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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The amendment to the specification filed on 3/12/24 has been entered.
Information Disclosure Statement
The information disclosure statement filed 7/18/24 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. A copy of the Galliet Biotechnology and Bioengineering Vol. 106, pages 203-215, 2010 does not appear to be filed. There is a blank page for this document.
The report on patentability of the IPEA and/or ISA has been considered by the examiner.
Claim Objections
Claims 1-3 and 25-26 are objected to because of the following informalities: there are several periods in the claims. There is supposed to be a period at the end of the claim or for an abbreviation. See MPEP 608.01(m). Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-4, 7 and 12 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 claimed invention embraces a method of expression a gene of interest in a CHO cell line comparing a gene of interest in a first CHO cell line and a second CHO cell line, the method comprising A) a first CHO cell line and second CHO cell line transfected with a nucleotide sequence in order from 5’ to 3’; a constitutive promoter operably linked to a cymene repressor element (CymR) response element, and operably linked to a nucleotide sequence encoding a rcTA; the first CHO cell line; B) the first CHO cell line transfected with a first vector comprising a cumate-responsive promoter operably linked to a gene of interest; C) the second CHO cell line transfected with a first vector comprising a cumate-responsive promoter operably linked to a gene of interest and a second vector comprising a first promoter operably linked to a CymR or transfecting the second cell line with a vector comprising a gene of interest operably linked to a cumate-responsive promoter and the second vector further comprises a promoter operably linked to a CymR; and culturing the both CHO cell lines in the presence of an effector molecule under conditions that allow the gene of interest to be expressed; and culturing both cell lines separately and comparing the expression of the gene of interest from both cell lines.
The claimed method embraces a genus of effector molecules used for allowing expression of the gene of interest in the CHO cell lines. The breadth of the genus refers to any small molecule, protein, polynucleotide or DNA. Thus, the structure of the “effector molecule” is unlimited.
The specification contemplates cumate or cumate analog as the effector molecule and provides a list of chemical compounds for the effector molecule (paragraph 69 on page 14). The list is limited to cumate analogs or para or 4-substituted benzoate. US 77455592, cited on an IDS, and US 20220307056 (paragraph 84) disclose that cumate analogs are well-known in the prior art. Note that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. However, the genus of effector molecules embraces a large number of molecules possibly having a different structure and/or function. Cumate, cumate analog, and the chemical compounds listed on page 14 are not considered a representative number of species, which adequately described and considered representative of the entire genus of effector molecules. The specification does not describe an essential structure of cumate, cumate analogs, or chemical compounds in paragraph 69 required for a molecule to have the desired biological activity. There is a substantial variation within the genus of effector molecules. The specification does not describe a sufficient variety of species to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163. Other than cumate or a cumate analog and the chemical compounds listed on page 14, the specification does not have written support for a genus of effector molecules, which could be considered an effector molecule that under conditions allow for the gene of interest to be expressed.
With respect to the limitation in claims 4 and 12 directed to a nucleotide sequence encoding a cumate transactivator (rcTA) having at least 80% sequence identity to the full length of the nucleotide sequence set forth in SEQ ID NO: 3, the specification does not provide written description for the limitation. Paragraph 71 defines rcTA as a fusion protein comprising a variant of CymR that binds to a CymR response element in the presence of cumate, fused to a VP16 activation domain as described in Mullick (BMC Biotechol 6 page 43 2006) or US 8728759, both cited on an IDS. Reverse cumate transactivator comprising a fusion protein comprising CymR fused to an activation domain in a configuration where cumate binding promotes DNA binding rather than release (Mullick, supra).
