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 .
Election/Restrictions
Applicant’s election without traverse of Group II, claim 12-22 in the reply filed on 12/08/2025 is acknowledged. Applicant’s amendments to the claims to cancel claim 1 and make claims 2-7 dependent on elected claim 12 is also acknowledged.
Applicant’s election without traverse of the species of CSQ tag (SEQ ID NO: 1), hydrolase cleavable peptide (TEV; see SEQ ID NO: 5), and protein of interest (SEQ ID NO: 16) in the reply filed on 12/08/2025 is acknowledged.
The species of CSQ tag amino acid sequence (SEQ ID NO: 2), CSQ tag nucleotide sequence (SEQ ID NO: 4), hydrolase-cleavable peptide (SEQ ID NOs: 6-8), and species of protein of interest (SEQ ID NOs 9-15, and 17-19) withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/08/2025.
Priority
The instant application claims benefit to US Application No. 17/601,125, PCT/KR2020/004463, filed on 01 April 2020, and claims foreign priority to KR10-2020-0039185, filed 31 March 2020 and KR10-2019-0040241, filed 05 April 2019 and is acknowledged. The instant claims herein are examined using the effective filing date of 05 April 2019 for the basis of any prior art rejections.
Claim Interpretation
The examiner has interpreted the limitation(s) as follows:
“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.
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 2-7 and 12-22 are 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 written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
Claim interpretation: The claims require, inter alia, “a method for expressing and purifying a protein of interest by using a CSQ tag, the method comprising: A) constructing an expressing vector carrying a nucleic acid a fusion protein comprising a CSQ tag and a protein of interest, wherein the CSQ tag acts to improve expression and water solubility of the protein of interest”. “A CSQ tag” as claimed has been interpreted to be any calsequestrin protein, including full and partial protein sequences of CSQ with the functional property of improving expression and water solubility of when fused with the protein of interest. The term "protein of interest" is defined on pg. 8 of the specification to refer to “a protein that is required to be obtained at high purity or in a large amount according to a specific purpose and is intended to encompass any native protein, variant protein, or novel recombinant protein”. The question at issue is whether the skilled artisan would understand the correlation between structure of a CSQ tag and its ability to “act to improve expression and water solubility” of any existing or non-existing protein, as there is no correlation or defining characteristic that would convey the identity of the structure necessary to perform the claimed function with any protein.
Reduction to practice and disclosure of drawings or structural chemical formulas: Applicant discloses in the specification that the CSQ tag “acts to improve expression and water solubility of the protein of interest” throughout the specification, but this merely repeats the claim language. Applicant further discloses 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 and can be separated and purified in a column-less manner by precipitation with calcium” (see pg. 4 of the specification).
Sufficient, relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure: Applicant has not provided information as to the defining structural characteristics that would lead one of ordinary skill in the art to the identity of a “CSQ tag” capable of “acting to improve expression and water solubility of the protein of interest”. Applicants are claiming a fusion protein comprising any CSQ tag or any protein of interest (existing or non-existing), where the CSQ tag acts to improve expression and water solubility of the protein of interest. This means that the CSQ tag has a functional limitation of improving expression and water solubility upon expression and subsequent purification. However, under broadest reasonable interpretation, the CSQ tag can encompass any sequence or portion thereof of a calsequestrin protein tag, but Applicants have not disclosed which portion of the tag is necessary for the functional limitation as claimed. Even with knowledge in the art regarding the purification of proteins using protein tags, one of ordinary skill would not know what structural features are required for the outcome of acting to improve water solubility and expression of the protein without a recognized correlation between structure and function. In essence, Applicants are describing a critical portion of their invention by function. This is not sufficient to meet the written description requirement.
Lack of support for massive genus of CSQ tags proteins of interest: Applicant also has not provided support for the genus of CSQ tags and protein of interest. As discussed above, according to the specification, the protein of interest can be any protein in existence or non-existing protein attached to any CSQ tag. The specification fails to teach and/or provide support for possession of the massive genus of CSQ tags and proteins of interest, as there is no correlation or defining characteristic that would convey the identity of a protein needing improved expression or water solubility when attached to a CSQ tag.
