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 .
Priority
This Application claims benefit of priority to Provisional Application 63/061,156 filed on 08/04/2020 and Provisional Application 63/209,138 filed on 06/10/2021. This Application is also a 371 of PCT/US2021/043266 filed on 07/27/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Amendment and Claim Status
In the reply filed 11/03/2025, Applicant amended claims 151 and 157-165 and added new claims 168-171. Claims 1-150, 152-156 and 166-167 are canceled. Claims 160-165 were previously withdrawn as not being encompassed by the elected group.
Claims 151, 157-165 and 168-171 are currently pending.
Claims 160-165 are withdrawn.
Claims 151, 157-159 and 168-171 are under examination.
Withdrawn Rejections
The 35 USC § 112 rejection of previously pending claims 151-152, 156-159 and 166-167 is withdrawn due to Applicant’s amendment to instant claim 151.
Claim Objections
Claim 168 is objected to because of the following informalities: Claim 168 recites an amino acid sequence greater than 4 amino acids in length without the appropriate sequence identifier (i.e., SEQ ID NO). It is acknowledged the sequence in claim 168 is SEQ ID NO: 25 as stated in Applicant’s Arguments filed 11/03/2025. However, where the description or claims of a patent application discuss a sequence that is set forth in the "Sequence Listing", a reference to the sequence identifier of that sequence is required at all occurrences, even if in the text of the description or claims where the sequence is set forth by enumeration of its residues. See MPEP 2422.01(V) and 37 CFR 1.821(d). Appropriate correction is required.
Maintained Rejections (with modification as 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 171 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 171 recites “A kit comprising the OMA1 reporter of claim 168. of a control without test molecule.” The claim is indefinite because the metes and bounds of the claim are unclear. It is unclear whether “of a control without test molecule” is a limitation of the claim or was an inadvertent addition. If “of a control without test molecule” is a limitation of the claim, it is unclear what ‘control’ and ‘test molecule’ are being referred to because the reporter of claim 168 only comprises an OMA1-cleavable complementation reporter and a targeting domain. Thus, claim 171 is indefinite as one of ordinary skill in the art would be unable to ascertain the metes and bounds of the claim. For the purposes of compact prosecution, claim 171 is being interpreted as “A kit comprising the OMA1 reporter of claim 168.”
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.
Claims 151, 157-159 and 168-171 are rejected under 35 U.S.C. 103 as being unpatentable over MacMillan-Crow (US 20190049430 A1, 02/14/2019) (IDS Reference of 01/24/2024) in view of UniProt (A0A2J8M6C5_PANTR, 03/28/2018) (Of Record).
Regarding claims 151 and 168, MacMillan-Crow disclose a reporter molecule comprising at least one cleavage site recognized by OMA1, a detection domain capable of emitting a signal and a repressor domain linked to the reporter molecule (Paragraph [0007]). Further, the reporter molecule may comprise functional domains that increase the availability or targeting of the reporter molecule to a cell, cellular organelle or sub-cellular domain, wherein the targeting domain may target the reporter molecule to the mitochondria via a mitochondrial targeting signal (Paragraph [0033]).
It is noted the instant Specification states a “targeting sequence” refers to a “peptide or polypeptide that can target a polypeptide, inter alia, to the cytosol, nucleus, …mitochondrial outer membrane, mitochondrial inner membrane, mitochondrial intermembrane space or matrix…” (Paragraph [147]). Thus, the functional domain disclosed by MacMillan-Crow reads on a targeting sequence. The detection domain is a fluorescent molecule, wherein the fluorescent molecule is a fluorescent peptide such as a green fluorescent protein (Paragraph [0023]).
In one embodiment, MacMillan-Crow disclose the OMA1-dependent processing site is reported to be between the 194 Arginine (R) and the 195 Alanine (A) residues. To test the theory, MacMillan-Crow synthesized a peptide based on the OPA1 sequence that did not include the 194-R and 195-A residues, which showed the 194-R is essential for OMA1 activity (Paragraph [0077]). MacMillan-Crow further disclose additional studies are underway to determine the minimal binding site required for the detection of OMA1 activity (Paragraph [0077]).
MacMillan-Crow does not disclose a targeting sequence having at least 75% identity to instant SEQ ID NO. 25.
However, UniProt discloses A0A2J8M6C5_PANTR, which is OPA1 isoform 7 that shares 100% sequence identity to instant SEQ ID NO. 25.
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the sequence of UniProt in the method of MacMillan-Crow as the sequence was a known OPA1 isoform as disclosed by UniProt. One of ordinary skill in the art would have been motivated to utilize said sequence in the reporter construct of MacMillan-Crow by the desire to determine the minimal binding site for OMA1. As discussed above regarding claim 151, MacMillan-Crow discloses it was reported that OMA-1 dependent OPA1 processing occurs between the 194-R and 195-A, but set out to determine if that was the only site for binding. Through experimenting, MacMillan-Crow found the 194-R residue was essential for binding, but stated further studies were underway to determine the minimal binding site for OMA1 (Paragraph [0077]). Therefore, it would have been obvious to utilize the sequence of UniProt in the method of MacMillan-Crow as it was a known OPA1 isoform, and MacMillan-Crow was going to further study the binding sites required for OMA1 on OPA1.
Regarding claims 157 and 169, MacMillan-Crow discloses nucleic acids encoding the reporter molecules disclosed, wherein the nucleic acid can be DNA or RNA and the DNA can be present in a vector (Paragraph [0035]). Further, the nucleic acid sequences may be inserted into a recombinant expression vector (Paragraph [0037]).
Regarding claims 158 and 170, MacMillan-Crow discloses a host cell comprising the nucleic acid (Claim 12) encoding the reporter molecule (Claim 11).
