DETAILED ACTION
Election/Restrictions
Applicant’s election of Group I claims 1, 2 and 8-19 and the Species: SEQ ID NO: 1 which corresponds to non-inflammatory Enterococcus sp. Isolate CC00149, in the reply filed on 6/23/26 is acknowledged. Because applicants 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)).
Claims 3-7 and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claim Objections
Claims 11-19 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend on another multi-dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claims 10-19 are objected to because of the following informalities: while the claims were amended to add “claim 1” in claims 9-19, Applicant failed to delete the words “any one of claim 1 to 9 (10, 11, 12, 13, 14, 15, 16, 18)” in these claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 2 and 8-19 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.
Claims 1, 2 and 8-19 are rejected in the first Office Action on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of bacteria with 44 different rRNA sequences is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use.
The instant claims comprise 41 different products in the claimed methods. Each bacterium is different with its own 16srRNA. They would not necessarily possess identical function or cause identical response in a subject. Additionally, the search for 44 different bacteria comprising 44 different 16s rRNA sequences would each require the search of the extensive sequence database followed by the analysis of the enormous results that accumulate after the search. This would impose a serious burden on the Examiner. Advances over the past years in automated sequencing polynucleotide/polypeptide characterization techniques have made such activities routine. The entire genome of several organisms, including humans, has been determined and deposited into nucleotide and polypeptide sequence databases. The advances in nucleic acid and polypeptide sequencing techniques have also led to the exponential growth in the size of nucleic acid and polypeptide sequence databases and an increase in the number and complexity of such databases. It now requires significantly more computational time to run individual nucleotide sequence searches for examination purposes and there is significantly more sequence search results and pertinent prior art to consider. To then search and examine methods with 44 different bacteria as the primary reagent when they comprise different sequences and potentially different therapeutic effects.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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) 1, 2, 8, 11, 12, 14-19 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Tanaka et al (US 20210205378; July 8/2021; provided by Applicants).
Instant claim 1 recites:
1. (Original) A method of reducing or preventing gastrointestinal tract mucosal inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a biotherapeutic composition comprising a non-inflammatory strain of Enterococcus sp.
Tanaka discloses a discloses a Enterococcus durans HS-08 strain and its use in treating dysbiosis of the gastrointestinal tract of humans, such as dysbiosis caused by a pathogenic bacterial infection (see Abstract; paragraphs [0009], [0012], [0073]-[0074]; claims 4 and 17). The 16s rRNA of E. durans HS-08 is encoded by SEQ ID NO: 13, which comprises sequences which share 95-99% identity with SEQ ID NO: 1 -6, 8-27, 29-51, 54-55, 58-61, 63-67, 69-74 of the present application. It is considered that the E. durans HS-08 strain, which comprises a sequence sharing 99% identity with non-inflammatory strain SEQ ID NO: 22, would inherently have the same non-inflammatory property. Tanaka also discloses a pharmaceutical composition comprising said Enterococcus sp. strain and a carrier (e.g. saline), buffer, preservative or stabilizers (see paragraphs [0026], [0036], [0045], [0050]-[0051], [0053], [0056], [0058]). The composition can be administered orally in the form of tablets or capsules (see paragraph [0048]). A biotherapeutic composition comprising the E. durans HS-08 strain is prepared by culturing the strain and adding a sucrose aqueous solution as a vehicle/carrier (see paragraph [0081]).
Claim(s) 1, 2, 8 and 15 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Shao et al (CN101629155; Jan 20, 2010; provided by Applicants).
Shao discloses a feed additive strain, Enterococcus faecium Anp01, and its use in treating dysbiosis of the gastrointestinal tract, including the regulation of the intestinal flora and suppression of the growth of pathogenic bacteria in the gastrointestinal tract (see "Summary of the invention", paragraph 4 and Embodiments 1-4). The 16s rRNA of E. faecium Anp01 comprises sequences which share at least 95-99% sequence identity to SEQ ID NO: 1 of the present application. It is considered that the E. faecium Anp01 strain, which comprises a sequence sharing 99% identity with non-inflammatory strain SEQ ID NO: 22, would inherently have the same non-inflammatory property.
Claim(s) 1, 8, 9, 11 and 12-19 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Chae et al (WO 2020226467, 11/12/2020; provided by Applicants).
