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 .
Response to Arguments
Applicant's arguments filed December 16, 2025 have been fully considered but they are not persuasive. Applicant has amended independent claim 1 to recite a plurality of engineered pore forming proteins comprising a plurality of alpha-helical pore forming proteins, or a plurality of beta-barrel pore forming proteins. Additionally, claim 1 has been amended to recite the engineered pore forming proteins having first, second, and third subunits coupled to first, second, and third subunits of the multimeric protein. Applicant has argued that the combination of Maglia et al., in view of Nivala et al., cited in the previous Office Action do not teach the limitations of amended claim 1. The Examiner respectfully disagrees.
With respect to the limitation regarding engineered pore forming proteins, the Examiner notes that both Maglia et al., and Nivala et al., teach engineered pore forming proteins, thus including engineered pore forming proteins into the claims do not overcome the teachings of the cited prior art.
With respect to the claimed first, second, and third monomers of the engineered pore forming proteins coupled to first, second, and third subunits of the multimeric protein, the Examiner contends that the amended limitations are unclear as the specification does not provide a definition for the claimed monomers or subunits. The instant specification does not describe the pore forming proteins as having first, second, and third monomers, thus the Examiner is unable to determine the metes and bounds of the claimed monomers. As such, it is unclear what Applicant regards as the first, second, and third monomers of the engineered pore forming proteins. Similarly, the specification does not provide a definition for the claimed first, second, and third subunits of the multimeric protein. The specification does not describe the multimeric protein having first, second, and third subunits, thus it is unclear what Applicant regards as the first, second, and third subunits of the multimeric protein. Absent a clear definition of what constitutes the first, second, and third monomers of the pore forming proteins, and first, second, and third subunits of the multimeric protein, the Examiner will read the teachings of Maglia et al., in view of Nivala et al., as teaching the limitations of amended claim 1. Therefore, in light of the teachings of the prior art, and the arguments provided here, the Examiner contends that the limitations of the instant claims are taught by the references cited below, thus the rejection is maintained.
Claim Interpretation
Content of Specification
(k) CLAIM OR CLAIMS: See 37 CFR 1.75 and MPEP § 608.01(m). The claim or claims must commence on a separate sheet or electronic page (37 CFR 1.52(b)(3)). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation. There may be plural indentations to further segregate subcombinations or related steps. See 37 CFR 1.75 and MPEP 608.01(i)-(p).
The claimed invention is defined by the positively claimed elements, the structural elements listed on separate indented lines listed in the body of the claim after the transitional phrase, “comprising”.
For claim 1, the Examiner notes that the phrase "different proteins" can be interpreted in multiple ways. For example, "different protein" may refer to proteins transcribed from different genes, and exhibiting differences in sequence, structure, and function. The phrase "different protein" also encompasses a single protein wherein one sequence is the wild-type sequence, and a second sequence having targeted mutations. The Examiner notes that either of the scenarios described above will be regarded as "different proteins" with respect to claim 1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 4-18, 20, and 22-27 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.
For claim 1, the “first monomer of the plurality of engineered pore-forming proteins,” “second monomer of the plurality of engineered pore-forming proteins,” and “third monomer of the plurality of engineered pore-forming proteins” are unclear as the instant specification does not define first, second, and third monomers of the pore forming proteins. The instant specification is silent with respect to the pore forming proteins having first, second, and third monomers, thus the Examiner is unable to determine what structures of the nanopore system make up the claimed monomers. For the purposes of examination, the Examiner will consider any nanopore having engineered pore forming proteins as having first, second, and third monomers. Additionally, the specification does not define first, second, and third subunits of the multimeric protein, thus the Examiner is unable to determine what structures of the nanopore system make up the claimed first, second, and third subunits of the multimeric protein. For the purposes of examination, the Examiner sill consider any multimeric protein as having first, second, and third subunits. Claims 2, 4-18, 20, and 22-27 depend directly, or indirectly from claim 1 and are also indefinite.
Claims 6, 8-11, 13, and 14 recites the limitation "the monomer" in line 1. There is insufficient antecedent basis for this limitation in the claim. The Examiner notes that it is unclear which monomer the phrase “the monomer” references as claim 1 recites a first, second, and third monomer. Additionally, “the monomer” is inconsistent with the language of claim 1 which recites first, second, and third monomers “of the plurality of engineered pore-forming proteins.” The Examiner request Applicant amend the claims so that the language with respect to the monomers is consistent.
