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 .
Disposition of Claims
Claims 1-17 are pending and will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2024/0035001 A1, Published 01 February 2024. Applicant’s amended Specification as presented on 10 October 2023 is acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed 01 December 2023 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. The NPL Document, Hiroyuki et al., is not in English. It has not been translated into English and no English equivalent was identified or provided. It has been placed in the application file, but the information referred to therein has not been considered.
The information disclosure statement (IDSes) submitted on 01 December 2023, 03 September 2025, 29 September 2025, and 6 March 2026 have been considered by the examiner. Any individual references with strikethroughs, however, have not been considered.
Drawings
The Drawings are objected to for containing references to colors. Specifically, Figures 7 and 8 reference colors (i.e., green, red) in the figure legends within the Specification. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: “The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.”
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The objection to the drawings will not be held in abeyance.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
Specification
The abstract of the disclosure is objected to for lack of clarity regarding the language used for the cyclic single-stranded DNA. As currently written, it is unclear if the phrase “containing a cyclic single-stranded DNA” is describing the bacterium or the bacteriophage. The instant Specification indicates that this phrase should be describing the phage (see Paragraph 0063, at least), but the placement of the phrase in the Abstract can be reasonably interpreted as describing the bacterium. It is suggested that the Abstract be amended to reflect Applicant’s intention, but Applicant is free to amend the Abstract as they deem necessary. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other forms of browser-executable code. The hyperlinks in question are: http://www.kazusa.or.jp/codon/index.html (Paragraph 0115); https://blast.ncbi.nlm.nih.gov/Blast.cgi (Paragraph 0160); http://www.ncbi.nlm.nih.gov/projects/gorf (Paragraph 0160); http://phast.wishartlab.com (Paragraph 0160); www.phaster.ca (Paragraph 016). See MPEP § 608.01.
The use of the terms SYBR (Paragraph 0056), Gibson Assembly (Paragraph 0115), OptiSeal (Paragraph 0146), OptiPrep (Paragraph 0146), Optima (Paragraph 0146), and QIAprep (Paragraph 0168), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 1-17 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.
The claims are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors.
In Claims 1, 6, 10, 13, and 17, the use of the phrase “a diabetes-inducible bacterium belonging to Fusimonas intestini” renders the claims indefinite because it is unclear what is meant by the phrase “belonging to”. The use of this phrase implies that what precedes it, “a diabetes-inducible bacterium”, is part of a larger group of what comes after the phrase, “Fusimonas intestini” (i.e., that the diabetes-inducible bacterium is a species of the genus Fusimonas intestini”). Fusimonas intestini is the species name, however. According to the Specification, this bacterium is part of the family Lachnospiraceae, so it would be more appropriate to say “a diabetes-inducible bacterium belonging to the family Lachnospiraceae”, for example. If Applicant wants to refer to the specific strain identified in Claim 7, AJ110941 (FERM BP-11443), then it is suggested that all instances of the phrase “a diabetes-inducible bacterium belonging to Fusimonas intestini” be amended to instead say “the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443)”, or similar language, but Applicant is free to amend the claims as they deem necessary.
In Claim 2, the use of the phrase “comprising at least a nucleotide sequence encoding any of the amino acid sequences in the following (a) to (c)” renders the claim indefinite. As currently written, the claim can be interpreted such that the nucleic acid sequence can encode more than one of options a-c, especially given the lack of a connecting word such as “and” or “or”, which also makes it unclear if the options are being claimed in the alternative or not. A similar issue is present in Claims 3 and 6 regarding the lack of a connecting word such as “and” or “or”, which makes it unclear if those respective options are being claimed in the alternative or not. It is suggested that Claim 2 be amended such that it recites the limitation “comprising at least one nucleotide sequence encoding an amino acid sequence selected from the group consisting…”, or similar language, but Applicant is free to amend the claim as they deem necessary.
In Claim 3, the use of the phrase “97 kinds of nucleotide sequences encoding any of the 97 kinds of amino acid sequences, respectively” renders the claim indefinite. As currently written, the claim can be interpreted such that any of the nucleotide sequences can encode more than one of options d-f, especially given the lack of a connecting word such as “and” or “or”, which also makes it unclear if the options are being claimed in the alternative or not. It is suggested that Claim 3 be amended such that it recites the limitation “97 nucleotide sequences, wherein each nucleotide sequence encodes a different amino acid sequence selected from the group consisting of…”, or similar language, but Applicant is free to amend the claim as they deem necessary.
In Claim 3, the use of the word “kinds” with regard to the nucleotide and amino acid sequences renders the claim indefinite because it is unclear what is meant by that word. For example, it is unclear if the claim language is referring to standard or non-standard nucleotides and/or amino acids. It is believed that Applicant’s intention was to simply refer to the numbers of sequences being claimed. It is suggested that all instances of the phrase “kinds of” be deleted from Claim 3, but Applicant is free to amend the claims as they deem necessary.
In Claim 6, the use of the phrase “A protein of any of the following” renders the claim indefinite. As currently written, the claim can be interpreted such that the protein can comprise more than one of options a-c, especially given the lack of a connecting word such as “and” or “or”, which also makes it unclear if the options are being claimed in the alternative or not. It is suggested that Claim 6 be amended such that it recites the limitation “A protein selected from the group consisting of…”, or similar language, but Applicant is free to amend the claim as they deem necessary.
In Claim 13, the phrase “detecting infection of the bacteriophage with the diabetes-inducible bacterium” renders the claim indefinite as it can be read in a way which would be contrary to Applicant’s intention. The claimed bacteriophage infects the recited bacterium, obviously. As currently written, however, the claim can be interpreted such that the bacteriophage is instead being infected by the bacterium. The claim language used is similar to how one would say “infection of a cell with a virus” or “infection of a cell by a virus”. It is suggested that the phrase be amended so that it instead reads “detecting infection of the diabetes inducible bacterium with the bacteriophage”, or similar language, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 1-17 are rejected on the grounds of being indefinite.
