DETAILED ACTION
Status of claim rejections
The rejections of record under 35 USC 103 are maintained and modified in view of Applicant’s amendments/arguments in the response filed 10/16/25.
The nonstatutory double patenting rejections of record are maintained and modified in view of Applicant’s amendments/arguments in the response filed 10/16/25.
This Action is FINAL, as necessitated by Applicant’s amendments.
Claim Interpretation
The examiner has interpreted the limitation(s) as follows:
“A fusion protein comprising a CSQ tag and a protein of interest” as in claim 1 has been interpreted to encompass a fusion protein of calcium binding protein calsequestrin (such as calsequestrin 1) and the proteins of interest listed in claim 1, where the calsequestrin functions to allow for increased expression and water solubility of the protein of interest. Support for this interpretation can be found on (for example) pg. 2 and 10 of the specification.
“Acts to improve expression and water solubility of the protein of interest” as in claim 1 has been interpreted to be an inherent functional property of the calsequestrin tag. Support for this interpretation can be found on pg. 6 of the specification.
Modified Claim Rejections - 35 USC § 103
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 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 and 6-11 are rejected under 35 U.S.C. 103 as being unpatentable over Kim ((KR 20170069452 A; 21 June 2017; cited in Applicant IDS; prior art of record) in view of Johnston et al (US 5532142A; 02 July 1996; hereinafter "Johnston"; prior art of record), Sanchez et al (J Biol Chem. 2012 Apr;287(14):11592-601); see also NCBI GenBank accession no. 3UOM_A; cited in applicant IDS; hereinafter “Sanchez”; prior art of record), and Coco et al (WO2002006469A2; 24 January 2002; hereinafter “Coco”; prior art of record).
Kim teaches a Z-domain/Z-protein and calsequestrin fusion protein (a fusion protein comprising a CSQ tag and a protein of interest as in claim 1) used for purification of antibodies (title, abstract, pg. 2, paragraph 001, and throughout document). Kim teaches a) preparing a recombinant vector comprising a nucleic acid encoding a Z domain and a calsequestrin fusion protein; b) transforming the recombinant vector into a host cell to obtain a transformant; c) expressing the Z-calsequestrin fusion protein from the transformant; and d) separating the Z-calsequestrin protein-bound antibody from the expressed transformant using calcium (see pg. 3, paragraph 3-4; see also claim 6-7). Kim teaches the Z domain protein and calsequestrin are fused through a linker (see claim 11). Kim also teaches an amino acid sequence of calsequestrin (see SEQ ID NO 3 of Kim) and that the calsequestrin can be used to precipitate the fusion protein using calcium via coagulation reaction that can replace column chromatography (see pg. 2, paragraph 5; throughout document).
The difference between Kim and the instant claim is that Kim does not explicitly teach that the CSQ is coded for by an amino acid sequence of instant SEQ ID NO: 1.
However, Sanchez teaches high-capacity Ca2+ binding of human skeletal calsequestrin (title). Sanchez also teaches that calsequestrin binds large amounts of Ca2+ (pg. 11592, col 1, paragraph 1), and specifically that human calsequestrin (hCASQ1) molecules can bind approximately 15 Ca2+ ions that shows a multi-phasic Ca2+ binding-capacity curve that indicates the stepwise formation of higher order polymeric structure as Ca2+concentration increases (pg. 11595 col 1-3; pg. 11597, Fig. 6). Sanchez specifically teaches a calsequestrin sequence (see Fig. 1 of Sanchez) that has 100% sequence identity to instantly claimed SEQ ID NO: 1 (as in claim 2) (see alignment below).
PNG
media_image1.png
1592
809
media_image1.png
Greyscale
Instant SEQ ID NO 1 vs sequence of Sanchez
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the calsequestrin fusion protein of Kim by using the calsequestrin isoform of Sanchez to arrive at the claimed invention. As the claimed invention relies on the creation of a fusion protein of calsequestrin and a protein of interest, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the calsequestrin amino acid sequence of Kim) with another (the calsequestrin amino acid sequence of Sanchez) with a reasonable expectation of success (creation of a fusion protein with calsequestrin and a protein of interest). One of ordinary skill would have been motivated to perform the substitution because Kim teaches calsequestrin can be used to precipitate fusion protein using calcium via coagulation reaction that can replace column chromatography, and Sanchez specifically teaches a sequence of human calsequestrin protein that can advantageously bind approximately 15 Ca2+ ions that shows a multi-phasic Ca2+ binding-capacity curve that indicates the stepwise formation of higher order polymeric structure as Ca2+concentration increases.
