DETAILED ACTION
Claims 145-164 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed on 05/20/2026 amending claims 147-152, 154, 159-161 and 164 is acknowledged.
Applicant elected Group I, drawn in part to a fusion protein comprising a Phi29 polymerase domain and one or more protein-protein interaction domains, wherein one or more of the protein-protein interaction domains comprise one or more dimerization domains, wherein the dimerization domain is a kinesin 1 domain, classified in C12N 9/1252. Claims 150-153, 157-158, 162 and 163 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a nonelected invention. Election was made without traverse in the reply filed on 05/20/2026. Claims 145-149, 154-156, 159-161 and 164 are at issue and will be examined only to the extent they encompass the elected invention.
Priority
Acknowledgement is made of a claim of domestic priority under 35 U.S.C. 119(e) to provisional application No. 63/434,027 filed on 12/20/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/18/2024 and 05/20/2026 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 12/19/2023 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Rejections - 35 USC § 112(b)
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 148, 154 and 161 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.
Claim 148 is indefinite in the recitation of “at least at or about” for the following reason. “At least 95%” and “about 95%” are different concepts. Combining them makes the scope unclear (is 94 – 94.99% included by “about 95%”, or is 95.0% the floor because of “at least 95%”? Correction is required.
Claim 154 is indefinite in the recitation of “at least at or about” for the following reason. “At least 95%” and “about 95%” are different concepts. Combining them makes the scope unclear (is 94 – 94.99% included by “about 95%”, or is 95.0% the floor because of “at least 95%”? Correction is required.
Claim 161 is indefinite in the recitation of “at least at or about” for the following reason. “At least 95%” and “about 95%” are different concepts. Combining them makes the scope unclear (is 94 – 94.99% included by “about 95%”, or is 95.0% the floor because of “at least 95%”? Correction is required.
Claim Rejections - 35 USC § 112(a)
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 145-149, 154-156, 159-161 and 164are 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.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claim 145 is directed to a fusion protein comprising any Phi29 polymerase domain and any “one or more protein-protein interaction domains”. Claims 146-149, 154-156, 159-161 and 164 depend directly or indirectly therefrom claim 145.
The specification discloses support for nucleic acid binding domains (HU domain, a helix-hairpin-helix (HhH) DNA binding motif, a helix-hairpin-helix fusion [(HhH)2] DNA binding motif, a single stranded DNA binding domain, an SD07 DNA binding motif, an SS07 DNA binding motif), dimerization domain from Kinesin 1 and a protein coupling domain (SpyCatcher & SpyTag domains). The claim exceeds what is actually described in the specification and does not convey that the applicants were in possession of any “one or more protein-protein interaction domain” as the protein-protein interaction domain universe is large and structurally diverse.
Claims 145-149, 154-156, 159-161 and 164 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 fusion proteins comprising a Phi29 polymerase domain and dimerization domains, nucleic acid binding domains and protein coupling domains, does not reasonably provide enablement for the large, structurally diverse classes of polypeptides that encompass any protein-protein interaction domain. 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.
Factors to be considered in determining whether undue experimentation is required are
summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows:
1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3)
the presence and absence of working examples, 4) the nature of the invention, 5) the state of
prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art,
and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the
specification fails to teach how to make and/or use the claimed invention without undue
experimentation, are addressed in detail below.
The breadth of the claims. Claims 145-149, 154-156, 159-161 and 164 broadly encompass any fusion protein comprising a Phi29 domain and one or more protein-protein interaction domains without limitation to any particular class, family, length or structure of such domains. Claim 164 further requires that such fusion proteins, across this broad genus, generate higher RCA signal intensity, more compact RCA products, higher RCA product density, and/or improved nucleic acid binding affinity and processivity compared to reference Phi29 polymerase. The breadth of these claims thus encompasses a very large number of potential fusion constructs and sequence variants.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. While individual Phi29 DNA polymerase and common protein-protein interaction domains are well known, the art does not appear to have established a general, predictable framework by which any such domain can be fused to Phi29 to reliably improve RCA signal intensity, compactness, product density, binding affinity and processivity. The unpredictability of how different domains, orientations, and linkers affect Phi29 activity means that the prior art does not fill in the gaps left by the limited working examples.
The protein engineering and nucleic acid amplification fields are not highly predictable. The effect of fusing diverse protein-protein interaction domains to Phi29 on processivity, RCA product structure, and signal intensity cannot be reliably predicted a priori.
Existence of working examples and quantity of experimentation required. The specification includes working examples for a relatively small number of specific fusion proteins and assay conditions (e.g., particular Phi29 fusions with specific dimerization, nucleic acid, or protein coupling domains, tested in certain RCA assays). While these examples may enable those specific constructs, they do not, without more, enable the full breadth of fusion proteins and sequence variants covered by the claims.
A skilled artisan seeking to practice the full scope of the claimed invention would need to design, construct, and empirically test a large number of diverse fusion proteins, varying the protein-protein interaction domain type, copy number, positioning relative to Phi29, linker sequences, and potential sequence variants to identify those that satisfy the functional requirements of claim 164. Such extensive screening and optimization go well beyond “a reasonable amount of routine experimentation” and amounts to undue experimentation.
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)(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 145-146, 149, 156, 159 and 160 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hanzel et al. (WO2007/075987A2, published 07/05/2007).