A search of publicly available database does not disclose any sequence having more than 50% identity to SEQ ID NO: 3. The rcTA taught by Mullick or ‘759 does not appear to have at least 80% identity to SEQ ID NO: 3. SEQ ID NO: 3 is 1045 nucleotides in length. 80% of SEQ ID NO: 3 reads on a sequence having at least 836 nucleotides in length of SEQ ID NO: 3. The specification does not disclose the essential structure (nucleotides) of instant SEQ ID NO: 3 that is required for use as a rcTA. There is a substantial variation within the genus of rcTA comprising at least 80% identity to the full length SEQ ID NO: 3. The specification does not describe a sufficient variety of species to reflect the variation within the genus. One of skill in the art would have to further experiment with any nucleotide sequence having at least 836 nucleotides of SEQ ID NO: 3 and determine if it has the desired biological activity. This indicates that the specification of the instant disclosure fails to convey to the skilled artisan that there was written description for the claimed genus of nucleotide encoding a rcTA having at least 80% to the full length of SEQ ID NO: 3 in claims 4 and 12 as of the effective filing date.
Claims 1-4 and 7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of expression a gene of interest in a CHO cell line comparing a gene of interest in a first CHO cell line and a second CHO cell line, the method comprising A) a first CHO cell line and second CHO cell line transfected with a nucleotide sequence in order from 5’ to 3’; a constitutive promoter operably linked to a cymene repressor element (CymR) response element, and operably linked to a nucleotide sequence encoding a rcTA; the first CHO cell line; B) the first CHO cell line transfected with a first vector comprising a cumate-responsive promoter operably linked to a gene of interest; C) the second CHO cell line transfected with a first vector comprising a cumate-responsive promoter operably linked to a gene of interest and a second vector comprising a first promoter operably linked to a CymR or transfecting the second cell line with a vector comprising a gene of interest operably linked to a cumate-responsive promoter and the second vector further comprises a promoter operably linked to a CymR; and culturing the both CHO cell lines in the presence of cumate, cumate analog or para- or 4-substituted benzoate under conditions that allow the gene of interest to be expressed; and culturing both cell lines separately and comparing the expression of the gene of interest from both cell lines, does not reasonably provide enablement for transfecting the same CHO cell line with different vectors set forth in claim 1 or using a genus of effector molecules under conditions to allow expression of the gene of interest. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claimed method embraces using the same CHO cell line to express a gene of interest comprising transfecting the cell line with the vectors of b(i) and c(i) or c(i’). The specification teaches using two different CHO cell lines for step b) and c) and does not appear to teach using the same CHO cell line for both steps (pages 30-33). Thus, the claimed method is not considered enabled for using the same CHO cell line for both steps.
In addition, the claimed invention embraces using a genus of effector molecules in the method under conditions to allow expression of the gene interest. The specification contemplates cumate or a cumate analog or 4-substituted benzoate (paragraphs 4 and 69). Neither the specification nor the prior art of record teach using any other type of effector molecule in the method. Thus, at the time of filing, the claimed method is only enabled for using cumate or a cumate analog or a para- or 4-substituted benzoate in the method. Other than contemplating the method and providing limited examples of effector molecules, the specification of the instant application does not disclose how to make and use a genus of effector molecules in the claimed invention. See Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: "Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention." Applicant cannot rely on the knowledge of one skilled in the art to supply information on the novel aspects of the claimed invention. Thus, in view of the reasons set forth above, it would take an undue amount of experimentation for one of skill in the art to practice the full scope of the claimed invention. Thus, claims 1-4 and 7 are not fully enabled.
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 32 and 42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 32 recites the limitation "the selectable marker" in lines 2 and 4. There is insufficient antecedent basis for this limitation in the claim.
Claim 32 recites the limitation "the nucleotide sequence encoding the cymene repressor" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 32 is dependent on claim 30 and claim 30 recites a third nucleotide sequence as defined in claim 11. The third nucleotide sequence in claim 11 contains a cymene repressor.
Claim 42 recites the limitation "a third nucleotide sequence as defined in claim 11" in line 6. There is insufficient antecedent basis for this limitation in the claim.