Neither Kim nor Sanchez explicitly teach that the CSQ tag acts to improve expression and water solubility of the protein of interest. However, applicant’s specification evidences that “a protein that is unlikely to express in an aqueous state or is likely to aggregate in an aqueous condition can be expressed in an aqueous state due to the high expression and water solubility of CSQ” (see pg. 6 of the specification). As interpreted in the previous office action, the ability of the calsequestrin to “act[s] to improve expression and water solubility of the protein of interest” as in claim 1 has been interpreted to be an inherent functional property of calsequestrin. According to MPEP 2112.01(I), where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established and the claimed properties or functions are presumed to be inherent. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). Furthermore, "products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present (see MPEP 2112.01(II)). Thus, absent evidence to the contrary, the calsequestrin in the fusion protein of Kim and Sanchez (i.e., the calsequestrin having 100% identity to the instantly claimed CSQ tag) would inherently improve expression and water solubility of the protein of interest in comparison to the fusion protein alone.
Kim does not teach using a peptide linker consisting of the amino acid sequences of SEQ ID NO: 5-8 that is degradable by a hydrolase.
However, Johnston teaches methods of isolation and purification of fusion polypeptides (title). Johnston also teaches the employment of plant virus proteinase to provide high yields of protein product to cleave expressed fusion proteins to obtain polypeptides (abstract). Johnston teaches that the functional tobacco etch virus (TEV) protease cleavage site, incorporated into recombinant protein, enables isolation of fusion polypeptides in the presence of relatively large amounts of added cell protease inhibitors (col 8, lines 13-24). Yields of polypeptides sensitive to cell proteases are thus significantly increased. Isolation of a desired polypeptide is more efficient because cleavage is selective for the unique potyvirus proteinase site (col 8, lines 13-24). Johnston further teaches a sequence of TEV protease cleavage site (SEQ ID NO 6) that has 100% sequence identity to instant SEQ ID NO 5 (as in claim 4) (see alignment below).
PNG
media_image2.png
515
927
media_image2.png
Greyscale
SEQ ID NO 6 of Johnston vs instant SEQ ID NO 5
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the calsequestrin fusion protein of Kim by using the hydrolase-cleavable peptide sequence of Johnston to arrive at the claimed invention. As the claimed invention relies on the creation of a fusion protein of calsequestrin and a protein of interest fused via a linker, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the linker sequence of Kim) with another (the TEV linker sequence of Johnston) with a reasonable expectation of success (creation of a fusion protein with calsequestrin and a protein of interest fused via a linker). One of ordinary skill would have been motivated to perform the substitution because Johnston teaches TEV protease cleavage site, when used in a fusion protein, advantageously enables isolation of fusion polypeptides in the presence of relatively large amounts of added cell protease inhibitors, significantly increases yield of polypeptides, and isolation of a desired polypeptide is more efficient because cleavage is selective for the unique potyvirus proteinase site.
The difference between Kim, Sanchez and Johnston and the instant claim is that none of the references explicitly teach that the protein of interest is a polymer protein, a glycoprotein, a cytokine, a growth factor, a blood factor, a vaccine, a hormone, an enzyme, and an antibody.
