said phenol in the gastrointestinal tract of a subject upon oral administration of the composition to the subject. See claim rejections under 35 USC § 112(b) for claim interpretation.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is no structural limitation with regard to the genus of glucuronidases and phenols required by the claims. While the specification in the instant application discloses a β-glucuronidase and a phenol, wherein said phenol is a tannin, a phenolic acid, a stilbene, a lignan, or a flavonoid, it provides no clue as to the structural elements required in any glucuronidase and any phenol to be effective at increasing either bioavailability or reabsorption of said phenol in a gastrointestinal tract of a subject upon oral administration. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which glucuronidase has increased bioavailability or reabsorption activity with any phenol.
The claims encompass a large genus of glucuronidases which are structurally unrelated, and phenols which are structurally unrelated. A sufficient written description of a genus of glucuronidases and phenols may be achieved by a recitation of a representative number of glucuronidases and phenols defined by the recitation of structural features common to members of the genuses, which features constitute a substantial portion of the genus. However, in the instant case, there is no recited structural feature which is representative of all the members of the genus of glucuronidases and phenols recited in the claims, and there is no information as to which are the structural elements required in any glucuronidase that has increased bioavailability or reabsorption activity with any phenol. Furthermore, while one could argue that the species disclosed is representative of the structure of all the members of the genus of glucuronidases and phenols required, it is noted that the art teaches several examples of how glucuronidases can have different structures and functions. For example, Pellock et al. (J Biol Chem. 2018 Oct 9;293 (48):18559–18573) teaches three structurally and functionally distinct β-glucuronidases that display differential processing capabilities (abstract). The are also examples of how the structure of a phenol is a factor that determines bioavailability. D’archivio et al. (International journal of molecular sciences 11.4: 1321-1342, 2010) teach that the chemical structure of phenols determines their bioavailability (table 1). Therefore, since minor structural differences may result in changes affecting function and bioavailability, and there is no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the species disclosed is representative of the structure of all the glucuronidases and phenols required by the claims. Therefore, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for having a composition wherein the phenol is a tannin, phenolic acid, stilbene, lignan, or flavonoid, does not reasonably provide enablement for a composition comprising a glucuronidase having any structure and a phenol having any structure, wherein the glucuronidase is effective at increasing bioavailability or reabsorption of said phenol in a gastrointestinal tract of a subject upon oral administration. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 1-10 broadly encompass a glucuronidase having any structure and a phenol having any structure, wherein the glucuronidase is effective at increasing bioavailability or reabsorption of the phenol in a gastrointestinal tract of a subject upon oral administration. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation. The enablement provided is not commensurate in scope with the claims due to the lack of information as to the structural features required in any glucuronidase being effective at increasing bioavailability or reabsorption of any phenol in a gastrointestinal tract of a subject upon oral administration. In the instant case, the specification enables a composition comprising phenol that is a tannin, phenolic acid, stilbene, lignan, or flavonoid.
The amount of direction or guidance presented and the existence of working examples. The specification discloses a composition comprising a β-glucuronidase and a phenol, the phenol is a tannin, phenolic acid, stilbene, lignan, or flavonoid. However, the specification fails to provide any clue as to the structural elements required in any glucuronidase, any phenol or the structural features found in the β-glucuronidase which are required in to be effective at increasing either one or both bioavailability or reabsorption of the phenol in a gastrointestinal tract of a subject upon oral administration of the composition to the subject. No correlation between structure and function has been presented.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The amino acid sequence of a enzyme determines its structural and functional properties and the structure of a phenol determines its bioavailability. While the art discloses a limited number of glucuronidases and phenols, neither the specification nor the art provide a correlation between structure and function such that one of skill in the art can envision the structure of any glucuronidase and phenol that can be used in the claimed composition. In addition, the art does not provide any teaching or guidance as to which changes can be made to the glucuronidase such that the resulting variant would display the desired functional characteristics, or the general tolerance of glucuronidase to structural modifications and the extent of such tolerance. The art clearly teaches that (a) glucuronidases can have different structures that affect functions, and (b) the structure of a phenol is a factor that determines bioavailability. For example, Pellock et al. (J Biol Chem. 2018 Oct 9;293 (48):18559–18573) teaches three structurally and functionally distinct β-glucuronidase from a single human gut commensal microbe that display differential processing capabilities (abstract). D’archivio et al. (International journal of molecular sciences 11.4: 1321-1342, 2010) teach that the structure of phenols determines their bioavailability (table 1). Therefore, there is unpredictability in determining which glucuronidase and phenol combination would increase bioavailability or reabsorption of said phenol in a gastrointestinal tract of a subject upon oral administration.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or isolating variants of a glucuronidase, enzymatic assays, and bioavailability assays for phenols were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of glucuronidases and phenols to find a glucuronidase and phenol composition that can be used as claimed. In the absence of (i) a rational and predictable scheme for selecting those glucuronidases and phenols most likely to have the desired functional features, and/or (ii) a correlation between structure and increased bioavailability or reabsorption activity, one of skill in the art would have to test an essentially infinite number of glucuronidase and phenols to determine which ones have the desired functional characteristics.
Therefore, taking into consideration the extremely broad scope of the claims, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Claim Rejections - 35 USC § 103 (AIA )
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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1-2 and 4-10 are rejected under 35 U.S.C. 103 as being unpatentable over Eichenbaum et al. (Journal of pharmaceutical sciences 101.7: 2545-2556 published 2012; hereby "Eichenbaum "), in view of D’Archivio et al. (International journal of molecular sciences 11.4: 1321-1342 published 2010; hereby “Archivio”), and Cheng et al. (US20220339233A1 published 2022; hereby “Cheng”).