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 21, 25, 26, 30, 32, 35, 38, 42, 46, and 49-50 are 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 21, 25, 26, 30, 32, 35, 38, 42, 46, and 49-50 recite nucleotides sequences of claim 11(30), but claim 11 is directed to an expression system comprising a CHO cells transfected with a first nucleotide sequence and two additional nucleotides, each in a separate vector. The expression system requires a CHO cell line and all of the nucleotide sequences.
Claim 30 recites nucleotide sequence of claim 11 and the second and third nucleotide sequence are comprised by a single vector, but claim 11 recites that the second and third nucleotide sequences are in different vectors (first and second vector).
Claim 42 recites vector comprising a second nucleotide sequence as defined in claim 11 and claim 11 already recites that the second nucleotide sequence is in a vector. Claim 42 also recites that the third nucleotide sequence of claim 11 and does not require a second vector for the third nucleotide sequence as set forth in claim 11.
Claim 46 recited an expression vector comprising a first nucleotide of claim 11, but claim 11 is directed to an expression system comprising a CHO cells transfected with a first nucleotide sequence and a vector with a second nucleotide sequence and another vector with a third nucleotide sequence.
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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The instant application claims priority to an international application
(PCT/IB2022/058588) and a written opinion in the international application was filed on
3/12/24. NOTE: instant claims 11, 20-21, 25, 26, 30, 32, 35, 38, 42, 46, and 49-50 and
claims 11, 20-21, 25, 26, 30, 32, 35, 38, 42, 46, and 49-50 from the international
application appear to embrace similar subject matter. There does not appear to be any
arguments and/or amendments in the international application to address the lack of novelty for claims 25 and 42 in view of Poulain et al. J Biotechnology Vol. 255, pages 16-27. Upon further review of the prior art, the reasons set forth on pages 3-5 of the written opinion for claims 25 and 42 are incorporated herein. See the following rejection.
Claims 11, 15, 20, 25, 42, 46, and 49 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Poulain et al. (J Biotechnology 2017, Vol. 255, pages 16-27, cited on an IDS).
Poulain discloses a cell line (CHOBRI/rcTA) allowing the inducible expression of recombinant proteins, based on the cumate gene switch. Poulain discloses CHOBRI/rcTA pools producing high levels of recombinant proteins. Poulain further discloses rapid protein production from stable CHO cell pools using plasmid vector and the cumate gene-switch. The CHOBRI/rcTA cell line contains an inducible expression system developed from the reverse activator configuration of the cumate-gene switch (Fig. 1). This cell line stably expresses both the cymene repressor (CymR), able to bind specifically to the CuO operator sequence in the absence of cumate, and the cumate reverse transactivator (rcTA). Upon transient or stable transfection, the expression of a gene of interest present in the plasmid vector is activated by the binding of the rcTA on the CR5 inducible promoter in the presence of cumate, a small non-toxic inducer. More precisely, into the CHOBRI/rcTA cell line, expression of the rcTA is controlled by the CMV5-CuO promoter, where the binding operator site CuO is placed downstream of the CMV transcription initiation site. The binding of the CymR (constitutively expressed) to the CuO site prevents rcTA expression. Upon cumate binding, a conformational change in the CymR structure occurs causing its dissociation from the CuO sequence, thus allowing rcTA expression. The rcTA is composed of the VP16 activation domain fused to the reverse CymR (able to bind the CuO sequence in the presence of cumate). The binding of cumate to the rcTA favors its association to the CR5 promoter that contains six repeats of the (CuO)2 sequence placed upstream of the cytomegalovirus promoter TATA box. This association will induce expression of the cDNA placed downstream of the CR5 promoter. See Figure 1.
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In view of the method steps taught in Poulain (Figure 1), the transfected CHO cell in Figure 1 would read on method steps of claims 25 and the structural limitations of the expression vector in instant claims 42, 46 and 49.
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.