Regarding claim 159 and 171, MacMillan-Crow does not explicitly disclose a kit. However, a kit can simply comprises the reporter. Additionally, it is noted the instant Specification states recombinant genes, recombinant protein and recombinant cells or recombinant organisms can be supplied individually, combined or as a kit (Paragraph [278]). Thus, the disclosure of MacMillan-Crow of the reporter, which can be in a recombinant cell, reads on a kit.
USC § 103 – Response to Arguments
Applicant's arguments filed 11/03/2025 have been fully considered but they are not persuasive.
Applicant argued on Page 9 (Labeled 1) that the Examiner has not established a prima facie case of obviousness because the differences between the prior art and the claimed invention were not considered. Applicant argues the sequence disclosed by the prior art, AOA2J8M6C5, does not share 100% sequence identity to instant SEQ ID NO: 25.
The Examiner disagrees. The differences between the prior art and the claimed invention were considered. Additionally, as evidenced above, SEQ ID NO: 25 and AOA2J8M6C5 do share 100% sequence identity. AOA2J8M6C5 shares 100% sequence identity to all 32 amino acids of instant SEQ ID NO: 25. Additionally, while SEQ ID NO: 25 may not encompass the mitochondrial import sequence of OPA1, this is not a limitation within the instant claims. Also, all of the claims being examined utilize open language as they recite ‘comprising.’ Thus, the prior art must include all of the limitations of the instant claims but it can also include additional components, including additional amino acids.
Applicant argued at the top of Page 10 (Labeled 2) that unexpected results were not considered.
It is the Examiner’s position that unexpected results are not shown. The Examiner fully considered Example 1, as indicated by Applicant, and the associated Figures. For example, Figure 3, showing a luciferase assay of Reporter #1 and Reporter #15 with Reporter #15 being SEQ ID NO: 15 which is comprised of both SEQ ID NOs: 25 and 27, as indicated by Applicant. While Figure 3 shows a significant difference in activity between Reporter #1 and Reporter #15, the claims are not commensurate in scope with showing. Claim 151 is directed to at one least of SEQ ID NO: 25 and SEQ ID NO: 27 and claim 168 is directed solely to SEQ ID NO: 25. While both claims could comprise additional sequences, they do not require additional sequences. Reporter #15 comprises both SEQ ID NO: 25 and SEQ ID NO: 27, not just SEQ ID NO: 25. Thus, the claims are not commensurate in scope with the showing. Additionally, when showing unexpected results, the results should be compared to the prior art. See MPEP § 716.02.
Applicant argued at the bottom of Page 10 (Labeled 3) that the Examiner failed to establish a prima facie case of obviousness because the Examiner did not show any reasonable motivation to modify the prior art because prediction programs show that OPA1 mitochondrial translocation depends on residues 1-87, therefore, one of ordinary skill in the art would not have a motivation or expectation of success using SEQ ID NO: 25.
It is the Examiner’s position that there is motivation to modify the prior art as explained in the Non-Final rejection mailed 08/20/2025 and reiterated above. Additionally, prediction programs are not part of the rejection set forth.
Applicant argued at the top of Page 11 (Labeled 4) that the cited art teaches away because instant SEQ ID NO: 25 comprises internal residues 88-119 of OPA1 and it is generally known in the art that the N-terminus of nuclear-encoded precursor proteins contain the sequence required for mitochondrial target and cites MacMillan-Crow, US 8735341 B2.
The Examiner disagrees for multiple reasons. First, the claims, as-written, contain open language as all claims being examined recite ‘comprising.’ Therefore, as the prior art ‘comprises’ the instantly claimed sequence, it meets the limitation as presented. Second, Applicant did not indicate where within US 8735341 B2 such a statement was made and the Examiner did not find such statement. Additionally, even if such statement was present, one prior art document does not represent what is ‘generally’ known within the entire field. Thus, the cited art does not teach away. Moreover, MacMillan-Crow, US 8735341 B2, is not the prior art cited by the Examiner.
Applicant argued middle of Page 11 (Labeled 5) that the prior art teaches away because the cited prior, Mac-Millan Crow, discloses 194 Arginine is essential and Applicant’s reporter functions successfully without Arginine 194.
The Examiner disagrees for multiple reasons. It is the Examiner’s position that “194 Arginine is essential” is an overgeneralization of the teachings of Mac-Millan Crow. Mac-Millan Crow teaches the ‘RA’ motif is required for activity utilizing the original FRET substrate peptide in one specific embodiment. However, Mac-Millan Crow, in Table 2, shows activity of OMA1 when the ‘essential’ Arginine is substituted for Lysine. Additionally, Mac-Millan Crow specifically discloses further studies are underway to determine the minimal binding site required for detection of OMA1 activity (Paragraph [0077]). Thus, the prior art does not teach away.
Applicant argued on the bottom of Page 11 through Page 12 (Labeled 6) that a person of ordinary skill in the art would not have selected the cited art nor had any reason to combine the cited art because a person of ordinary skill in the art would not have selected the specified artificial targeting domain because SEQ ID NO: 25 does not include the ‘essential’ 194 Arginine nor does it contain an R-A motif.
This argument was addressed immediately above. Additionally, the cited prior art, Mac-Millan Crow, is directed to reporter molecules that are cleavable by OMA1, making it directly correlated to the instant invention and obvious for one of ordinary skill in the art to select. Similarly, the sequence utilized, A0A2J8M6C5, was a known OPA1 isoform. Thus, both references would have been obvious to one of ordinary skill in the art and there is motivation to combine as Mac-Millan Crow was determining OMA1 cleavage sites on OPA1.
Conclusion
Claims 151, 157-159 and 168-171 are rejected.
No claims are allowed.
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.
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/A.T.W./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653