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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/16/2025 has been entered.
Status of the Claims
The Amendment filed 06/26/2025 in which claims 1, 2, 20 were amended, new claims 23-28 were added, and claims 4-9 were canceled, has been entered. Claims 18 and 19 were previously canceled,. Claims 14-17 were previously withdrawn.
It is noted that new claims 27-28 depend on withdrawn claim 14. Accordingly, claims 27-28 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
Claims 1-3, 10-13, 20-26 are under examination on the merits.
Claim Objections
(New objection, necessitated by amendment as to claim 1) Claim 1 is objected to because of the following informalities:
On claim 1, the recitation of “fragment antigen-bind (Fab) fragment” should read “antigen-binding fragment (Fab)”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(New rejection, necessitated by amendment as to claims 1-3, 10-13, 20-28) Claims 1-3, 10-13, 20-28 were 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.
See claims 1-3, 10-13, 20-28 as submitted on 10/16/2025.
Claim 1 recites: “wherein the first construct is configured to be separate from the second construct before binding…” It is unclear what is meant by this recitation because the neither the claim nor the Specification define or explain what the term “configured” means in the context of the first and second constructs of claim 1. For instance, it is not clear if the term “configured” encompasses specific modifications on the first and second constructs such that their protein products remain separate before bonding to the target epitope(s). Further, it is noted that a construct is not a protein itself, but rather the genetic material that encodes a specific protein. Therefore, separating the first from the second construct before epitope(s) binding does not pertain separation of their respective protein products. In other words, the claim seemingly recites separation of the constructs which are comprised of nucleic acids and not the proteins said nucleic acids encode. Separation of the nucleic acid constructs itself does not mean separation of the protein products such nucleic acids encode. The dependent claims do not add additional clarity and, therefore, are also indefinite. For purposes of compact prosecution and applying prior art, claim 1 was interpreted herein as referring to “wherein the protein products encoded by the first and second constructs are in a separate steady-state before epitope(s) binding…”
Claims 3 and 13 recite "the protein". There is insufficient antecedent basis for this recitation in the claim because amended claim 1, which claims 3 and 13 depend on, no longer recites “a protein”. Claim 1 now recites “a split enzyme”. For purposes of compact prosecution and applying prior art, claims 3 and 13 were interpreted herein as referring to the split enzyme of claim 1.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office Action.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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)(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.
(Previous rejection, withdrawn as to claims 1-3, 6-13, 20-22) Claims 1-3, 6-13 and 20-22 were rejected under 35 U.S.C. 102(a)(2) as being anticipated by Wells et al., as evidenced by Liu H, et al. (prior art of record).
See claims 1-3, 6-13 and 20-22 as submitted on 10/16/2025.
The previous rejections of claims 6-9 are moot in view of Applicant’s cancelation of these claims.
Applicant’s amendment to claims 1, 2, 20 have overcome previous rejection to claims 1-3, 6-13 and 20-22.
(Previous rejection, withdrawn as to claims 4-9, maintained and modified as necessitated by amendment as to claims 1, 3, 10-13, 20) Claims 1, 3, 10-13, 20 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Mackernan, as evidenced by Liu et al. (prior art of record).
See claims 1, 3, 10-13, 20 as submitted on 10/16/2025.
The previous rejections of claims 4-9 are moot in view of Applicant’s cancelation of these claims.
Applicant’s amendment to claims 1, 2, 20 have overcome previous rejection to claims 1, 3, 10-13 and 20.
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.
(New rejection, necessitated by amendment as to claims 1-3, 10-13, 20-23, 25) Claims 1-3, 10-13, 20-23, 25 are rejected under 35 U.S.C. 103 as being unpatentable over Martell et al. 2016 (cited in Applicant’s IDS submitted on 03/30/2022), in view of patent application No. WO 2022/094622 A1 to Kossiakoff et al. effectively filed 11/02/2020 (See PTO-892: Notice of References Cited).
See claims 1, 3, 10-13, 20-23, 25 as submitted on 10/16/2025.
Regarding claims 1 and 20, Martell et al. teach a reporter protein-fragment complementation assay (PCA) based on a split horseradish peroxidase (HRP) enzyme, for detection of protein-protein interactions wherein two proteins of interest are fused to complementary fragments of the split HRP reporter enzyme, and reporter activity is reconstituted only if a protein-protein interaction occurs (Abstract, page 1). Martell et al. further teach such PCA composition comprises two constructs, a first and a second construct comprising a first and a second portion of the split HRP reporter enzyme respectively, wherein each split HRP portion is fused to a protein of interest (pages 1-2, Fig. 1). Martell et al. further teach said HRP reporter protein requires a disulfide bond between the HRP fragments (Cys97-Cys301) for reconstitution and subsequent signal (page 3, Supplementary Fig. 4A–B), wherein cysteine residue at position 97 in the first HRP fragment and cysteine residue at position 301 in the second HPR fragment comprise each a sulfhydryl group and said sulfhydryl groups form the disulfide bond between the HRP fragments upon binding of the proteins of interest to their target epitope(s) (page 3).
