DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/06/2026 has been entered.
Status of claim rejections
The rejections under 35 USC 103 have been withdrawn in view of Applicant’s amendments to the claims in the response filed 04/06/2026.
The double patenting rejections of record against copending Application No. 17/936657 is withdrawn in view of Applicant’s amendments to the claims.
The double patenting rejections of record against copending Application No. 18/453,221 have been maintained in view of Applicant’s amendments/arguments in the response filed 04/06/2026.
Response to arguments
Applicant’s arguments, see pg. 5-7, filed 04/06/2026, with respect to the rejections of the claims under 35 USC 103 have been fully considered and are persuasive.
The examiner notes that the closest prior art of record (see previously cited Kim reference) teaches a Z-domain/Z-protein and calsequestrin fusion protein 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). Sanchez teaches the CSQ tag amino acid sequence of SEQ ID NO: 1 (see previous office action), and 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). The previously cited Coco reference 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 (pg. 29, lines 11-30; pg. 30, lines 1-18).
The instant claims require the exclusion of a Z-domain, which is included in the protein of Kim. Furthermore, the Z-domain is not the protein of interest, rather Z-calsequestrin fusion is used to bind an IgG, which is the target for antibody purification. The prior art fails to adequately teach, suggest, or motivate one of ordinary skill to exclude the Z-domain and include a protein of interest to arrive at the fusion protein as instantly claimed. Thus, the rejections of record have been withdrawn.
Claim interpretation
The examiner is interpreting the claims as follows:
Claim 1 has been amended to recite “a protein of interest that is a poorly expressed protein or an insoluble protein when expressed without a fusion partner, 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”. The examiner has interpreted (under broadest reasonable interpretation of the claim language) each of the species of protein of interest recited in the Markush group to be proteins that are poorly expressed or insoluble when expressed without a fusion partner, absent evidence to the contrary. This interpretation is also supported by Applicant’s arguments (see pg. 6, paragraph 3).
It is noted that the claims are drawn to a fusion protein comprising a CSQ tag, a protein of interest, and a hydrolase cleavable peptide between the CSQ tag and protein of interest, and not a method of expressing the fusion protein. As such, the limitations reciting “. . . during an expression stage compared to those of the protein of interest when expressed without the CSQ tag, and wherein the fusion protein is expressed in a transformant and the protein of interest is separated from the fusion protein with the hydrolase after precipitating the fusion protein from a host cell with aid of calcium” has been interpreted as an intended use of the claimed fusion protein.
Claim Rejections - 35 USC § 112 New Matter
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.
Claim 1, 3, and 6-11 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.
The claims have been amended to recite “a fusion protein, comprising: a calsequestrin (CSQ) tag that is coded for by an amino acid sequence of SEQ ID NO: 1 or2; a protein of interest that is a poorly expressed protein or an insoluble protein when expressed without a fusion partner, 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; and a peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOS: 5 to 8, wherein the peptide is linked between the CSQ tag and the protein of interest, the peptide being degradable by a hydrolase; wherein the fusion protein does not comprise a Z domain, wherein the CSQ tag acts to improve expression and water solubility of the protein of interest during an expression stage compared to those of the protein of interest when expressed without the CSQ tag, and wherein the fusion protein is expressed in a transformant and the protein of interest is separated from the fusion protein with the hydrolase after precipitating the fusion protein from a host cell with aid of calcium.
Neither the instant specification nor the originally filed claims appear to provide support for the recitation of “wherein the fusion protein does not comprise a Z domain”. The instant specification is silent to any Z-domains (i.e., the use or exclusion thereof), and Applicant has not pointed to anywhere in the specification to support the amendment (see Applicant’s remarks, pg. 5-7).
Any negative limitation or exclusionary proviso must have basis in the original disclosure. If alternative elements are positively recited in the specification, they may be explicitly excluded in the claims. See In re Johnson, 558 F.2d 1008, 1019, 194 USPQ 187, 196 (CCPA 1977). See also MPEP 2173.05(i).
Thus, such a recitation constitutes NEW MATTER. In response to this rejection, Applicant is required to point to support for the recitation of “a previously determined threshold dose” or to cancel the new matter.
Maintained 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 requires 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 04/06/2026 have been fully considered but they are not persuasive.
On pg. 7-8, Applicant argues that the rejections of the claims are premature and requests the rejections be withdrawn until scope of allowable claims is determined. Applicant further argues that Applicant reserves the right to file a terminal disclaimer 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.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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