Claim 7 recites the limitation "the subunit" in line 1. There is insufficient antecedent basis for this limitation in the claim. The Examiner notes that claim 1 recites first, second, and third subunits, thus it is unclear which of the first, second, or third subunits “the subunit” in claim 7 references.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 4-9, 12-18, 20, and 22-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maglia et al., (US 2018/0364214) in view of Nivala et al., (US 2016/0032236).
Regarding claims 1 and 12, Maglia et al., teach a process comprising providing a nanopore system (paragraph 0137) comprising an aqueous pore (fluid chamber,paragraph0137), and a membrane (paragraph 0137) that separates the aqueous pore into cis and trans sides (figure 1A). Maglia et al., also teach a plurality of engineered pore forming proteins comprising a plurality of monomers (paragraphs 0022, 0043, 0107,0108, figure 1) wherein the monomers are derived from different proteins (paragraphs 0107,0108). The Examiner notes that the modified subunit polypeptides comprise different proteins in that the modified subunits are different forms of the ClyA nanopore subunits taught by Maglia et al. Also, the Examiner notes that this view is consistent with the interpretation of claim 1 detailed above in the claim interpretation section. With respect to the first, second, and third, monomers, the Examiner notes that the claim is being read in light of the rejection under 35 U.S.C. 112(b) in which the monomers are unclear as they are not defined in the specification. As such, the Examiner contends that reference to Maglia et al., teach engineered pore forming proteins having first, second, and third monomers. Maglia et al., do not teach a multimeric protein coupled to the pore forming proteins.
Nivala et al., teach a nanopore sensor for protein translocation comprising a multimeric protein (ClpA/X, paragraph 0080) wherein the multimeric protein is coupled to a nanopore (paragraph 0080). Nivala et al., also teach ClpA/X translocating a substrate protein through the nanopore (paragraphs 0055, 0056, 0058, 0061). Nivala et al., teach that it is advantageous to utilize a ClpA/X protein for translocation as a means of providing a technique to unfold proteins for controlled, sequential translocation (paragraphs 0011, 0013).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Maglia et al., wherein ClpA/X is coupled to a plurality of pore forming proteins in order to provide a technique to unfold proteins for controlled and sequential translocation as taught by Nivala et al.
Regarding claim 2, Maglia et al., teach protein translocating through the aqueous pore (paragraph 0188).
Regarding claims 4 and 25, Maglia et al., does not teach the aqueous pore comprising a portion of alpha-hemolysin protein (whole document).
Regarding claims 5, 7, and 26, Maglia et al., do not teach a multimeric protein as recited in claim 5.
Nivala et al., teach a nanopore system for protein translocation wherein AAA+ proteins are taught as suitable multimeric proteins (paragraph 0052). The Examiner notes that AAA+ proteins comprise subunits that are proteosomes (paragraphs 0052, 0061). The Examiner is reading this combination as combining prior art elements according to known methods to yield predictable results which would have been obvious to one of ordinary skill in the art. Reference to Nivala et al., teach that AAA+ proteins are suitable multimeric proteins for translocation through a nanopore, thus one of ordinary skill in the art would have recognized that AAA+ proteins can be utilized in a nanopore system. Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Maglia et al., in view of Nivala et al., wherein AAA+ proteins are utilized as combining prior art elements according to known methods to yield predictable results requires only routine skill in the art.
Regarding claim 6, Maglia et al., teach a transmembrane portion (paragraphs 0043, 0044, 0193, 0201).
Regarding claim 8, Maglia et al., teach the pore comprising at least 10 subunits (paragraph 0106), thus a single monomer is unable to form a pore. Additionally, the multimeric protein of Nivala et al., does not form a pore (paragraph 0082, figure 10A).
Regarding claim 9, Maglia et al., do not teach a monomer of the engineered pore forming proteins adjacent to a subunit of the multimeric protein.
Nivala et al., teach the multimeric protein adjacent to the nanopore (paragraph 0082, figures 1 and 10B). The Examiner notes that the term adjacent does not require a connection between the pore and the multimeric protein. The Examiner is reading this combination as combining prior art elements according to known methods to yield predictable results which would have been obvious to one of ordinary skill in the art. Reference to Nivala et al., teach a nanopore system having the claimed arrangement, thus one of ordinary skill in the art would have recognized that a nanopore system would be capable of operating with an engineered pore forming protein adjacent to a subunit of a multimeric protein. Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Maglia et al., wherein a pore forming protein is adjacent to a subunit of a multimeric protein as combining prior art elements according to known methods to yield predictable results requires only routine skill in the art.