Martell et al. do not teach a first and a second antigen-recognizing amino acid sequences each comprising at least one single chain variable fragment (scFv), at least one antigen-binding fragment (Fab), or at least one antibody as the element(s) fused to the split enzyme fragments wherein said first and a second antigen-recognizing amino acid sequences bind one or more antigen epitopes.
However, Kossiakoff et al. teach kits and compositions for a PCA comprising two portions of a split enzyme, each fused to a target-binding molecule for example, a single chain variable fragment [scFv] for detection of one or more epitopes on a target molecule (for example, an antigen wherein the antigen is a viral surface protein (for example, the SARS-CoV-2 spike protein) (Abstract, ¶¶ [0021]-[0026], [0221], [0226], [0052], [0084], Figs. 5A-5B). Kossiakoff et al. further teach the use of antibody fragments allows for reduction of unintended cross interactions between antibodies and reducing immunogenicity (¶¶ [0065], [0080]). Fig. 5B is reproduced below.
PNG
media_image1.png
609
1104
media_image1.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to have incorporated the scFv fragments taught by Kossiakoff et al. as target-binding molecules fused to the two portions of the HPR split enzyme of Martell et al. for the benefit of targeting one or more epitopes on an antigen and reducing unintended cross interactions between antibodies and reducing immunogenicity. See MPEP 2144.07. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
One of ordinary skill in the art would have had reasonable expectation of success in incorporating the scFv fragments of Kossiakoff et al. as target-binding molecules fused to the two portions of the HPR split enzyme of Martell et al. given that the methods of formulating compositions comprising the HRP split enzyme fused to antibodies fragments for detection of antigens are well known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Regarding claims 2 and 25, Kossiakoff et al. teach wherein the antigen epitopes comprise two different viral surface antigen epitopes or the same viral surface antigen epitope (¶¶ [0221]-[0223], [0089]-[0106]).
Regarding claims 3 and 13, Martell et al. teach the composition explained above wherein the reporter protein comprises horseradish peroxidase or HRP (Abstract, page 1).
Regarding claims 10-12, As previously explained, Kossiakoff et al. teach constructs further comprising additional sequences such as sequences tags such as a histidine tag to facilitate purification (¶ [0117]).
Regarding claims 21 and 22, Kossiakoff et al. teach a buffer to adjust the pH of the reaction, for example a buffer comprising 1M Tris-HCl buffer of pH 8.5 (¶ [0227). It is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II.
Regarding claim 23, Kossiakoff et al. teach an analyte comprising a SARS-CoV-2 virus (¶¶ [0021]-[0026], Figs. 5A-5B).
Accordingly, claims 1, 3, 10-13, 20-23, 25 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
(New rejection, necessitated by amendment as to claims 24 and 26) Claims 24, 26 are rejected under 35 U.S.C. 103 as being unpatentable over Martell et al. and Kossiakoff et al. as applied to claims 1, 3, 10-13, 20-23, 25 above, further in view of Mackernan (prior art of record).
See claims 24 and 26 as submitted on 10/16/2025.
Regarding claim 24, the teachings of Martell et al. and Kossiakoff et al. teach the composition of claim 1. Neither Martell et al. nor Kossiakoff et al. teach wherein the analyte is insulin.
However, Mackernan teaches wherein the analyte is insulin and the composition of claim 1 is used as a medical diagnostic to measure insulin levels with higher accuracy (¶¶ [0205], [0233]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to have incorporated the teachings of Mackernan about measuring insulin levels into the composition of Martell et al. and Kossiakoff et al. for the benefit of formulating a medical diagnostic too with higher accuracy. See MPEP 2144.07. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
One of ordinary skill in the art would have had reasonable expectation of success in incorporating the insulin analyte of Mackernan with the composition of Martell et al. and Kossiakoff et al. given that the methods of formulating compositions comprising the HRP split enzyme fused to antibodies fragments for detection of analytes relevant to human health are well known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Regarding claim 26, Mackernan teaches the composition further comprises a sample containing the analyte, wherein the sample comprises a biological fluid sample such as blood (¶¶ [0136], [0138]).
Accordingly, claims 24 and 26 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 10/16/2025 have been fully considered and they were found persuasive.
Applicant contends on pages 6 of the Remarks submitted on 10/16/2025:
The Examiner acknowledges the clear and concise explanation of the prior art of record in relation to the claimed invention provided by Applicant. In view of Applicant’s amendments and the discussion provided by Applicant, the previous rejections under 35 USC § 102 are herein withdrawn. In view of Applicant’s amendments a new set of rejections under 35 USC § 103 is set forth in the present Office Action.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARLENE V BUCKMASTER whose telephone number is (703)756-5371. The examiner can normally be reached M-F 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J Visone can be reached at (571) 270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARLENE V BUCKMASTER/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672