The instant application claims priority to an international application
(PCT/IB2022/058588) and a written opinion in the international application was filed on
3/12/24. NOTE: instant claims 11, 20-21, 25, 26, 30, 32, 35, 38, 42, 46, and 49-50 and
claims 11, 20-21, 25, 26, 30, 32, 35, 38, 42, 46, and 49-50 from the international
application appear to embrace similar subject matter. There does not appear to be any
arguments and/or amendments in the international application to address the lack of an inventive step of claims 11, 15, 20, 21, 32, 35, 46, and 49-50 by Poulain et al. (supra). The reasons set forth on pages 3-5 of the written opinion are incorporated herein as set forth in the 103 rejections.
Claims 1-3, 7 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Poulain et al. (supra) as applied to claims 11, 15, 20, 25, 42, 46, and 49 above.
Poulain teaches CHO cell are a useful alternative to large-scale transient gene expression (abstract). High level recombinant protein production requires a well optimized expression system. Studies for making expression systems involve constitutive and inducible promoters for expression of proteins in CHO cells. Poulain teaches studying rcTA, CymR and cumate inducible features for expression in CHO cells. Poulain produced a cell line that expressed CymR (able to bind specifically to the CuO operator sequence in the absence of cumate) and rcTA. Upon transfection, the expression of the gene of interest present in a vector is activated by the binding of the rcTA on the CR5 inducible promoter in the presence of cumate.
Poulain does not specifically teach a method of expression a gene of interest in a CHO cell line comparing a gene of interest in a first CHO cell line and a second CHO cell line, the method comprising A) a first CHO cell line and second CHO cell line transfected with a nucleotide sequence in order from 5’ to 3’; a constitutive promoter operably linked to a cymene repressor element (CymR) response element, and operably linked to a nucleotide sequence encoding a rcTA; the first CHO cell line; B) the first CHO cell line transfected with a first vector comprising a cumate-responsive promoter operably linked to a gene of interest; C) the second CHO cell line transfected with a first vector comprising a cumate-responsive promoter operably linked to a gene of interest and a second vector comprising a first promoter operably linked to a CymR or transfecting the second cell line with a vector comprising a gene of interest operably linked to a cumate-responsive promoter and the second vector further comprises a promoter operably linked to a CymR; and culturing the both CHO cell lines in the presence of cumate under conditions that allow the gene of interest to be expressed; and culturing both cell lines separately and comparing the expression of the gene of interest from both cell lines.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to use the disclosure in Poulain et al. combined with the understanding of one of ordinary skill in the art would make the claimed subject matter of claims 1-3 and 7 obvious to a person skilled in the art. See MPEP 2141(II)C. Rationales to support rejections under 35 U.S.C. 103 recites, “Prior art is not limited to the references being applied, but includes the understanding of one of ordinary skill in the art.”
MPEP 2141. FACTORS TO CONSIDER IN DETERMINING LEVEL OF ORDINARY SKILL
The person of ordinary skill in the art is a hypothetical person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (1) "type of problems encountered in the art;" (2) "prior art solutions to those problems;" (3) "rapidity with which innovations are made;" (4) "sophistication of the technology; and" (5) "educational level of active workers in the field." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995). "In a given case, every factor may not be present, and one or more factors may predominate." Id. See also Custom Accessories, Inc. v. Jeffrey-Allan Indust., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983).
The cumate inducible expression in CHO cells which comprise transactivator rcTA and CymR would be obvious to a skilled person in view of Poulain (see Fig. 1) or Poulain taught that all the elements recited in the instant claims, such as rcTA, CymR and cumate inducible features for expression in CHO cells are known in the prior art. In view of this, the claimed subject matter in claims 1-3 and 7 is considered an obvious variant because one of ordinary skill in the art would have been motivated to try studying gene expression in both CHO cell lines to determine the optimal method for producing a gene of interest. One of ordinary skill in the art would have been motivated to combine the teaching to try the combination of sequences in a CHO cell line to study expression of a gene of interest in the CHO cell line. See MPEP 2143(I)E. Since CHO cell lines are used for protein production, it would have been obvious to isolate and/or purify the gene of interest.
