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 .
Detailed Action
This Office Action is in response to the Applicant’s reply received 7/2/26. Claims 1-15 and 21-25 are pending and are considered on the merits.
Claim Interpretation
The Specification defines biologic:
As used herein, "biologic" refers to any biologically active product capable
of being expressed from a gene. The biologic can be biologically active in
vivo in any prokaryote or eukaryote or in vitro in any in vitro biochemical
system. The biologic can have any activity, whether enzymatic or binding,
structural, etc. (Specification page 15, lines 5-10).
In light of this, the recombinant proteins expressed by the claimed microorganism meet this definition since they are expressed by a gene and are biologically active in a prokaryote. The claims do not limit the biologic must differ from those listed in the SEQ ID No’s in the Specification.
Claims 8 and 15 a wherein clause that limits the “ recombinant microorganism exhibits a growth rate during exponential phase of growth no less than 90% of a growth rate exhibited by the corresponding microorganism during exponential phase of growth”. This change in growth rate reads as an intended result of the modifications of claim 1 and 14 without adding any additional structural changes to the microbe. MPEP 2111.04 state:
“Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure"
Therefore these limitations are not afforded significant patentable weight and art reading on the structural limitations in claims 1 and 14 will also read on the intended results since the same structure should obviously yield the same results. However if these results are an unexpected improvement, then this should be pointed out by the Applicant and the claims made commensurate in scope with the results shown. Applicant is encouraged to contact the Examiner if any questions about this arise.
Claims 1 recites:
the recombinant microorganism comprising one or more modifications… wherein the one or more modifications reduce, in the recombinant microorganism… expression and/or activity of one or more proteins expressed…, wherein the one or more proteins comprise any three or more, any four or more, any five or more, any six or more, or each of a sortase, a sortase-dependent protein, a fibronectin-binding protein, an autolysin, a surface-layer protein, an aggregation-promoting factor, and a collagen binding protein. [emphasis added]
The Applicant appears to amend the claims to require 3-6 or more of the listed proteins are modified. This does not agree with the broadest interpretation of the claim. Initially there is one or more modifications to the microorganism. These modifications in turn reduce the expression/activity of the one or more proteins, wherein the one or more proteins comprise each of a sortase, sortase, a sortase-dependent protein, a fibronectin-binding protein, an autolysin, a surface-layer protein, an aggregation-promoting factor, and a collagen binding protein. The ‘or of each’ remaining in the claim appears to allow the interpretation where only one modification of one protein is inside the scope. As an alternative explanation, the Examiner is reading the claim as follows:
A recombinant microorganism comprising one or more modifications with respect to a corresponding microorganism not comprising the one or more modifications, wherein the one or more modifications reduce, in the recombinant microorganism with respect to the corresponding microorganism, expression and/or activity of one or more
proteins expressed by the corresponding microorganism, wherein the one or more proteins comprise any
The phrase “comprise any or each” appears to allow only one protein to be modified.
This interpretation of claim 1 is also used in claim 21 since both claims contain the same limitations for the recombinant microorganism.
Claim 11 is interpreted differently since it has been separated from claim 1. This recombinant microorganism comprises one or more modifications that reduce the expression and/or activity of the one more proteins which comprise any three or more of a sortase, a sortase-dependent protein, a fibronectin-binding protein, an autolysin, a surface-layer protein, and an aggregation-promoting factor.
The focus for interpreting this claim is ‘one or more modifications that reduce the activity of the one or more proteins comprising any thee or more’ of those listed. The Specification defines “Activity” as follows (see Specification, pg. 7 lines, 1-5):
"Activity" used with respect to a protein broadly encompasses any particular activity of the protein within the cell, such that a reduction of any one or more particular activities constitutes a reduction of the activity of the protein generally.
The claim does not limit that the one or more modifications is to three or more proteins (e.g. three modified proteins), only that the one or more modifications reduce the activity of the three or more proteins expressed. This ‘activity’ is any particular activity of the protein within the cell. Since all of these proteins are directed to cell adhesion, then one modification that reduces the cell adhesion (e.g. one activity), also reduces the activity of the other proteins, even if they are unmodified. This is supported by the above definition by the phrase “a reduction of any one or more particular activities constitutes a reduction of the activity of the protein generally”. In this case the cell adhesion activity is reduced, then the activity of all cell adhesion proteins are generally reduced.
New Rejections Necessitated by Amendment
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.
Claim 1-15 and 21-25 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.