In support of the claimed genus, the specification demonstrates an increase in water solubility and expression from various vectors using CSQ (SEQ ID NO: 1 and 2) as it relates to purification of human fibronectin extra domain B (EDB) proteins (EDB14, EDB21, and EDB26; corresponding with SEQ ID NOs 9-11 respectively), as well as the expression of EGF, TGF, KGF1, VEGF, FGF2, BMP2, GLP-1, and HRP (see Examples 1-8). However, there is no support in the specification for the increased water solubility and expression of any existing or non-existing protein using CSQ as a protein tag. Applicant has not provided any information that would allow one of ordinary skill to reasonably understand that any known or unknown protein is capable of having increased expression and water solubility when fused with CSQ. For example, it is unclear if human serum albumin or a-lactalbumin proteins (proteins that are already highly water soluble) would have an “improvement” in expression and solubility if fused to CSQ.
Furthermore, it is unclear which CSQ proteins would be capable of increasing the expression of the massive genus of proteins of interest. A fusion protein of CSQ with any protein is (by necessity) already expressed. As interpreted above, CSQ proteins can be any calsequestrin protein, including full and partial protein sequences of CSQ with the functional property claimed. The specification fails to teach an “improvement of expression” using any CSQ protein/subsequence, other than CSQ1 or CSQ2 (SEQ ID NOs: 1 and 2), when included in a vector/fused to the proteins recited above and subsequently purified. The specification only teaches that the “improvement” as claimed is compared to similar vector systems in which proteins (such as EDB14) is cloned into vectors with His or GST tags when expressed and subsequently detected in E. coli supernatant. One of ordinary skill would not be able to identify Applicant to have been in possession of the massive genus of possible CSQ proteins for use in a fusion protein, that allows for the subsequent “improvement of expression” and water solubility of a massive genus of protein of interest.
Thus, the data generated for purification of human fibronectin extra domain B (EDB) proteins (EDB14, EDB21, and EBD26; corresponding with SEQ ID NOs 9-11 respectively), as well as the expression of EGF, TGF, KGF1, VEGF, FGF2, BMP2, GLP-1, and HRP cannot reasonably be extrapolated to and applied to support possession of the entire claimed genus of “protein of interest” as claimed, because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1966).
The specification, then, is considered devoid of sufficiently detailed, relevant, identifying characteristics demonstrating that Applicant was in possession of the claimed genus of subject(s) in need thereof, i.e., additional complete or partial structures, other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure, or some combination thereof demonstrating possession of the claimed genus. Therefore, claims 2-7 and 12-22 are rejected under 35 U.S.C. 112(a) for lack of written description.
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 2-7 and 12-22 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.
The term “improve expression and water solubility” in claim 12 is a relative term which renders the claim indefinite. The term “improve” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claim requires an improvement of expression/water solubility, which necessarily requires a standard to compare it to. It is unclear whether the expression and solubility must be improved compared to any possible system that is capable of expressing proteins of interest or some other unknown metric. Furthermore, it is unclear from the claims or the specification what the metes and bounds are of determining if the expression and water solubility have been improved. Thus, the limitation renders the claim indefinite. Please note that dependent claims 2-7 and 13-22 are also indefinite for dependency on indefinite claim 12.
Claim 12 recites “D) precipitating the fusion protein including the CSQ tag and the protein of interest from the transformant in presence of at least one metal ion selected from the group consisting of manganese, barium, strontium, lanthanum, nickel, magnesium, copper, zinc and calcium”, however claim 22 recites “the method according to claim 12, wherein said at least one metal excludes calcium”. It is unclear how the instantly claimed method can require calcium (i.e., in the Markush group) and also exclude calcium. Thus, the claim is indefinite.