Eichenbaum teaches coadministration of β-glucuronidase to increase oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation (abstract). Eichenbaum teaches using β -glucuronidase to convert glucuronides back to the parent compound (abstract). Eichenbaum teaches that the glucuronide is cleaved back to parent compound and the parent compound is reabsorbed into the enterocyte (Page 2552 [2]). Eichenbaum discloses that their potential next steps include testing other compounds that undergo reversible conjugation (page 2553 [2]). Eichenbaum teaches that oral coadministration of β-glucuronidase can be used to alter drug PK and metabolism and increase oral bioavailability and exposure (page 2554 [5]). Eichenbaum teaches that using an appropriate drug delivery device, such as an enteric coated capsule or a controlled-release delivery system, could be used to increase bioavailability and reduce the required dose, thereby offering potential benefits with respect to tolerability and safety (page 2554 [5]). Eichenbaum teaches that the β -Glucuronidase is derived from Escherichia coli (Page 2547 [3]).
Eichenbaum does not teach that the glucuronidated compound is a phenol. Eichenbaum does not teach that glucuronidase is produced by recombinant genetic technology. Eichenbaum does not teach that the phenol comprises a glycoside or ester of the phenol.
D’Archivio teaches that native forms of polyphenols cannot be absorbed and must be hydrolyzed by the intestinal enzymes or by the colonic microflora before absorption. D’Archivio teaches that colonic microflora hydrolyzes glycosides into aglycones and degrades them to simple phenolic acids (Page 1327 [5]). D’Archivio teaches that polyphenols undergo structural modifications due to the conjugation process that takes place in the small intestine wherein the conjugation includes glucuronidation (Page 1328 [2]). D’Archivio discloses flavonoids as a phenolic compound (Page 1325 [2]).
Cheng discloses compositions that include an herbal extract YIV-906, which comprises herbal extracts of Scutellaria baicalensis (S), Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z), or β-glucuronidase treated YIV-906 (YIV-906GU) (abstract) . Cheng teaches that the compositions include flavonoids [0015]. Cheng teaches that after oral administration, most flavonoids of YIV-906 will be subjected to de-glucuronidation by β-glucuronidase from the gut microbiome [0064]. Cheng teaches that YIV-906GU is pre-treated with recombinant E.coli β-glucuronidase to mimic intestine conditions [0155].
Claims 1-2 and 4-10 are directed in part to a composition comprising a glucuronidase and a phenol, wherein the glucuronidase is effective at increasing either one or both bioavailability or reabsorption of the phenol in a gastrointestinal tract of a subject upon oral administration of the composition to the subject; wherein the composition is provided in an enteric coating; wherein the glucuronidase is produced by or isolated from bacteria; wherein the glucuronidase is produced by recombinant genetic technology; wherein the phenol is a tannin, phenolic acid, stilbene, lignan, or flavonoid; wherein the phenol comprises a glycoside or ester of the phenol; wherein the glucuronidase is involved in the transformation of a metabolite of the phenol back into the phenol.
It would have been obvious to one of ordinary skill in the art before the effective filing date to substitute the glucuronidated compound of Eichenbaum with the phenolic compounds taught by D’Archivio, or modify the flavonoid containing compositions and methods taught by Cheng to include β-glucuronidase produced by recombinant genetic technology. A person of ordinary skill in the art is motivated to incorporate β-glucuronidase with phenolic compounds because D’Archivio teaches phenolic compounds undergo glucuronidation and Eichenbaum teaches that β-glucuronidase can convert compounds that undergo glucuronidation back to the parent compound to improve bioavailability and be reabsorbed. Furthermore, Cheng teaches that β-glucuronidase can be produced by recombinant genetic technology, thereby providing a suitable source of β-glucuronidase for use in the recited composition. One of ordinary skill in the art has a reasonable expectation of success at arriving to administering a composition comprising β-glucuronidase and phenolic compounds because all that is required combining β-glucuronidase and phenolic compounds to increase the bioavailability and absorption of the phenolic compounds.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Eichenbaum et al. (Journal of pharmaceutical sciences 101.7: 2545-2556 published 2012; hereby "Eichenbaum "), in view of D’Archivio et al. (International journal of molecular sciences 11.4: 1321-1342 published 2010; hereby “D’Archivio”), and of Cheng et al. (US20220339233A1 published 2022; hereby “Cheng”), as applied to claim 1 above, in further view of, Xu et al. (Journal of drug delivery 2013.1: 340315 published 2013; hereby “Xu”).
The teachings of Eichenbaum, D’Archivio, and Cheng are discussed above.
Cheng teaches that the pharmaceutically acceptable carrier for the composition is an encapsulating material [0033].
Xu teaches that micelles can overcome limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1) protection of the loaded drug from the harsh environment of the GI tract, (2) release of the drug in a controlled manner at target sites, (3) prolongation of the residence time in the gut by mucoadhesion, and (4) inhibition of efflux pumps to improve the drug accumulation (abstract).
Claim 3 is directed in part to the composition of claim 1, wherein the composition comprises the glucuronidase and the phenol encapsulated in a micelle.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to encapsulate glucuronidase and phenol in a micelle. A person of ordinary skill in the art is motivated to encapsulate glucuronidase and phenol in a micelle because Xu teaches that micelles enhance absorption. One of ordinary skill in the art has a reasonable expectation of success at arriving to encapsulating glucuronidase and phenol in a micelle because all that is required is incorporating the teachings of Xu with the combined teachings of Eichenbaum, D’Archivio, and Cheng. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance
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/SYNPHANE L SHELTON/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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