Claims 1, 4, 6-7, 10-11, and 13, and dependent claims 2-5 and 7-16 thereof, 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.
Regarding Claims 1, 4, 6-7, 10-11, and 13, they all recite the limitation of a “diabetes-inducible bacterium”. In Paragraph 0003 of the instant Specification, it references “a bacterium capable of inducing the onset of diabetes (hereinafter also to be referred to as ‘diabetes-inducible bacterium’)”. The title of the instant application is “Bacteriophage Infecting Diabetes-Inducing Bacterium and Use Thereof”. The instant Specification and title both describe a bacterium which induces, or causes, diabetes. The limitation recited in the instant claims, however, suggests that the bacterium is induced, or activated, by diabetes. These two are not the same thing. While Applicant is obviously allowed to be their own lexicographer, the instant application is a translation of a foreign application and Examiner wants to be sure that the translation is accurate and that what is being claimed is actually what Applicant wants to have patented. It is suggested that the claims be amended so that they say “diabetes-inducing bacterium” instead of “diabetes-inducible bacterium”, but Applicant is free to amend the claims as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 1, 4, 6-7, 10-11, and 13 are rejected on the grounds of being indefinite. Claims 2-5 and 7-16 are also rejected, since they depend upon Claims 1 and 6 but do not remedy the deficiencies of Claims 1 and 6.
Claims 1, and dependent claims 2-4 and 10-14 thereof, 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.
Regarding Claim 1, it recites the limitation “A bacteriophage capable of infecting and lysing a diabetes-inducible bacterium belonging to Fusimonas intestini, comprising a cyclic single-stranded DNA, which consists of the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence having 90% or more identity thereto, as its genome”. The phrase “comprising a cyclic single-stranded DNA” renders the claim indefinite because it is not clear if this limitation is in reference to the bacteriophage or the bacterium due to how this phrase is written in the claim. Its proximity to the bacterium’s name can be reasonably interpreted such that it is describing said bacterium and not the bacteriophage. The same can be said of the phrase “which consists of the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence having 90% or more identity thereto, as its genome”. Its placement in the claim can be reasonably interpreted such that it is further describing the bacterium and not the bacteriophage. The instant Specification indicates that these phrases describe the bacteriophage (see Paragraph 0063, at least). See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite."). If the intention was for these phrases to further describe the bacteriophage, then the claim should be amended such that it instead recites “A bacteriophage, comprising a cyclic single-stranded DNA, which consists of the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence having 90% or more identity thereto, as its genome, capable of infecting and lysing the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443)”, or similar language, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 1 is rejected on the grounds of being indefinite. Claims 2-4 and 10-14 are also rejected, since they depend upon Claim 1 but do not remedy the deficiencies of Claim 1.
Claims 2-3 and 6, and dependent claims 7-9 and 15-17 thereof, 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.
Regarding Claims 2 and 6, they both recite the limitation “an amino acid sequence wherein 1 to several amino acids are substituted, deleted, inserted or added in the amino acid sequence of (a)”. Regarding Claim 3, it recites the limitation “wherein 1 to several amino acids are substituted, deleted, inserted or added in one or more sequences thereof”. While it is clear that different kinds of changes are encompassed by “substituted” and “deleted”, it is unclear how the changes encompassed by “inserted” and “added” are different from each other. There are no special definitions in the instant Specification for either term which differentiate between the two and which would justify the inclusion of both in the claim language. As such, the use of both is redundant and Applicant appears to be claiming duplicate embodiments. It is suggested that the claims be amended so that either “inserted” or “added” is used, not both, but Applicant is free to amend the claims as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 2-3 and 6 are rejected on the grounds of being indefinite. Claims 7-9 and 15-17 are also rejected, since they depend upon Claim 6 but do not remedy the deficiencies of Claim 6.
Claims 2-3 and 6, and dependent claims 7-9 and 15-17 thereof, 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.
Regarding Claims 2-3 and 6, they all recite the limitation “wherein 1 to several amino acids are substituted, deleted, inserted or added” relative to a specified base sequence. The use of the term “several” renders these claims indefinite because the term “several” in claims 2-3 and 6 is a relative term. The term “several” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While Paragraphs 0069, 0077, and 0111 of the instant Specification contain language reciting “wherein 1 to several (e.g., 2, 3, 4, 5, 6) amino acids are substituted, deleted, inserted, or added”, these paragraphs do not constitute a proper and specific definition. Additionally, it is improper to incorporate limitations from the Specification into the claims. Furthermore, the specific claim limitations which use the term “several”, part (c) of Claim 2, part (f) of Claim 3, and part (c) of Claim 6, do not contain any percent identity thresholds which would serve as guidance to possibly limit what is encompassed by “several”. As such, it cannot be determined what the metes and bounds of the term “several” are. It is suggested that the claims be amended by deleting the term entirely, by replacing it with specific numbers, or by replacing it with a percent identity threshold, but Applicant is free to amend the claims as they deem necessary.
Since a skill artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 2-3 and 6 are rejected on the grounds of being indefinite. Claims 7-9 and 15-17 are also rejected, since they depend upon Claim 6, but do not remedy the deficiencies of Claim 6.
Claims 2-3 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.
