DETAILED ACTION
Notice of 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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-4, 6-8, 14, 19, 23, 26 in the reply filed on 25 March 2026 is acknowledged. The requirement is deemed proper and therefore made Final.
Status of Application
Claims 1-9, 14, 19, 23, 26-27, 29, 39, 44, 46 and 48 are pending; Claims 5, 9, 27, 29, 39, 44, 46 and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Thus, claims 1-4, 6-8, 14, 19, 23, 26 are subject to examination on the merits.
Priority
The instant application is a 371 of PCT/US2022/076529 filed 16 September 2022 which claims benefit of foreign priority document US Provisional 63/245,329 filed 17 September 2021 is acknowledged. Said document has been received.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 18 August 2025, 19 May 2025, 10 May 2024 and 13 March 2024 have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 6-8, 14, 23 and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a natural phenomenon) without additional elements that integrate the judicial exception into a practical application. An analysis with respect to the claims as a whole reveals that they do not include additional elements that integrate the judicial exception into a practical application. See MPEP 2106.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of the following steps:
Step (1) whether the claim is directed to one of the four categories recited in §101 (process, machine, manufacture or composition of matter);
Step (Revised 2A - Prong 1) do the claims recite an abstract idea (mathematical concepts, mental processes or method of organizing human activity), law of nature or natural phenomenon;
Step (Revised 2A - Prong 2) do the claims recite additional elements that integrate the judicial exception into a practical application; and
Step (2B) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. (See 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG)).
Step 1: Yes; the claims are directed to a composition of matter.
Step 2A – Prong 1: Yes, the claims recite a natural phenomenon, namely, a naturally occurring product/protein.
Step 2A – Prong 2: No, the claims do not recite any additional elements that integrate the judicial exception into a practical application because the claims are merely drawn to what already exists in nature. As disclosed in Benham (FEBS Journal, 2019 – cited herein) many naturally occurring protein disulfide isomerases (PDI) naturally possess an N-terminal signal sequence that targets said PDI to the ER. Upon entering the ER, said signal peptide is naturally deleted (See Figure 2, reproduced herein).
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In this respect, Zhu et la. (Reproduction, 2010 – cited herein) teach naturally occurring PDI Grp58/ERp59 possesses an N-terminal ER signal sequence which naturally gets cleaved. Said PDI further naturally comprises a nucleal localization signal at the C-terminus (See Figure 1A).
Regarding claims 7-8, Galligan et al. (Human Genomics, 2012 – cited herein) reiterate that all human PDI’s, including those of human PDIs of ERp29, PDIA2 and TXNDC12 all have N-terminal ER signal sequences that are cleaved/deleted from the mature form of the PDI upon translocation into the ER (See Figure 1 and p. 2, 1st col., 1st full paragraph).
Thus, the claims read on a naturally occurring proteins that necessarily exist in nature, e.g. a naturally occurring mature PDI.
Step 2B: As noted in answering that of 2A – Prong 2 above, there is nothing in the claims which amounts to significantly more in terms of structure and/or function and the claims read on naturally occurring enzymes. Thus, the claims are drawn to a judicial exception, namely, a naturally occurring product.
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.
Claim(s) 1-2, 14, 19 and 23 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Ruddock, L. (US 9238817 – cited herein).
Ruddock teaches:
Regarding claims 1-2, 14, 19 and 23 protein disulfide isomerases, PDI and DsbC, which have their N-terminal ER signal sequences removed (to aid in folding of proteins in the cytoplasm of prokaryotic cells) – See Figure 5; Col. 14, line 51 to Col. 16, line 28. Specific embodiments in Examples 4-7 utilize a gene encoding the mature form of DsbC comprising SEQ ID NO: 10 having the N-terminal signal sequence removed e.g. amino acids 1-20, which is expressed via a vector in a recombinant host cell – See Example 4.
Claim(s) 1-2, 6, 14, 19, 23 and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hirrano et al. (Eur. J. Biochem., 1995 – cited herein) as evidenced by Zhu et al. (Reproduction, 2010 – cited herein).