However, Coco teaches formation of chimeric (i.e., fusion) polynucleotides (title, abstract). Coco teaches various useful polypeptides in chimeric polynucleotides that includes various medically useful polypeptides such as insulin, erythropoietin, interferons, colony stimulating factors such as granulocyte colony stimulating factor, growth hormones such as human growth hormone, Insulin-Like Growth Factors I and II, Angiopoietin I and π, LHRH analogs, LHRH antagonists, tissue plasminogen activator, somatostatin analog, Factor VIH, Factor IX, calcitonin, dornase alpha, polysaccharides, AG337, bone inducing protein, bone morphogenic protein, brain derived growth factor, gastrin 17 immunogen, interleukins such as IL-2, PEF superoxide, permeability increasing protein-21, platelet derived growth factor, stem cell factor, thyrotropin, EGF, Tie-2 ligands, and somatomedin A and C (glycoprotein, cytokine, growth factor, hormone, enzyme, or antibody as in claim 1) (pg. 29, lines 11-30; pg. 30, lines 1-18).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the Z-protein-calsequestrin fusion protein of Kim, Sanchez and Johnston by using EGF as taught by Coco as the protein of interest to arrive at the claimed invention. As the claimed invention relies on the creation of a fusion protein of calsequestrin and a protein of interest, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the Z-protein/Z-domain of Kim, Sanchez and Johnston) with another (the EGF of Coco) with a reasonable expectation of success (creation of a fusion protein with calsequestrin and a protein of interest). One of ordinary skill would have been motivated to perform the substitution because Coco teaches that EGF advantageously is a medically useful polypeptide that can successfully be used in a chimeric protein.
Regarding claim 6, Coco teaches use of interleukin-2, EGF, claimed growth factors, etc. as in claim 6) (pg. 29, lines 11-30; pg. 30, lines 1-18).
Regarding claim 7, Coco further teaches an amino acid sequence of EGF (see Example 2; and Fig. 3 SEQ ID NO: 17) that has 100% sequence identity with instant SEQ ID NO: 12 (as in claim 7) (see alignment below).
PNG
media_image3.png
1444
828
media_image3.png
Greyscale
SEQ ID NO 17 of Coco vs instant SEQ ID NO 12
Regarding claim 8, Kim teaches a nucleic acid sequence, including a nucleotide sequence encoding the fusion protein of claim 1 (see claim 1 and 11 of Kim and pg. 2, paragraph 15).
Regarding claim 9, Kim teaches a recombinant vector comprising the nucleic acid of calsequestrin and protein (see claim 6, pg. 2, paragraph 17, pg. 3 paragraph 2-4).
Regarding claim 10-11, Kim teaches a host cell transformed with the expression vector (see pg. 3, paragraph 3-4) and specifically that the host cell can be E. coli; Bacillus such as Bacillus subtilis, and Pseudomonas (pg. 3, paragraph 4).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, absent evidence to the contrary.
Second rejection
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Kim, Sanchez, Johnston, and Coco as applied to claims 1, and 6-11 above, and further in view of Rosen et al (US 20040018969 A1; 29 January 2004; hereinafter “Rosen”; prior art of record).
As discussed above, claims 1, and 6-11 were rendered prima facie obvious by the teachings of Kim, Sanchez and Johnston.
Kim also teaches a nucleic acid/nucleotide sequence of calsequestrin (see SEQ ID NO 4) and that the calsequestrin can be used to precipitate the fusion protein using calcium via coagulation reaction that can replace column chromatography (see pg. 2, paragraph 5; throughout document).
The difference between the references and the instant claim is that none of the references explicitly teach that the CSQ is coded for by a nucleotide of instant SEQ ID NO: 3.
However, Rosen teaches nucleic acids, proteins and antibodies used in vectors, host cells, recombination and the production of isolated human polynucleotides and polypeptides (abstract, paragraph 0003). Rosen teaches an isolated nucleic acid molecule comprising a polynucleotide or fragment of SEQ ID NO: X or variant of SEQ ID NO: X (see claim 1(a) or 1(g)-(h) of Rosen), and specifically teaches that the polynucleotide encodes polypeptides that can be included in a fusion protein (paragraph 0070). Rosen further teaches a nucleic acid sequence HCMSL08 of human calsequestrin (SEQ ID NO: 258) that has 100% sequence identity to instant SEQ ID NO: 3 (as in claim 3) (see alignment below).
PNG
media_image4.png
1662
994
media_image4.png
Greyscale
SEQ ID NO 28 of Rosen vs instant SEQ ID NO 3
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the calsequestrin fusion protein of Kim, Sanchez and Johnston by using the calsequestrin nucleic acid sequence of Rosen to arrive at the claimed invention. As the claimed invention relies on the creation of a fusion protein of calsequestrin and a protein of interest, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the calsequestrin nucleic acid sequence of Kim and Johnston) with another (the calsequestrin nucleic acid sequence of Rosen) with a reasonable expectation of success (creation of a fusion protein with calsequestrin and a protein of interest). One of ordinary skill would have been motivated to perform the substitution because Kim teaches calsequestrin can be used to precipitate the fusion protein using calcium via coagulation reaction that can replace column chromatography, and Rosen teaches a known nucleic acid sequence of calsequestrin that can advantageously be used in a fusion protein.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, absent evidence to the contrary.