Regarding Claims 2-3, they recite the limitations “(c) an amino acid sequence wherein 1 to several amino acids are substituted, deleted, inserted or added in the amino acid sequence of (a)” and “(f) 97 kinds of amino acid sequences shown in (d), wherein 1 to several amino acids are substituted, deleted, inserted or added in one or more sequences thereof”, respectively. Due to the lack of clarity regarding the term “several” (see indefiniteness rejection above), it is unclear what the metes and bounds of Claims 2 and 3 are as they appear to contradict the claim language used in Claim 1, upon which both Claims 2 and 3 depend. The claim language in Claim 1 in question is “consists of”, which restricts the claim to the limitations recited. It is unclear how Claims 2 and 3 can be limited by the 90% cutoff provided, at a minimum, in Claim 1, while also claiming sequences with “several” mutations, given that “several” is undefined. This lack of clarity renders the claims indefinite. It is suggested that the Claims 2-3 be amended by removing the claim language in question, but Applicant is free to amend the claims as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 2-3 are rejected on the grounds of being indefinite.
Claims 4 and 7 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.
Regarding Claims 4 and 7, it is unclear if the recited element within parentheses (See e.g., "(FERM BP-11443)") is a required element of the claim. It is suggested that Applicant amend the claims by removing the parentheses and instead reciting the limitation “wherein the diabetes-inducible bacterium is Fusimonas intestini strain AJ110941 deposited under accession No. FERM BP-11443”, or similar language, but Applicant is free to amend the claims as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 4 and 7 are rejected on the grounds of being indefinite.
Claim 9 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.
Regarding Claim 9, it recites the limitation "the nucleic acid" in Line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 6, upon which Claim 9 depends, does not introduce the limitation of “a nucleic acid”. The only other claim which recites a nucleic acid is Claim 8. The lack of antecedence of this claim limitation in Claim 9 renders the claim indefinite. It is suggested that the claim be amended by replacing “the” with “a” or by making Claim 9 dependent on Claim 8 instead, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 9 is rejected on the grounds of being indefinite.
Claims 10, 13, and 17, and dependent claims 11-12 and 14 thereof, 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.
Regarding Claims 10, 13, and 17, they all recite the limitation “a diabetes-inducible bacterium belonging to Fusimonas intestini”. The use of “a” renders these claims indefinite because it is unclear if they are referring to the same diabetes-inducible bacterium belonging to Fusimonas intestini introduced in Claim 1, for Claims 10 and 13, and Claim 6, for Claim 17, or different ones. “A/An” is an indefinite article, while “the” is a definite article. “The” refers back to a specific bacterium from Claims 1 and 6, while “A” can refer back to any non-specific bacterium and is not clear that it is only referencing the bacterium of Claims 1 and 6. It is suggested that the claims be amended by replacing “a” with “the”, but Applicant is free to amend the claims as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 10, 13,and 17 are rejected on the grounds of being indefinite. Claims 11-12 and 14 are also rejected, since they depend upon Claims 10 and 13, respectively, but do not remedy the deficiencies of Claims 10 and 13.
Claim Interpretation
In light of the issues raised above, the claims are being interpreted as reading upon the following:
Claim 1 is drawn to a bacteriophage, comprising a cyclic single-stranded DNA, which consists of the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence having 90% or more identity thereto, as its genome, capable of infecting and lysing the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443)”.
Claim 6 is drawn to a protein of any of the following (a) to (c): (a) a protein consisting of the amino acid sequence represented by SEQ ID NO: 93; (b) a protein comprising an amino acid sequence having 95% or more identity with the amino acid sequence of (a), and capable of lysing the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443)”; or (c) a protein comprising an amino acid sequence wherein 1 to several amino acids are substituted, deleted, inserted or added in the amino acid sequence of (a), and capable of lysing the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443).
Further limitations on the bacteriophage according to Claim 1 are:
2. The bacteriophage according to claim 1, comprising at least a nucleotide sequence encoding any of the amino acid sequences in the following (a) to (c): (a) the amino acid sequence represented by SEQ ID NO: 99; (b) an amino acid sequence having 95% or more identity with the amino acid sequence of (a); or (c) an amino acid sequence wherein 1 to several amino acids are substituted, deleted, inserted or added in the amino acid sequence of (a).
3. The bacteriophage according to claim 2, further comprising 97 nucleotide sequences encoding any of the 97 amino acid sequences, respectively, in the following (d) to (f): (d) 97 kinds of amino acid sequences represented by SEQ ID NOs: n, wherein n is an integer of 2-98; (e) 97 amino acid sequences each having 95% or more identity with the respective amino acid sequences shown in (d); (f) 97 amino acid sequences shown in (d), wherein 1 to several amino acids are substituted, deleted, inserted or added in one or more sequences thereof.
4. The bacteriophage according to claim 1, wherein the diabetes-inducible bacterium is Fusimonas intestini strain AJ110941 (FERM BP-11443).
5. The bacteriophage according to claim 1, comprising a cyclic single-stranded DNA, which consists of the nucleotide sequence represented by SEQ ID NO: 1, as its genome.
10. An agent for suppressing the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443), comprising the bacteriophage according to claim 1.
11. The agent according to claim 10 for removing or reducing the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443) from the intestine of an animal.
12. The agent according to claim 11 for the prophylaxis or treatment of diabetes in the animal.
13. A method of detecting the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443) in a sample, comprising contacting the bacteriophage according to claim 1 with the sample, and detecting infection of the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443) with the bacteriophage.
14. The method according to claim 13, wherein a lytic enzyme gene of the bacteriophage is inactivated.
Further limitations on the protein according to Claim 6 are:
7. The protein according to claim 6, wherein the diabetes-inducing bacterium is Fusimonas intestini strain AJ110941 (FERM BP-11443).