These claims contain a narrow range and broad range in the claims claim. They recite a recombinant microorganism with one or more modifications that reduce the expression of one or more proteins but limit the ‘one or more proteins’ to any 3-6 or more of the listed proteins. The broader range is the initial “one or more proteins” and the narrower range is the “any three or more proteins”. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Also there seems to be a disconnect limiting the modification in the cell to the proteins. The claims do not limit the modification is to the proteins, only that the one or more modifications reduce the expression and/or activity of the claimed proteins. This reads on a host of recombinant techniques that reduce protein expression and activity including a plasmid that expresses an RNAi specific to the claimed proteins or a mutation to the cell that terminates the cell. Therefore the metes and bounds of the modifications that accomplish this method are not clearly defined.
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.
Claim(s) 1, 4-9, and 13 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jensen et al. (Microbiology 2014 in IDS 1/2/26).
Jensen et al. teach L. reuteri with mutations to SrtA (sortase A), and five sortase-dependent proteins (SDPs) including mucus-binding protein A (cmbA), 10146, 11993, 10802, and 10154 (see Table 1). The Applicant’s Specification lists cmbA as a SDP (Specification, pg. 64, lines 5-10). They teach that mutations to srtA, cmbA and 10802 significantly reduce L. reuteri adhesion mucus from pig small intestine (Fig 1. B).
Therefore the invention as a whole is anticipated by the reference.
Response To Applicant’s Arguments
Applicant's arguments have been fully considered but they are not persuasive. The Applicant argues:
Jensen et al. does not teach a microorganism with modifications to reduce expression or activity of any three or more of a sortase, a sortase-dependent protein, a fibronectin-binding protein, an autolysin, a surface-layer protein, an aggregation-promoting factor, and a collagen- binding protein, as recited in claim 1.
This argument is not commensurate in scope with the claim. The claim does not require the rejection of “any three or more” but can also include one protein because of the alternative phrase “comprise any or each”.
Furthermore, The ‘one or more modifications’ to the microorganism is not directed to the structure of the proteins claimed but to reduce the expression or activity of these proteins. As mentioned in the Claim Interpretation section above, any one modification that lowers the adhesion of the cells, will also read as lowering the adhesive activity of the proteins based on the Applicant’s definition in the Specification for “Activity”. In short, Jensen et al. teach a modification that reduces the adhesion of the whole cell, therefore the activity of all the proteins listed is reduced.
Claim Rejections - 35 USC § 102/103
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.
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) 1-10, and 13-15 remain rejected under 35 U.S.C. 102(a)(1) or under 35 U.S.C. 103 as being anticipated by or obvious over Jensen et al. (Microbiology 2014) in light of support by NCBI Blast of SEQ ID No: 2. While Jensen et al. was submitted in an IDS, a copy is provided with this action since this rejection requires information in the supplemental contents attached to this article.
As detailed below, Jensen et al. teach a product that appears substantially identical in structure to the claimed composition but does not explicitly state all the functional limitations such as the sequence of srtA in their article matches srtA of SEQ ID NO: 2 of the Specification. Therefore a dual rejection under 102/103 is made since the composition of Jensen et al. either inherently meets the claims (M.P.E.P 2112 III and V) or is prima facie obvious since the compositions are structurally similar and share a similar utility and therefore are expected to have similar properties (MPEP 2144.09).
Jensen et al. teach L. reuteri with mutations to srtA (sortase A), and five sortase-dependent proteins (SDPs) including mucus-binding protein A (cmbA), 10146, 11993, 10802, 10154 (see Table 1). The Applicant’s specification lists cmbA as a SDP (Specification, pg. 64, lines 5-10). They teach that mutations to srtA, cmbA and 10802 significantly reduce L. reuteri adhesion mucus from pig small intestine (Fig 1. B).
Jensen et al. does not provide their sequence for srtA to compare to the srtA of SEQ ID NO: 2 in the Specification. However an NCBI BLAST search of SEQ ID NO: 2 shows it is a 100% match for srtA of L. reuteri (see BLAST search results). Therefore it appears that the L. reuteri srtA by Jensen et al. is identical or nearly identical to SEQ ID NO:2. Jensen et al. teaches that their srtA mutation is for 1 amino acid (Table S1, 10255, srtA). Therefore the single amino acid mutation of srtA by Jensen et al. overlaps in scope with SEQ ID NO: 2, since a single amino acid substitution to srtA would have at least 95% similarity since the total srtA is ~230 amino acids in length.
Therefore the invention as a whole is either anticipated or obvious by the reference.
Response To Applicant’s Arguments
Applicant's arguments have been fully considered but they are not persuasive. The Applicant argues:
Jensen et al. and NCBI Blast of SEQ ID NO: 2 do not teach a microorganism with modifications to reduce expression or activity of any three or more of a sortase, a sortase-dependent protein, a fibronectin-binding protein, an autolysin, a surface-layer protein, an aggregation-promoting factor, and a collagen- binding protein, as recited in claim 1.
This argument is not commensurate in scope with the claim. The claim does not require the rejection of “any three or more” but can also include one protein because of the alternative phrase “comprise any or each”.