Regarding claims 13 and 14, Maglia et al., do not teach a monomer comprising an α-helical pore, or a β-barrel pore.
Nivala et al., teach a nanopore system wherein a transmembrane sequence comprises an α-helix or a β-barrel (paragraphs 0046-0047). Nivala et al., teach that it is advantageous to utilize a protein having α-helices and β-barrels as a means of developing pores in a cellular membrane (paragraph 0047).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Maglia et al., in view of Nivala et al., wherein the monomer comprises α-helices and β-barrels in order to develop pores in a cellular membrane as taught by Nivala et al.
Regarding claims 15-17, Maglia et al., teach measuring a current while the biopolymer is translocated through the aqueous pore and determining a characteristic of the biopolymer based on the measurements (paragraphs 0022, 0095, 0135, 0136, 0139). Maglia et al., also teach sequencing the biopolymer (paragraph 0189).
Regarding claim 18, Maglia et al., teach an electrical circuit that applies a voltage to the cis or trans side of the membrane (paragraphs 0027, 0032).
Regarding claim 20, Maglia et al., do not teach a translocase coupled to a nanopore.
Nivala et al., teach a nanopore system wherein a translocase is coupled to a nanopore (paragraph 0080). Nivala et al., teach that it is advantageous to couple a translocase to a nanopore as a means of controlling movement of proteins through a nanopore sensor (paragraph 0080).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Maglia et al., wherein a translocase is coupled to a nanopore in order to control movement of proteins through a nanopore sensor as taught by Nivala et al.
Regarding claim 22, Maglia et al., also teach a plurality of pore forming proteins comprising a plurality of monomers (paragraphs0107, 0108) wherein the monomers are derived from different proteins (paragraphs 0107, 0108). The Examiner notes that the modified subunit polypeptides comprise different proteins in that the modified subunits are different forms of the ClyA nanopore subunits taught by Maglia et al. Also, the Examiner notes that this view is consistent with the interpretation of claim 1 detailed above in the claim interpretation section.
Regarding claims 23 and 27, Maglia et al., do not teach the engineered pore forming proteins coupled to a subunit of the multimeric protein.
Nivala et al., teach a nanopore system wherein a multimeric protein is coupled to a nanopore (paragraph 0080). Nivala et al., teach that it is advantageous to couple a pore forming protein to a multimeric protein as a means of controlling movement of proteins through a nanopore sensor (paragraph 0080).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Maglia et al., wherein a pore forming protein is coupled to a multimeric protein in order to control movement of proteins through a nanopore sensor as taught by Nivala et al.
Regarding claim 24, Maglia et al., do not teach a multimeric protein on the cis and/or trans side of the membrane.
Nivala et al., teach a nanopore system wherein a multimeric protein is located on either the cis side or the trans side of the membrane. The Examiner is reading this combination as combining prior art elements according to known methods to yield predictable results which would have been obvious to one of ordinary skill in the art. Reference to Nivala et al., teach that a multimeric protein can be placed on the cis side, or the trans side of a membrane, thus one of ordinary skill in the art would have found it obvious to form a multimeric protein on the cis side, or the trans side of a membrane as combining prior art elements according to known methods to yield predictable results requires only routine skill in the art.
Claim(s) 10 and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maglia et al., (2018/0364214) in view of Nivala et al., (US 2016/0032236) as applied to claim 1 above, and further in view of Jayasinghe et al., (US 2019/0071721).
Regarding claims 10 and 11, Maglia et al., in view of Nivala et al., do not teach multimeric subunits coupled by peptide bonds.
Jayasinghe et al., teach a nanopore wherein a binding protein is coupled to two monomers by peptide bond linkers (paragraphs 0368, 0384). Jayasinghe et al., teach that it is advantageous to couple two monomers by peptide bond linkers as a means of constraining mobility of the monomers (paragraph 0384).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Maglia et al., in view of Nivala et al., to couple the multimeric subunits with a peptide linker in order to constrain mobility of the monomers as taught by Jayasinghe et al.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DWAN A GERIDO whose telephone number is (571)270-3714. The examiner can normally be reached Mon-Fri 10-6.
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/DWAN A GERIDO/Examiner, Art Unit 1797 /LYLE ALEXANDER/Supervisory Patent Examiner, Art Unit 1797