8. A nucleic acid encoding the protein according to claim 6.
9. A method of producing the protein according to claim 6, comprising synthesizing the protein in an expression system comprising the nucleic acid encoding the protein in a form capable of expressing the same.
15. An agent for suppressing a bacterium resistant to one or more antibiotics, comprising the protein according to claim 6.
16. The agent according to claim 15, wherein the bacterium can form a biofilm.
17. An agent for suppressing the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443), comprising the protein according to claim 6.
Claim Rejections - 35 USC § 112(a); First Paragraph
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 1-17 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 a bacteriophage capable of infecting and lysing a diabetes-inducing bacterium belonging to Fusimonas intestini, which consists of a nucleotide sequence with 100% sequence identity to SEQ ID NO: 1 and comprising amino acid sequences or nucleotide sequences encoding amino acid sequences with 100% sequence identity to SEQ ID NOs: 2-99, does not reasonably provide enablement for a bacteriophage capable of infecting and lysing a diabetes-inducible bacterium belonging to Fusimonas intestini, which consists of a nucleotide sequence having less than 100% sequence identity to SEQ ID NO: 1 and comprising amino acid sequences or nucleotide sequences encoding amino acid sequences with less than 100% sequence identity to SEQ ID NOs: 2-99. 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.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a bacteriophage, comprising a cyclic single-stranded DNA, which consists of the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence having 90% or more identity thereto, as its genome, capable of infecting and lysing the diabetes-inducible bacterium identified as Fusimonas intestini strain AJ110941 (FERM BP-11443). The claims are also drawn to a protein consisting of the amino acid sequence represented by SEQ ID NO: 93, a protein comprising 95% or more identity with SEQ ID NO: 93, or a protein comprising 1 to several amino acid substitutions, deletions or insertions/additions of SEQ ID NO: 93, these proteins are capable of lysing a diabetes-inducible bacterium belonging to Fusimonas intestine; and a method of detecting diabetes-inducible bacterium belonging to Fusimonas intestine by using the claimed bacteriophage.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Working examples. No working examples of the claimed variants are disclosed in the specification. Example 3 discloses the growth suppression of the F. intestini strain AJ110941 using purified LSP1, which presumably has a sequence that is 100% identical to instant SEQ ID NO: 1. This purified phage was used to infect and cause bacteriolysis of this specific bacterial strain (see Paragraphs 0163-0165). Example 5 discloses lysis of the F. intestini strain AJ110941 using purified LysF enzyme, which presumably has a sequence that is 100% identical to instant SEQ ID NO: 93. This purified endolysin was used to cause bacteriolysis of this specific bacterial strain (see Paragraphs 0167-0170).
Guidance in the specification. The specification provides guidance towards substitutions with similar amino acids (i.e., conservative amino acid substitutions) (see Paragraph 0073), but does not disclose which regions of the claimed sequences can tolerate such changes. This also applies to the insertion and deletion mutations recited in the Specification. The instant Specification also fails to identify the essential or critical residues or bases of the claimed amino acid sequences and nucleotide sequences, respectively.
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide or nucleotide variants of known sequences will function intended, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed.
Claims 8-9 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 an isolated nucleic acid and a method using said isolated nucleic acid, does not reasonably provide enablement for a transgene within a transgenic animal or a method using said transgene. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. Applicant broadly claims a nucleic acid encoding the protein according to claim 6 and a method of producing the protein according to claim 6 comprising synthesizing the protein in an expression system comprising the nucleic acid encoding the protein in a form capable of expressing the same. The claim reads on a transgene within a transgenic animal and a method using said transgene given that the term “isolated” is not denoted in describing the nucleic acid.
State of the prior art/Predictability of the art. With respect to the unisolated host transgenes as “nucleic acid” of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et Al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second).
Working examples. No working example of a transgenic animal is disclosed in the specification. The terms “transgene” and “transgenic” do not appear anywhere in the specification.
Guidance in the specification. The specification provides guidance towards a nucleic acid encoding the claimed endolysin protein corresponding to instant SEQ ID NO: 93 (see Paragraphs 0035-0036, 0065, 0108, 0112, 0114-0115, 0122) and a method of producing the claimed endolysin by expressing the nucleic acid encoding said endolysin in an expression system (see Paragraphs 0016, 0036, 0114, 0116-0122, 0167).
Amount of experimentation necessary. At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claim as written, encompassing a transgene in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation "nucleic acid" and by amending the claims to specify they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional nucleic acids that produce the claimed protein, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed protein is functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Claim 12 is 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 the infection and/or bacteriolysis of Fusimonas intestini and Acidovorax sp. MR-S7, M2, and M6, does not reasonably provide enablement for the treatment or the prophylaxis of any kind of diabetes. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a bacteriophage capable of infecting and lysing a diabetes-inducible bacterium belonging to Fusimonas intestini, comprising a cyclic single-stranded DNA, which consists of the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence having 90% or more identity thereto, as its genome, an agent for suppressing a diabetes-inducible bacterium belonging to Fusimonas intestini, comprising the bacteriophage according to claim 1, the agent according to claim 10 for removing or reducing the diabetes-inducible bacterium from the intestine of an animal, and the agent according to claim 11 for the prophylaxis or treatment of diabetes in the animal.