Poulain teaches using a CMV5 promoter and a CR5 promoter in the CHO cell to produce a gene of interest.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 21, 30, 32, 35, 38, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Poulain (supra) as applied to claims 11, 15, 20, 25, 42, 46, and 49 above, and further in view of Mullick et al. BMC Biotechnology Vol. 6, pages 43, 1-18.
Poulain do not specifically teach the vector further comprising a fourth nucleotide comprising a second cumate-responsive promoter and an insertion site to allow insertion of a second gene of interest in operable linkage with the second cumate-responsive promoter.
Mullick discloses the regulatory mechanisms of bacterial operons (cmt and cym) to regulate gene expression in mammalian cells using three different strategies. See abstract and Figure 1.
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In the repressor configuration, regulation is mediated by the binding of the repressor (CymR) to the operator site (CuO), placed downstream of a strong constitutive promoter. Addition of cumate relieves the repression. In the transactivator configuration, a chimeric transactivator (cTA) protein, formed by the fusion of CymR with the activation domain of VP16, is able to activate transcription when bound to multiple copies of CuO, placed upstream of the CMV minimal promoter. Cumate addition abrogates DNA binding and therefore transactivation by cTA. Mullick also discloses an adenoviral library of cTA mutants was screened to identify a reverse cumate activator (rcTA), which activates transcription in the presence rather than the absence of cumate (Figure 7A). NOTE: it is acknowledge that on page 31 (paragraph 116) applicant found that expression of rcTA alone was sufficient to drive protein expression from the CR5 promoter and this expression was not modulated by cumate, at least in CHO cells, as found in the teaching of Mullick. Mullick is cited to show that one of ordinary skill in the art would possess the knowledge that codon-optimization of a sequence (rcTA) or using IRES in a vector to connect two different sequences was well known in the prior art. In addition, that one of ordinary skill in the art would have a reasonable expectation of success of making a vector further comprising a fourth nucleotide comprising a second cumate-responsive promoter and an insertion site to allow insertion of a second gene of interest in operable linkage with the second cumate-responsive promoter.
In view of Mullick, it would have been obvious to try a codon-optimized rcTA in the vector recited in instant claim 21 to study its ability to regulate gene expression.
Instant claim 32 (NOTE: claim 32 lacks antecedent basis because the terms “the nucleotide sequence encoding the cymene repressor” and ‘the selectable marker’ were not recited in a claim from which claim 32 depends from). The claim embraces the gene of interest or the nucleotide sequence encoding the rcTA being the selectable marker and a IRES between that sequence and a nucleotide sequence encoding a cymeme repressor (CymR). It would have also been obvious in view of Poulain when combined with Mullick to make an expression system comprising a marker gene(s) and CymR in CHO cells (pages 9-10 and Figures 1 and 7 of Mullick). Since IRES can be used to connect different genes in a vector, it would have been obvious to place the nucleotide sequences in a single vector to reduce the time in having to transfect the CHO cell lines with two different vectors.
Instant claim 50, it would have also been obvious in view of Poulain when combined with Mullick, which discloses IRES in relation to expression of two marker genes in CHO cells (pages 9-10 and Figures 1 and 7 of Mullick). Since IRES can be used to connect different genes in a vector, it would have been obvious to place the second nucleotide and third nucleotide sequence in a single vector to reduce the time in having to transfect the CHO cell lines with two different vectors.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Allowable Subject Matter
SEQ ID NO: 3 in claim 4 and 12 is free of the prior art. The prior art does not teach or suggest making a rcTA having at least 80% identity to the full length of the nucleotide sequence set forth in SEQ ID NO: 3. A search of the prior art indicates that the closest nucleotide sequence to SEQ ID NO: 3 has 50% identity to the instant SEQ ID NO:.
Conclusion
See attached PTO-326 for disposition of claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