Claim 4 recites the limitation “. . . via a hydrolase-cleavable peptide composed of an amino acid sequence”. This limitation renders the claim indefinite because it is unclear whether the peptide is “comprising of” or “consisting of” the recited Markush group of amino acid sequences. As “composed of” is not defined in the specification, it is unclear if the peptide sequence is supposed to require the full sequence of hydrolase cleavable peptides (consisting of) or some subsequence thereof (comprising). Thus, the limitation renders the claim indefinite. For the purposes of compact patent prosecution, the claim has been interpreted to require the full sequence of hydrolase cleavable peptide.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-7 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 2-7 have been amended to be dependent on claim 12. The numbering of the claims is improper, as a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
First rejection
Claims 4 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Kim ((KR 20170069452 A; 21 June 2017; cited in Applicant IDS of parent application 17/601,125) in view of Johnston et al (US 5532142A; 02 July 1996; hereinafter "Johnston”).
Kim teaches a method of 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 (as in claim 12; see pg. 3, paragraph 3-4; see also claim 6-7), where the Z-domain/Z-protein and calsequestrin fusion protein (a fusion protein comprising a CSQ tag and a protein of interest as in claim 12) is used for purification of antibodies (title, abstract, pg. 2, paragraph 001, and throughout document). 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).
Kim does not 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 would inherently improve expression and water solubility of the protein of interest in comparison to the fusion protein alone.
Kim does not explicitly teach separating the protein of interest from the fusion protein with a hydrolase.
However, Johnston teaches methods of isolation and purification of fusion polypeptides (title). Johnston also teaches the employment of plant virus proteinase (i.e., hydrolases) 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).
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 TEV hydrolase-cleavable peptide of Johnston to arrive at the claimed invention. As the claimed invention relies on the creation of a fusion protein of calsequestrin to express a protein of interest using a hydrolase, 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 for TEV protease cleavage of Johnston) with a reasonable expectation of success (creation of a fusion protein of calsequestrin to express a protein of interest using a hydrolase). 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.
Regarding claim 4, 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).
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SEQ ID NO 6 of Johnston vs instant SEQ ID NO 5
Regarding claim 13, Kim teaches precipitating using calcium (see above).
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 2 is rejected under 35 U.S.C. 103 as being unpatentable over Kim and Johnston as applied to claims 4 and 12-13 above, in view of Sanchez et al (J Biol Chem. 2012 Apr;287(14):11592-601); see also NCBI GenBank accession no. 3UOM_A; hereinafter “Sanchez”).
As discussed above, claims 4 and 12-13 were rendered prima facie obvious by the teachings of Kim and Johnston.
None of the references explicitly teach wherein the CSQ tag is coded for by an amino acid sequence of SEQ ID NO: 1 (Applicant’s elected species).
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).
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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 to precipitate the 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.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, absent evidence to the contrary.
Third rejection
Claim 3 is are rejected under 35 U.S.C. 103 as being unpatentable over Kim and Johnston as applied to claims 4, and 12-13 above, and further in view of Rosen et al (US 20040018969 A1; 29 January 2004; hereinafter “Rosen”).
As discussed above, claims 4 and 12-13 were rendered prima facie obvious by the teachings of Kim 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).
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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 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.
Fourth rejection
Claim 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Kim and Johnston as applied to claims 4, and 12-13 above, and further in view of Coco et al (WO2002006469A2; 24 January 2002; hereinafter “Coco”).
As discussed above, claims 4 and 12-13 were rendered prima facie obvious by the teachings of Kim and Johnston.
The difference between the references and the instant claim is that none of the references explicitly teach 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 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 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. (pg. 29, lines 11-30; pg. 30, lines 1-18).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, absent evidence to the contrary.
Fifth rejection
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Kim and Johnston as applied to claims 4, and 12-13 above, and further in view of Israel et al (WO 1993009229 A1; hereinafter “Israel”).
As discussed above, claims 4 and 12-13 were rendered prima facie obvious by the teachings of Kim and Johnston.