State of the prior art/Predictability of the art. With regard to the state of the art regarding the connection between Fusimonas intestini and diabetes, Kusada et al. (Kusada, H., Kameyama, K., Meng, XY. et al. Fusimonas intestini gen. nov., sp. nov., a novel intestinal bacterium of the family Lachnospiraceae associated with diabetes in mice. Sci Rep 7, 18087 (2017).) found that Fusimonas intestini strain AJ110941 contributes to Type II diabetes development in mice (see Abstract) and that the bacterial strain is involved in the development of obesity and diabetes in germ-free (GF) ob/ob mice and that colonization of the mice induced the typical symptoms such as significant increases in fasting blood glucose levels together with liver and mesenteric adipose tissue weights, and decrease in plasma insulin levels and HOMA-β values (see Page 2, Paragraph 2). Takeuchi et al. (Takeuchi T, Kameyama K, Miyauchi E, Nakanishi Y, Kanaya T, Fujii T, Kato T, Sasaki T, Tachibana N, Negishi H, Matsui M, Ohno H. Fatty acid overproduction by gut commensal microbiota exacerbates obesity. Cell Metab. 2023 Feb 7;35(2):361-375.e9.) found that Fusimonas intestini strain AJ110941 is highly colonized in both humans and mice with obesity and hyperglycemia, produces long-chain fatty acids such as elaidate, and facilitates diet-induced obesity (see Abstract). They also found that the fatty acids produced by Fusimonas intestini impair gut integrity to exacerbate metabolic endotoxemia (see Page 368, Right Column, Paragraphs 2-3 and Page 369, Left Column, Paragraph 1) and that this gut integrity impairment has been implicated in the progression of obesity and related pathologies (see Page 370, Left Column, Paragraph 1). Gao et al. (Gao, Yuhua et al. “Interactions between the Host Dietary Habits and the Gut Microbiota Influence Weight Management.” Life medicine 2.3 (2023)) observed that Fusimonas intestini was abundant in patients with metabolic diseases and that E. coli and Fusimonas intestini di-colonized mice showed increased body mass gain, adipose tissue weight, blood glucose levels, total serum cholesterol, and pro-inflammatory cytokines compared to E. coli monocolonized mice when fed a high-fat diet (HDR) rather than a normal chow diet (see Page 1, Right Column, Paragraph 1). Liu et al. also note that in mice subjected to a high-fat diet and colonized by Fusimonas intestini, there was an observed increase in the expression of pro-inflammatory genes such as TNF-α, LPS-binding protein, and leptin, all of which are markers associated with low-grade inflammation and that there is a positive correlation between body-mass index (BMI) and the presence of the family Lachnospiraceae, to which Fusimonas intestini belongs (see Page 10, Right Column, Paragraph 1).
Working examples. No working example of prophylaxis or prevention of diabetes is disclosed in the specification. There is also no example of prevention of the colonization of Fusimonas intestini in an animal model using the claimed bacteriophage.
Guidance in the specification. The specification provides guidance towards lysing F. intestini strain AJ110941 using the LSP1 phage and/or the LSP1 phage-derived endolysin, LysF (see Examples 3 and 5, Paragraphs 0163-0164 and 0167-0170). The instant Specification also provides guidance towards Fusimonas intestini causing reduced insulin secretory ability and hyperglycemia in a germ-free obesity model mouse after the mice were colonized with the bacteria (see Paragraph 0007) and the bacteria having activity which induces either or both of insulin resistance and/or reduced insulin secretory capacity (see Paragraphs 0061, 0100).
Amount of experimentation necessary. Additional research is required in order to determine how effective the claimed bacteriophage would be at preventing the onset of any kind of diabetes, including Type I and Type II diabetes, as well as treating other kinds of diabetes aside from Type II diabetes.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products and/or methods.
Claims 15-16 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 the bacteriolysis of the multidrug-resistant bacteria Acidovorax sp. MR-S7, M2, and M6, which can form biofilms, with a combination of the endolysin LysF and EDTA, does not reasonably provide enablement for any agent comprising the endolysin LysF or the endolysin LysF alone for suppressing biofilm formation in any multidrug-resistant bacterium. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a protein of any of the following (a) to (c): (a) a protein consisting of the amino acid sequence represented by SEQ ID NO: 93; (b) a protein comprising an amino acid sequence having 95% or more identity with the amino acid sequence of (a), and capable of lysing a diabetes-inducible bacterium belonging to Fusimonas intestini; (c) a protein comprising an amino acid sequence wherein 1 to several amino acids are substituted, deleted, inserted or added in the amino acid sequence of (a), and capable of lysing a diabetes-inducible bacterium belonging to Fusimonas intestini, and an agent for suppressing a bacterium resistant to one or more antibiotics, comprising the protein according to claim 6, wherein the bacterium can form a biofilm.
State of the prior art/Predictability of the art. With regard to the state of the art regarding multidrug resistance and biofilm formation in bacteria, Muhammad et al. (Muhammad MH, Idris AL, Fan X, Guo Y, Yu Y, Jin X, Qiu J, Guan X and Huang T (2020) Beyond Risk: Bacterial Biofilms and Their Regulating Approaches. Front. Microbiol. 11:928.) note that about 40-80% of bacterial cells on earth can form biofilms (see Page 1, Paragraph 1). Prinzi and Rohde (2023) note that bacteria living in a biofilm can exhibit a 10 to 1000-fold increase in antibiotic resistance compared to similar bacteria living in a planktonic state (see Page 3, Paragraph 1). They also note that biofilms are often polymicrobial, making them even more difficult, if not impossible, to treat (see Page 2, Paragraph 2). This point is also echoed by Zhao et al. (Zhao A, Sun J, Liu Y. Understanding bacterial biofilms: From definition to treatment strategies. Front Cell Infect Microbiol. 2023 Apr 6;13:1137947.), who state that a bacterial biofilm can be composed of a single microorganism or a mixture of bacteria, fungi, archaea, protozoa, and yeasts (see Page 1, Paragraph 2).