Response to Arguments
Applicant’s arguments filed 10/16/25 have been fully considered but they are not persuasive.
On pg. 5-6, Applicant argues that the prior art of Kim does not provide a teaching, suggestion, or motivation to combine Kim’s CSQ tag with the broad group of proteins recited in amended claim 1. Applicant argues that Coco (used to reject cancelled claim 5) does not teach using CSQ tag for improving expression and solubility of the claimed group of proteins, and none of the other cited references provide any motivation or suggestion to combine the listed proteins of Coco with the tag of Kim to improve solubility of insoluble proteins. Applicant argues that Z-domain can function as a solubilizing fusion tag and affinity purification, and Kim does not contemplate the use of CSQ as a detachable tag or any cleavage site that would allow release of the target protein while the present invention the technical contribution is using CSQ as a versatile solubility and purification tag for diverse target proteins and the Office has not provided evidence that such a result would be expected.
In response, the examiner disagrees. First, the specification clearly states that “by using CSQ tag of the present disclosure, a protein that is unlikely to express in an aqueous state or is likely to aggregate in an aqueous condition can be expressed in an aqueous state due to the high expression and water solubility of CSQ and can be separated and purified in a column-less manner by precipitation with calcium” (see pg. 6 of the specification). Put simply, the instant specification discloses that the increased water solubility and high expression solely depends on the CSQ tag (or properties of the tag) itself. Thus, Kim does not have to disclose improvement of solubility of proteins because this is an inherent property of the CSQ tag (which is the same tag as used by Applicant). According to MPEP 2112.01(I), where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established and the claimed properties or functions are presumed to be inherent. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) (see MPEP 2112.01).
Second, Kim does not have to disclose use of CSQ as a detachable tag, because the prior art already contemplates use of detachable linkers (see Johnston; which is the same linker as used by Applicant) to create fusion proteins with hydrolysable linkers. The invention requires a linker (to create the fusion protein) of SEQ ID NO 5-8, that is capable of being cleaved by a hydrolase for downstream purification (see claim 1). Johnston provides the teaching, suggestion, and motivation to one of ordinary skill in the art to do so, as Johnston teaches that the TEV protease cleavage linker, when used in a fusion protein, advantageously enables isolation of fusion polypeptides in the presence of relatively large amounts of added cell protease inhibitors, significantly increases yield of polypeptides, and isolation of a desired polypeptide is more efficient (col 8, lines 13-24).
Third, if Applicant is arguing an unexpected result in comparison to the prior art fusion protein, such an argument must be accompanied by empirical evidence. An argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (see MPEP 2145(I)). Thus, the rejections are maintained as set forth above.
Maintained/Modified Non-statutory double patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, and 6-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 18/453,221 (reference application).
Regarding claim 1, copending claim 1 teaches a CSQ tag; and a protein of interest, wherein the CSQ tag acts to improve expression and water solubility of the protein of interest, and copending claim 4 teaches the CSQ tag and the protein of interest are fused to each other via a hydrolase-cleavable peptide. Copending claim 2 teaches the CSQ tag is coded for by an amino acid sequence of SEQ ID NO: 1 or 2. Copending claim 4 teaches hydrolase-cleavable peptide composed of an amino acid sequence selected from the group consisting of SEQ ID NOS: 5 to 8. Copending claim 5 teaches the protein of interest comprises at least one selected from the group consisting of a polymer protein, a glycoprotein, a cytokine, a growth factor, a blood factor, a vaccine, a hormone, an enzyme, and an antibody.
Regarding claim 3, copending claim 3 teaches the CSQ tag is encoded by a nucleotide sequence of SEQ ID NO: 3 or 4.
Regarding claim 6, copending claim 6 teaches all of the proteins of interest as claimed.
Regarding claim 7, copending claim 7 teaches the protein of interest is coded for by an amino acid sequence selected from the group consisting of SEQ ID NOS: 9 to 19.
Regarding claim 8, copending claim 8 teaches a nucleic acid.