The difference between the references and the instant claim is that none of the references explicitly teach the protein of interest is coded for by an amino acid sequence of SEQ ID NO: 16.
However, Isreal teaches methods for producing recombinant heterodimeric BMP proteins (see title, abstract). Israel teaches culturing a host cell containing a sequence encoding a BMP or fragment thereof and a sequence encoding a second selected BMP or fragment thereof, said sequences each being under the control of a suitable regulatory sequence capable of directing co-expression of said proteins, and isolating said heterodimeric (i.e., fusion) protein from the culture medium (see claim 1). Israel teaches the BMP protein is capable of treating bone defects, healing bone injury and in wound healing in general (see abstract). Israel further teaches a suitable sequence of BMP protein for use in the heterodimeric protein (see pg. 117; SEQ ID NO: 13) that has 100% sequence identity to SEQ ID NO: 16 (see alignment below):
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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 and Johnston by using BMP as taught by Israel 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 and Johnston) with another (the BMP of Israel) 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 Israel teaches that BMP is advantageously capable of treating bone defects, healing bone injury and in wound healing in general when used in a fusion protein expressed from a suitable host cell.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, absent evidence to the contrary.
Sixth rejection
Claims 14-22 are rejected under 35 U.S.C. 103 as being unpatentable over Kim and Johnston as applied to claims 4, and 12-13 above, and further in view of Gaburjakova et al. (Functional interaction between calsequestrin and ryanodine receptor in the heart. Cell Mol Life Sci. 2013 Aug;70(16):2935-45. doi: 10.1007/s00018-012-1199-7. Epub 2012 Oct 30; see “Gaburjakova”).
As discussed above, claims 4 and 12-13 were rendered prima facie obvious by the teachings of Kim and Johnston.
The difference between the references and the instant claim is that none of the references explicitly teach the metal comprises Mg2+, Mn2+, Ba2+, Sr2+, La3+, Cu2+, Ni2+, or Zn2+ (claims 14-21).
However, Gaburjakova teaches calsequestrin (CSQ1 and CSQ2), as the major Ca2+-binding protein in the sarcoplasmic reticulum of cardiac myocytes (see abstract). Gaburjakova specifically teaches that many cations such as lanthanum, cadmium, manganese, and zinc interfere with calcium binding to CSQ1, and this indicates that they may have higher affinity for cation-binding sites on CSQ1 than calcium (see pg. 2940, col 1, paragraph 2). Gaburjakova further teaches that other divalent cations such as magnesium, strontium, nickel, copper and barium can cause compaction of CSQ as well as aggregation and polymerization of CSQ (see pg. 2940, col 1 and 2).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of Kim and Johnston by using any of the cations as taught by Gaburjakova to arrive at the claimed invention. One of ordinary skill would have been motivated to make the modification because Gaburjakova teaches that metal cations such as lanthanum, cadmium, manganese, zinc, etc. compete with calcium for binding to the protein with higher affinity than calcium for the cation-binding sites.
Regarding claim 22, it would have been prima facie obvious to one of ordinary skill to exclude calcium, as Gaburjakova teaches various metals capable of binding calsequestrin protein that have higher affinity for the cation-binding sites than calcium does (see above).
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.
First rejection
Claims 2-7 and 12-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/601,125 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons set forth below.
Regarding claim 12 and 2, copending claim 12 teaches a method for expressing and purifying a protein of interest by using a CSQ tag, the method comprising the steps of: A) constructing an expressing vector carrying a nucleic acid coding for the fusion protein of claim 1; B) transducing the expression vector into a host cell to obtain a transformant; C) expressing the fusion protein including the CSQ tag and the protein of interest in the transformant; D) precipitating the fusion protein including the CSQ tag and the protein of interest from the transformant with aid of calcium; and E) separating the protein of interest from the fusion protein with a hydrolase. Copending claim 1 teaches a fusion protein, comprising: a calsequestrin (CSQ) tag that is coded for by an amino acid sequence of SEQ ID NO: 1 or 2, wherein the CSQ tag acts to improve expression and water solubility of the protein of interest and precipitating the fusion protein from a host cell with aid of calcium.