With regard to the state of the art regarding bacteriophage therapy for the treatment of infections by multidrug resistant bacteria and the disruption of bacterial biofilms, Viertel et al. (Viertel, T. M, K Ritter, and H.-P Horz. “Viruses versus Bacteria--Novel Approaches to Phage Therapy as a Tool against Multidrug-Resistant Pathogens.” Journal of antimicrobial chemotherapy 69.9 (2014): 2326–2336.) notes that, like phages themselves, endolysins exhibit high target specificity in the case of Gram-positive bacteria (see Page 2329, Left Column, Last Paragraph) while endolysins targeting Gram-negative bacteria do not necessarily need to have a specific bonding to the peptidoglycan of their host (see Page 2329, Right Column, Last Paragraph). They also note, however, that the outer lipid layer membrane of Gram-negative bacteria protects the peptidoglycan from potential contact with exogenous endolysin and thus serves as a barrier against most endolysins (see Page 2329, Right Column, Last Paragraph and Page 2330, Left Column, First Paragraph). Additionally, they note that the use of lytic phages that directly kill bacteria via host cell lysis risk the release of toxic substances, such as endotoxin in the case of Gram-negative bacteria (see Page 2328, Right Column, Paragraph 4). Further emphasizing the differences between Gram-positive and Gram-negative bacteria in the context of endolysins, Briers et al. (Briers, Yves et al. “Engineered Endolysin-Based ‘Artilysins’ To Combat Multidrug-Resistant Gram-Negative Pathogens.” mBio 5.4 (2014): e01379.) engineered outer membrane-penetrating endolysins, or (Artilysins) in order to overcome the hurdle of the impermeable lipopolysaccharide (LPS) layer surrounding the cell wall of Gram-negative bacteria (see Abstract). Koulenti et al. (Koulenti, Despoina et al. “Infections by Multidrug-Resistant Gram-Negative Bacteria: What’s New in Our Arsenal and What’s in the Pipeline?” International journal of antimicrobial agents 53.3 (2019): 211–224.) note that bacteriophages expressing endolysins can enter target cells when combined with permeabilisers (see Page 218, Right Column, Paragraph 2). They also note that a clinical trial using bacteriophage PP1131 against P. aeruginosa was halted prematurely due to insufficient efficacy of the phage. While there were some positive findings from the clinical trial, such as a clinically-relevant reduced bacterial burden and fewer serious adverse events in the phage group, Koulenti et al. also noted that a major limitation of the study was that stability issues resulted in a lower than expected dose in the phage group and that, at low doses, the phage induced a slower clinical response than standard-of-care, and treatment-resistant bacteria were also isolated in patients with failed treatments (see Page 218, Right Column, Paragraph 2). Liu et al. (Liu, H., Hu, Z., Li, M. et al. Therapeutic potential of bacteriophage endolysins for infections caused by Gram-positive bacteria. J Biomed Sci 30, 29 (2023).) also discuss the potential safety concern with respect to the use of endolysins to treat Gram-positive bacterial infections being the release of pro-inflammatory factors and bacterial components during bacteriolysis (see Page 12, Left Column, Paragraph 2). They also note, however, that endolysins have more advantages compared with phage particles and can eradicate staphylococcal and streptococcal biofilms in a short time (see Page 2, Left Column, Paragraph 2 and Right Column, Paragraph 1) and that intrinsic endolysin resistance is rare (see Page 6, Right Column, Paragraph 1). İşlek et al. (İşlek, Yelda et al. “Isolation and Characterization a Novel Acinetobacter Bacteriophage with Activity against Several Multidrug-Resistant Gram-Negative Bacteria.” Microbial pathogenesis 203 (2025)) discuss the isolation and characterization of a previously unknown bacteriophage, vB_AbaM_YNAF, which infects Acinetobacter bacteria (see Abstract), but was able to infect and inhibit multidrug resistant A. baumannii and K. pneumoniae strains (see Page 10, Right Column, Paragraph 4).
Working examples. Only three working examples of multidrug resistant bacteria which can form biofilms are disclosed in the specification, Acidovorax sp. MR-S7, M2, and M6. The only working example of an agent which acted against the three multidrug resistant bacteria in question was the LysF endolysin derived from the LSP1 phage when used in combination with EDTA (see Examples 6-7, Paragraphs 0171-0174).
Guidance in the specification. The specification provides guidance towards the use of the LysF endolysin derived from the LSP1 phage, in combination with EDTA, against Gram negative multidrug-resistant bacteria Acidovorax sp. MR-S7, M2, and M6, which are capable of forming a biofilm, specifically by lysing the bacteria (see Examples 6-7, Paragraphs 0171-0174). The specification also provides guidance towards the use of the LSP1 phage and its LysF endolysin against Gram positive F. intestini, specifically by lysing the bacteria (see Examples 3 and 5, Paragraphs 0163-0165 and 0167-0170).
Amount of experimentation necessary. Additional research is required in order to determine how effective the claimed endolysin in combination with other compounds or the claimed endolysin alone would be at suppressing any multidrug resistant bacteria which can form a biofilm.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products and/or methods.