Chae discloses a strain of Enterococcus lactis Wikim0107 and its use in improving inflammatory bowel discase (IBD), such as ulcerative colitis or Crohn's discase (see Description, line 1; sec page 2, paragraph 2; sec claims 1 and 6; sec Example 6). The E. lactis strain is described as anti-inflammatory and non-cytotoxic (see Examples 1-2; see page 2, paragraph 12). Chae also discloses a pharmaceutical composition comprising the strain in addition to a carrier, a preservative (e.g. sugar), or a stabiliser (e.g. alginate or gelatin) (see claim 7; see page 3, paragraphs 8 and 12), wherein the composition can be administered orally in the form of tablets or capsules with an enteric coating (see page 3, paragraphs 12 and 16; see Example 6) to a human (see page 3, paragraph 15). The E. lactis strain is identified through 16s ribosomal DNA gene sequence analysis (amplification of 16s ribosomal DNA gene of extracted DNA) (see Example 1).
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.
Claim(s) 1, 2 and 8-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al (US 20210205378; July 8/2021), Shao et al (CN101629155; Jan 20, 2010; provided by Applicants) or Chae et al (WO 2020226467, 11/12/2020; provided by Applicants) in view of Ziv (J Vis Exp. 2013 Oct 14, 2013;(80):50168; pages 1-10) and Kelly, D (US Patent No. 11,013,773) in further view of (GenBank Accession No. MK748276 10 April 2019; provided by Applicants).
The teachings of Tanaka, Shao and Chae are set forth above. The primary references do not particularly exemplify the use of a prebiotic or a chemostat medium and though not instantly claimed, they also do not teach an Enterococcus with 100% identity to SEQ ID NO: 1.
Ziv teaches that one of the most important features of chemostats is that microorganisms can be grown in a physiological steady state under constant environmental conditions. In this steady state, growth occurs at a constant specific growth rate and all culture parameters remain constant (culture volume, dissolved oxygen concentration, nutrient and product concentrations, pH, cell density, etc.). In addition, environmental conditions can be controlled by the experimenter.
Kelly teaches lactic acid bacteria compositions and teaches that, typically, a probiotic is optionally combined with at least one suitable prebiotic compound. A prebiotic is usually a non-digestible carbohydrate such as an oligo- or polysaccharide, or a sugar alcohol which is not degraded or absorbed in the upper digestive tract. Known prebiotics include commercial products such as inulin and transgalacto-oligosaccharides. Preferably, the composition of the present invention includes a prebiotic in an amount of from about 1 to about 30% by weight, respect to the total weight composition, preferably from 5 to 20% by weight. Preferred carbohydrates are selected from: fructo-oligosaccharides (or FOS), short-chain fructo-oligosaccharides, inulin, isomalt-oligosaccharides, pectins, xylo-oligosaccharides (or XOS), chitosan-oligosaccharides (or COS), beta-glucans, arable gum modified and resistant starches, polydextrose, D-tagatose, acacia fibers, carob, oats, and citrus fibers. Particularly preferred prebiotics are the short-chain fructo-oligosaccharides (for simplicity shown hereinbelow as FOSs-c.c); said FOSs-c.c. are not digestable glucides, generally obtained by the conversion of the beet sugar and including a saccharose molecule to which three glucose molecules are bonded. Combining probiotics with prebiotics, known as symbiotics, enhances gut health by feeding beneficial bacteria and supporting their survival and activity. See paragraphs [112]-[113].
GenBank Accession No. MK748276 10 April 2019; 100% identical to SEQ ID NO: 1. The citation specifically discloses the organism from which the ribosomal RNA is sourced, e.g., Enterococcus sp. Given the strain has the same 16s rRNA 100% sequence identity, it would inherently possess the same non-inflammatory properties.
It would have been obvious to one of ordinary skill in the art to administer related non-inflammatory Enterococcus strains with a reasonable expectation that they too will treat gastrointestinal inflammation. Given the strain GenBank Accession No. MK748276 has the same 16s rRNA 100% sequence identity, it would inherently possess the same non-inflammatory properties and be an attractive strain for use in the claimed methods. Further the use of medium, such as the use of a chemostat, and the addition of prebiotics involve mere optimization steps which represent standard laboratory techniques well-known in the art as shown be the cited references, Ziv and Kelly.
Claim Rejections - 35 USC § 112
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, 2 and 8-19 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 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.
The method of instant claim 1 uses a composition comprising any “non-inflammatory strain of Enterococcus sp.” with no other identifying information, e.g., no deposit information or 16s rRNA information, to reduce or prevent gastrointestinal mucosal inflammation in a subject.
With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that "merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim's functional boundaries."). Abbvie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 U.S.P.Q.2d 1780, 1790, 2014 BL 183329, 12 (Fed. Cir. 2014).
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention.