Hirrano et al. teach:
Regarding claims 1-2, 14, 19, 23 and 26, the protein disulfide isomerase GRP58/ERp57 comprising an N-terminal deletion of amino acids 1-26 which includes the N-terminal ER signal sequence and an additional two amino acids. Said protein was encoded by a nucleic acid, placed in an expression vector, and produced in a host cell (See Materials and Methods, p. 337, 2nd col. and Results, p. 338, 1st col). Said protein was further purified and was in a pharmaceutically acceptable buffer (See Materials and Methods, p. 337, 2nd col.).
Regarding claim 6, Zhu evidences GRP58/ERp57 comprises a nuclear localization signal at the C-terminus – See Figure 1 (reproduced herein).
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Claim(s) 1-4, 7, 14, 19, 23 and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (J. Thromb. And Heam., 2019 – cited herein; hereafter Wang 2019) as evidenced by Wang et al. (Antioxidants & Redox Signaling, 2013 – cited herein; hereafter Wang 2013) and Galligan et al. (Human Genomics, 2012 – cited herein).
Wang 2019 teach:
Regarding claims 1-4, 7, 14, 19, 23, and 26 a protein disulfide isomerase (PDI) comprising various functional fragments. Said fragments lack the N-terminal ER signal sequence and further comprise a N-terminal methionine fused to a Hisx6 epitope tag (MHHHHHH). Said fragments were encoded by nucleic acids, placed in expression vectors and expressed in host cells and purified into PBS which is a pharmaceutically acceptable buffer -See Figure 2A reproduced below and p. 372, 2nd col., Generation of PDI Fragments and PDI Mutants. Wang 2019 refer to Wang 2013 for specific reference to the domain boundaries. Wang 2012 further evidences that the PDI utilized in Wang 2019 is human PDI (See Wang 2019, p. 372, 2nd col., last full paragraph, 1st line: “Fragments of PDI were generated (Fig. 2A) with the boundaries of the domains as described previously [16].” Wang 2013 show the domain boundaries as follows:
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FIG. 1. The overall structure of reduced hPDI. (A) Domain organization of the hPDI molecule. The residue numbering is for hPDI with signal sequence. The fragment (residues-19 to 0) is the MH6SSGLEVLFQGPGS tag derived from the vector. The CGHC motifs in the a and a¢ domains are active sites.
Also the Materials and Methods stipulate: The gene encoding hPDI without the C-terminal tail and signal sequence (residues from 18–479) was cloned into modified pET32a, and the resulting protein contains an N terminal MH6SSGLEVLFQGPGS tag.
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Galligan et al. further evidences that all proteins in the human PDI gene family have N-terminal ER signal sequences (See Figure 1 and p. 2, 1st col., 1st full paragraph). Thus, while Wang 2019 as evidenced by Wang 2013 suggests the N-terminal ER signal peptide of the first three constructs in Figure 2a is missing, minimally the last two constructs inherently will have no N-terminal signal sequence and will further comprise MHHHHHH at the N-terminus. The fragment of ‘bx’a was still functionally active for binding platelets (See p. 374, 1st col., 1st full paragraph).
Claim(s) 1-4, 7, 14, 19, 23 and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (Antioxidants & Redox Signaling, 2013 – cited herein; hereafter Wang 2013)
Wang 2013 teach:
Regarding claims 1-4, 7, 14, 19, 23 and 26 the gene encoding hPDI without the C-terminal tail and signal sequence (residues from 18–479) was cloned into modified pET32a, and the resulting protein contains an N terminal MH6SSGLEVLFQGPGS tag (See Materials and Methods). The nucleic acid was placed into an expression vector and transformed into a host cell. The resultant protein was purified in a pharmaceutically acceptable buffer (50 mM Tris-HCl, pH 8.0, 0.1 mM NaCl, and 1mM EDTA).
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FIG. 1. The overall structure of reduced hPDI. (A) Domain organization of the hPDI molecule. The residue numbering is for hPDI with signal sequence. The fragment (residues-19 to 0) is the MH6SSGLEVLFQGPGS tag derived from the vector. The CGHC motifs in the a and a¢ domains are active sites.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUZANNE M NOAKES whose telephone number is (571)272-2924. The examiner can normally be reached M-F (7-4).
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 14 April 2026
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