Claims 1-17 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 instant application attempts to tie sequence identity to function in the context of a bacteriophage capable of infecting and lysing a diabetes-inducible bacterium belonging to Fusimonas intestini, comprising a cyclic single-stranded DNA, which consists of the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence having 90% or more identity thereto, as its genome, wherein the bacteriophage comprises at least a nucleotide sequence encoding any of the amino acid sequences in the following (a) to (c): (a) the amino acid sequence represented by SEQ ID NO: 99; (b) an amino acid sequence having 95% or more identity with the amino acid sequence of (a); (c) an amino acid sequence wherein 1 to several amino acids are substituted, deleted, inserted or added in the amino acid sequence of (a), and further comprises 97 kinds of nucleotide sequences encoding any of the 97 kinds of amino acid sequences, respectively, in the following (d) to (f): (d) 97 kinds of amino acid sequences represented by SEQ ID NOs: n, wherein n is an integer of 2-98; (e) 97 kinds of amino acid sequences each having 95% or more identity with the respective amino acid sequences shown in (d); (f) 97 kinds of amino acid sequences shown in (d), wherein 1 to several amino acids are substituted, deleted, inserted or added in one or more sequences thereof, as well as a protein of any of the following (a) to (c): (a) a protein consisting of the amino acid sequence represented by SEQ ID NO: 93; (b) a protein comprising an amino acid sequence having 95% or more identity with the amino acid sequence of (a), and capable of lysing a diabetes-inducible bacterium belonging to Fusimonas intestini; (c) a protein comprising an amino acid sequence wherein 1 to several amino acids are substituted, deleted, inserted or added in the amino acid sequence of (a), and capable of lysing a diabetes-inducible bacterium belonging to Fusimonas intestini. While the claims recite a percent identity cutoff, the instant Specification fails to identify the essential or critical residues or bases of the claimed amino acid sequences and nucleotide sequences, respectively. The instant Specification discusses substitutions with similar amino acids (i.e., conservative amino acid substitutions) (see Paragraph 0073), but does not disclose which regions of the claimed sequences can tolerate such changes. This also applies to the insertion and deletion mutations recited in the Specification. As such, it would be unclear to a person having ordinary skill in the art to know what to change and what not to change.
Furthermore, while it is not explicitly stated, it is assumed that the constructs used in the instant Specification have sequences which are 100% identical to the claimed sequences. Even if that is not the case, the data provided do not explicitly include any claimed variants having as little as 90% sequence identity, or even 91-99% sequence identity, relative to the claimed sequences, raising questions about how effective these claimed variants would be in the data provided. Thus, it is not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genera being claimed by Applicant have not been identified or disclosed.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contributions to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle and Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient details that one skilled in the art can reasonably conclude that the invention had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
MPEP § 2163 states that 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, 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 applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the peptide or nucleotide variants can have any sequences which vary from instant SEQ ID NOs: 1-99 by as much as 5% or 10%, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any peptide or nucleotide variants with the required sequence identity other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genera, the claims encompassing the same clearly fail the written description requirement.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014).
Overall, at the time the invention was made, the level of skill for preparing peptide and nucleotide variants and then selecting those peptides and nucleic acids which meet the desired percent identity cutoff was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identity peptide and nucleotide variants with the recited percent identity cutoff, the written description provision of 35 U.S.C. 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010). Absent the conserved structure provided by a core peptide or nucleotide sequence, the skilled artisan would not be able to visualize or otherwise predict, a priori, what any peptide or nucleotide which meets the recited percent identity cutoffs would look like structurally.
While applicant has described a few species within the genera recited, and the art may provide more, each genus is very large and would encompass peptide and nucleotide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide or nucleotide structures encompassed by the claimed/recited genera only defined by sequence identity. Any future peptide and nucleotide variants may or may not be encompassed, as if they are, they would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genera of peptide and nucleotide variants. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Therefore, the claims are rejected here.
As such, it does not appear Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claims 1-17 do not meet the written description requirement.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-3 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding Claims 2-3, as noted above in the indefiniteness rejection, they recite the limitations “(c) an amino acid sequence wherein 1 to several amino acids are substituted, deleted, inserted or added in the amino acid sequence of (a)” and “(f) 97 kinds of amino acid sequences shown in (d), wherein 1 to several amino acids are substituted, deleted, inserted or added in one or more sequences thereof”, respectively. Due to the lack of clarity regarding the term “several” (see indefiniteness rejection above), it is unclear what the metes and bounds of Claims 2 and 3 are as they appear to contradict the claim language used in Claim 1, upon which both Claims 2 and 3 depend. The claim language in Claim 1 in question is “consists of”, which restricts the claim to the limitations recited. It is unclear how Claims 2 and 3 can be limited by the 90% cutoff provided, at a minimum, in Claim 1, while also claiming sequences with “several” mutations, given that “several” is undefined. The language used in Claims 2-3 also means that they broaden the scope of Claim 1 and that the claims do not include all of the limitations of the claim upon which they depend as the scope of “several” falls outside the 90% cutoff of Claim 1, especially in light of the lack of a definition for “several” and the use of the “consists of” language in Claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-12 and 15-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claims, Claim 1 in particular, recite a bacteriophage capable of infecting and lysing a diabetes-inducible bacterium belonging to Fusimonas intestini, comprising a cyclic single-stranded DNA, which consists of the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence having 90% or more identity thereto, as its genome. Claims 1 and 5 are ineligible because they recite a sequence that is a naturally-occurring nucleotide sequence which is not markedly different from its naturally-occurring counterpart because it conveys the same genetic information. Claims 2-3 and 6 are ineligible because they recite sequences that are naturally-occurring amino acid sequences which are not markedly different from their naturally-occurring counterparts because they convey the same genetic information. Claim 8 is ineligible because it simply recites nucleic acid encoding the naturally-occurring protein of Claim 6, which makes the nucleic acid a naturally-occurring product as well. Claims 4 and 7 are ineligible because they simply identify the naturally-occurring bacteria that the naturally-occurring bacteriophage infects and that the naturally-occurring protein acts upon, respectively. Claim 9 is drawn to an ineligible method because, under the broadest reasonable interpretation of the claims as written, the term “expression system” can be interpreted as simply the naturally-occurring bacteriophage expressing the naturally-occurring protein recited in Claim 6 or the naturally-occurring bacteria after it is infected by said bacteriophage. Claims 10-12 and 15-17 are ineligible because they simply recite intended uses of the naturally-occurring bacteriophage of Claim 1 and the naturally-occurring protein of Claim 6, respectively, and do not recite specific, active method steps for using the naturally-occurring bacteriophage and protein. Additionally, these claims recite products or agents comprising the naturally-occurring bacteriophage or protein, but do not recite any additional elements as required features of the claims. As such, the claimed products can simply be the naturally-occurring bacteriophage and protein, which are indistinguishable from their naturally-occurring counterparts, as the sole component of their respective products.