Claims 145-146 are directed to a fusion protein comprising a Phi29 polymerase domain and one or more protein-protein interaction domains, wherein the one or more protein-protein interaction domains comprise one or more dimerization domains. Claim 149 is the fusion protein of claim 146, wherein when a first fusion protein molecule and a second fusion protein molecule are present in proximity, the one or more dimerization domains interact to produce a dimer comprising the first fusion protein molecule and the second fusion protein molecule. Claim 156 is directed to the fusion protein of claim 145, wherein the fusion protein further comprises one or more heterologous nucleic acid binding domains, linkers, and/or tags. Claims 159 and 160 are directed in part to the fusion protein of claim 145 wherein the fusion protein comprises a tag, wherein the tag is selected from a poly histidine (HIS) tag, a solubility enhancement tag (SET), a small ubiquitin-like modifier modified (SUMO) tag, a Fasciola hepatica 8-kDa antigen (Fh8) tag, a thioredoxin (Trx) tag, a glutathione-s-transferase (GST) tag, a maltose-binding protein (MBP) tag, an IgG domain B 1 of protein G (GB 1) tag, a mutated dehalogenase (Halo) tag, a steptavidin-binding peptide (SBP) tag, and a Tamavidin tag.
Hanzel et al. teaches the Phi29 polymerase domain of SEQ ID NO:1 (see sequence alignment below; SEQ ID NO:1, Example 1). Hanzel et al. teaches GST, His and S tags were added as surface coupling domains (see Example 1, pg. 34, paragraph [0100]). Hanzel et al. teaches that the surface coupling domain comprises a recombinant dimer domain of the protein, a large extraneous polypeptide domain, a polyhistidine tag, a HIS-6 tag, a His-10 tag, a biotin, an avidin sequence, a GST sequence, a glutathione, a AviTag sequence, an S tag, a recombinant polymerase domain, a dye, an acceptor, a quencher, or a combination thereof (see claim 12, pg. 42 and paragraph [0040] on pg. 12).
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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.
Claims 147-148 are rejected under 35 U.S.C. 103 as being unpatentable over Hanzel et al. (WO2007/075987A2, published 07/05/2007) as applied to claims 145-146, 149, 156, 159 and 160 above, Gray (WO2013102081A2, published 07/04/2013) and further in view of Lang et al. (WO2012/122125A2, published 09/13/2012).
The teachings of Hanzel et al. have been discussed above. Hanzel et al. does not teach the dimerization that comprises a kinesin 1 dimerization domain.
Gray teaches a DNA polymerase fusion protein attached to a kinesin (see claim 21, pg. 37, claim 42, pg. 39). Gray teaches that kinesin has an alpha-helical coiled-coil region that mediates dimerization (see pg. 4).
Lang et al. teaches a kinesin-1 protein from a fruit fly that has a sequence that comprises 100% sequence identity to SEQ ID NO: 18 (see sequence alignment below).
Claims 147-148 are directed in part to the fusion protein of claim 146, wherein the one or more dimerization domains comprise a kinesin 1 dimerization domain, wherein the kinesin 1 dimerization domain comprises the sequence set forth in SEQ ID NO: 18 or 20 or a sequence that has at least at or about 95% sequence identity to the sequence set forth in SEQ ID NO: 18 or 20.
It would have been obvious to one of ordinary skill in the art before the effective date filing date of the claimed invention to substitute a kinesin 1 dimerization domain for the dimerization domain of the fusion protein taught by Hanzel et al.
A person of ordinary skill in the art is motivated to substitute a kinesin 1 dimerization domain in place of the dimerization domain of Hanzel et al. because it is known in the art that kinesin can be fused to a DNA polymerase and dimerized as taught by Gray. One is motivated to use the kinesin 1 protein as taught by Lang et al. as it is a well-known kinesin-1 protein from fruit flies.
One of ordinary skill in the art has a reasonable expectation of success at producing a dimer by substituting the dimerization domain of Hanzel et al. with the kinesin-1 protein of Lang et al. because it is well-known in the art that kinesin proteins can be used to help dimerize DNA polymerases as evidenced by Gray. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
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Claim 154 is rejected under 35 U.S.C. 103 as being unpatentable over Hanzel et al. (WO2007/075987A2, published 07/05/2007) as applied to claims 145-146, 149, 156, 159 and 160 above and Nikiforov (US2010/0261185A1, published 10/14/2010).
The teachings of Hanzel et al. have been discussed above. Hanzel et al. does not teach the fusion protein having the Phi29 polymerase domain comprising the sequence set forth by SEQ ID NO: 3 or a sequence having at least at or about 95% sequence identity to the sequence set forth in SEQ ID NO: 3.
Nikiforov teaches a Phi29 polymerase with 100% sequence identity to SEQ ID NO: 3 (see sequence alignment below).
Claim 154 is directed to the fusion protein of claim 145, wherein the Phi29 polymerase domain comprising the sequence set forth by SEQ ID NO: 3 or a sequence having at least at or about 95% sequence identity to the sequence set forth in SEQ ID NO: 3.
It would have been obvious to one of ordinary skill in the art before the effective date filing date of the claimed invention to substitute the Phi29 polymerase domain of Nikiforov for the Phi29 domain of Hanzel et al.
A person of ordinary skill in the art is motivated to substitute the Phi29 polymerase domain of Nikiforov for the Phi29 domain of Hanzel et al. because the Phi29 polymerase of Nikiforov is well-known in the art.
One of ordinary skill in the art has a reasonable expectation of success at obtaining the fusion protein of claim 154 by substituting the Phi29 polymerase of Nikiforov for the Phi29 domain of Hanzel et al. because the sequence of Nikiforov is identical to SEQ ID NO: 3. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
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Conclusion
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALTON EDWARD KIEFER whose telephone number is (571)272-1235. The examiner can normally be reached M-F 7:30-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached at 408 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DALTON EDWARD KIEFER/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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