The purpose of the "written description" requirement is broader than toThe present specification describes the 74 Enterococcus. sp isolates which each have a different 16s rRNA nucleotide sequence (see pages 7-11). As demonstrated in the examples, the isolates are further categorized into two distinct groups using 16s rRNA gene sequencing- (1) strains comprising a 16s rRNA gene encoded by SEQ ID NO: 1-44 shown to have a non-inflammatory response, and (2) strains comprising a 16s rRNA gene encoded by SEQ ID NO: 45-74 shown to have an inflammatory response (see page 47). However, the present specification does not further elaborate on why certain sequences are associated with inflammation whilst others are associated with a non-inflammatory state. The sequences of the 16s ribosomal genes are not considered to sufficiently describe the specific strains and therefore, the specification does not provide enough detail that would allow the person skilled in the art to work the invention over its full scope in a manner that is repeatable, that is produce any one of the claimed Enterococcus sp. strains with certainty that they exhibit either inflammatory or non- inflammatory properties. Whilst the deposit of biological materials can be used to meet the requirements of clear enough and complete enough disclosure of the invention, the specification only details deposits of certain strains (see page 47).
The claims either generally define an inflammatory/non-inflammatory Enterococcus sp. strain or a strain which comprises a 16s rRNA gene having a nucleotide sequence with at least 95% sequence identity to one or more of SEQ ID NO:1-74. The present application only demonstrates that strains comprising a 16s rRNA gene having 100% sequence identity to one or more of SEQ ID NO:1-74 exhibit the inflammatory/non-inflammatory properties (see Example 2). An alignment of SEQ ID NO: 1 (non- inflammatory) and SEQ ID NO: 45 (inflammatory) reveals that the 16s rRNA nucleotide sequence of the two strains share more than 95% identity. This indicates that there is no certainty that strains having a ribosomal RNA with varying identity to those specifically disclosed having SEQ ID NO:1-74 will have the same inflammatory or non-inflammatory characteristics as the parent strain. Given that the effects of each strain vary despite there being high % identity between the 16s ribosomal RNA nucleotide sequence, it cannot be reasonably predicted that strains, other than those exemplified in the present specification, will offer the same inflammatory or non-inflammatory effects. As such, there is undue burden for the person skilled in the art to perform the invention across the full scope of the claims.
The claims extend beyond the subject matter and written description disclosed in specification. The claims encompass any inflammatory/non-inflammatory Enterococcus sp. strain or a strain which comprises a 16s rRNA gene having a nucleotide sequence with at least 95% sequence identity to one or more of SEQ ID NO:1-74. The specification only exemplifies strains comprising a 16s rRNA encoded by nucleotide sequences at 100% sequence identity to one or more of SEQ ID NO:1-74, and even with these sequences, there is no apparent association between the ribosomal RNA sequence and the inflammatory/non-inflammatory characteristics of the strains. Therefore, it is not reasonable to predict all possible non-inflammatory and inflammatory strains which are also used in the specified methods defined by the claims. Additionally,
Tanaka et al (US 20210205378; July 8/2021; cited above) elaborates on this unpredictability by stating that the effects of lactic acid bacteria, such as Enterococcus, may greatly vary depending on the bacterial strains, even when the bacterial strains belong to the same bacterial species (see paragraph 100031).
It is also unclear because SEQ ID NO: 1 and SEQ ID NO: 4 appear to have 100% identity to one another, yet they are considered different strains in the instant specification.
Page 2, lines 13-14, of the instant specification recite the elected bacterium’s deposit information:
Enterococcus sp. CC00149 deposited under V19/018754 on 9 September 2019 at the National Measurement Institute, Australia,
an inflammatory strain of the invention is a member of clade 64 as mentioned herein (see, for example, the clade in Figure 4 covering strains CC00620 (100%), CC00261 (99.8%), CC00260, CC00149 and CC00259).
It appears the deposit of the bacterium is critical for the method claimed. However, the instant specification does not appear to have satisfied the Deposit requirements, nor is the deposit information in the claims. The prior art and pertinent art cited below, demonstrate that Enterococcus of completely different species may have as much as 99.9% or more sequence identity to that of elected SEQ ID NO: 1. Applicant's attention is directed to In re Lundak, 773 F.2d. 1216, 227 USPQ 90 (CAFC 1985) and 37 CFR §1.801-1.809 for further information concerning deposit practice.