Regarding claim 9, copending claim 9 teaches the expression vector.
Regarding claim 10, copending claim 10 teaches a cell with the expression vector.
Regarding claim 11, copending claim 11 teaches the cell is Escherichia coli, Bacillus subtilis, Bacillus thuringiensis, Salmonella typhimurium, Serratia marcescens, Pseudomonas spp. yeast, insect cells, CHO (Chinese hamster ovary) cells, W138, BHK, COS-7, 293, HepG2, 3T3, RIN, MDCK cells, or plant cells.
The instant invention and the copending claims are clearly obvious variants of each other with significant overlap.
This is a provisional non-statutory double patenting rejection.
Second rejection
Claims 1 and 2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/936657 (reference application) in view of Johnston. Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons set forth below.
Regarding claim 1 and 2, copending claim 1 teaches a fusion protein of Z-domain (a protein of interest) and calsequestrin tag linked by a linker. The claimed calsequestrin amino acid sequence (SEQ ID NO: 1) has 100% sequence identity to copending SEQ ID NO: 5.
None of the claims teach that the linker is a hydrolase-cleavable peptide of SEQ ID NO: 5-8.
However, Johnston teaches methods of isolation and purification of fusion polypeptides (title). Johnston also teaches the employment of plant virus proteinase to provide high yields of protein product to cleave expressed fusion proteins to obtain polypeptides (abstract). Johnston teaches that the functional tobacco etch virus (TEV) protease cleavage site, incorporated into recombinant protein, enables isolation of fusion polypeptides in the presence of relatively large amounts of added cell protease inhibitors (col 8, lines 13-24). Yields of polypeptides sensitive to cell proteases are thus significantly increased. Isolation of a desired polypeptide is more efficient because cleavage is selective for the unique potyvirus proteinase site (col 8, lines 13-24). Johnston also teaches a sequence of peptide that is 100% identical to SEQ ID NO: 5 (see alignment in 103 rejection above).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the calsequestrin fusion protein of ‘657 by using the hydrolase-cleavable peptide sequence of Johnston to arrive at the claimed invention. As the claimed invention relies on the creation of a fusion protein of calsequestrin and a protein of interest fused via a linker, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the linker sequence of ‘657) with another (the TEV linker sequence of Johnston) with a reasonable expectation of success (creation of a fusion protein with calsequestrin and a protein of interest fused via a linker). One of ordinary skill would have been motivated to perform the substitution because Johnston teaches TEV protease cleavage site, when used in a fusion protein, advantageously enables isolation of fusion polypeptides in the presence of relatively large amounts of added cell protease inhibitors, significantly increases yield of polypeptides, and isolation of a desired polypeptide is more efficient because cleavage is selective for the unique potyvirus proteinase site.
It is clear that the claimed inventions are obvious variants of each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 10/16/25 have been fully considered but they are not persuasive.
On pg. 7, Applicant argues that the claims of ‘221 and ‘657 do not claim or render unpatentable the fusion protein as recited in the claims. Applicant further argues that filing of a terminal disclaimed will be considered to overcome the rejections upon indication of allowable subject matter.
In response, the rejections are maintained because both copending applications are, as discussed above, obvious variants of the claimed invention, as set forth above. Please note that only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Therefore, an application must not be allowed unless the required compliant terminal disclaimer is filed and/or the withdrawal of the nonstatutory double patenting rejection is made of record by the examiner (see MPEP § 804.02 (IV) for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995).
Conclusion
NO CLAIMS ALLOWED.
THIS ACTION IS MADE FINAL. 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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Beard, Nicole A. et al. (Biophysical Journal, Volume 88, Issue 5, 3444-3454): Rabbit skeletal calsequestrin was subcloned into a pGEX5x1 vector (BamHI at the 5′ end and XhoI at the 3′ end), containing an N-terminal GST tag and expression of calsequestrin as GST fusion proteins in Escherichia coli strain BL21DE3 colonies and purified by glutathione Sepharose 4B chromatography (abstract, “Expression of rabbit skeletal recombinant CSQ”, throughout document).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGIANA C REGLAS whose telephone number is (571)270-0995. The examiner can normally be reached M-Th: 8:00am-2:00pm.
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, Melenie Gordon can be reached at 571-272-8037. 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.
/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672