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 4, copending claim 1 teaches a peptide consisting of an amino acid sequence selected from SEQ ID NO: 5-8.
Regarding claim 5, copending claim 1 teaches the protein of interest is polymer protein, a glycoprotein, a cytokine, a growth factor, a blood factor, a vaccine, a hormone, an enzyme, and an antibody.
Regarding claim 6, copending claim 6 teaches the protein of interest is selected from the group consisting of interleukin-2, blood clotting factor VII, blood clotting factor VIII, blood clotting factor IX, an immunoglobulin, horseradish peroxidase (HIRP), a cytokine, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF), placental growth factor (PlGF), hepatocyte growth factor (HGF), fibroblast growth factor 1 and 2 (FGF-1 and -2), keratinocyte growth factor (KGF), glucagon-like peptide-1 (GLP- 1), exendin, somatostatin, LHRH (luteinizing hormone-releasing hormone), adrenocorticotropic hormone, growth hormone-releasing hormone, oxytocin, thymosin alpha-1, corticotropin- releasing factor, calcitonin, bivalirudin, vasopressin, phospholipase-activating protein (PLAP), insulin, tumor necrosis factor (TNF), follicle-stimulating hormone, thyroid-stimulating hormone, antidiuretic hormone, pigmentary hormone, parathyroid hormone, luteinizing hormone, calcitonin gene-related peptide (CGRP), enkephalin, somatomedin, erythropoietin, hypothalamic releasing factor, prolactin, chorionic gonadotropin, tissue plasminogen activator, growth hormone releasing peptide (GHPR), thymic humoral factor (THF), asparaginase, arginase, arginine deiminase, adenosine deaminase, peroxidase dismutase, endotoxinase, catalase, chymotrypsin, lipase, uricase, adenosine diphosphatase, tyrosinase, bilirubin oxidase, glucose oxidase, glucosidase, galactosidase, glucocerebrosidase, and glucuronidase.
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 13, copending claim 1 teaches precipitating the fusion protein from a host cell with aid of calcium.
Thus, 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.
Second rejection
Claims 14-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/601,125 (reference application) in view of Gaburjakova. Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons set forth below.
As discussed above, the ‘125 claims are obvious variants of the instant claims.
None of the copending claims teach the metal comprises Mg2+, Mn2+, Ba2+, Sr2+, La3+, Cu2+, Ni2+, or Zn2+ (claims 14-21).
However, Gaburjakova teaches calsequestrin (CSQ1 and CSQ2), as the major Ca2+-binding protein in the sarcoplasmic reticulum of cardiac myocytes (see abstract). Gaburjakova specifically teaches that many cations such as lanthanum, cadmium, manganese, and zinc interfere with calcium binding to CSQ1, and this indicates that they may have higher affinity for cation-binding sites on CSQ1 than calcium (see pg. 2940, col 1, paragraph 2). Gaburjakova further teaches that other divalent cations such as magnesium, strontium, nickel, copper and barium can cause compaction of CSQ as well as aggregation and polymerization of CSQ (see pg. 2940, col 1 and 2).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of ‘125 by using any of the cations as taught by Gaburjakova to arrive at the claimed invention. One of ordinary skill would have been motivated to make the modification because Gaburjakova teaches that metal cations such as lanthanum, cadmium, manganese, zinc, etc. compete with calcium for binding to the protein with higher affinity than calcium for the cation-binding sites.
Regarding claim 22, it would have been prima facie obvious to one of ordinary skill to exclude calcium, as Gaburjakova teaches various metals capable of binding calsequestrin protein that have higher affinity for the cation-binding sites than calcium does (see above).
Thus, 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.
Conclusion
NO CLAIMS ALLOWED.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672