Furthermore, The ‘one or more modifications’ to the microorganism is not directed to the structure of the proteins claimed but to reduce the expression or activity of these proteins. As mentioned in the Claim Interpretation section above, any one modification that lowers the adhesion of the cells, will also read as lowering the adhesive activity of the proteins based on the Applicant’s definition in the Specification for “Activity”. In short, Jensen et al. and NCBI Blast teach a modification that reduces the adhesion of the whole cell, therefore the activity of all the proteins listed is reduced.
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) 1-15 remain rejected under 35 U.S.C. 103 as being unpatentable over Jensen et al. (Microbiology 2014) in light of support by NCBI Blast of SEQ ID No: 2.
Jensen et al. teach L. reuteri with mutations to srtA (sortase A), and five sortase-dependent proteins (SDPs) including mucus-binding protein A (cmbA), 10146, 11993, 10802, 10154 (see Table 1). The Applicant’s specification lists cmbA as a SDP (Specification, pg. 64, lines 5-10). They teach that mutations to srtA, cmbA and 10802 significantly reduce L. reuteri adhesion mucus from pig small intestine (Fig 1. B).
Jensen et al. does not provide their sequence for srtA to compare to the srtA of SEQ ID NO: 2 in the Specification. However an NCBI BLAST search of SEQ ID NO: 2 shows it is a 100% match for srtA of L. reuteri (see BLAST search results). Therefore it appears that the L. reuteri srtA by Jensen et al. is identical or nearly identical to SEQ ID NO:2. Jensen et al. teaches that their srtA mutation is for 1 amino acid (Table S1, 10255, srtA). Therefore the single amino acid mutation of srtA by Jensen et al. overlaps in scope with SEQ ID NO: 2, since a single amino acid substitution to srtA would have at least 95% similarity since the total srtA is ~230 amino acids in length.
Response To Applicant’s Arguments
Applicant's arguments have been fully considered but they are not persuasive. The Applicant argues:
Jensen et al. and NCBI Blast of SEQ ID NO: 2 do not teach a microorganism with modifications to reduce expression or activity of any three or more of a sortase, a sortase-dependent protein, a fibronectin-binding protein, an autolysin, a surface-layer protein, an aggregation-promoting factor, and a collagen- binding protein, as recited in claim 1.
This argument is not commensurate in scope with the claim. The claim does not require the rejection of “any three or more” but can also include one protein because of the alternative phrase “comprise any or each”.
Furthermore, The ‘one or more modifications’ to the microorganism is not directed to the structure of the proteins claimed but to reduce the expression or activity of these proteins. As mentioned in the Claim Interpretation section above, any one modification that lowers the adhesion of the cells, will also read as lowering the adhesive activity of the proteins based on the Applicant’s definition in the Specification for “Activity”. In short, Jensen et al. and NCBI Blast teach a modification that reduces the adhesion of the whole cell, therefore the activity of all the proteins listed is reduced.
Claim(s) 21-25 remain rejected under 35 U.S.C. 103 as being unpatentable over Jensen et al. (Microbiology 2014) in light of support by NCBI Blast of SEQ ID No: 2 as applied to claims 1-15 above, and further in view of Mu et al. (Frontiers in Microbiology, 2018).
Jensen et al. teach a L. reuteri with mutations srtA (sortase), cmbA (a SDP), or 10802 (a SDP). While Jensen et al. teach their L. reuteri is marketed as a probiotic (Jensen, Abstract), and tests their adhesive properties in vitro, they do not teach administering their L. reuteri orally to a subject. However this would be an obvious next step to determine the adhesive properties in vivo and determine how adhesion affects the therapeutic benefits of a probiotic. Mu et al. teach L. reuteri is administered orally for several therapeutic benefits (pg. 4, Histamine, pg. 5, Gut Microbiota). Therefore it would be obvious to apply the L. reuteri of Jensen et al. orally to a subject to obtained in vivo adhesive results to determine the therapeutic effects of the mutated L. reuteri, and because Mu et al. teaches that orally administration is common for this probiotic.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response To Applicant’s Arguments
Applicant did not argue this rejection directly. The responses to in the prior rejections over Jensen et al. and NCBI Blast of SEQ ID No: 2 will also apply to this rejection as well.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
In response to this office action the applicant should specifically point out the support for any amendments made to the disclosure, including the claims (MPEP 714.02 and 2163.06).
CONTACT INFORMATION
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THANE E UNDERDAHL whose telephone number is (303) 297-4299. The examiner can normally be reached Monday through Thursday, M-F 8-5 MST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Fereydoun Sajjadi can be reached at (571) 272-3311.The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/THANE UNDERDAHL/Primary Examiner, Art Unit 1699
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