The established threshold for identifying different bacterial species by 16S rRNA sequences is at least 97% (Rossi-Tamisier et al. Int J Syst Evol Microbiol. 2015 Jun;65(Pt 6):1929-1934; see p.1930). The prior art recognizes that some species require a higher percent identity, and others fall just short of this threshold (see for example Edgar, Bioinformatics, Volume 34, Issue 14, July 2018, Pages 2371–2375 and Beye et al., New Microbes New Infect. 2017 Dec 29 Vol 22:24–29). The 1994 proposal of a 97% threshold to identify to species level has been determined too low in many species of bacteria, with recent recommendations for increasing to 99% in order to properly identify species (Edgar, p.2374, Discussion). Also, some genera show that these thresholds do not prove applicable to clearly establish a particular species (Beye See p.24). Rossi-Tamisier shows that different genera have different thresholds, suggesting that some genera thresholds for Clostridium are not exhibited at 95% (p.1932) and that while these sequences can be used as indicators, they are not appropriate for classifying bacterial strains (p.1933).
Additionally, the typical percent identity of 16S rDNA gene sequences among different strains of Enterococcus sp. is very high, usually around:
≥97-99%
The 16S rDNA gene is highly conserved, especially within the same species.
In many cases, strains within the same species differ by <1% (i.e., >99% identity).
Because 16S rDNA is so conserved, it’s not always reliable for distinguishing closely related Enterooccus species or enough to identify a particular strain.
The 16S rDNA is an inherent property of a bacterium and it is also not very distinguishing for different strains in the same species, 16S alone isn’t enough to distinguish among the strains. Applicants should consider limiting the claims to the deposited strain.
Pertintent art, not presently relied upon:
It is noted that the prior art is replete with disclosures of a strain of Enterococcus sp. comprising 16s rRNA encoded by a nucleotide sequence sharing at least 95% sequence identity to any one of SEQ ID NO: 1-74, and the following citations are provided as mere examples selected from many in a well-traversed art. See, for instance:
Pan et al CN107254424-A; 10/1/17; Enterococcus faecalis 16S rDNA gene, SEQ ID 1. 99.9% identical to seq id no: 1
Enterococcus faecium CCTCC NO: M20211220 16S rRNA gene, SEQ 1.March 1, 2022 99.7% treating tumors
Hu et al (CN 120683015) Lactiplantibacillus plantarum 16S rDNA gene, SEQ ID NO: 1. 100% identity to applicants seq id no:1
Wang et al CN105754889-A.; 7/13/16 Enterococcus faecium CGMCC1.15321 16S ribosomal DNA (16S rDNA), SEQ ID:1. 99.7%
Kohn et al (Patent No. 9193979) Enterococcus with a 99.3% gene to SEQ ID NO: 1.
PCT/US09,06035 Enterococcus with a 99.3% gene to SEQ ID NO: 1.
PCT-US20-28569A-3643 ORGANISM: Enterococcus sp. HMSC072F0 with a 99.2% match to SEQ ID NO: 1.
Henn et al (US Patent No. 8,906,668) with a 99.0% match to SEQ ID NO: 1.
Us Patent No. 10.046,015) Enterococcus faecium with a 99.0% match to SEQ ID NO: 1.
Us Patent No. 1067531; Novel Lactic Acid Bacterium 98.9% to SEQ ID NO: 1.
CN120607992-A. Enterococcus lactis strain WD06 16S ribosomal DNA (16S rDNA), SEQ: 1;strain WD06 CCTCC NO: 33727; XU CN120607992-A. 99.9% to SEQ ID NO: 1.
KR 920019930 4/8/1992; Probiotic " Use of Enterococcus faeche strain NCIMB 40371 used in the preparation of a composition for administration to a patient with gastrointestinal disorders, especially with IBS symptoms. "
" A method of alleviating gastrointestinal symptoms of a patient by orally administering an edible composition containing viable bacteria of Enterococcus faeche strain NCIMB 40371 in an amount sufficient to stabilize and / or maintain a population of said"
" An edible composition containing the viable bacteria of Enterococcus paquent monarch NCIMB 40371, packaged in a carrier material, with supporting recommendations for the mode of administration for patients with gastrointestinal disease. "
Correspondence regarding this application should be directed to Group Art Unit 1645. Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center located in Remsen. The faxing of such papers must conform with the notice published in the Official Gazette, 1096 OG 30 (November 15,1989). The Group 1645 Fax number is 571-273-8300 which is able to receive transmissions 24 hours/day, 7 days/week.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer E. Graser whose telephone number is (571) 272-0858. The examiner can normally be reached on Monday-Friday from 8:00 AM-4 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Thomas Visone, can be reached on (571) 270-0684.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-0500.
/JENNIFER E GRASER/ Primary Examiner, Art Unit 1645 8/27/26
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