This judicial exception is not integrated into a practical application because, as written, the claimed invention is not used to provide a particular treatment or prophylaxis for a disease or medical condition. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claimed invention, as written, simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception. It is suggested that the claims be amended to recite sequences that are not naturally occurring by incorporating non-natural nucleotides or amino acids, heterologous sequence elements, or tags, for example. It is suggested that the method be amended such that it does not read on expression of the naturally-occurring protein from the naturally-occurring bacteriophage or the natural infection of the bacteria with the bacteriophage. It is suggested that the products or agents recite required additional components, such as heterologous carriers or molecules, which would markedly distinguish them from the naturally-occurring bacteriophage and protein. Applicant is free to amend the claims as they deem necessary, as long as said amendments do not introduce new matter, or persuasively argue that the claims are patent eligible.
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.
Claims 6-9 and 15-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Potvin et al. (Potvin C, Leclerc D, Tremblay G, Asselin A, Bellemare G. Cloning, sequencing and expression of a Bacillus bacteriolytic enzyme in Escherichia coli. Mol Gen Genet. 1988 Oct;214(2):241-8.).
Potvin et al. teach a protein comprising an amino acid sequence wherein 1 to several amino acids are substituted, deleted, or inserted in the amino acid sequence of SEQ ID NO: 93. Specifically, Potvin et al. teach NCBI Reference Sequence WP_160579566.1 (see attached sequence), which is 47.1% identical to instant SEQ ID NO: 93 (see attached sequence alignment Appendix A). For Claim 6 part (C), the mutations that could be read into “several amino acids” relative to SEQ ID NO: 93 allow the prior art to read on the instant claims. This is due to the lack of a specific definition of the term “several”, as noted above, as well as the lack of a percent identity cutoff in this part of the claim, also noted above. While the prior art (NCBI Reference Sequence WP_160579566) does not mention lysing Fusimonas intestini, based on how this part of the instant claim is written, the ability to lyse Fusimonas intestini would be an inherent function of the prior art protein or any other protein with mutations relative to SEQ ID NO: 93 (consider MPEP 2112 II.). Additionally, in Table 1-2 of the instant Specification, ORF92, which corresponds to instant SEQ ID NO: 93, is identified as an N-acetylcinnamoyl-L-alanine amidase. The prior art sequence corresponds to an N-acetylmuramoyl-L-alanine amidase. Furthermore, Potvin et al. teach that this enzyme possesses bacteriolytic activity (see Summary). As such, the prior art disclosure teaches the limitations of instant Claims 6-7.
Potvin et al. also teach a nucleic acid encoding said protein as well as a method of producing said protein comprising synthesizing the protein in an expression system comprising the nucleic acid encoding the protein. Specifically, Potvin et al. teach isolated clones, pBH2500, pBH929, and pBH703, expressed in E. coli strain NM522 or via in vitro transcription and translation, which was found to code for the lytic enzyme or active fragments thereof (see Summary; Figure 3; Page 244, Right Column, Paragraph 2; Page 245, Left Column, Paragraph 2 and Right Column, Paragraph 1). As such, the prior art disclosure teaches the limitations of instant Claims 8-9.
Additionally, Potvin et al. teach agents for suppressing Fusimonas intestini and an agent for suppressing a bacterium resistant to one or more antibiotics, wherein said bacterium can form a biofilm, wherein said agents comprise the protein corresponding to NCBI Reference Sequence WP_160579566.1 (see attached sequence; see Summary; Figure 3; Page 244, Right Column, Paragraph 2; Page 245, Left Column, Paragraph 2 and Right Column, Paragraph 1). The recited limitations in instant Claims 15 and 17 are being interpreted as intended uses. Even if they are not interpreted as such, however, the prior art disclosure still meets those claim limitations as such activities would be inherent functions of the prior art protein or any other protein with mutations relative to SEQ ID NO: 93 (consider MPEP 2112 II.) since the prior art protein already meets the limitations of the instant protein. Furthermore, the claimed instant agents themselves do not require any additional components other than the claimed protein itself. As such, the minimum required component is the protein recited in instant Claim 6, which Potvin et al. already teach. Thus, the prior art disclosure teaches the limitations of instant Claims 15-17.
For at least these reasons, Potvin et al. teach the limitations of instant Claims 6-9 and 15-17 and anticipate the invention encompassed by said claims.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Bowerman et al. (2021)
Bowerman et al. disclose GenBank Accession Number MDE6917401.1, which is a sequence with 68.1% sequence identity to instant SEQ ID NO: 93. This sequence corresponds to an N-acetylmuramoyl-L-alanine amidase (see attached sequence alignment Appendix B). This reference has not been utilized, as rejection would have been redundant to those set forth above.
Cheng et al. (1994)
Cheng et al. also teach NCBI Reference Sequence WP_160579566.1, which is 47.1% identical to instant SEQ ID NO: 93. This reference has not been utilized, as rejection would have been redundant to those set forth above.
Wang et al. (1991)
Wang et al. also teach NCBI Reference Sequence WP_160579566.1, which is 47.1% identical to instant SEQ ID NO: 93. This reference has not been utilized, as rejection would have been redundant to those set forth above.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671
/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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